This work was supported by the National Science Foundation Graduate Research Fellowship: 1745302 (E.W.), the National Institutes of Health: 1-R61-AI161805-01 and U19AI057229 (A.K.C.), the National Institutes of Health: P01-AI165075 (P.J.B.), Wellcome Leap (P.J.B.), Bill and Melinda Gates Foundation: INV-034638 (P.J.B.), the Coalition for Epidemic Preparedness Innovations (CEPI) (P.J.B.), and the Merkin Institute for Translational Research (Caltech). E.W. and A.K.C. acknowledge the MIT SuperCloud and Lincoln Laboratory Supercomputing Center for providing HPC resources that have contributed to the research results reported within this work.
\nWe thank Jesse Bloom (Fred Hutchinson), Allie Greaney (University of Washington), and Tyler Starr (University of Utah) for RBD libraries and help setting up DMS at Caltech, Noor Youssef (Harvard Medical School) and Ziyan Wu (Caltech) for radar plot Python scripts, Jost Vielmetter, Luisa Segovia, Annie Lam, and the Caltech Beckman Institute Protein Expression Center for protein production, Igor Antoshechkin and the Caltech Millard and Muriel Jacobs Genetics and Genomics Laboratory for Illumina sequencing, Chengcheng Fan for generating RBD-NP models, Labcorp Drug Development (Denver, PA) for performing mouse immunizations, and Anthony West for calculating the probabilities of identical neighboring RBDs.
\n\nConceptualization: E.W, A.K.C., A.A.C., P.J.B.; Methodology: E.W, A.K.C. (computations); J.R.K., A.V.R., Y.M.A., P.N.P.G. (experiments); Computation and Software: E.W., A.K.C.; Investigation: E.W. (computations); J.R.K., A.V.R., Y.M.A., P.N.P.G. (experiments); Writing – original draft: E.W., A.K.C, A.A.C, L.F.C., P.J.B.; Writing – review and editing: E.W., A.K.C, A.A.C, L.F.C., P.J.B.; Visualization: E.W., A.A.C, L.F.C.; Supervision: A.K.C, P.J.B.; Project Administration: A.K.C., P.J.B.; Funding: A.K.C., P.J.B.
\n\nA.K.C. is a consultant (titled “Academic Partner”) for Flagship Pioneering, consultant and Strategic Oversight Board Member of its affiliated company, Apriori Bio, and is a consultant and Scientific Advisory Board Member of another affiliated company, Metaphore Bio.
\nP.J.B. and A.A.C. are inventors on a US patent application (17/523,813) filed by the California Institute of Technology that covers mosaic RBD-NPs. P.J.B. is a scientific advisor for Vaccine Company, Inc. and for Vir Biotechnology.
", "abstract": "Using computational methods, we designed 60-mer nanoparticles displaying SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs) by (i) creating RBD sequences with 6 mutations in the SARS-COV-2 WA1 RBD that were predicted to retain proper folding and abrogate antibody responses to variable epitopes (mosaic-2COMs; mosaic-5COM), and (ii) selecting 7 natural sarbecovirus RBDs (mosaic-7COM). These antigens were compared with mosaic-8b, which elicits cross-reactive antibodies and protects from sarbecovirus challenges in animals. Immunizations in naïve and COVID-19 pre-vaccinated mice revealed that mosaic-7COM elicited higher binding and neutralization titers than mosaic-8b and related antigens. Deep mutational scanning showed that mosaic-7COM targeted conserved RBD epitopes. Mosaic-2COMs and mosaic-5COM elicited higher titers than homotypic SARS-CoV-2 Beta RBD-nanoparticles and increased potencies against some SARS-CoV-2 variants than mosaic-7COM. However, mosaic-7COM elicited more potent responses against zoonotic sarbecoviruses and highly mutated Omicrons. These results support using mosaic-7COM to protect against highly mutated SARS-CoV-2 variants and zoonotic sarbecoviruses with spillover potential.
\nWe thank Jesse Bloom (Fred Hutchinson) and Tyler Starr (University of Utah) for RBD libraries and help setting up DMS at Caltech, Noor Youssef (Harvard Medical School) and Ziyan Wu (Caltech) for radar plot Python scripts, Jost Vielmetter, Luisa Segovia, Annie Lam, and the Caltech Beckman Institute Protein Expression Center for protein production, Igor Antoshechkin and the Caltech Millard and Muriel Jacobs Genetics and Genomics Laboratory for Illumina sequencing, S. Alison Arnold, Connor Bowen, Sharon Versteeg, Jack E. Kay, Joseph Moores-Poole, and Vasilis Tsakonitis (Ingenza, Ltd.) for expressing and purifying Bacillus mi3 and Pichia RBDs, Marta Murphy for help making figures, the Viral Vector Core Facility (Oxford University) for ChAdOx1 nCoV-19, Helix Biotech for Pfizer-like WA1 and BA.5 mRNA-LNP, Jeffrey Ravetch (Rockefeller University) for the Moderna WA1 mRNA-LNP vaccine, Labcorp Drug Development (Denver, PA) for performing BALB/c mouse immunizations for the mRNA-LNP and ChAdOx1 nCoV-19 experiments, T. Kurosaki and T. Okada (U. Osaka, RIKEN-Yokohama) for S1pr2-CreERT2 BAC-transgenic mice, and Alain Townsend and Jack T. K. Tan (Oxford), Andrew DeLaitsch and Magnus Hoffmann (Caltech), and Bjorkman lab members for helpful discussions. These studies were funded by Wellcome Leap (P.J.B.), the National Institutes of Health: [P01-AI165075 (P.J.B.), R01AI119006 and R01AI173086 (G.D.V.), R01AI153064 (N.P.)], Bill and Melinda Gates Foundation INV-034638 (P.J.B.), the Coalition for Epidemic Preparedness Innovations (CEPI) (P.J.B., I.F.), the Merkin Institute for Translational Research (Caltech), and the Stavros Niarchos Foundation Institute (Rockefeller).
\nP.J.B. and A.A.C. are inventors on a US patent application (17/523,813) filed by the California Institute of Technology that covers the mosaic nanoparticles described in this work. A.I.R. and J.D.P. are inventors on a US patent (11,780,888) that covers the chimeric sequence of RBD fused to the HA2 stem of influenza hemagglutinin. A.J.G. is an inventor on a Fred Hutchinson Cancer Center-optioned technology related to DMS of the RBD of SARS-CoV-2 spike protein. L.M., S.B., R.C., C.S-A., and I.G.F. are inventors on U.S. Patent Applications (16/952,983) and (17/651,476) filed by Ingenza Ltd. that cover Bacillus and Pichia strains established to manufacture endotoxin-free vaccine products. J.H.E. is an employee of HDT Bio that provided the repRNA-LION vaccine. D.H.F. is a co-founder of Orlance, Inc. that is developing gene gun delivery of DNA and repRNA vaccines. S.B., R.C., M.Q.-A., E.R., C.S.-A., L.M., and I.G.F. are employees of Ingenza, LTD. P.J.B. and G.D.V. are scientific advisors for Vaccine Company, Inc, and P.J.B. is a scientific advisor for Vir Biotechnology. N.P. is named on patents describing the use of nucleoside-modified mRNA in lipid nanoparticles as a vaccine platform. N.P. served on the mRNA strategic advisory board of Sanofi Pasteur in 2022 and the mRNA technology advisory board of Pfizer in 2023 and is a member of the Scientific Advisory Board of AldexChem and Bionet-Asia. P.J.C.L. is an employee of Acuitas Therapeutics, a company developing LNP delivery systems for RNA therapeutics.
\nImmunization with mosaic-8b [60-mer nanoparticles presenting 8 SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs)] elicits more broadly cross-reactive antibodies than homotypic SARS-CoV-2 RBD-only nanoparticles and protects against sarbecoviruses. To investigate original antigenic sin (OAS) effects on mosaic-8b efficacy, we evaluated effects of prior COVID-19 vaccinations in non-human primates and mice on sarbecovirus response breadths elicited by mosaic-8b, admix-8b (8 homotypics), and homotypic SARS-CoV-2, finding greatest cross-reactivity for mosaic-8b. As demonstrated by molecular fate-mapping in which antibodies derived from specific cohorts of B cells are differentially detected, B cells primed by WA1 spike mRNA-LNP dominated antibody responses after RBD-nanoparticle boosting. While mosaic-8b- and homotypic-nanoparticles boosted cross-reactive antibodies, de novo antibodies were predominantly induced with mosaic-8b boosting, and these were specific for variant RBDs with increased identity to RBDs on mosaic-8b. These results inform OAS mechanisms and support using mosaic-8b to protect COVID-19 vaccinated/infected humans against as-yet-unknown SARS-CoV-2 variants and animal sarbecoviruses with human spillover potential.
\nSubmitted - 2023.03.09.23286855v1.full.pdf
", "abstract": "Importance. At-home rapid COVID-19 tests utilize nasal-swab specimens and require high viral loads to reliably give positive results. Longitudinal studies from the onset of infection have found infectious virus can present in oral specimens days before nasal. Detection and initiation of infection-control practices may therefore be delayed when nasal-swab rapid tests are used, resulting in greater exposure and transmission to contacts. \n\nObjective. We assessed whether index cases first identified by rapid nasal-swab COVID-19 tests had more transmission to household contacts than index cases who used other test types (tests with higher analytical sensitivity but longer turnaround times, and/or that utilize non-nasal specimen types). \n\nDesign. In this observational cohort study, members of households with a recent COVID-19 case were screened for infection at least daily by RT-qPCR on one or more self-collected upper-respiratory specimen types. Participants reported demographic/medical information (including COVID-19 testing), symptom and exposure information, and household infection-control practices. A two-level random intercept model was used to assess the association between the infection outcome of household contacts and each covariable (household size, race/ethnicity, age, vaccination status, viral variant, infection-control practices, and whether a rapid nasal-swab test was used to initially identify the household index case). \n\nSetting. Southern California, September 2020\u2014June 2021 and November 2021\u2014March 2022. \n\nParticipants. Cohort of 370 individuals from 85 households. \n\nMain Outcome(s) and Measure(s)Transmission was quantified by adjusted secondary attack rates (aSAR) and adjusted odds ratios (aOR). \n\nResults. An aSAR of 53.6% (95% CI 38.8\u201368.3%) was observed among households where the index case first tested positive by a rapid nasal-swab COVID-19 test, which was significantly higher than the aSAR for households where the index case utilized another test type (27.2% 95% CI 19.5\u2013 35.0%,P=0.003 pairwise comparisons of predictive margins). We observed an aOR of 4.90 (95% CI 1.65\u201314.56) for transmission to household contacts when a nasal-swab rapid test was used to identify the index case, compared to other test types. \n\nConclusions and Relevance. Use of nasal-swab rapid COVID-19 tests for initial detection of infection and initiation of infection control may not limit transmission as well as other test types. \n\nKey Points: \nQuestion: Does identification of index cases by rapid nasal-swab tests limit household transmission of SARS-CoV-2 as well as other test types? \n\nFinding. Significantly higher adjusted secondary attack rates and adjusted odds ratios for transmission were observed in households where the index case used a nasal rapid COVID-19 test for initial detection versus other test types.\n\nMeaning. The use of nasal-swab rapid COVID-19 tests for initial detection of infection and initiation of infection control may not limit transmission as well as other test types.", "date": "2023-03-10", "date_type": "published", "id_number": "CaltechAUTHORS:20230323-420614000.1", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230323-420614000.1", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Bill and Melinda Gates Foundation", "grant_number": "INV-023124" }, { "agency": "Ronald and Maxine Linde Center for New Initiatives" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "UCLA" }, { "agency": "John Stauffer Charitable Trust" }, { "agency": "Caltech Summer Undergraduate Research Fellowship (SURF)" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2023.03.09.23286855", "primary_object": { "basename": "2023.03.09.23286855v1.full.pdf", "url": "https://authors.library.caltech.edu/records/act7x-zp783/files/2023.03.09.23286855v1.full.pdf" }, "pub_year": "2023", "author_list": "Ji, Jenny; Winnett, Alexander Viloria; et al." }, { "id": "https://authors.library.caltech.edu/records/pc9de-h1854", "eprint_id": 120130, "eprint_status": "archive", "datestamp": "2023-10-09 22:03:11", "lastmod": "2026-03-27 20:18:49", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Hills-Rory-A", "name": { "family": "Hills", "given": "Rory A." }, "orcid": "0000-0002-5698-9538" }, { "id": "Tan-Tiong-Kit-Jack", "name": { "family": "Tan", "given": "Tiong Kit" }, "orcid": "0000-0001-8746-8308" }, { "id": "Cohen-Alexander-A", "name": { "family": "Cohen", "given": "Alexander A." }, "orcid": "0000-0002-2818-656X" }, { "id": "Keefe-Jennifer-R", "name": { "family": "Keeffe", "given": "Jennifer R." }, "orcid": "0000-0002-5317-6398" }, { "id": "Keeble-Anthony-H", "name": { "family": "Keeble", "given": "Anthony H." }, "orcid": "0000-0002-4873-6960" }, { "id": "Gnanapragasam-Priyanthi-N-P", "name": { "family": "Gnanapragasam", "given": "Priyanthi N. P." } }, { "id": "Storm-Kaya-N", "name": { "family": "Storm", "given": "Kaya N." } }, { "id": "Hill-Michelle-L", "name": { "family": "Hill", "given": "Michelle L." }, "orcid": "0000-0002-9289-5811" }, { "id": "Liu-Sai", "name": { "family": "Liu", "given": "Sai" } }, { "id": "Gilbert-Jaramillo-Javier", "name": { "family": "Gilbert-Jaramillo", "given": "Javier" }, "orcid": "0000-0003-1268-2304" }, { "id": "Afzal-Madeeha", "name": { "family": "Afzal", "given": "Madeeha" }, "orcid": "0000-0001-8954-8934" }, { "id": "Napier-Amy", "name": { "family": "Napier", "given": "Amy" } }, { "id": "James-William-S", "name": { "family": "James", "given": "William S." }, "orcid": "0000-0002-2506-1198" }, { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990" }, { "id": "Townsend-Alain-R", "name": { "family": "Townsend", "given": "Alain R." }, "orcid": "0000-0002-3702-0107" }, { "id": "Howarth-Mark", "name": { "family": "Howarth", "given": "Mark" }, "orcid": "0000-0001-8870-7147" } ] }, "title": "Multiviral Quartet Nanocages Elicit Broad Anti-Coronavirus Responses for Proactive Vaccinology", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. \n\nWe thank Dr. David Staunton from the University of Oxford Department of Biochemistry Biophysical Suite for help with biophysical analysis. We thank the Centre for the AIDS Programme of Research in South Africa (CAPRISA) and Gavin Screaton (University of Oxford) for supplying SARS-CoV-2 variant isolates. The BtKY72 K493Y/T498W Spike plasmid for generating pseudovirus was a kind gift to the Bjorkman lab from David Veesler (University of Washington). \n\nFunding for this study was provided by: Biotechnology and Biological Sciences Research Council (BBSRC BB/S007369/1) (A.H.K. and M.H.); Rhodes Trust (R.H.); EPA Cephalosporin Early Career Teaching and Research Fellowship (T.K.T.); Townsend-Jeantet Prize Charitable Trust (Charity Number 1011770) (T.K.T.); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant no. 2018-I2M-2-002) (A.R.T.); University of Oxford COVID-19 Research Response Fund and its donors (reference 0009517) (M.H.) National Institutes of Health (NIH) NIH AI165075 (P.J.B.); Caltech Merkin Institute (P.J.B.);\nGeorge Mason University Fast Grant (P.J.B.). \n\nAuthor Contributions: R.A.H. performed all experiments except T.K.T. performed mouse immunizations, J.R.K., P.N.P.G. and K.N.S. tested pseudovirus neutralization, and W.S.J., M.L.H., S.L., J.G-J., M.A. and A.N. tested virus neutralization. A.H.K. designed and purified initial Quartet constructs. R.A.H., T.T., A.A.C., W.S.J., P.J.B., A.R.T. and M.H. designed the project. R.A.H. and M.H. wrote the manuscript. All authors read and approved the manuscript. \n\nData availability: Sequences of constructs are available in GenBank, as described in the section \"Plasmids and Cloning\". Plasmids encoding pDEST14-SpySwitch, pET28aSpyCatcher003-mi3, pET28a-SpyTag-MBP, pcDNA3.1-SpyTag-Quartet, pcDNA3.1-Alternate Quartet and pcDNA3.1-Quartet [SARS1] will be deposited before publication in the Addgene repository (https://www.addgene.org/Mark_Howarth/). Further information and request for resources and reagents should be directed to and will be fulfilled by the lead contact, M.H. (mh2186@cam.ac.uk). \n\nCompeting Interest Statement. M.H. is an inventor on a patent on spontaneous amide bond formation (EP2534484) and a SpyBiotech co-founder and shareholder. M.H. and A.H.K. are inventors on a patent on SpyTag003:SpyCatcher003 (UK Intellectual Property Office 1706430.4). P.J.B. and A.A.C. are inventors on a US patent application filed by the California Institute of Technology that covers the methodology to generate cross-reactive antibodies using mosaic nanoparticles. P.J.B., and A.A.C. are inventors on a US patent application filed by the California Institute of Technology that covers the monoclonal antibodies elicited by vaccination with Mosaic nanoparticles described in this work. P.J.B., A.A.C. and J.R.K. are inventors on a US patent application filed by the California Institute of Technology that covers the methods of isolating cross-reactive antibodies by vaccination with mosaic nanoparticles. All other authors have no competing interests to declare.\n\nSubmitted - 20230224-529520v1full.pdf
Supplemental Material - media-1.pdf
", "abstract": "Defending against future pandemics may require vaccine platforms that protect across a range of related pathogens. The presentation of multiple receptor-binding domains (RBDs) from evolutionarily-related viruses on a nanoparticle scaffold elicits a strong antibody response to conserved regions. Here we produce quartets of tandemly-linked RBDs from SARS-like betacoronaviruses coupled to the mi3 nanocage through a SpyTag/SpyCatcher spontaneous reaction. These Quartet Nanocages induce a high level of neutralizing antibodies against several different coronaviruses, including against viruses not represented on the vaccine. In animals primed with SARS-CoV-2 Spike, boost immunizations with Quartet Nanocages increased the strength and breadth of an otherwise narrow immune response. Quartet Nanocages are a strategy with potential to confer heterotypic protection against emergent zoonotic coronavirus pathogens and facilitate proactive pandemic protection.", "date": "2023-02-24", "date_type": "published", "id_number": "CaltechAUTHORS:20230316-182086000.11", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230316-182086000.11", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Biotechnology and Biological Sciences Research Council (BBSRC)", "grant_number": "BB/S007369/1" }, { "agency": "Rhodes Trust" }, { "agency": "EPA Cephalosporin Early Career Teaching and Research Fellowship" }, { "agency": "Townsend-Jeantet Prize Charitable Trust", "grant_number": "1011770" }, { "agency": "Chinese Academy of Medical Sciences", "grant_number": "2018-I2M-2-002" }, { "agency": "University of Oxford", "grant_number": "0009517" }, { "agency": "NIH", "grant_number": "AI165075" }, { "agency": "Caltech Merkin Institute for Translational Research" }, { "agency": "George Mason University" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Richard-Merkin-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2023.02.24.529520", "pmcid": "PMC9980174", "primary_object": { "basename": "media-1.pdf", "url": "https://authors.library.caltech.edu/records/pc9de-h1854/files/media-1.pdf" }, "related_objects": [ { "basename": "20230224-529520v1full.pdf", "url": "https://authors.library.caltech.edu/records/pc9de-h1854/files/20230224-529520v1full.pdf" } ], "pub_year": "2023", "author_list": "Hills, Rory A.; Tan, Tiong Kit; et al." }, { "id": "https://authors.library.caltech.edu/records/6g151-9b339", "eprint_id": 120161, "eprint_status": "archive", "datestamp": "2023-10-09 22:03:32", "lastmod": "2025-11-21 00:07:32", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Hoffmann-Magnus-A-G", "name": { "family": "Hoffmann", "given": "Magnus A. G." }, "orcid": "0000-0003-4923-9568" }, { "id": "Yang-Zhi-MCB", "name": { "family": "Yang", "given": "Zhi" }, "orcid": "0000-0001-8680-3784" }, { "id": "Huey-Tubman-Kathryn-E", "name": { "family": "Huey-Tubman", "given": "Kathryn E." }, "orcid": "0000-0002-4683-8138" }, { "id": "Cohen-Alexander-A", "name": { "family": "Cohen", "given": "Alexander A." }, "orcid": "0000-0002-2818-656X" }, { "id": "Gnanapragasam-Priyanthi-N-P", "name": { "family": "Gnanapragasam", "given": "Priyanthi N. P." } }, { "id": "Nakatomi-Leesa-M", "name": { "family": "Nakatomi", "given": "Leesa M." } }, { "id": "Storm-Kaya-N", "name": { "family": "Storm", "given": "Kaya N." } }, { "id": "Moon-Woohyun-J", "name": { "family": "Moon", "given": "Woohyun J." } }, { "id": "Lin-Paulo-J-C", "name": { "family": "Lin", "given": "Paulo J. C." } }, { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990" } ] }, "title": "ESCRT recruitment to mRNA-encoded SARS-CoV-2 spike induces virus-like particles and enhanced antibody responses", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \n\nWe thank J. Vielmetter and the Caltech Protein Expression Center for assistance with protein production, K. Dam for biotinylated proteins for ELISAs, M. Anaya for a BirA expression plasmid, and J. Bloom (Fred Hutchinson) and P. Bieniasz (Rockefeller University) for neutralization assay reagents. We thank J. Keeffe, A. West, Y. Tam (Acuitas Therapeutics), C. Barnes (Stanford), H. Kleanthous (Bill and Melinda Gates Foundation), B. Wold, G. Tolomiczenko, and the Caltech Merkin Institute for Translational Research for helpful discussions and A. West for careful reading of the manuscript. Electron tomography was performed in the Caltech Cryo-EM Center with assistance from S. Chen. We thank Labcorp Drug Development\u2013Antibody Reagents and Vaccines (Denver, PA) (formerly Covance, Inc.) for mouse immunization studies, BIOQUAL, Inc. (Rockville, MD) for PRNT50 assays, and R. Sukhovershin and RNAcore (Houston Methodist Research Institute) for synthesis of mRNAs and helpful discussion. Figures 1A and 3A were created with Biorender.com. This work was supported by the Bill and Melinda Gates Foundation INV-034638 (P.J.B.), the Caltech Merkin Institute (P.J.B.), the George Mason University Fast Grants (P.J.B.), the Rothenberg Innovation Initiative (RI2 475 ) (P.J.B.), and Wellcome Leap (P.J.B.). M.A.G.H. was supported by an NIH Director's Early Independence Award (FAIN# DP5OD033362). \n\nAuthor contributions: M.A.G.H. and P.J.B. conceived the study, acquired funding, analyzed the data, and wrote the manuscript with contributions from other authors (Z.Y., P.J.C.L.). M.A.G.H. and K.E.H.T. generated, expressed, and evaluated EABR constructs by Western blot and flow cytometry analysis. M.A.G.H., K.E.H.T., P.N.P.G., L.M.K., and K.N.S. evaluated serum antibody responses from immunized mice by ELISA and neutralization assays. Z.Y. performed cryo-electron tomography and interpreted results. A.A.C. prepared S-mi3 immunogens for immunization studies in mice. W.J.M. and P.J.C.L. prepared mRNA-LNP for immunization studies in mice. \n\nData availability. All data are available in the main text or the supplementary information. Materials are available upon request to the corresponding authors with a signed material transfer agreement. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other included in the article that is credited to a third party; obtain authorization from the rights holder before using such material. \n\nCompeting Interest Statement. M.A.G.H. and P.J.B. are inventors on a US patent application filed by the California Institute of Technology that covers the EABR technology described in this work. W.J.M. and P.J.C.L. are employees of Acuitas Therapeutics, a company developing lipid nanoparticle delivery technology; P.J.C.L. holds equity in Acuitas Therapeutics.\n\nSubmitted - 20221226-521940v1full.pdf
Supplemental Material - media-1.mov
", "abstract": "Prime-boost regimens for COVID-19 vaccines elicit poor antibody responses against Omicron-based variants and employ frequent boosters to maintain antibody levels. We present a natural infection-mimicking technology that combines features of mRNA- and protein nanoparticle-based vaccines through encoding self-assembling enveloped virus-like particles (eVLPs). eVLP assembly is achieved by inserting an ESCRT- and ALIX-binding region (EABR) into the SARS-CoV-2 spike cytoplasmic tail, which recruits ESCRT proteins to induce eVLP budding from cells. Purified spike-EABR eVLPs presented densely-arrayed spikes and elicited potent antibody responses in mice. Two immunizations with mRNA-LNP encoding spike-EABR elicited potent CD8+ T-cell responses and superior neutralizing antibody responses against original and variant SARS-CoV-2 compared to conventional spike-encoding mRNA-LNP and purified spike-EABR eVLPs, improving neutralizing titers >10-fold against Omicron-based variants for three months post-boost. Thus, EABR technology enhances potency and breadth of vaccine-induced responses through antigen presentation on cell surfaces and eVLPs, enabling longer-lasting protection against SARS-CoV-2 and other viruses.", "date": "2022-12-27", "date_type": "published", "id_number": "CaltechAUTHORS:20230316-182651000.48", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230316-182651000.48", "funders": { "items": [ { "agency": "Bill and Melinda Gates Foundation", "grant_number": "INV-034638" }, { "agency": "Caltech Merkin Institute for Translational Research" }, { "agency": "George Mason University" }, { "agency": "Rothenberg Innovation Initiative (RI2)" }, { "agency": "Wellcome Leap" }, { "agency": "NIH", "grant_number": "DP5OD033362" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Richard-Merkin-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2022.12.26.521940", "pmcid": "PMC9810232", "primary_object": { "basename": "media-1.mov", "url": "https://authors.library.caltech.edu/records/6g151-9b339/files/media-1.mov" }, "related_objects": [ { "basename": "20221226-521940v1full.pdf", "url": "https://authors.library.caltech.edu/records/6g151-9b339/files/20221226-521940v1full.pdf" } ], "pub_year": "2022", "author_list": "Hoffmann, Magnus A. G.; Yang, Zhi; et al." }, { "id": "https://authors.library.caltech.edu/records/fddph-qkq10", "eprint_id": 120390, "eprint_status": "archive", "datestamp": "2023-08-20 08:54:46", "lastmod": "2025-11-21 03:21:39", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kim-Soo-Kyung", "name": { "family": "Kim", "given": "Soo-Kyung" }, "orcid": "0000-0002-4498-5441" }, { "id": "Suebka-Sartanee", "name": { "family": "Suebka", "given": "Sartanee" } }, { "id": "Gin-Adley-N", "name": { "family": "Gin", "given": "Adley" }, "orcid": "0000-0002-4906-8781" }, { "id": "Nguyen-Phuong-Diem", "name": { "family": "Nguyen", "given": "Phuong-Diem" } }, { "id": "Tang-Yisha", "name": { "family": "Tang", "given": "Yisha" } }, { "id": "Su-Judith", "name": { "family": "Su", "given": "Judith" }, "orcid": "0000-0002-1005-1755" }, { "id": "Goddard-W-A-III", "name": { "family": "Goddard", "given": "William A., III" }, "orcid": "0000-0003-0097-5716" } ] }, "title": "Prediction and experimental validation of drug candidates that bind specifically to the SARS-CoV-2 receptor-binding domain to prevent entry via Angiotensin-converting enzyme 2 (ACE2)", "ispublished": "unpub", "full_text_status": "public", "note": "The content is available under CC BY NC ND 4.0 License. \n\nThe computational studies at Caltech were supported by a grant from the NIH (R01HL155532). The experimental studies at Arizona were supported by NIH R35GM137988. Some computational resources for this research were provided by the Anton2 computer at the Pittsburgh National Supercomputing Center (MCB180091P). P-D Nguyen thanks Yelena Feinstein (University of Arizona) for her assistance in mass spectrometry.\n\nSupplemental Material - prediction-and-experimental-validation-of-drug-candidates-to-prevent-covid-19-infection.pdf
", "abstract": "The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 (SARS-CoV-2) virus has created enormous public health and economic crises. The SARS-CoV-2 spike protein binds to its host receptor, human angiotensin-converting enzyme 2 (hACE2), through its receptor binding domain (RBD) and is proteolytically activated by human protease TMPRSS2 to process the SARS-CoV-2 spike protein to facilitate host cell entry. To identify new candidate drugs to inhibit binding of the RBD to hACE2 (the first step of virus entry), we used in silico screening (Phase VS from Schr\u04e7dinger) to predict the RBD binding site and energetics for molecules in the ZINC FDA approved Drug Bank database (1,657 drugs), which includes clinical trial drugs approved by FDA. Using a pharmacophore (1 acceptor, 1 donor, 3 negatively charged, 1 positively charged) derived from the 2.5-\u00c5 X-ray structure SARS-CoV-2 RBD complexed with hACE2 (PDB ID: 6LZG), we found 29 unique hits. To refine the binding energies and bonding sites, we applied our DarwinDock complete sampling method, predicting that 4 of these 29 should bind strongly to the RBD site. Next, we tested 3 of these experimentally using FLOWER, a label-free optical whispering gallery mode sensing technique that can measure ligand-receptor binding affinities down to attomolar levels. We measure that methotrexate (MTX) and Diethylenetriamine pentaacetate (DTPA) bind with an inhibitory constant (Ki) of 0.2 pM in Tricine buffer, which is 1.832 million fold increase in binding strength compared to hACE2 (Kd: 366.4 nM). We then tested these ligands against common mutations: alpha, delta, and omicron. Our measured binding studies demonstrate that MTX provides inhibition against all four variants of SARS-coV-2. Indeed, the clinical and experimental data have shown that humans taking WT MTX are protected against infection by SARS-CoV-2.", "date": "2022-12-21", "date_type": "published", "id_number": "CaltechAUTHORS:20230324-284930000.4", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230324-284930000.4", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01HL155532" }, { "agency": "NIH", "grant_number": "R35GM137988" }, { "agency": "Pittsburgh National Supercomputing Center", "grant_number": "MCB180091P" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.26434/chemrxiv-2022-nrhzz", "primary_object": { "basename": "prediction-and-experimental-validation-of-drug-candidates-that-bind-specifically-to-the-sars-co-v-2-receptor-binding-domain-to-prevent-entry-via-angiotensin-converting-enzyme-2-ace2.pdf", "url": "https://authors.library.caltech.edu/records/fddph-qkq10/files/prediction-and-experimental-validation-of-drug-candidates-that-bind-specifically-to-the-sars-co-v-2-receptor-binding-domain-to-prevent-entry-via-angiotensin-converting-enzyme-2-ace2.pdf" }, "related_objects": [ { "basename": "prediction-and-experimental-validation-of-drug-candidates-to-prevent-covid-19-infection.pdf", "url": "https://authors.library.caltech.edu/records/fddph-qkq10/files/prediction-and-experimental-validation-of-drug-candidates-to-prevent-covid-19-infection.pdf" } ], "pub_year": "2022", "author_list": "Kim, Soo-Kyung; Suebka, Sartanee; et al." }, { "id": "https://authors.library.caltech.edu/records/z8sb8-e1n32", "eprint_id": 120313, "eprint_status": "archive", "datestamp": "2023-08-20 08:38:22", "lastmod": "2025-11-21 18:49:43", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zvyagin-Maxim", "name": { "family": "Zvyagin", "given": "Maxim" } }, { "name": { "family": "Brace", "given": "Alexander" }, "orcid": "0000-0001-9873-9177" }, { "name": { "family": "Hippe", "given": "Kyle" } }, { "name": { "family": "Deng", "given": "Yuntian" } }, { "name": { "family": "Zhang", "given": "Bin" } }, { "name": { "family": "Orozco Bohorquez", "given": "Cindy" } }, { "name": { "family": "Clyde", "given": "Austin" }, "orcid": "0000-0002-3697-7070" }, { "name": { "family": "Kale", "given": "Bharat" } }, { "name": { "family": "Perez-Rivera", "given": "Danilo" } }, { "name": { "family": "Ma", "given": "Heng" }, "orcid": "0000-0002-7667-922X" }, { "name": { "family": "Mann", "given": "Carla M." } }, { "name": { "family": "Irvin", "given": "Michael" } }, { "name": { "family": "Pauloski", "given": "J. Gregory" }, "orcid": "0000-0002-6547-6902" }, { "name": { "family": "Ward", "given": "Logan" }, "orcid": "0000-0002-1323-5939" }, { "name": { "family": "Hayot-Sasson", "given": "Valerie" }, "orcid": "0000-0002-4830-4535" }, { "name": { "family": "Emani", "given": "Murali" } }, { "name": { "family": "Foreman", "given": "Sam" } }, { "name": { "family": "Xie", "given": "Zhen" } }, { "name": { "family": "Lin", "given": "Diangen" } }, { "name": { "family": "Shukla", "given": "Maulik" } }, { "name": { "family": "Nie", "given": "Weili" } }, { "name": { "family": "Romero", "given": "Josh" } }, { "name": { "family": "Dallago", "given": "Christian" }, "orcid": "0000-0003-4650-6181" }, { "name": { "family": "Vahdat", "given": "Arash" } }, { "name": { "family": "Xiao", "given": "Chaowei" }, "orcid": "0000-0002-7043-4926" }, { "name": { "family": "Gibbs", "given": "Thomas" } }, { "name": { "family": "Foster", "given": "Ian" }, "orcid": "0000-0003-2129-5269" }, { "name": { "family": "Davis", "given": "James J." }, "orcid": "0000-0003-0104-5852" }, { "name": { "family": "Papka", "given": "Michael E." }, "orcid": "0000-0002-6418-5767" }, { "name": { "family": "Brettin", "given": "Thomas" }, "orcid": "0000-0001-9301-9760" }, { "name": { "family": "Stevens", "given": "Rick" } }, { "id": "Anandkumar-A", "name": { "family": "Anandkumar", "given": "Anima" }, "orcid": "0000-0002-6974-6797" }, { "name": { "family": "Vishwanath", "given": "Venkatram" } }, { "name": { "family": "Ramanathan", "given": "Arvind" }, "orcid": "0000-0002-1622-5488" } ] }, "title": "GenSLMs: Genome-scale language models reveal SARS-CoV-2 evolutionary dynamics", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \n\nWe thank the Argonne Leadership Computing Facility (ALCF) supported by the DOE under DE-AC02-06CH11357 and the National Energy Research Scientific Computing Center (NERSC) at Lawrence Berkeley National Laboratory supported by the DOE under Contract No. DE-AC02-05CH11231. We thank Bill Allcock, Silvio Rizzi and ALCF, Wahid Bhimji and NERSC for their timely help in enabling us to run these jobs at scale. We also thank Defne Gorgun, Lorenzo Casalino and Rommie Amaro for stimulating discussions. This research was supported by the Exascale Computing Project (17-SC-20-SC), a collaborative effort of the US DOE Office of Science and the National Nuclear Security Administration, the National Institute of Allergy and Infectious Diseases, National Institutes of Health Award Number P01AI165077 (AR), the National Science Foundation Award Number 2117896 and supported by the DOE through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on response to COVID-19, with funding from the Coronavirus CARES Act. \n\nThe authors have declared no competing interest.\n\nSubmitted - 2022.10.10.511571v2.full.pdf
", "abstract": "We seek to transform how new and emergent variants of pandemiccausing viruses, specifically SARS-CoV-2, are identified and classified. By adapting large language models (LLMs) for genomic data, we build genome-scale language models (GenSLMs) which can learn the evolutionary landscape of SARS-CoV-2 genomes. By pretraining on over 110 million prokaryotic gene sequences and finetuning a SARS-CoV-2-specific model on 1.5 million genomes, we show that GenSLMs can accurately and rapidly identify variants of concern. Thus, to our knowledge, GenSLMs represents one of the first whole genome scale foundation models which can generalize to other prediction tasks. We demonstrate scaling of GenSLMs on GPU-based supercomputers and AI-hardware accelerators utilizing 1.63 Zettaflops in training runs with a sustained performance of 121 PFLOPS in mixed precision and peak of 850 PFLOPS. We present initial scientific insights from examining GenSLMs in tracking evolutionary dynamics of SARS-CoV-2, paving the path to realizing this on large biological data.", "date": "2022-10-11", "date_type": "published", "id_number": "CaltechAUTHORS:20230322-101633000.20", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230322-101633000.20", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-06CH11357" }, { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-05CH11231" }, { "agency": "Department of Energy (DOE)", "grant_number": "17-SC-20-SC" }, { "agency": "NIH", "grant_number": "P01AI165077" }, { "agency": "NSF", "grant_number": "DMR-2117896" }, { "agency": "Coronavirus CARES Act" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2022.10.10.511571", "pmcid": "PMC9709791", "primary_object": { "basename": "2022.10.10.511571v2.full.pdf", "url": "https://authors.library.caltech.edu/records/z8sb8-e1n32/files/2022.10.10.511571v2.full.pdf" }, "pub_year": "2022", "author_list": "Zvyagin, Maxim; Brace, Alexander; et al." }, { "id": "https://authors.library.caltech.edu/records/1cnh8-6rf45", "eprint_id": 120328, "eprint_status": "archive", "datestamp": "2023-10-09 22:04:36", "lastmod": "2025-11-20 20:43:19", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Schulte-Samuel-J", "name": { "family": "Schulte", "given": "Samuel J." }, "orcid": "0000-0001-9982-6504" }, { "id": "Huang-Jining", "name": { "family": "Huang", "given": "Jining" }, "orcid": "0000-0002-3798-4790" }, { "id": "Pierce-N-A", "name": { "family": "Pierce", "given": "Niles A." }, "orcid": "0000-0003-2367-4406" } ] }, "title": "HCR Lateral Flow Assays for Amplified Instrument-Free At-Home SARS-CoV-2 Testing", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. \n\nWe thank M. Schwarzkopf and K. S. Lee for performing preliminary studies. We thank M. E. Bronner for reading a draft of the manuscript. We thank M. Schwarzkopf, K. S. Lee, L. M. Hochrein, G. Shin, B. J. Wold, and R. F. Ismagilov for helpful discussions. We thank G. Shin of the Molecular Technologies resource within the Beckman Institute at Caltech for providing HCR reagents. This work was funded by the Shurl and Kay Curci Foundation, by the Richard N. Merkin Institute for Translational Research at Caltech, by the National Aeronautics and Space Administration (Translational Research Institute for Space Health; NNX16AO69A), and by the National Institutes of Health (NIBIB R01EB006192 and NIGMS training grant GM008042 to S.J.S.).\n\nCompeting Interest Statement. Patents, pending patent applications, and the startup company Molecular Instruments.\n\nSubmitted - 20220918-508442v1full.pdf
Supplemental Material - media1.pdf
Supplemental Material - media2.mp4
Supplemental Material - media3.mp4
", "abstract": "The lateral flow assay format enables rapid, instrument-free, at-home testing for SARS-CoV-2. Due to the absence of signal amplification, this simplicity comes at a cost in sensitivity. Here, we enhance sensitivity by developing an amplified lateral flow assay that incorporates isothermal, enzyme-free signal amplification based on the mechanism of hybridization chain reaction (HCR). The simplicity of the user experience is maintained using a disposable 3-channel lateral flow device to automatically deliver reagents to the test region in three successive stages without user interaction. To perform a test, the user loads the sample, closes the device, and reads the result by eye after 60 minutes. Detecting gamma-irradiated SARS-CoV-2 virions in a mixture of saliva and extraction buffer, the current amplified HCR lateral flow assay achieves a limit of detection of 200 copies/\u03bcL using available antibodies to target the SARS-CoV-2 nucleocapsid protein. By comparison, five commercial unamplified lateral flow assays that use proprietary antibodies exhibit limits of detection of 500 copies/\u03bcL, 1000 copies/\u03bcL, 2000 copies/\u03bcL, 2000 copies/\u03bcL, and 20,000 copies/\u03bcL. By swapping out antibody probes to target different pathogens, amplified HCR lateral flow assays offer a platform for simple, rapid, and sensitive at-home testing for infectious disease. As an alternative to viral protein detection, we further introduce an HCR lateral flow assay for viral RNA detection.", "date": "2022-09-19", "date_type": "published", "id_number": "CaltechAUTHORS:20230322-367067000.13", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230322-367067000.13", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Shurl and Kay Curci Foundation" }, { "agency": "Caltech Merkin Institute for Translational Research" }, { "agency": "NASA", "grant_number": "NNX16AO69A" }, { "agency": "NIH", "grant_number": "R01EB006192" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "GM008042" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Richard-Merkin-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2022.09.18.508442", "primary_object": { "basename": "20220918-508442v1full.pdf", "url": "https://authors.library.caltech.edu/records/1cnh8-6rf45/files/20220918-508442v1full.pdf" }, "related_objects": [ { "basename": "media1.pdf", "url": "https://authors.library.caltech.edu/records/1cnh8-6rf45/files/media1.pdf" }, { "basename": "media2.mp4", "url": "https://authors.library.caltech.edu/records/1cnh8-6rf45/files/media2.mp4" }, { "basename": "media3.mp4", "url": "https://authors.library.caltech.edu/records/1cnh8-6rf45/files/media3.mp4" } ], "pub_year": "2022", "author_list": "Schulte, Samuel J.; Huang, Jining; et al." }, { "id": "https://authors.library.caltech.edu/records/m19jz-cyp83", "eprint_id": 120353, "eprint_status": "archive", "datestamp": "2023-08-20 08:28:07", "lastmod": "2025-11-20 21:05:11", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Braet-Sean-M", "name": { "family": "Braet", "given": "Sean M." }, "orcid": "0000-0003-3782-2262" }, { "id": "Buckley-Theresa-S-C", "name": { "family": "Buckley", "given": "Theresa S. C." } }, { "id": "Venkatakrishnan-Varun", "name": { "family": "Venkatakrishnan", "given": "Varun" } }, { "id": "Dam-Kim-Marie-A", "name": { "family": "Dam", "given": "Kim-Marie A." }, "orcid": "0000-0002-1416-4757" }, { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990" }, { "id": "Anand-Ganesh-Srinivasan", "name": { "family": "Anand", "given": "Ganesh S." }, "orcid": "0000-0001-8995-3067" } ] }, "title": "Timeline of changes in spike conformational dynamics in emergent SARS-CoV-2 variants reveal progressive stabilization of trimer stalk and enhanced NTD dynamics", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. \n\nStartup funding from the Pennsylvania State University (PSU) to GSA. \n\nWe thank Rosa Viner (Thermo Scientific, San Jose, CA) for spike protein glycan analysis. \n\nData and Materials availability: Mass Spectrometry data: ProteomeXchange Consortium via the PRIDE partner repository. All data is available in the main text and supplemental information. Information on recombinant proteins and reagents is available upon request. \n\nThe authors have declared no competing interest.\n\nSubmitted - 2022.08.26.505369v1.full.pdf
", "abstract": "SARS-CoV-2 emergent variants are characterized by increased transmissibility and each show multiple mutations predominantly localized to the spike (S) protein. Here, amide hydrogen/deuterium exchange mass spectrometry has been applied to track correlative changes in S dynamics from multiple SARS-CoV-2 variants. Our results highlight large differences across variants at two loci with impacts on S dynamics and stability. A significant enhancement in stabilization first occurred with the emergence of D614G S followed by smaller, progressive stabilization in Omicron BA.1 S traced through Alpha S and Delta S variants. Stabilization preceded progressive enhancement in dynamics in the N-terminal domain, wherein Omicron BA.1 S showed the largest magnitude increases relative to other preceding variants. Changes in stabilization and dynamics resulting from specific S mutations detail the evolutionary trajectory of S protein in emerging variants. These carry major implications for SARS-CoV-2 viral fitness and offer new insights into variant-specific therapeutic development.", "date": "2022-08-29", "date_type": "published", "id_number": "CaltechAUTHORS:20230322-368453000.40", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230322-368453000.40", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Pennsylvania State University" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2022.08.26.505369", "primary_object": { "basename": "2022.08.26.505369v1.full.pdf", "url": "https://authors.library.caltech.edu/records/m19jz-cyp83/files/2022.08.26.505369v1.full.pdf" }, "pub_year": "2022", "author_list": "Braet, Sean M.; Buckley, Theresa S. C.; et al." }, { "id": "https://authors.library.caltech.edu/records/k5v8y-gam02", "eprint_id": 118541, "eprint_status": "archive", "datestamp": "2023-08-20 08:27:30", "lastmod": "2025-11-20 23:13:27", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Wang-Zichao", "name": { "family": "Wang", "given": "Zichao" } }, { "id": "Nie-Weili", "name": { "family": "Nie", "given": "Weili" } }, { "id": "Qiao-Zhuoran", "name": { "family": "Qiao", "given": "Zhuoran" }, "orcid": "0000-0002-5704-7331" }, { "id": "Xiao-Chaowei", "name": { "family": "Xiao", "given": "Chaowei" }, "orcid": "0000-0002-7043-4926" }, { "id": "Baraniuk-Richard-G", "name": { "family": "Baraniuk", "given": "Richard" }, "orcid": "0000-0002-0721-8999" }, { "id": "Anandkumar-A", "name": { "family": "Anandkumar", "given": "Anima" }, "orcid": "0000-0002-6974-6797" } ] }, "title": "Retrieval-based Controllable Molecule Generation", "ispublished": "unpub", "full_text_status": "public", "note": "ETHICS STATEMENT. Applications that involve molecule generation such as drug discovery are high-stake in nature. These applications are highly regulated to prevent potential misuse (Hill and Richards, 2022). RetMol as a technology to improve controllable molecule generation has the potential to be subjected to malicious use. For example, one could change the retrieval database and the design criteria into harmful ones, such as increased drug toxicity. However, we note that RetMol is a computational tool useful for in silico experiments. As a result, although RetMol can suggest new molecules according to arbitrary design criteria, the properties of the generated molecules are estimations of the real chemical and biological properties and need to be further validated in lab experiments. Thus, while RetMol's real-world impact is limited to in silico experiments, it is also prevented from directly generating real drugs that can be readily used. In addition, controllable molecule generation is an active area of research; we hope that our work contribute to this ongoing line of research and make ML methods safe and reliable for molecule generation applications in the real world. \n\nREPRODUCIBILITY STATEMENT. To ensure the reproducibility of the empirical results, we provide the implementation details of each task (i.e., experimental setups, hyperparameters, dataset specifications, etc.) in Appendix B. The source code will be released in the future.\n\nSubmitted - 2208.11126.pdf
", "abstract": "Generating new molecules with specified chemical and biological properties via generative models has emerged as a promising direction for drug discovery. However, existing methods require extensive training/fine-tuning with a large dataset, often unavailable in real-world generation tasks. In this work, we propose a new retrieval-based framework for controllable molecule generation. We use a small set of exemplar molecules, i.e., those that (partially) satisfy the design criteria, to steer the pre-trained generative model towards synthesizing molecules that satisfy the given design criteria. We design a retrieval mechanism that retrieves and fuses the exemplar molecules with the input molecule, which is trained by a new self-supervised objective that predicts the nearest neighbor of the input molecule. We also propose an iterative refinement process to dynamically update the generated molecules and retrieval database for better generalization. Our approach is agnostic to the choice of generative models and requires no task-specific fine-tuning. On various tasks ranging from simple design criteria to a challenging real-world scenario for designing lead compounds that bind to the SARS-CoV-2 main protease, we demonstrate our approach extrapolates well beyond the retrieval database, and achieves better performance and wider applicability than previous methods.", "date": "2022-08-23", "date_type": "published", "publisher": "arXiv", "id_number": "CaltechAUTHORS:20221221-004642358", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20221221-004642358", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.48550/arXiv.2208.11126", "primary_object": { "basename": "2208.11126.pdf", "url": "https://authors.library.caltech.edu/records/k5v8y-gam02/files/2208.11126.pdf" }, "pub_year": "2022", "author_list": "Wang, Zichao; Nie, Weili; et al." }, { "id": "https://authors.library.caltech.edu/records/x0cjg-kxg25", "eprint_id": 115693, "eprint_status": "archive", "datestamp": "2023-08-20 08:12:09", "lastmod": "2025-11-21 00:12:50", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Winnett-Alexander-Viloria", "name": { "family": "Winnett", "given": "Alexander Viloria" }, "orcid": "0000-0002-7338-5605" }, { "id": "Akana-Reid", "name": { "family": "Akana", "given": "Reid" }, "orcid": "0000-0003-4422-587X" }, { "id": "Shelby-Natasha", "name": { "family": "Shelby", "given": "Natasha" }, "orcid": "0000-0001-9097-3663" }, { "id": "Davich-Hannah", "name": { "family": "Davich", "given": "Hannah" }, "orcid": "0000-0001-6880-3086" }, { "id": "Caldera-Saharai", "name": { "family": "Caldera", "given": "Saharai" }, "orcid": "0000-0001-5057-9186" }, { "id": "Yamada-Taikun", "name": { "family": "Yamada", "given": "Taikun" } }, { "id": "Reyna-John-Raymond-B", "name": { "family": "Reyna", "given": "John Raymond B." } }, { "id": "Romano-Anne-E", "name": { "family": "Romano", "given": "Anna E." }, "orcid": "0000-0002-7148-0668" }, { "id": "Carter-Alyssa-M", "name": { "family": "Carter", "given": "Alyssa M." }, "orcid": "0000-0002-2776-9421" }, { "id": "Kim-Mi-Kyung", "name": { "family": "Kim", "given": "Mi Kyung" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" }, { "id": "Tognazzini-Colten", "name": { "family": "Tognazzini", "given": "Colten" }, "orcid": "0000-0002-2754-3588" }, { "id": "Feaster-Matthew", "name": { "family": "Feaster", "given": "Matthew" }, "orcid": "0000-0001-9966-2845" }, { "id": "Goh-Ying-Ying", "name": { "family": "Goh", "given": "Ying-Ying" }, "orcid": "0000-0001-5136-7214" }, { "id": "Chew-Yap-Ching", "name": { "family": "Chew", "given": "Yap Ching" }, "orcid": "0000-0002-1686-6541" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Why Daily SARS-CoV-2 Nasal Rapid Antigen Testing Poorly Detects Infected and Infectious Individuals", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. \n\nWe sincerely thank the study participants for making this work possible. We thank Lauriane Quenee, Grace Fisher-Adams, Junie Hildebrandt, Megan Hayashi, RuthAnne Bevier, Chantal D'Apuzzo, Ralph Adolphs, Victor Rivera, Steve Chapman, Gary Waters, Leonard Edwards, Gaylene Ursua, Cynthia Ramos, and Shannon Yamashita for their assistance and advice on study implementation and/or administration. We thank Jessica Leong, Ojas Pradhan, Si Hyung Jin, Emily Savela, Bridget Yang, Ekta Patel, Hsiuchen Chen, Paresh Samantaray, Zeynep Turan, Cindy Kim, Trinity Lee, Vanessa Mechan, Katherine Stiefel, Rosie Zedan, Rahulijeet Chadha, Minkyo Lee, and Jenny Ji for volunteering their time to help with this study. We thank Prabhu Gounder, Tony Chang, Jennifer Howes, and Nari Shin for their support with recruitment. Finally, we thank all the case investigators and contact tracers at the Pasadena Public Health Department and Caltech Student Wellness Services for their efforts in study recruitment and their work in the pandemic response. \n\nThis work was supported in part by a grant from the Ronald and Maxine Linde Center for New Initiatives at the California Institute of Technology (to R.F.I.) and the Jacobs Institute for Molecular Engineering for Medicine at the California Institute of Technology (to R.F.I.). A.V.W. is supported by a UCLA DGSOM Geffen Fellowship.\n\nAUTHOR CONTRIBUTIONS (listed alphabetically by last name): \n\nReid Akana (RA): Collaborated with AVW in creating digital participant symptom surveys; assisted with data quality\ncontrol/curation with NS, HD, SC; created current laboratory information management system (LIMS) for specimen logging and tracking. Creation of iOS application for sample logging/tracking. Configured an SQL database for data storage. Created an Apache server and websites to view study data. Configured FTPS server to catalog PCR data. Wrote a Python package to access study data. Trained study coordinators on SQL. Troubleshooting and QC of LIMS. Made Figures 4, 5, S2, S3, S4, S5. Wrote and edited the manuscript with AVW and NS. \n\nAlyssa M. Carter (AMC): Assisted with the inventory and archiving of >6,000 samples at Caltech; coordinated shipment of samples to Caltech with AER and JRBR; assisted with procurement of antigen tests; assisted with organizing volunteers and making participant kits; assisted AER in developing and implementing QC for participant kits. Led the in-lab investigation of antigen false-positive results; designed and performed experiments for lot analysis of the Quidel QuickVue At-Home Covid-19 tests. Provided feedback and edited the manuscript. \n\nYap Ching Chew (YCC): Primary liaison with Caltech team. Prepared and provided Zymo SafeCollect kits and related\nmaterials to Caltech team. Supervised the extraction, PCR, and QC teams at Pangea Laboratory. Sent PCR results daily to\nCaltech team. Arranged for Pangea team to perform viral-variant sequencing on selected samples; reported results and\nprovided sequencing files. \n\nSaharai Caldera (SC): Study coordinator; recruited, enrolled and maintained study participants with NS and HD; study-data\nquality control, curation and archiving with RA, NS, HD and MKK; supplies acquisition with AER, NS, HD and MKK. \n\nHannah Davich (HD): Lead study coordinator; co-wrote participant informational sheets with NS; developed recruitment strategies and did outreach with NS; participant kit creation and co-coordinated kit-making by volunteers with AER; recruited, enrolled and maintained study participants with NS and SC; managed the study-coordinator inventory; study-data quality control, curation and archiving with RA, NS, SC and MKK; supplies acquisition with AER, NS, SC and MKK. \n\nMatthew Feaster (MF): Co-investigator; collaborated with AVW, MMC, NS, YG, RFI on study design and recruitment strategies; provided guidance and expertise on SARS-CoV-2 epidemiology and local trends. \n\nYing-Ying Goh (Y-YG): Co-investigator; collaborated with AVW, MMC, NS, MF, RFI on study design and recruitment strategies; provided guidance and expertise on SARS-CoV-2 epidemiology and local trends. \n\nRustem F. Ismagilov (RFI): Principal investigator; collaborated with AVW, MMC, NS, MF, YYG on study design and recruitment strategies; provided leadership, technical guidance, oversight of all analyses, and was responsible for obtaining the primary funding for the study. \n\nMi Kyung Kim (MKK): Study coordinator (part-time); maintaining participants with NS, HD, and SC; study-data quality control, curation and archiving with RA, NS, SC and HD; supplies acquisition with AER, NS, SC and HD; collected contact info for local university/college student health centers for recruitment outreach; assembled Table S1 with NS. \n\nJohn Raymond B. Reyna (JRBR): Organized sample labeling and short-term storage of all samples at Pangea Laboratories. Arranged shipment of all samples to Caltech team. Assisted with processing of the specimens. \n\nAnna E. Romano (AER): Co-coordinated kit-making by volunteers with HD; implemented QC process for kit-making; participated in kit making; managed logistics for the inventory and archiving of >6,000 samples at Caltech; supplies acquisition with HD, NS, SC and MKK; assisted with securing funding; compiled antigen lot data to assist false-positive antigen test investigation; organized and performed QC on sequencing data. Provided feedback and edited the manuscript. \n\nNatasha Shelby (NS): Study administrator; collaborated with AVW, RFI, YG, MF on initial study design and recruitment strategies; co-wrote IRB protocol and informed consent with AVW; co-wrote enrollment questionnaire and post-study questionnaire with AVW; initiated the collaboration with Zymo and served as primary liaison throughout study; reviewed pilot sampling data and amended instructional sheets/graphics for specimen collections in collaboration with Zymo; cowrote participant informational sheets with HD; hired, trained, and supervised the study-coordinator team; developed recruitment strategies and did outreach with HD; recruited, enrolled and maintained study participants with HD and SC; co-developed participant keep/drop criteria with AVW; performed the daily upload, review, and QC of PCR data received from Zymo; made the daily keep/drop decisions based on viral-load trajectories in each household; made all phone calls to alert presumptive positives of their status and provide resources; study-data quality control, curation and archiving with RA, HD, SC and MKK; organized archiving of all participant data and antigen-test photographs; supplies acquisition with AER, HD, SC and MKK; assisted with securing funding; managed the overall study budget; assembled Fig 1 with AVW; assembled Table S1 with MKK; made Fig 3 with AVW; managed citations and reference library; verified the underlying data with AVW and RA; co-wrote and edited the manuscript with AVW and RA. \n\nMatt Thomson (MT): Assisted with statistical approach and analyses. \n\nColten Tognazzini (CT): Coordinated the recruitment efforts at PPHD with case investigators and contact tracers; provided guidance and expertise on SARS-CoV-2 epidemiology and local trends. \n\nAlexander Viloria Winnett (AVW): Collaborated with NS, RFI, YG, MF on initial study design and recruitment strategies; co-wrote IRB protocol and informed consent with NS; co-wrote enrollment questionnaire and post-study questionnaire with NS; co-developed participant keep/drop criteria with NS; funding acquisition; designed and coordinated LOD validation experiments; selected and prepared specimen for viral-variant sequencing with NS, YC, and AER; assisted with the inventory and archiving of >6,000 specimen at Caltech with AER and AMC; minor role supporting outreach by HD and NS; minor role supporting kit-making by AER, HD and AMC; verified the underlying data with NS and RA; assembled Fig 1 with NS; made Fig 3 with NS; performed analysis and prepared Fig 2, Fig 6, Fig S1, and Table S2. Co-wrote and edited the manuscript with NS and RA. \n\nTaikun Yamada (TY): Performed the RT-qPCR COVID-19 testing at Pangea Laboratory. \n\nDATA AVAILABILITY\nThe data underlying the results presented in the study can be accessed via CaltechDATA:\nhttps://data.caltech.edu/records/20223. \n\nCOMPETING INTERESTS STATEMENT. RFI is a co-founder, consultant, and a director and has stock ownership of Talis Biomedical Corp. All other authors declare that they have no competing interests.\n\nSubmitted - 2022.07.13.22277513v2.full.pdf
", "abstract": "Background. In a recent household-transmission study of SARS-CoV-2, we found extreme differences in SARS-CoV-2 viral loads among paired saliva, anterior-nares swab (ANS) and oropharyngeal swab specimens collected from the same timepoint. We hypothesized these differences may hinder low-analytical-sensitivity assays (including antigen rapid diagnostic tests, Ag-RDTs) using a single specimen type (e.g., ANS) from reliably detecting infected and infectious individuals. \n\nMethods. We evaluated a daily at-home ANS Ag-RDT (Quidel QuickVue) in a cross-sectional analysis of 228 individuals and in a longitudinal analysis (throughout infection) of 17 individuals enrolled early in the course of infection. Ag-RDT results were compared to RT-qPCR results and high, presumably infectious viral loads (in each, or any, specimen type). \n\nResults. The ANS Ag-RDT correctly detected only 44% of timepoints from infected individuals on cross-sectional analysis, and in this population had an inferred limit of detection of 7.6 \u00d7 10\u2076 copies/mL. From the longitudinal cohort, daily Ag-RDT clinical sensitivity was very low (<3%) during the early, pre-infectious period of the infection. Further, the Ag-RDT detected \u226463% of presumably infectious timepoints. The poor observed clinical sensitivity of the Ag-RDT was similar to what was predicted based on quantitative ANS viral loads and the inferred limit of detection of the ANS Ag-RDT being evaluated, indicating high-quality self-sampling. \n\nConclusion. Nasal Ag-RDTs, even when used daily, can miss individuals infected with the Omicron variant and even those presumably infectious. Evaluations of Ag-RDT detection of infected or infectious individuals should be compared with a composite (multi-specimen) infection status to correctly assess performance. \n\nKey points. Nasal-swab rapid antigen tests have low analytical sensitivity and the sampling of only the nasal cavity hinders their ability to detect infected individuals, including those with high and presumably infectious viral loads in throat or saliva specimens.", "date": "2022-07-15", "date_type": "published", "id_number": "CaltechAUTHORS:20220720-917093000", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220720-917093000", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Ronald and Maxine Linde Center for New Initiatives" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "UCLA" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2022.07.13.22277513", "primary_object": { "basename": "2022.07.13.22277513v2.full.pdf", "url": "https://authors.library.caltech.edu/records/x0cjg-kxg25/files/2022.07.13.22277513v2.full.pdf" }, "pub_year": "2022", "author_list": "Winnett, Alexander Viloria; Akana, Reid; et al." }, { "id": "https://authors.library.caltech.edu/records/vtef0-x7037", "eprint_id": 115694, "eprint_status": "archive", "datestamp": "2023-08-20 08:12:21", "lastmod": "2025-11-20 22:34:25", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Winnett-Alexander-V", "name": { "family": "Winnett", "given": "Alexander Viloria" }, "orcid": "0000-0002-7338-5605" }, { "id": "Akana-Reid", "name": { "family": "Akana", "given": "Reid" }, "orcid": "0000-0003-4422-587X" }, { "id": "Shelby-Natasha", "name": { "family": "Shelby", "given": "Natasha" }, "orcid": "0000-0001-9097-3663" }, { "id": "Davich-Hannah", "name": { "family": "Davich", "given": "Hannah" }, "orcid": "0000-0001-6880-3086" }, { "id": "Caldera-Saharai", "name": { "family": "Caldera", "given": "Saharai" }, "orcid": "0000-0001-5057-9186" }, { "id": "Yamada-Taikun", "name": { "family": "Yamada", "given": "Taikun" } }, { "id": "Reyna-John-Raymond-B", "name": { "family": "Reyna", "given": "John Raymond B." } }, { "id": "Romano-Anne-E", "name": { "family": "Romano", "given": "Anna E." }, "orcid": "0000-0002-7148-0668" }, { "id": "Carter-Alyssa-M", "name": { "family": "Carter", "given": "Alyssa M." }, "orcid": "0000-0002-2776-9421" }, { "id": "Kim-Mi-Kyung", "name": { "family": "Kim", "given": "Mi Kyung" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" }, { "id": "Tognazzini-Colten", "name": { "family": "Tognazzini", "given": "Colten" }, "orcid": "0000-0002-2754-3588" }, { "id": "Feaster-Matthew", "name": { "family": "Feaster", "given": "Matthew" }, "orcid": "0000-0001-9966-2845" }, { "id": "Goh-Ying-Ying", "name": { "family": "Goh", "given": "Ying-Ying" }, "orcid": "0000-0001-5136-7214" }, { "id": "Chew-Yap-Ching", "name": { "family": "Chew", "given": "Yap Ching" }, "orcid": "0000-0002-1686-6541" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Extreme differences in SARS-CoV-2 viral loads among respiratory specimen types during presumed pre-infectious and infectious periods", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. \n\nPaper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv. \n\nThis work was funded in part by a grant from the Ronald and Maxine Linde Center for New Initiatives at the California Institute of Technology (to RFI), a grant from the Jacobs Institute for Molecular Engineering for Medicine at the California Institute of Technology (to RFI), and a DGSOM Geffen Fellowship at the University of California, Los Angeles (to AVW). We sincerely thank the study participants for making this work possible. We thank Lauriane Quenee, Grace Fisher-Adams, Junie Hildebrandt, Megan Hayashi, RuthAnne Bevier, Chantal D'Apuzzo, Ralph Adolphs, Victor Rivera, Steve Chapman, Gary Waters, Leonard Edwards, Gaylene Ursua, Cynthia Ramos, and Shannon Yamashita for their assistance and advice on study implementation and/or administration. We thank Jessica Leong, Ojas Pradhan, Si Hyung Jin, Emily Savela, Bridget Yang, Ekta Patel, Hsiuchen Chen , Paresh Samantaray, Zeynep Turan, Cindy Kim, Trinity Lee, Vanessa Mechan, Katherine Stiefel, Rosie Zedan, Rahulijeet Chadha, Minkyo Lee, and Jenny Ji for volunteering their time to help with this study. We thank Prabhu Gounder, Tony Chang, Jennifer Howes, and Nari Shin for their support with recruitment. Finally, we thank all the case investigators and contact tracers at the Pasadena Public Health Department and Caltech Student Wellness Services for their efforts in study recruitment and their work in the pandemic response. \n\nAUTHOR CONTRIBUTIONS (listed alphabetically by last name):\n\nReid Akana (RA): Collaborated with AVW in creating digital participant symptom surveys; assisted with data quality control/curation with NS, HD, SC; created current laboratory information management system (LIMS) for specimen logging and tracking. Creation of iOS application for sample logging/tracking. Configured an SQL database for data storage. Created an Apache server and websites to view study data. Configured FTPS server to catalog PCR data. Wrote a Python package to access study data. Trained study coordinators on SQL. Troubleshooting and QC of LIMS. Made Fig 3(C-D) and SI Figs S3, S4, S5, Table S2, S3, S4, S5, S6. Wrote and edited the manuscript with AVW and NS.\n\nAlyssa M. Carter (AMC): Assisted with the inventory and archiving of >6,000 samples at Caltech; coordinated shipment of samples to Caltech with AER and JRBR; assisted with procurement of antigen tests; assisted with organizing volunteers and making participant kits; assisted AER in developing and implementing QC for participant kits. Provided feedback and edited the manuscript.\n\nYap Ching Chew (YCC): Primary liaison with Caltech team. Prepared and provided Zymo SafeCollect kits and related materials to Caltech team. Supervised the extraction, PCR, and QC teams at Pangea Laboratory. Sent PCR results daily to Caltech team. Arranged for Pangea team to perform viral-variant sequencing on selected samples; reported results and provided sequencing files.\n\nSaharai Caldera (SC): Study coordinator; recruited, enrolled and maintained study participants with NS and HD; study-data quality control, curation and archiving with RA, NS, HD and MKK; supplies acquisition with AER, NS, HD and MKK.\n\nHannah Davich (HD): Lead study coordinator; co-wrote participant informational sheets with NS; developed recruitment strategies and did outreach with NS; participant kit creation and co-coordinated kit-making by volunteers with AER; recruited, enrolled and maintained study participants with NS and SC; managed the study-coordinator inventory; study-data quality control, curation and archiving with RA, NS, SC and MKK; supplies acquisition with AER, NS, SC and MKK.\n\nMatthew Feaster (MF): Co-investigator; collaborated with AVW, MMC, NS, YG, RFI on study design and recruitment strategies; provided guidance and expertise on SARS-CoV-2 epidemiology and local trends.\n\nYing-Ying Goh (Y-YG): Co-investigator; collaborated with AVW, MMC, NS, MF, RFI on study design and recruitment strategies; provided guidance and expertise on SARS-CoV-2 epidemiology and local trends.\n\nRustem F. Ismagilov (RFI): Principal investigator; collaborated with AVW, MMC, NS, MF, YYG on study design and recruitment strategies; provided leadership, technical guidance, oversight of all analyses, and was responsible for obtaining the primary funding for the study.\n\nMi Kyung Kim (MKK): Study coordinator (part-time); maintaining participants with NS, HD, and SC; study-data quality control, curation and archiving with RA, NS, SC and HD; supplies acquisition with AER, NS, SC and HD; collected contact info for local university/college student health centers for recruitment outreach; assembled Table S1 with NS.\n\nJohn Raymond B. Reyna (JRBR): Organized sample labeling and short-term storage of all samples at Pangea Laboratories. Arranged shipment of all samples to Caltech team. Assisted with processing of the specimens.\n\nAnna E. Romano (AER): Co-coordinated kit-making by volunteers with HD; implemented QC process for kit-making; participated in kit-making; managed logistics for the inventory and archiving of >6,000 samples at Caltech; supplies acquisition with HD, NS, SC and MKK; assisted with securing funding; compiled Table S3; organized and performed QC on sequencing data. Provided feedback and edited the manuscript.\n\nNatasha Shelby (NS): Study administrator; collaborated with AVW, RFI, YG, MF on initial study design and recruitment strategies; co-wrote IRB protocol and informed consent with AVW; co-wrote enrollment questionnaire and post-study questionnaire with AVW; initiated the collaboration with Zymo and served as primary liaison throughout study; reviewed pilot sampling data and amended instructional sheets/graphics for specimen collections in collaboration with Zymo; co-wrote participant informational sheets with HD; hired, trained, and supervised the study-coordinator team; developed recruitment strategies and did outreach with HD; recruited, enrolled and maintained study participants with HD and SC; co-developed participant keep/drop criteria with AVW; performed the daily upload, review, and QC of PCR data received from Zymo; made the daily keep/drop decisions based on viral-load trajectories in each household; made all phone calls to alert presumptive positives of their status and provide resources; study-data quality control, curation and archiving with RA, HD, SC and MKK; organized archiving of all participant data and antigen-test photographs; supplies acquisition with AER, HD, SC and MKK; assisted with securing funding; managed the overall study budget; assembled Fig 1 with AVW; assembled Table S1 with MKK; made Fig 2 with AVW; managed citations and reference library; verified the underlying data with AVW and RA; co-wrote and edited the manuscript with AVW and RA.\n\nMatt Thomson (MT): Assisted with statistical approach and analyses.\n\nColten Tognazzini (CT): Coordinated the recruitment efforts at PPHD with case investigators and contact tracers; provided guidance and expertise on SARS-CoV-2 epidemiology and local trends.\n\nAlexander Viloria Winnett (AVW): Collaborated with NS, RFI, YG, MF on initial study design and recruitment strategies; co-wrote IRB protocol and informed consent with NS; co-wrote enrollment questionnaire and post-study questionnaire with NS; co-developed participant keep/drop criteria with NS; funding acquisition; designed and coordinated LOD validation experiments; selected and prepared specimen for viral-variant sequencing with NS, YC, and AER; assisted with the inventory and archiving of >6,000 specimen at Caltech with AER and AMC; minor role supporting outreach by HD and NS; minor role supporting kit-making by AER, HD and AMC; verified the underlying data with NS and RA; assembled Fig 1 with NS; made Fig 2 with NS; performed analysis and prepared Figs 4-7, Table S2, Fig S1, S2, S6, S7, S8, S9. Co-wrote and edited the manuscript with NS and RA.\n\nTaikun Yamada (TY): Performed the RT-qPCR COVID-19 testing at Pangea Laboratory.\n\nDATA AVAILABILITY. The data underlying the results presented in the study can be accessed at CaltechDATA: https://data.caltech.edu/records/20223. \n\nCOMPETING INTERESTS STATEMENT. RFI is a co-founder, consultant, and a director and has stock ownership of Talis Biomedical Corp.\n\nSubmitted - 2022.07.13.22277113v2.full.pdf
", "abstract": "SARS-CoV-2 viral load measurements from a single specimen type are used to establish diagnostic strategies, interpret clinical-trial results for vaccines and therapeutics, model viral transmission, and understand virus-host interactions. However, measurements from a single specimen type are implicitly assumed to be representative of other specimen types. We quantified viral-load timecourses from individuals who began daily self-sampling of saliva, anterior nares (nasal), and oropharyngeal (throat) swabs before or at the incidence of infection with the Omicron variant. Viral loads in different specimen types from the same person at the same timepoint exhibited extreme differences, up to 109 copies/mL. These differences were not due to variation in sample self-collection, which was consistent. For most individuals, longitudinal viral-load timecourses in different specimen types did not correlate. Throat-swab and saliva viral loads began to rise up to 7 days earlier than nasal-swab viral loads in most individuals, leading to very low clinical sensitivity of nasal swabs during the first days of infection. Individuals frequently exhibited presumably infectious viral loads in one specimen type while viral loads were low or undetectable in other specimen types. Therefore, defining an individual as infectious based on assessment of a single specimen type underestimates the infectious period, and overestimates the ability of that specimen type to detect infectious individuals. For diagnostic COVID-19 testing, these three single specimen types have low clinical sensitivity, whereas a combined throat-nasal swab, and assays with high analytical sensitivity, were inferred to have significantly better clinical sensitivity to detect presumed pre-infectious and infectious individuals.", "date": "2022-07-15", "date_type": "published", "id_number": "CaltechAUTHORS:20220720-917402000", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220720-917402000", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Ronald and Maxine Linde Center for New Initiatives" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "UCLA" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2022.07.13.22277113", "primary_object": { "basename": "2022.07.13.22277113v2.full.pdf", "url": "https://authors.library.caltech.edu/records/vtef0-x7037/files/2022.07.13.22277113v2.full.pdf" }, "pub_year": "2022", "author_list": "Winnett, Alexander Viloria; Akana, Reid; et al." }, { "id": "https://authors.library.caltech.edu/records/17vnm-7wt88", "eprint_id": 122581, "eprint_status": "archive", "datestamp": "2023-10-09 15:10:05", "lastmod": "2025-11-20 20:12:15", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Cohen-Alexander-A", "name": { "family": "Cohen", "given": "Alexander A." }, "orcid": "0000-0002-2818-656X" }, { "id": "van-Doremalen-Neeltje-A", "name": { "family": "van Doremalen", "given": "Neeltje" }, "orcid": "0000-0003-4368-6359" }, { "id": "Greaney-Alison-J", "name": { "family": "Greaney", "given": "Allison J." }, "orcid": "0000-0001-7202-3349" }, { "id": "Andersen-Hanne", "name": { "family": "Andersen", "given": "Hanne" } }, { "id": "Sharma-Ankur", "name": { "family": "Sharma", "given": "Ankur" } }, { "id": "Starr-Tyler-N", "name": { "family": "Starr", "given": "Tyler N." }, "orcid": "0000-0001-6713-6904" }, { "id": "Keeffe-Jennifer-R", "name": { "family": "Keeffe", "given": "Jennifer R." }, "orcid": "0000-0002-5317-6398" }, { "id": "Fan-Chengcheng", "name": { "family": "Fan", "given": "Chengcheng" }, "orcid": "0000-0003-4213-5758" }, { "id": "Schulz-Jonathan-E", "name": { "family": "Schulz", "given": "Jonathan E." } }, { "id": "Gnanapragasam-Priyanthi-N-P", "name": { "family": "Gnanapragasam", "given": "Priyanthi N. P." } }, { "id": "Kakutani-Leesa-M", "name": { "family": "Kakutani", "given": "Leesa M." }, "orcid": "0000-0003-3822-7449" }, { "id": "West-Anthony-P-Jr", "name": { "family": "West", "given": "Anthony P., Jr." }, "orcid": "0000-0003-4213-5184" }, { "id": "Saturday-Greg", "name": { "family": "Saturday", "given": "Greg" }, "orcid": "0000-0002-0803-6177" }, { "id": "Lee-Yu-Erica", "name": { "family": "Lee", "given": "Yu E." }, "orcid": "0000-0001-5989-326X" }, { "id": "Gao-Han", "name": { "family": "Gao", "given": "Han" } }, { "id": "Jette-Claudia-A", "name": { "family": "Jette", "given": "Claudia A." }, "orcid": "0000-0002-5085-8027" }, { "id": "Lewis-Mark-G", "name": { "family": "Lewis", "given": "Mark G." }, "orcid": "0000-0001-7852-0135" }, { "id": "Tan-Tiong-K", "name": { "family": "Tan", "given": "Tiong K." }, "orcid": "0000-0001-8746-8308" }, { "id": "Townsend-Alain-R", "name": { "family": "Townsend", "given": "Alain R." }, "orcid": "0000-0002-3702-0107" }, { "id": "Bloom-Jesse-D", "name": { "family": "Bloom", "given": "Jesse D." }, "orcid": "0000-0003-1267-3408" }, { "id": "Munster-Vincent-J", "name": { "family": "Munster", "given": "Vincent J." }, "orcid": "0000-0002-2288-3196" }, { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990" } ] }, "title": "Mosaic RBD nanoparticles protect against multiple sarbecovirus challenges in animal models", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \n\nWe thank Jost Vielmetter and the Caltech Protein Expression Center for assistance with protein production, Mark Howarth (Oxford) and Sumi Biswas (SpyBiotech) for helpful discussions about SpyCatcher-SpyTag methodology, Francis Laurent and Ruben Caputo (SPI Pharma) and Harshet Jain (Panacea Biotec) for VAC20 and MF59 adjuvants, respectively, Alexandra Walls and David Veesler (University of Washington) for a modified BtKY72 S gene for pseudovirus neutralization assays, Myndi Holbrook, Emmie de Wit, Brandi Williamson, Andrew Pekosz, Craig Martens, Kent Barbian, Stacey Ricklefs, Sarah Anzick, Ricki Feldmann, and the Public Health Agency of Canada for viruses used at RML, Kestrel Almquist, Allison Darrow, Kaitlyn Bauer, Amanda Weidow, Richard Cole, Lisa Heaney, Maarit Culbert, Brandon Bailes, Corey Henderson, Shane Gallogly, Lydia Crawford, and Taylor Lippincott for animal care at RML, and Claude Kwe Yinda (RML) for technical support. The following reagents were obtained through BEI Resources, NIAID, NIH: Cercopithecus aethiops Kidney Epithelial Cells Expressing Transmembrane Protease, Serine 2 and Human Angiotensin-Converting Enzyme 2 (Vero E6-TMPRSS2-T2AACE2), NR-54970. We thank Labcorp Drug Development\u2013Antibody Reagents and Vaccines (Denver, PA) (formerly Covance, Inc.) for carrying out BALB/c mice immunizations for the RBD epitope mapping study. \n\nFunding:\nWellcome Leap (PJB);\nBill and Melinda Gates Foundation INV-034638 (PJB); INV-004949 and INV-016575 (JDB)\nCaltech Merkin Institute (PJB) ;\nGeorge Mason University Fast Grant (PJB);\nIntramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID),\nNational Institutes of Health (NIH) (1ZIAAI001179-01) (VJM);\nNIAID/NIH contract numbers HHSN272201400006C and 75N93021C00015 (JDB);\nNational Institutes of Health grant R01AI141707 (JDB);\nORIP grant S10OD028685 (The Scientific Computing Infrastructure at Fred Hutch);\nCaribbean Primate Research Center (Grants P40 OD012217 and 2U42OD021458 from ORIP/OD/NIH) (MGL);\nTNS is a Howard Hughes Medical Institute Fellow of the Damon Runyon Cancer Research Foundation (DRG-2381-19).\nJDB is an Investigator of the Howard Hughes Medical Institute.\nTKT is funded by the Townsend-Jeantet Charitable Trust (charity number 1011770) and the EPA Cephalosporin Early Career Researcher Fellowship. \n\nAuthor contributions: \nConceptualization: AAC, TKT, ART, PJB\nMethodology: AAC, NvD, AJG, HA, AS, TNS, JRK, JES, MGL, JDB, VJM, PJB \nInvestigation: AAC, NvD, AJG, HA, AS, JRK, CF, JES, PNPG, LMK, APW, GS, YEL, HG, CAJ \nVisualization: AAC, CF, AJG, JES, JDB \nFunding acquisition: PJB, JDB, VJM \nProject administration: JRK, MGL, JDB, VJM, PJB\nSupervision: AAC, NvD, HA, AS, JRK, APW, MGL, JDB, VJM, PJB \nWriting \u2013 original draft: AAC, PJB \nWriting \u2013 review & editing: AAC, NvD, AJG, HA, JRK, CF, TKT, ART, TNS, JDB, VJM, PJB \n\nCompeting interests:\nP.J.B. and A.A.C. are inventors on a US patent application filed by the California Institute of Technology that covers the mosaic nanoparticles described in this work. J.D.B. consults for Moderna and Flagship Labs 77 on topics related to viral evolution. A.J.G, T.N.S., and J.D.B have the potential to receive a share of IP revenue as inventors on a Fred Hutch optioned technology related to deep mutational scanning of viral proteins and RBD-based vaccine formulations. \n\nData and materials availability:\nAll data are available in the main text or the supplementary materials. Raw Illumina sequencing data for the antibody-escape mapping experiments are available on the NCBI Short Read Archive (SRA) at BioProject PRJNA770094, BioSample SAMN26315988. Antibody-escape scores are available at https://github.com/jbloomlab/SARS-CoV-2-RBD_Beta_mosaic_np_vaccine/blob/main/results/supp_data/all_raw_data.csv. Materials are available upon request to the corresponding author with a signed material transfer agreement. \n\nThis work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.\n\nSubmitted - 20220325-485875v1full.pdf
", "abstract": "To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.", "date": "2022-03-29", "date_type": "published", "publisher": "bioRxiv", "id_number": "CaltechAUTHORS:20231006-213721063", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20231006-213721063", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Wellcome Trust" }, { "agency": "Bill and Melinda Gates Foundation", "grant_number": "INV-034638" }, { "agency": "Bill and Melinda Gates Foundation", "grant_number": "INV-004949" }, { "agency": "Bill and Melinda Gates Foundation", "grant_number": "INV-016575" }, { "agency": "Caltech Merkin Institute for Translational Research" }, { "agency": "George Mason University" }, { "agency": "NIH", "grant_number": "1ZIAAI001179-01" }, { "agency": "NIH", "grant_number": "HHSN272201400006C" }, { "agency": "NIH", "grant_number": "75N93021C00015" }, { "agency": "NIH", "grant_number": "R01AI141707" }, { "agency": "NIH", "grant_number": "S10OD028685" }, { "agency": "NIH", "grant_number": "P40 OD012217" }, { "agency": "NIH", "grant_number": "2U42OD021458" }, { "agency": "Howard Hughes Medical Institute (HHMI)" }, { "agency": "Damon Runyon Cancer Research Foundation", "grant_number": "DRG-2381-19" }, { "agency": "Townsend-Jeantet Charitable Trust", "grant_number": "1011770" }, { "agency": "Environmental Protection Agency (EPA)" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Richard-Merkin-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2022.03.25.485875", "pmcid": "PMC8978945", "primary_object": { "basename": "20220325-485875v1full.pdf", "url": "https://authors.library.caltech.edu/records/17vnm-7wt88/files/20220325-485875v1full.pdf" }, "pub_year": "2022", "author_list": "Cohen, Alexander A.; van Doremalen, Neeltje; et al." }, { "id": "https://authors.library.caltech.edu/records/wkjh4-6nf06", "eprint_id": 113768, "eprint_status": "archive", "datestamp": "2023-08-20 07:12:54", "lastmod": "2025-11-21 03:45:23", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Winnett-Alexander-Viloria", "name": { "family": "Winnett", "given": "Alexander Viloria" }, "orcid": "0000-0002-7338-5605" }, { "id": "Porter-Michael-K", "name": { "family": "Porter", "given": "Michael K." }, "orcid": "0000-0002-0777-7563" }, { "id": "Romano-Anna-E", "name": { "family": "Romano", "given": "Anna E." }, "orcid": "0000-0003-1871-1727" }, { "id": "Savela-Emily-S", "name": { "family": "Savela", "given": "Emily S." }, "orcid": "0000-0001-9614-4276" }, { "id": "Akana-Reid", "name": { "family": "Akana", "given": "Reid" }, "orcid": "0000-0003-4422-587X" }, { "id": "Shelby-Natasha", "name": { "family": "Shelby", "given": "Natasha" }, "orcid": "0000-0001-9097-3663" }, { "id": "Reyes-Jessica-A", "name": { "family": "Reyes", "given": "Jessica A." }, "orcid": "0000-0002-5507-7633" }, { "id": "Schlenker-Noah-W", "name": { "family": "Schlenker", "given": "Noah W." }, "orcid": "0000-0002-8581-4403" }, { "id": "Cooper-Matthew-M", "name": { "family": "Cooper", "given": "Matthew M." }, "orcid": "0000-0002-5868-5159" }, { "id": "Carter-Alyssa-M", "name": { "family": "Carter", "given": "Alyssa M." }, "orcid": "0000-0002-2776-9421" }, { "id": "Ji-Jenny", "name": { "family": "Ji", "given": "Jenny" }, "orcid": "0000-0002-7901-5605" }, { "id": "Barlow-Jacob-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Tognazzini-Colten", "name": { "family": "Tognazzini", "given": "Colten" }, "orcid": "0000-0002-2754-3588" }, { "id": "Feaster-Matthew", "name": { "family": "Feaster", "given": "Matthew" }, "orcid": "0000-0001-9966-2845" }, { "id": "Goh-Ying-Ying", "name": { "family": "Goh", "given": "Ying-Ying" }, "orcid": "0000-0001-5136-7214" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Morning SARS-CoV-2 testing yields better detection of infection due to higher viral loads in saliva and nasal swabs upon waking", "ispublished": "unpub", "full_text_status": "public", "keywords": "COVID\u201019, SARS\u2010CoV\u20102, pandemic, diagnostic, testing, screening, sensitivity, saliva, nasal swab, outpatient, \nambulatory, mild, circadian, rhythm, morning, evening, collection, sample, viral load", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. \n\nPaper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv. \n\nThis study is based on research funded in part by the Bill & Melinda Gates Foundation (INV-023124). The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation. This work was also funded by the Ronald and Maxine Linde Center for New Initiatives at the California Institute of Technology and the Jacobs Institute for Molecular Engineering for Medicine at the California Institute of Technology. AVW is supported by a National Institutes of Health NIGMS Predoctoral Training Grant (GM008042) and a UCLA DGSOM Geffen Fellowship; MMC is supported by a Caltech Graduate Student Fellowship; and MKP and JTB were each partially supported by National Institutes of Health Biotechnology Leadership Predoctoral Training Program (BLP) fellowships from Caltech's Donna and Benjamin M. Rosen Bioengineering Center (T32GM112592). \n\nDATA AVAILABILITY: Data are available on CaltechDATA at: https://data.caltech.edu/records/20049. \n \nCOMPETING INTERESTS STATEMENT: RFI is a co\u2010founder, consultant, and a director and has stock ownership of Talis Biomedical Corp. \n\nAuthor Declarations:\nI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.\n\nYes.\n\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:\n\nInstitutional Review Board of the California Institute of Technology gave ethical approval for this work (IRB protocol #20-1026).\n\nI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.\n\nYes.\n\nI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).\n\nYes.\n\nI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.\n\nYes.\n\nSubmitted - 2022.03.02.22271724v1.full.pdf
", "abstract": "Background. The analytical sensitivities of SARS-CoV-2 diagnostic tests span 6 orders of magnitude. Optimizing sample-collection methods to achieve the most reliable detection for a given sensitivity would increase the effectiveness of testing and minimize COVID-19 outbreaks. \n\nMethods. From September 2020 to April 2021 we performed a household-transmission study in which participants self-collected samples every morning and evening throughout acute SARS-CoV-2 infection. Seventy mildly symptomatic participants collected saliva and, of those, 29 also collected nasal-swab samples. Viral load was quantified in 1194 saliva and 661 nasal-swab samples using a high-analytical-sensitivity RT-qPCR assay (LOD, 1,000 SARS-CoV-2 RNA copies/mL).\n\nFindings. Viral loads in both saliva and nasal-swab samples were significantly higher in morning-collected samples than evening-collected samples after symptom onset. We used these quantitative measurements to infer which diagnostic tests would have detected infection (based on sample type and test analytical sensitivity). We find that morning collection would have resulted in significantly improved detection and that this advantage would be most pronounced for tests with low to moderate analytical sensitivity, which would likely have missed infections if sampling in the evening. \n\nInterpretation. Collecting samples for COVID-19 testing in the morning offers a simple and low-cost improvement to clinical diagnostic sensitivity of low- to moderate-analytical-sensitivity tests. The phenomenon of higher viral loads in the morning may also have implications related to when transmission is more likely to occur. \n\nFunding. Bill & Melinda Gates Foundation, Ronald and Maxine Linde Center for New Initiatives (Caltech), Jacobs Institute for Molecular Engineering for Medicine (Caltech)\n\nRESEARCH IN CONTEXT. Evidence before this studyReliable COVID-19 diagnostic testing is critical to reducing transmission of SARS-CoV-2 and reducing cases of severe or fatal disease, particularly in areas with limited vaccine access or uptake. Saliva and anterior-nares nasal swabs are common sample types; however, different diagnostic tests using these sample types have a range of analytical sensitivities spanning 6 orders of magnitude, with limits of detection (LODs) between 102 and 108 genomic copy equivalents of SARS-CoV-2 RNA (copies) per mL of sample. Due to limitations in clinical laboratory capacity, many low-resource settings rely on COVID-19 tests that fall on the moderate (LODs of 104 to 105 copies/mL) to lower (LODs of 105 to 108 copies/mL) end of this spectrum of analytical sensitivity. Alterations in sample collection methods, including time of sample collection, may improve the performance of these diagnostics.Added value of this studyThis study quantifies viral loads from saliva and nasal-swab samples that were longitudinally self-collected by symptomatic patients in the morning immediately after waking and in the evening just prior to sleeping throughout the course of acute SARS-CoV-2 infection. The study cohort was composed of mildly or moderately symptomatic individuals (outpatients). This analysis demonstrates significantly higher viral loads in samples collected in the morning, relative to those collected in the evening. When using moderate to lower analytical sensitivity test methods, these loads are inferred to result in significantly better detection of infected individuals in the morning. \n\nImplications of available evidence. These findings suggest that samples collected in the morning immediately after waking will better detect SARS-CoV-2 infection in symptomatic individuals tested by moderate to lower analytical sensitivity COVID-19 diagnostic tests (LODs at or above 104 viral copies per mL of sample), such as many rapid antigen tests currently available.", "date": "2022-03-04", "date_type": "published", "id_number": "CaltechAUTHORS:20220307-188444000", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220307-188444000", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Bill and Melinda Gates Foundation", "grant_number": "INV-023124" }, { "agency": "Ronald and Maxine Linde Center for New Initiatives" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "GM008042" }, { "agency": "UCLA" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32GM112592" }, { "agency": "Donna and Benjamin M. Rosen Bioengineering Center" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Rosen-Bioengineering-Center" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2022.03.02.22271724", "primary_object": { "basename": "2022.03.02.22271724v1.full.pdf", "url": "https://authors.library.caltech.edu/records/wkjh4-6nf06/files/2022.03.02.22271724v1.full.pdf" }, "pub_year": "2022", "author_list": "Winnett, Alexander Viloria; Porter, Michael K.; et al." }, { "id": "https://authors.library.caltech.edu/records/35vn4-2w279", "eprint_id": 113083, "eprint_status": "archive", "datestamp": "2023-08-20 06:50:10", "lastmod": "2025-11-20 23:55:45", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nguyen-Minhphuong", "name": { "family": "Nguyen", "given": "Minhphuong" } }, { "id": "Paul-Eric", "name": { "family": "Paul", "given": "Eric" } }, { "id": "Mills-Paul-K", "name": { "family": "Mills", "given": "Paul K." } }, { "id": "Paul-Simon", "name": { "family": "Paul", "given": "Simon" } } ] }, "title": "Risk of COVID-19 Reinfection and Vaccine Breakthrough Infection, Madera County, California, 2021", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \n\nThis study did not receive any funding. \n\nAll data produced in the present work are contained in the manuscript \n\nThe authors have declared no competing interest. \n\nAuthor Declarations:\nI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.\n\nYes.\n\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:\n\nThis study was reviewed by the County of Fresno, Department of Public Health Institutional Review Board, and was approved on January 20, 2022.\n\nI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.\n\nYes.\n\nI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).\n\nYes.\n\nI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.\n\nYes.\n\nSubmitted - 2022.01.22.22269105v1.full.pdf
", "abstract": "The probability of either testing COVID-19 positive or dying for three cohorts in Madera County, California in 2021 was compared. These cohorts included 1. those unvaccinated, 2. those vaccinated and 3. persons with a previous COVID-19 infection. The three groups were made generally comparable by matching on age, gender, postal zip code of residence, and the date of either COVID-19 infection or of vaccination. \nThe hazard ratio (HR) for death (from all causes) after COVID-19 infection vs. vaccination was 11.7 (95% CI 5.91-23.1, p14 days after initial COVID-19 infection or after completing primary COVID-19 vaccination was 1.98 (95% CI 1.53-2.58 p<0.001). As the majority of positive COVID-19 tests in the post COVID-19 cohort occurred within 90 days of the initial infection, and as these early positives may not represent a new infection, we also compared rates of testing COVID-19 positive 90 days after initial infection or vaccination. After removing these early positive COVID-19 tests that occurred between days 14-90, the HR ratio for testing COVID-19 positive is now lower for the post COVID-19 cohort compared with the vaccinated cohort. The risk for having a positive COVID-19 test occurring 90 days after an initial COVID-19 infection or after vaccination was 0.54 (95% CI 0.33-0.87, p<0.05) for the post COVID-19 group vs Vaccinated group. \nThus the risk for testing COVID-19 positive was higher in the first 90 days after COVID-19 infection compared to those vaccinated. However, from 90 to 300 days after COVID-19 infection, the post COVID-19 infection cohort had a lower risk of testing COVID-19 positive than those fully vaccinated.", "date": "2022-01-23", "date_type": "published", "id_number": "CaltechAUTHORS:20220124-214548000", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220124-214548000", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2022.01.22.22269105", "primary_object": { "basename": "2022.01.22.22269105v1.full.pdf", "url": "https://authors.library.caltech.edu/records/35vn4-2w279/files/2022.01.22.22269105v1.full.pdf" }, "pub_year": "2022", "author_list": "Nguyen, Minhphuong; Paul, Eric; et al." }, { "id": "https://authors.library.caltech.edu/records/et7fc-jkz72", "eprint_id": 118345, "eprint_status": "archive", "datestamp": "2023-08-20 06:21:46", "lastmod": "2026-03-29 19:52:37", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Karthikeyan-Smruthi", "name": { "family": "Karthikeyan", "given": "Smruthi" }, "orcid": "0000-0001-6226-4536" }, { "name": { "family": "Levy", "given": "Joshua I." }, "orcid": "0000-0001-7573-7793" }, { "name": { "family": "De Hoff", "given": "Peter" } }, { "name": { "family": "Humphrey", "given": "Greg" } }, { "name": { "family": "Birmingham", "given": "Amanda" } }, { "name": { "family": "Jepsen", "given": "Kristen" } }, { "name": { "family": "Farmer", "given": "Sawyer" } }, { "name": { "family": "Tubb", "given": "Helena M." } }, { "name": { "family": "Valles", "given": "Tommy" } }, { "name": { "family": "Tribelhorn", "given": "Caitlin E." } }, { "name": { "family": "Tsai", "given": "Rebecca" } }, { "name": { "family": "Aigner", "given": "Stefan" } }, { "name": { "family": "Sathe", "given": "Shashank" } }, { "name": { "family": "Moshiri", "given": "Niema" } }, { "name": { "family": "Henson", "given": "Benjamin" } }, { "name": { "family": "Mark", "given": "Adam M." } }, { "name": { "family": "Hakim", "given": "Abbas" } }, { "name": { "family": "Baer", "given": "Nathan A." } }, { "name": { "family": "Barber", "given": "Tom" } }, { "name": { "family": "Belda-Ferre", "given": "Pedro" }, "orcid": "0000-0001-6532-1161" }, { "name": { "family": "Chac\u00f3n", "given": "Marisol" } }, { "name": { "family": "Cheung", "given": "Willi" } }, { "name": { "family": "Cresini", "given": "Evelyn S." } }, { "name": { "family": "Eisner", "given": "Emily R." } }, { "name": { "family": "Lastrella", "given": "Alma L." } }, { "name": { "family": "Lawrence", "given": "Elijah S." } }, { "name": { "family": "Marotz", "given": "Clarisse A." } }, { "name": { "family": "Ngo", "given": "Toan T." } }, { "name": { "family": "Ostrander", "given": "Tyler" } }, { "name": { "family": "Plascencia", "given": "Ashley" } }, { "name": { "family": "Salido", "given": "Rodolfo A." } }, { "name": { "family": "Seaver", "given": "Phoebe" } }, { "name": { "family": "Smoot", "given": "Elizabeth W." } }, { "name": { "family": "McDonald", "given": "Daniel" }, "orcid": "0000-0003-0876-9060" }, { "name": { "family": "Neuhard", "given": "Robert M." } }, { "name": { "family": "Scioscia", "given": "Angela L." } }, { "name": { "family": "Satterlund", "given": "Alysson M." } }, { "name": { "family": "Simmons", "given": "Elizabeth H." }, "orcid": "0000-0002-0646-3458" }, { "name": { "family": "Abelman", "given": "Dismas B." } }, { "name": { "family": "Brenner", "given": "David" } }, { "name": { "family": "Bruner", "given": "Judith C." } }, { "name": { "family": "Buckley", "given": "Anne" } }, { "name": { "family": "Ellison", "given": "Michael" } }, { "name": { "family": "Gattas", "given": "Jeffrey" } }, { "name": { "family": "Gonias", "given": "Steven L." } }, { "name": { "family": "Hale", "given": "Matt" } }, { "name": { "family": "Hawkins", "given": "Faith" } }, { "name": { "family": "Ikeda", "given": "Lydia" } }, { "name": { "family": "Jhaveri", "given": "Hemlata" } }, { "name": { "family": "Johnson", "given": "Ted" } }, { "name": { "family": "Kellen", "given": "Vince" } }, { "name": { "family": "Kremer", "given": "Brendan" } }, { "name": { "family": "Matthews", "given": "Gary" } }, { "name": { "family": "McLawhon", "given": "Ronald W." } }, { "name": { "family": "Ouillet", "given": "Pierre" } }, { "name": { "family": "Park", "given": "Daniel" } }, { "name": { "family": "Pradenas", "given": "Allorah" } }, { "name": { "family": "Reed", "given": "Sharon" } }, { "name": { "family": "Riggs", "given": "Lindsay" } }, { "name": { "family": "Sanders", "given": "Alison" } }, { "name": { "family": "Sollenberger", "given": "Bradley" } }, { "name": { "family": "Song", "given": "Angela" } }, { "name": { "family": "White", "given": "Benjamin" } }, { "name": { "family": "Winbush", "given": "Terri" } }, { "name": { "family": "Aceves", "given": "Christine M." } }, { "name": { "family": "Anderson", "given": "Catelyn" } }, { "name": { "family": "Gangavarapu", "given": "Karthik" } }, { "name": { "family": "Hufbauer", "given": "Emory" } }, { "name": { "family": "Kurzban", "given": "Ezra" } }, { "name": { "family": "Lee", "given": "Justin" }, "orcid": "0000-0002-3657-4386" }, { "name": { "family": "Matteson", "given": "Nathaniel L." } }, { "name": { "family": "Parker", "given": "Edyth" } }, { "name": { "family": "Perkins", "given": "Sarah A." }, "orcid": "0000-0002-0557-3102" }, { "name": { "family": "Ramesh", "given": "Karthik S." } }, { "name": { "family": "Robles-Sikisaka", "given": "Refugio" } }, { "name": { "family": "Schwab", "given": "Madison A." }, "orcid": "0000-0002-1761-0951" }, { "name": { "family": "Spencer", "given": "Emily" } }, { "name": { "family": "Wohl", "given": "Shirlee" } }, { "name": { "family": "Nicholson", "given": "Laura" }, "orcid": "0000-0002-1761-0951" }, { "name": { "family": "Mchardy", "given": "Ian H." }, "orcid": "0000-0002-2121-5460" }, { "name": { "family": "Dimmock", "given": "David P." }, "orcid": "0000-0001-6690-2523" }, { "name": { "family": "Hobbs", "given": "Charlotte A." } }, { "name": { "family": "Bakhtar", "given": "Omid" } }, { "name": { "family": "Harding", "given": "Aaron" } }, { "name": { "family": "Mendoza", "given": "Art" } }, { "name": { "family": "Bolze", "given": "Alexandre" }, "orcid": "0000-0001-7399-2766" }, { "name": { "family": "Becker", "given": "David" } }, { "name": { "family": "Cirulli", "given": "Elizabeth T." } }, { "name": { "family": "Isaksson", "given": "Magnus" }, "orcid": "0000-0001-6278-0522" }, { "name": { "family": "Schiabor Barrett", "given": "Kelly M." }, "orcid": "0000-0001-6194-787X" }, { "name": { "family": "Washington", "given": "Nicole L." }, "orcid": "0000-0001-8936-9143" }, { "name": { "family": "Malone", "given": "John D." } }, { "name": { "family": "Murphy Schafer", "given": "Ashleigh" }, "orcid": "0000-0002-5131-8399" }, { "name": { "family": "Gurfield", "given": "Nikos" } }, { "name": { "family": "Stous", "given": "Sarah" } }, { "name": { "family": "Fielding-Miller", "given": "Rebecca" }, "orcid": "0000-0002-5099-0589" }, { "name": { "family": "Garfein", "given": "Richard S." } }, { "name": { "family": "Gaines", "given": "Tommi" } }, { "name": { "family": "Anderson", "given": "Cheryl" } }, { "name": { "family": "Martin", "given": "Natasha K." } }, { "name": { "family": "Schooley", "given": "Robert" }, "orcid": "0000-0002-2498-8426" }, { "name": { "family": "Austin", "given": "Brett" } }, { "name": { "family": "MacCannell", "given": "Duncan R." } }, { "name": { "family": "Kingsmore", "given": "Stephen F." } }, { "name": { "family": "Lee", "given": "William" } }, { "name": { "family": "Shah", "given": "Seema" } }, { "name": { "family": "McDonald", "given": "Eric" } }, { "name": { "family": "Yu", "given": "Alexander T." } }, { "name": { "family": "Zeller", "given": "Mark" } }, { "name": { "family": "Fisch", "given": "Kathleen M." } }, { "name": { "family": "Longhurst", "given": "Christopher A." }, "orcid": "0000-0003-4908-6856" }, { "name": { "family": "Maysent", "given": "Patty" } }, { "name": { "family": "Pride", "given": "David" } }, { "name": { "family": "Khosla", "given": "Pradeep K." } }, { "name": { "family": "Laurent", "given": "Louise C." } }, { "name": { "family": "Yeo", "given": "Gene W." }, "orcid": "0000-0002-0799-6037" }, { "name": { "family": "Andersen", "given": "Kristian G." }, "orcid": "0000-0001-6431-5982" }, { "name": { "family": "Knight", "given": "Rob" }, "orcid": "0000-0002-0975-9019" } ] }, "title": "Wastewater sequencing uncovers early, cryptic SARS-CoV-2 variant transmission", "ispublished": "unpub", "full_text_status": "public", "note": "Paper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv. \n\nThis work has been funded by CDC BAA contracts 75D30121P10258 (Helix) and 75D30120C09795 (G.W.Y., R.K., L.C.L., and K.G.A.), NIH NIAID 3U19AI135995-03S2 (K.G.A.), U19AI135995 (K.G.A.), U01AI151812 (K.G.A.), NIH NCATS UL1TR002550 (K.G.A.), the Conrad Prebys Foundation (K.G.A.), NIH 5T32AI007244-38 (J.I.L.), NIH Pioneer Grant 1DP1AT010885 (R.K), NSF RAPID 2029069 (R.K.), San Diego County Health and Human Services Agency (R.F.M), NIH S10OD026929 (K.J.). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the Centers for Disease Control and Prevention.", "abstract": "As SARS-CoV-2 continues to spread and evolve, detecting emerging variants early is critical for public health interventions. Inferring lineage prevalence by clinical testing is infeasible at scale, especially in areas with limited resources, participation, or testing/sequencing capacity, which can also introduce biases. SARS-CoV-2 RNA concentration in wastewater successfully tracks regional infection dynamics and provides less biased abundance estimates than clinical testing. Tracking virus genomic sequences in wastewater would improve community prevalence estimates and detect emerging variants. However, two factors limit wastewater-based genomic surveillance: low-quality sequence data and inability to estimate relative lineage abundance in mixed samples. Here, we resolve these critical issues to perform a high-resolution, 295-day wastewater and clinical sequencing effort, in the controlled environment of a large university campus and the broader context of the surrounding county. We develop and deploy improved virus concentration protocols and deconvolution software that fully resolve multiple virus strains from wastewater. We detect emerging variants of concern up to 14 days earlier in wastewater samples, and identify multiple instances of virus spread not captured by clinical genomic surveillance. Our study provides a scalable solution for wastewater genomic surveillance that allows early detection of SARS-CoV-2 variants and identification of cryptic transmission.", "date": "2021-12-29", "date_type": "published", "id_number": "CaltechAUTHORS:20221215-540121000.6", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20221215-540121000.6", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Centers for Disease Control and Prevention", "grant_number": "75D30121P10258" }, { "agency": "Centers for Disease Control and Prevention", "grant_number": "75D30120C09795" }, { "agency": "NIH", "grant_number": "3U19AI135995-03S2" }, { "agency": "NIH", "grant_number": "U19AI135995" }, { "agency": "NIH", "grant_number": "U01AI151812" }, { "agency": "NIH", "grant_number": "UL1TR002550" }, { "agency": "Conrad Prebys Foundation" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5T32AI007244" }, { "agency": "NIH", "grant_number": "1DP1AT010885" }, { "agency": "NSF", "grant_number": "AGS-2029069" }, { "agency": "San Diego County" }, { "agency": "NIH", "grant_number": "S10OD026929" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2021.12.21.21268143", "pmcid": "PMC8996633", "pub_year": "2021", "author_list": "Karthikeyan, Smruthi; Levy, Joshua I.; et al." }, { "id": "https://authors.library.caltech.edu/records/a1zkg-8c529", "eprint_id": 113328, "eprint_status": "archive", "datestamp": "2023-08-20 05:59:05", "lastmod": "2026-03-30 07:11:24", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Dommer-Abigail", "name": { "family": "Dommer", "given": "Abigail" }, "orcid": "0000-0003-4847-4136" }, { "name": { "family": "Casalino", "given": "Lorenzo" }, "orcid": "0000-0003-3581-1148" }, { "name": { "family": "Kearns", "given": "Fiona" }, "orcid": "0000-0002-5469-9035" }, { "name": { "family": "Rosenfeld", "given": "Mia" }, "orcid": "0000-0002-8961-8231" }, { "name": { "family": "Wauer", "given": "Nicholas" }, "orcid": "0000-0002-1230-9166" }, { "name": { "family": "Ahn", "given": "Surl-Hee" } }, { "name": { "family": "Russo", "given": "John" }, "orcid": "0000-0002-2813-6554" }, { "name": { "family": "Oliveira", "given": "Sofia" } }, { "name": { "family": "Morris", "given": "Clare" } }, { "name": { "family": "Bogetti", "given": "Anthony" }, "orcid": "0000-0003-0610-2879" }, { "name": { "family": "Trifan", "given": "Anda" }, "orcid": "0000-0003-4808-9502" }, { "name": { "family": "Brace", "given": "Alexander" } }, { "name": { "family": "Sztain", "given": "Terra" }, "orcid": "0000-0002-1327-8541" }, { "name": { "family": "Clyde", "given": "Austin" }, "orcid": "0000-0002-3697-7070" }, { "name": { "family": "Ma", "given": "Heng" }, "orcid": "0000-0002-7667-922X" }, { "name": { "family": "Chennubhotla", "given": "Chakra" }, "orcid": "0000-0002-0024-1627" }, { "name": { "family": "Lee", "given": "Hyungro" }, "orcid": "0000-0002-4221-7094" }, { "name": { "family": "Turilli", "given": "Matteo" }, "orcid": "0000-0003-0527-1435" }, { "name": { "family": "Khalid", "given": "Syma" }, "orcid": "0000-0002-3694-5044" }, { "name": { "family": "Tamayo-Mendoza", "given": "Teresa" } }, { "name": { "family": "Welborn", "given": "Matthew" } }, { "name": { "family": "Christensen", "given": "Anders" } }, { "name": { "family": "Smith", "given": "Daniel G. A." } }, { "id": "Qiao-Zhuoran", "name": { "family": "Qiao", "given": "Zhuoran" }, "orcid": "0000-0002-5704-7331" }, { "name": { "family": "Sirumalla", "given": "Sai Krishna" } }, { "name": { "family": "O'Connor", "given": "Michael" } }, { "name": { "family": "Manby", "given": "Frederick" }, "orcid": "0000-0001-7611-714X" }, { "id": "Anandkumar-A", "name": { "family": "Anandkumar", "given": "Anima" }, "orcid": "0000-0002-6974-6797" }, { "name": { "family": "Hardy", "given": "David" } }, { "name": { "family": "Phillips", "given": "James" } }, { "name": { "family": "Stern", "given": "Abraham" } }, { "name": { "family": "Romero", "given": "Josh" } }, { "name": { "family": "Clark", "given": "David" } }, { "name": { "family": "Dorrell", "given": "Mitchell" } }, { "name": { "family": "Maiden", "given": "Tom" } }, { "name": { "family": "Huang", "given": "Lei" } }, { "name": { "family": "McCalpin", "given": "John" } }, { "name": { "family": "Woods", "given": "Christopher" } }, { "name": { "family": "Gray", "given": "Alan" } }, { "name": { "family": "Williams", "given": "Matt" } }, { "name": { "family": "Barker", "given": "Bryan" } }, { "name": { "family": "Rajapaksha", "given": "Harinda" } }, { "name": { "family": "Pitts", "given": "Richard" } }, { "name": { "family": "Gibbs", "given": "Tom" } }, { "name": { "family": "Stone", "given": "John" }, "orcid": "0000-0001-7215-762X" }, { "name": { "family": "Zuckerman", "given": "Daniel" }, "orcid": "0000-0001-7662-2031" }, { "name": { "family": "Mulholland", "given": "Adrian" } }, { "id": "Miller-T-F-III", "name": { "family": "Miller", "given": "Thomas, III" }, "orcid": "0000-0002-1882-5380" }, { "name": { "family": "Jha", "given": "Shantenu" } }, { "name": { "family": "Ramanathan", "given": "Arvind" }, "orcid": "0000-0002-1622-5488" }, { "name": { "family": "Chong", "given": "Lillian" }, "orcid": "0000-0002-0590-483X" }, { "name": { "family": "Amaro", "given": "Rommie" }, "orcid": "0000-0002-9275-9553" } ] }, "title": "#COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy of Delta SARS-CoV-2 in a Respiratory Aerosol", "ispublished": "unpub", "full_text_status": "public", "keywords": "molecular dynamics, deep learning, multiscale simulation, weighted ensemble, computational virology, SARS-CoV-2, aerosols, COVID-19, HPC, AI, GPU, Delta", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. \n\nWe thank Prof. Kim Prather for inspiring and informative discussions about aerosols and for her commitment to convey the airborne nature of SARS-CoV-2. We thank D. Veesler for sharing the Delta spike NTD coordinates in advance of publication. We thank B. Messer, D. Maxwell, and the Oak Ridge Leadership Computing Facility at Oak Ridge National Laboratory supported by the DOE under Contract DE-AC05-00OR22725. We thank the Texas Advanced Computing Center Frontera team, especially D. Stanzione and T. Cockerill, and for compute time made available through a Director's Discretionary Allocation (NSF OAC-1818253). We thank the Argonne Leadership Computing Facility supported by the DOE under DE-AC02-06CH11357. We thank the Pittsburgh Supercomputer Center for providing priority queues on Bridges-2 through the XSEDE allocation NSF TG-CHE060063. We thank N. Kern and J. Lee of the CHARMM-GUI support team for help converting topologies between NAMD and GROMACS. We thank J. Copperman, G. Simpson, D. Aristoff, and J. Leung for valuable discussions and support from NIH grant GM115805. NAMD and VMD are funded by NIH P41-GM104601. This work was supported by the NSF Center for Aerosol Impacts on Chemistry of the Environment (CAICE), National Science Foundation Center for Chemical Innovation (NSF CHE-1801971), as well as NIH GM132826, NSF RAPID MCB-2032054, an award from the RCSA Research Corp., a UC San Diego Moore's Cancer Center 2020 SARS-CoV-2 seed grant, to R.E.A. This work was also supported by Oracle Cloud credits and related resources provided by the Oracle for Research program. \n\nThe authors have declared no competing interest.\n\nSubmitted - 2021.11.12.468428v1.full.pdf
", "abstract": "We seek to completely revise current models of airborne transmission of respiratory viruses by providing never-before-seen atomic-level views of the SARS-CoV-2 virus within a respiratory aerosol. Our work dramatically extends the capabilities of multiscale computational microscopy to address the significant gaps that exist in current experimental methods, which are limited in their ability to interrogate aerosols at the atomic/molecular level and thus ob-scure our understanding of airborne transmission. We demonstrate how our integrated data-driven platform provides a new way of exploring the composition, structure, and dynamics of aerosols and aerosolized viruses, while driving simulation method development along several important axes. We present a series of initial scientific discoveries for the SARS-CoV-2 Delta variant, noting that the full scientific impact of this work has yet to be realized.", "date": "2021-11-16", "date_type": "published", "id_number": "CaltechAUTHORS:20220208-947187000", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220208-947187000", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC05-00OR22725" }, { "agency": "NSF", "grant_number": "OAC-1818253" }, { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-06CH11357" }, { "agency": "NSF", "grant_number": "TG-CHE060063" }, { "agency": "NIH", "grant_number": "GM115805" }, { "agency": "NIH", "grant_number": "P41-GM104601" }, { "agency": "NSF", "grant_number": "CHE-1801971" }, { "agency": "NIH", "grant_number": "GM132826" }, { "agency": "NSF", "grant_number": "MCB-2032054" }, { "agency": "RCSA Research Corp." }, { "agency": "University of California, San Diego" }, { "agency": "Oracle for Research program" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2021.11.12.468428", "pmcid": "PMC8609898", "primary_object": { "basename": "2021.11.12.468428v1.full.pdf", "url": "https://authors.library.caltech.edu/records/a1zkg-8c529/files/2021.11.12.468428v1.full.pdf" }, "pub_year": "2021", "author_list": "Dommer, Abigail; Casalino, Lorenzo; et al." }, { "id": "https://authors.library.caltech.edu/records/pm62a-jxw02", "eprint_id": 118352, "eprint_status": "archive", "datestamp": "2023-08-20 05:41:26", "lastmod": "2026-03-29 19:53:27", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Fielding-Miller-Rebecca", "name": { "family": "Fielding-Miller", "given": "Rebecca" }, "orcid": "0000-0002-5099-0589" }, { "id": "Karthikeyan-Smruthi", "name": { "family": "Karthikeyan", "given": "Smruthi" }, "orcid": "0000-0001-6226-4536" }, { "name": { "family": "Gaines", "given": "Tommi" } }, { "name": { "family": "Garfein", "given": "Richard S." }, "orcid": "0000-0003-3663-7153" }, { "name": { "family": "Salido", "given": "Rodolfo" }, "orcid": "0000-0003-0631-2817" }, { "name": { "family": "Cantu", "given": "Victor" } }, { "name": { "family": "Kohn", "given": "Laura" } }, { "name": { "family": "Martin", "given": "Natasha K." }, "orcid": "0000-0001-8344-1810" }, { "name": { "family": "Wijaya", "given": "Carrissa" } }, { "name": { "family": "Flores", "given": "Marlene" } }, { "name": { "family": "Omaleki", "given": "Vinton" }, "orcid": "0000-0003-4639-2241" }, { "name": { "family": "Majnoonian", "given": "Araz" } }, { "name": { "family": "Gonzalez-Zuniga", "given": "Patricia" } }, { "name": { "family": "Nguyen", "given": "Megan" } }, { "name": { "family": "Vo", "given": "Anh V." } }, { "name": { "family": "Le", "given": "Tina" } }, { "name": { "family": "Duong", "given": "Dawn" } }, { "name": { "family": "Hassani", "given": "Ashkan" }, "orcid": "0000-0001-7863-559X" }, { "name": { "family": "Dahl", "given": "Austin" } }, { "name": { "family": "Tweeten", "given": "Samantha" } }, { "name": { "family": "Jepsen", "given": "Kristen" } }, { "name": { "family": "Henson", "given": "Benjamin" } }, { "name": { "family": "Hakim", "given": "Abbas" } }, { "name": { "family": "Birmingham", "given": "Amanda" }, "orcid": "0000-0002-4117-3317" }, { "name": { "family": "Mark", "given": "Adam M." } }, { "name": { "family": "Nasamran", "given": "Chanond A." } }, { "name": { "family": "Rosenthal", "given": "Sara Brin" }, "orcid": "0000-0002-6548-9658" }, { "name": { "family": "Moshiri", "given": "Niema" }, "orcid": "0000-0003-2209-8128" }, { "name": { "family": "Fisch", "given": "Kathleen M." }, "orcid": "0000-0002-0117-7444" }, { "name": { "family": "Humphrey", "given": "Greg" } }, { "name": { "family": "Farmer", "given": "Sawyer" } }, { "name": { "family": "Tubb", "given": "Helena M." } }, { "name": { "family": "Valles", "given": "Tommy" } }, { "name": { "family": "Morris", "given": "Justin" } }, { "name": { "family": "Kang", "given": "Jaeyoung" }, "orcid": "0000-0003-1048-1285" }, { "name": { "family": "Khaleghi", "given": "Behnam" }, "orcid": "0000-0002-3655-0501" }, { "name": { "family": "Young", "given": "Colin" }, "orcid": "0000-0002-1907-8276" }, { "name": { "family": "Akel", "given": "Ameen D." } }, { "name": { "family": "Eilert", "given": "Sean" } }, { "name": { "family": "Eno", "given": "Justin" } }, { "name": { "family": "Curewitz", "given": "Ken" } }, { "name": { "family": "Laurent", "given": "Louise C." } }, { "name": { "family": "Rosing", "given": "Tajana" }, "orcid": "0000-0002-6954-997X" }, { "name": { "family": "Knight", "given": "Rob" }, "orcid": "0000-0002-0975-9019" } ] }, "title": "Wastewater and surface monitoring to detect COVID-19 in elementary school settings: The Safer at School Early Alert project", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \n\nPaper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv. \n\nWe are deeply grateful to the leadership, staff, students, and families at our partner school districts and school sites across San Diego County. This project would not have been possible without their enthusiasm and generosity. We thank our colleagues at the County of San Diego, Health and Human Services Agency for their vision and support, particularly John Malone, Sarah Stous, and Rorick Luepton. At UCSD, Isabella Cuturrofo, Jeanessa Mendoza, Kristine Ngo, Jessica Ni, and Elizabeth Frost all provided vital support with project implementation. RFM thanks Ms. Esther Krohne for inspiring the project. \n\nThe opinions and assertions expressed herein are those of the authors and do not necessarily reflect the official policy or position of the County of San Diego Health and Human Services Agency.\n\nCounty of San Diego, Health and Human Services Agency (RFM) \n\nNational Institutes of Health Grant K01MH112436 (RFM) \n\nNational Institute of Health Grant UL1TR001442 \n\nNational Institute of Health Grant S10OD026929 (Jepsen) \n\nNSF Grants Numbers 1730518, 1826967, 1659104, 2100237, 2112167, 2052809, 2028040 (Rosing) \n\nCenters for Disease Control BAA Contract 75D30120C09795 (Andersen)\n\nThis work was supported in part by CRISP, one of six centers in JUMP, an SRC program sponsored by DARPA (Rosing). \n\nAuthors declare they have no competing interests. \n\nData and materials availability: School-level data are available from the first author on reasonable request. All wastewater and nasal-swab sequencing data have been deposited to GISAID and their accession details provided in Supplemental File Data S1.", "abstract": "Schools are high-risk settings for SARS-CoV-2 transmission, but necessary for children's educational and social-emotional wellbeing. While wastewater monitoring has been implemented to mitigate outbreak risk in universities and residential settings, its effectiveness in community K-12 sites is unknown. We implemented a wastewater and surface monitoring system to detect SARS-CoV-2 in nine elementary schools in San Diego County. Ninety-three percent of identified cases were associated with either a positive wastewater or surface sample; 67% were associated with a positive wastewater sample, and 40% were associated with a positive surface sample. The techniques we utilized allowed for near-complete genomic sequencing of wastewater and surface samples. Passive environmental surveillance can complement approaches that require individual consent, particularly in communities with limited access and/or high rates of testing hesitancy.One sentence summaryPassive wastewater and surface environmental surveillance can identify up to 93% of on-campus COVID-19 cases in public elementary schools; positive samples can be sequenced to monitor for variants of concerns with neighborhood level resolution.", "date": "2021-10-21", "date_type": "published", "id_number": "CaltechAUTHORS:20221215-540378000.16", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20221215-540378000.16", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "San Diego County" }, { "agency": "NIH", "grant_number": "K01MH112436" }, { "agency": "NIH", "grant_number": "UL1TR001442" }, { "agency": "NIH", "grant_number": "S10OD026929" }, { "agency": "NSF", "grant_number": "1730518" }, { "agency": "NSF", "grant_number": "OAC-1826967" }, { "agency": "NSF", "grant_number": "OAC-1659104" }, { "agency": "NSF", "grant_number": "CNS-2100237" }, { "agency": "NSF", "grant_number": "OAC-2112167" }, { "agency": "NSF", "grant_number": "EEC-2052809" }, { "agency": "NSF", "grant_number": "DEB-2028040" }, { "agency": "Centers for Disease Control and Prevention", "grant_number": "75D30120C09795" }, { "agency": "Defense Advanced Research Projects Agency (DARPA)" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "corp_creators": { "items": [ "SEARCH" ] }, "doi": "10.1101/2021.10.19.21265226", "pmcid": "PMC8547528", "pub_year": "2021", "author_list": "Fielding-Miller, Rebecca; Karthikeyan, Smruthi; et al." }, { "id": "https://authors.library.caltech.edu/records/ktsk8-bbe70", "eprint_id": 111485, "eprint_status": "archive", "datestamp": "2023-08-20 05:35:32", "lastmod": "2026-03-30 07:56:52", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Trifan-Anda", "name": { "family": "Trifan", "given": "Anda" } }, { "name": { "family": "Gorgun", "given": "Defne" } }, { "id": "Li-Zongyi", "name": { "family": "Li", "given": "Zongyi" }, "orcid": "0000-0003-2081-9665" }, { "name": { "family": "Brace", "given": "Alexander" } }, { "name": { "family": "Zvyagin", "given": "Maxim" } }, { "name": { "family": "Ma", "given": "Heng" } }, { "name": { "family": "Clyde", "given": "Austin" } }, { "name": { "family": "Clark", "given": "David" } }, { "name": { "family": "Salim", "given": "Michael" } }, { "name": { "family": "Hardy", "given": "David J." } }, { "name": { "family": "Burnley", "given": "Tom" } }, { "name": { "family": "Huang", "given": "Lei" }, "orcid": "0000-0002-1923-227X" }, { "name": { "family": "McCalpin", "given": "John" } }, { "name": { "family": "Emani", "given": "Murali" } }, { "name": { "family": "Yoo", "given": "Hyenseung" } }, { "name": { "family": "Yin", "given": "Junqi" } }, { "name": { "family": "Tsaris", "given": "Aristeidis" } }, { "name": { "family": "Subbiah", "given": "Vishal" } }, { "name": { "family": "Raza", "given": "Tanveer" } }, { "name": { "family": "Liu", "given": "Jessica" } }, { "name": { "family": "Trebesch", "given": "Noah" } }, { "name": { "family": "Wells", "given": "Geoffrey" } }, { "name": { "family": "Mysore", "given": "Venkatesh" } }, { "name": { "family": "Gibbs", "given": "Thomas" } }, { "name": { "family": "Phillips", "given": "James" } }, { "name": { "family": "Chennubhotla", "given": "S. Chakra" } }, { "name": { "family": "Foster", "given": "Ian" } }, { "name": { "family": "Stevens", "given": "Rick" } }, { "id": "Anandkumar-A", "name": { "family": "Anandkumar", "given": "Anima" } }, { "name": { "family": "Vishwanath", "given": "Venkatram" } }, { "name": { "family": "Stone", "given": "John E." } }, { "name": { "family": "Tajkhorshid", "given": "Emad" }, "orcid": "0000-0001-8434-1010" }, { "name": { "family": "Harris", "given": "Sarah A." } }, { "name": { "family": "Ramanathan", "given": "Arvind" } } ] }, "title": "Intelligent Resolution: Integrating Cryo-EM with AI-driven Multi-resolution Simulations to Observe the SARS-CoV-2 Replication-Transcription Machinery in Action", "ispublished": "unpub", "full_text_status": "public", "keywords": "multi-resolution simulations, SARS-CoV-2, COVID19, HPC, AI", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \n\nWe thank the Argonne Leadership Computing Facility supported by the DOE under DE-AC02-06CH11357, the Oak Ridge Leadership Computing Facility at Oak Ridge National Laboratory supported by the DOE under Contract DE-AC05-00OR22725, and the National Energy Research Scientific Computing Center at Lawrence Berkeley National Laboratory supported by the DOE under Contract No. DE-AC02-05CH11231. We also thank the Texas Advanced Computing Center Frontera team, especially D. Stanzione and T. Cockerill, and for compute time made available through a Director's Discretionary Allocation (NSF MCB-20024). NAMD and VMD are funded by NIH P41-GM104601. The NAMD team thanks Intel and M. Brown for contributing the AVX-512 tile list kernels. Anda Trifan acknowledges support from a DOE CSGF (DE-SC0019323). This research was supported by the Exascale Computing Project (17-SC-20-SC), a collaborative effort of the US DOE Office of Science and the National Nuclear Security Administration. Research was supported by the DOE through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on response to COVID-19, with funding from the Coronavirus CARES Act. This work used resources, services, and support from the COVID-19 HPC Consortium (https://covid19-hpc-consortium.org/), a private-public effort uniting government, industry, and academic leaders who are volunteering free compute time and resources in support of COVID-19 research. \n\nThe authors have declared no competing interest.\n\nSubmitted - 2021.10.09.463779v1.full.pdf
", "abstract": "The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replication transcription complex (RTC) is a multi-domain protein responsible for replicating and transcribing the viral mRNA inside a human cell. Attacking RTC function with pharmaceutical compounds is a pathway to treating COVID-19. Conventional tools, e.g., cryo-electron microscopy and all-atom molecular dynamics (AAMD), do not provide sufficiently high resolution or timescale to capture important dynamics of this molecular machine. Consequently, we develop an innovative workflow that bridges the gap between these resolutions, using mesoscale fluctuating finite element analysis (FFEA) continuum simulations and a hierarchy of AI-methods that continually learn and infer features for maintaining consistency between AAMD and FFEA simulations. We leverage a multi-site distributed workflow manager to orchestrate AI, FFEA, and AAMD jobs, providing optimal resource utilization across HPC centers. Our study provides unprecedented access to study the SARS-CoV-2 RTC machinery, while providing general capability for AI-enabled multi-resolution simulations at scale.", "date": "2021-10-13", "date_type": "published", "id_number": "CaltechAUTHORS:20211015-222208091", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20211015-222208091", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-06CH11357" }, { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC05-00OR22725" }, { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-05CH11231" }, { "agency": "NSF", "grant_number": "MCB-20024" }, { "agency": "NIH", "grant_number": "P41-GM104601" }, { "agency": "Department of Energy (DOE)", "grant_number": "DE-SC0019323" }, { "agency": "Department of Energy (DOE)", "grant_number": "17-SC-20-SC" }, { "agency": "Coronavirus CARES Act" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2021.10.09.463779", "primary_object": { "basename": "2021.10.09.463779v1.full.pdf", "url": "https://authors.library.caltech.edu/records/ktsk8-bbe70/files/2021.10.09.463779v1.full.pdf" }, "pub_year": "2021", "author_list": "Trifan, Anda; Gorgun, Defne; et al." }, { "id": "https://authors.library.caltech.edu/records/gzajr-zzr25", "eprint_id": 118342, "eprint_status": "archive", "datestamp": "2023-08-20 02:50:59", "lastmod": "2026-03-29 19:41:26", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Knyazev-Sergey", "name": { "family": "Knyazev", "given": "Sergey" }, "orcid": "0000-0003-0385-1831" }, { "id": "Chhugani-Karishma", "name": { "family": "Chhugani", "given": "Karishma" }, "orcid": "0000-0003-1328-5028" }, { "id": "Sarwal-Varuni", "name": { "family": "Sarwal", "given": "Varuni" }, "orcid": "0000-0001-7563-9835" }, { "id": "Ayyala-Ram", "name": { "family": "Ayyala", "given": "Ram" }, "orcid": "0000-0001-7275-271X" }, { "id": "Singh-Harman", "name": { "family": "Singh", "given": "Harman" }, "orcid": "0000-0002-3970-6276" }, { "id": "Karthikeyan-Smruthi", "name": { "family": "Karthikeyan", "given": "Smruthi" }, "orcid": "0000-0001-6226-4536" }, { "id": "Deshpande-Dhrithi", "name": { "family": "Deshpande", "given": "Dhrithi" }, "orcid": "0000-0003-3794-7364" }, { "id": "Comarova-Zoia", "name": { "family": "Comarova", "given": "Zoia" } }, { "id": "Lu-Angela", "name": { "family": "Lu", "given": "Angela" } }, { "id": "Porozov-Yuri", "name": { "family": "Porozov", "given": "Yuri" }, "orcid": "0000-0002-5450-3135" }, { "id": "Wu-Aiping", "name": { "family": "Wu", "given": "Aiping" } }, { "id": "Abedalthagafi-Malak-S", "name": { "family": "Abedalthagafi", "given": "Malak S." }, "orcid": "0000-0003-1786-3366" }, { "id": "Nagaraj-Shivashankar-H", "name": { "family": "Nagaraj", "given": "Shivashankar H." } }, { "id": "Smith-Adam-L", "name": { "family": "Smith", "given": "Adam L." } }, { "id": "Skums-Pavel", "name": { "family": "Skums", "given": "Pavel" }, "orcid": "0000-0003-4007-5624" }, { "id": "Ladner-Jason", "name": { "family": "Ladner", "given": "Jason" }, "orcid": "0000-0001-7751-4366" }, { "id": "Lam-Tommy-Tsan-Yuk", "name": { "family": "Lam", "given": "Tommy Tsan-Yuk" }, "orcid": "0000-0002-9769-1527" }, { "id": "Wu-Nicholas-C", "name": { "family": "Wu", "given": "Nicholas C." }, "orcid": "0000-0002-9078-6697" }, { "id": "Zelikovsky-Alex", "name": { "family": "Zelikovsky", "given": "Alex" }, "orcid": "0000-0003-4424-4691" }, { "id": "Knight-Rob", "name": { "family": "Knight", "given": "Rob" }, "orcid": "0000-0002-0975-9019" }, { "id": "Crandall-Keith-A", "name": { "family": "Crandall", "given": "Keith A." }, "orcid": "0000-0002-0836-3389" }, { "id": "Mangual-Seghei", "name": { "family": "Mangul", "given": "Serghei" }, "orcid": "0000-0003-4770-3443" } ] }, "title": "Unlocking capacities of viral genomics for the COVID-19 pandemic response", "ispublished": "unpub", "full_text_status": "public", "note": "We thank William M. Switzer and Ellsworth M. Campbell from the Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, 30333 GA, USA for useful discussions and suggestions. We also thank numerous anonymous reviewers who helped improve our manuscript by their valuable comments on the manuscript. \n\nS.M. was partially supported by National Science Foundation grants 2041984. Tommy Lam is supported by NSFC Excellent Young Scientists Fund (Hong Kong and Macau) (31922087) and Health and Medical Research Fund (COVID190223). Pavel Skums was supported by the National Institutes of Health grant 1R01EB025022. Malak Abedalthagafi MA a acknowledge King Abdulaziz City for Science and Technology and the Saudi Human Genome Project for technical and financial support (https://shgp.kacst.edu.sa) Nicholas Wu: startup funds from the University of Illinois at Urbana-Champaign Adam Smith: acknowledge funding from NSF grant no. 2029025. Alex Zelikovsky: A.Z. has been partially supported by NSF Grant CCF-1619110 and NIH Grant 1R01EB025022-01. Sergey Knyazev S.K. has been partly supported by Molecular Basis of Disease at Georgia State University. Rob Knight: NSF project 2038509, RAPID: Improving QIIME 2 and UniFrac for Viruses to Respond to COVID-19. CDC project 30055281 with Scripps led by Kristian Andersen, Genomic sequencing of SARS-CoV-2 to investigate local and cross-border emergence and spread.\n\nAccepted Version - 2104.14005.pdf
", "abstract": "More than any other infectious disease epidemic, the COVID-19 pandemic has been characterized by the generation of large volumes of viral genomic data at an incredible pace due to recent advances in high-throughput sequencing technologies, the rapid global spread of SARS-CoV-2, and its persistent threat to public health. However, distinguishing the most epidemiologically relevant information encoded in these vast amounts of data requires substantial effort across the research and public health communities. Studies of SARS-CoV-2 genomes have been critical in tracking the spread of variants and understanding its epidemic dynamics, and may prove crucial for controlling future epidemics and alleviating significant public health burdens. Together, genomic data and bioinformatics methods enable broad-scale investigations of the spread of SARS-CoV-2 at the local, national, and global scales and allow researchers the ability to efficiently track the emergence of novel variants, reconstruct epidemic dynamics, and provide important insights into drug and vaccine development and disease control. Here, we discuss the tremendous opportunities that genomics offers to unlock the effective use of SARS-CoV-2 genomic data for efficient public health surveillance and guiding timely responses to COVID-19.", "date": "2021-04-28", "date_type": "published", "publisher": "arXiv", "id_number": "CaltechAUTHORS:20221215-185439493", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20221215-185439493", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "DBI-2041984" }, { "agency": "National Natural Science Foundation of China", "grant_number": "31922087" }, { "agency": "Health and Medical Research Fund (China)", "grant_number": "COVID190223" }, { "agency": "NIH", "grant_number": "1R01EB025022" }, { "agency": "King Abdulaziz City for Science and Technology (KACST)" }, { "agency": "Saudi Human Genome Project" }, { "agency": "University of Illinois Urbana-Champaign" }, { "agency": "NSF", "grant_number": "CBET-2029025" }, { "agency": "NSF", "grant_number": "CCF-1619110" }, { "agency": "NIH", "grant_number": "1R01EB025022-01" }, { "agency": "Georgia State University" }, { "agency": "NSF", "grant_number": "DBI-2038509" }, { "agency": "Centers for Disease Control and Prevention", "grant_number": "30055281" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.48550/arXiv.2104.14005", "pmcid": "PMC8095210", "primary_object": { "basename": "2104.14005.pdf", "url": "https://authors.library.caltech.edu/records/gzajr-zzr25/files/2104.14005.pdf" }, "pub_year": "2021", "author_list": "Knyazev, Sergey; Chhugani, Karishma; et al." }, { "id": "https://authors.library.caltech.edu/records/w1w4f-qt651", "eprint_id": 108865, "eprint_status": "archive", "datestamp": "2023-08-20 02:48:20", "lastmod": "2026-03-29 21:02:27", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Sarma-Anish-A", "name": { "family": "Sarma", "given": "Anish A." } }, { "id": "Sarma-Aartik", "name": { "family": "Sarma", "given": "Aartik" }, "orcid": "0000-0002-7508-7345" }, { "id": "Csete-Marie-E", "name": { "family": "Csete", "given": "Marie" }, "orcid": "0000-0003-4591-0510" }, { "id": "Lee-Peter-P", "name": { "family": "Lee", "given": "Peter P." }, "orcid": "0000-0002-2660-4377" }, { "id": "Doyle-J-C", "name": { "family": "Doyle", "given": "John C." }, "orcid": "0000-0002-1828-2486" } ] }, "title": "Control-theoretic immune tradeoffs explain SARS-CoV-2 virulence and transmission variation", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license. \n\nThis version posted April 26, 2021.\n\nSubmitted - 2021.04.25.441372v1.full.pdf
", "abstract": "Dramatic variation in SARS-CoV-2 virulence and transmission between hosts has driven the COVID-19 pandemic. The complexity and dynamics of the immune response present a challenge to understanding variation in SARS-CoV-2 infections. To address this challenge, we apply control theory, a framework used to study complex feedback systems, to establish rigorous mathematical bounds on immune responses. Two mechanisms of SARS-CoV-2 biology are sufficient to create extreme variation between hosts: (1) a sparsely expressed host receptor and (2) potent, but not unique, suppression of interferon. The resulting model unifies disparate and unexplained features of the SARS-CoV-2 pandemic, predicts features of future viruses that threaten to cause pandemics, and identifies potential interventions.", "date": "2021-04-26", "date_type": "published", "id_number": "CaltechAUTHORS:20210429-095332336", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210429-095332336", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2021.04.25.441372", "primary_object": { "basename": "2021.04.25.441372v1.full.pdf", "url": "https://authors.library.caltech.edu/records/w1w4f-qt651/files/2021.04.25.441372v1.full.pdf" }, "pub_year": "2021", "author_list": "Sarma, Anish A.; Sarma, Aartik; et al." }, { "id": "https://authors.library.caltech.edu/records/egfm3-vtg98", "eprint_id": 108855, "eprint_status": "archive", "datestamp": "2023-08-22 09:38:43", "lastmod": "2026-03-28 22:33:11", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Toubat-Omar", "name": { "family": "Toubat", "given": "Omar" } }, { "id": "Berg-Anders-H", "name": { "family": "Berg", "given": "Anders H." } }, { "id": "Sobhani-Kimia", "name": { "family": "Sobhani", "given": "Kimia" } }, { "id": "Mulligan-Karen", "name": { "family": "Mulligan", "given": "Karen" } }, { "id": "Hori-Acacia-M", "name": { "family": "Hori", "given": "Acacia M." }, "orcid": "0000-0001-5868-348X" }, { "id": "Bhattacharya-Jay", "name": { "family": "Bhattacharya", "given": "Jay" } }, { "id": "Sood-Neeraj", "name": { "family": "Sood", "given": "Neeraj" } } ] }, "title": "Manufacturer Signal-to-Cutoff Threshold Underestimates Cumulative Incidence of SARS-CoV-2 Infection: Evidence from the Los Angeles Firefighters Study", "ispublished": "unpub", "full_text_status": "public", "keywords": "COVID-19; SARS-CoV-2; seroprevalence; serology", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \n\nThis version posted April 23, 2021. \n\nData Availability: The primary data included in the manuscript may be available upon request through email of the corresponding author of the research team. \n\nCompeting Interest Statement: Dr. Sood reported receiving funding and in kind support from Burns and Allen Research Institute at the Cedars Sinai Medical Center, the Mayoral Office of the City of Los Angeles, the Rockefeller Foundation, Abbott Diagnostics, and the Conrad R. Hilton Foundation for the study. Dr. Sood also reported serving as a scientific advisor to Payssurance, the American Medical Association, and has received grants from the Agency for Healthcare, Research, and Quality, the National Institutes of Health, the Health Care Services Corporation, and the Patient-Centered Outcomes Research Institute outside the submitted work. Omar Toubat is supported in part by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number F30HL154324 outside of the submitted work. \n\nThis work was supported by the Rockefeller Foundation, Conrad N. Hilton Foundation, Burns and Allen Research Institute at Cedars-Sinai Medical Center, and Office of Mayor Eric Garcetti, City of Los Angeles. Funding organizations and donors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. \n\nAuthor Declarations:\nI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.\n\nYes.\n\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:\n\nThe Los Angeles County Department of Public Health Institutional Review Board approved this study.\n\nAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.\n\nYes.\n\nI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).\n\nYes.\n\nI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.\n\nYes.\n\nSubmitted - 2021.04.20.21255829v1.full.pdf
", "abstract": "While SARS-CoV-2 serologic testing is used to measure cumulative incidence of COVID-19, appropriate signal-to-cut off (S/Co) thresholds remain unclear. We demonstrate S/Co thresholds based on known negative samples significantly increases seropositivity and more accurately estimates cumulative incidence of disease compared to manufacturer-based thresholds.", "date": "2021-04-23", "date_type": "published", "id_number": "CaltechAUTHORS:20210428-092309187", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210428-092309187", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Rockefeller Foundation" }, { "agency": "Conrad N. Hilton Foundation" }, { "agency": "Cedars-Sinai Medical Center" }, { "agency": "City of Los Angeles" }, { "agency": "Abbott Diagnostics" }, { "agency": "Agency for Healthcare Research and Quality" }, { "agency": "Health Care Services Corporation" }, { "agency": "Patient-Centered Outcomes Research Institute" }, { "agency": "NIH Postdoctoal Fellwoship", "grant_number": "F30HL154324" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2021.04.20.21255829", "primary_object": { "basename": "2021.04.20.21255829v1.full.pdf", "url": "https://authors.library.caltech.edu/records/egfm3-vtg98/files/2021.04.20.21255829v1.full.pdf" }, "pub_year": "2021", "author_list": "Toubat, Omar; Berg, Anders H.; et al." }, { "id": "https://authors.library.caltech.edu/records/0qq73-my993", "eprint_id": 108382, "eprint_status": "archive", "datestamp": "2023-10-03 22:39:26", "lastmod": "2026-03-30 05:39:16", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Muecksch-Frauke", "name": { "family": "Muecksch", "given": "Frauke" }, "orcid": "0000-0002-0132-5101" }, { "name": { "family": "Weisblum", "given": "Yiska" }, "orcid": "0000-0002-9249-1745" }, { "id": "Barnes-Christopher-O", "name": { "family": "Barnes", "given": "Christopher O." }, "orcid": "0000-0003-2754-5951" }, { "name": { "family": "Schmidt", "given": "Fabian" } }, { "name": { "family": "Schaefer-Babajew", "given": "Dennis" }, "orcid": "0000-0002-5380-2950" }, { "name": { "family": "Lorenzi", "given": "Julio C. C." }, "orcid": "0000-0003-2492-3961" }, { "id": "Flyak-Andrew-I", "name": { "family": "Flyak", "given": "Andrew I." }, "orcid": "0000-0002-8722-479X" }, { "id": "DeLaitsch-Andrew-T", "name": { "family": "DeLaitsch", "given": "Andrew T." }, "orcid": "0000-0002-3458-3449" }, { "id": "Huey-Tubman-Kathryn-E", "name": { "family": "Huey-Tubman", "given": "Kathryn E." }, "orcid": "0000-0002-4683-8138" }, { "name": { "family": "Hou", "given": "Shurong" }, "orcid": "0000-0001-5143-0797" }, { "name": { "family": "Schiffer", "given": "Celia A." }, "orcid": "0000-0003-2270-6613" }, { "name": { "family": "Gaebler", "given": "Christian" }, "orcid": "0000-0001-7295-8128" }, { "name": { "family": "Wang", "given": "Zijun" }, "orcid": "0000-0002-2095-2151" }, { "name": { "family": "Da Silva", "given": "Justin" } }, { "id": "Poston-Daniel", "name": { "family": "Poston", "given": "Daniel" }, "orcid": "0000-0001-9900-6717" }, { "name": { "family": "Finkin", "given": "Shlomo" }, "orcid": "0000-0003-4474-2658" }, { "name": { "family": "Cho", "given": "Alice" }, "orcid": "0000-0001-6354-6148" }, { "name": { "family": "Cipolla", "given": "Melissa" }, "orcid": "0000-0001-8156-2512" }, { "name": { "family": "Oliveira", "given": "Thiago Y." }, "orcid": "0000-0002-2654-0879" }, { "name": { "family": "Millard", "given": "Katrina G." }, "orcid": "0000-0003-2247-3178" }, { "name": { "family": "Ramos", "given": "Victor" }, "orcid": "0000-0001-8572-1621" }, { "name": { "family": "Gazumyan", "given": "Anna" }, "orcid": "0000-0002-5976-9717" }, { "name": { "family": "Rutkowska", "given": "Magdalena" }, "orcid": "0000-0002-8090-3503" }, { "name": { "family": "Caskey", "given": "Marina" }, "orcid": "0000-0003-1727-8693" }, { "name": { "family": "Nussenzweig", "given": "Michel C." }, "orcid": "0000-0003-0592-8564" }, { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990" }, { "name": { "family": "Hatziioannou", "given": "Theodora" }, "orcid": "0000-0002-7889-0766" }, { "name": { "family": "Bieniasz", "given": "Paul D." }, "orcid": "0000-0002-2368-3719" } ] }, "title": "Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies", "ispublished": "unpub", "full_text_status": "public", "keywords": "SARS-CoV-2, Antibodies, Neutralization", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \n\nThis version posted March 8, 2021. \n\nWe thank all study participants and clinical staff. We thank members of the Bjorkman, Nussenzweig, and Bieniasz laboratories for helpful discussions, Dr. Jost Vielmetter, Pauline Hoffman, and the Protein Expression Center in the Beckman Institute at Caltech for expression assistance. Electron microscopy was performed in the Caltech Beckman Institute Resource Center for Transmission Electron Microscopy with assistance from Dr. Songye Chen. We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support the Molecular Observatory (Dr. Jens Kaiser, director), and Drs. Silvia Russi, Aina Cohen, and Clyde Smith and the beamline staff at SSRL for data collection assistance. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-c76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (P41GM103393). This work was supported by NIH grants R37-AI64003 (to P.D.B.), R01AI78788 (to T.H.), P01-AI138938-S1 (P.J.B. and M.C.N.), K99 AI153465 (to A.I.F.), 2U19AI111825 (to M.C.N.). This work was also supported by a George Mason University Fast Grant (P.J.B.), a grant from the NSF GRFP DGE-1745301 (to A.T.D.), and by the Caltech Merkin Institute for Translational Research (P.J.B.). C.O.B was supported by the Hanna Gray Fellowship Program from the Howard Hughes Medical Institute and the Postdoctoral Enrichment Program from the Burroughs Wellcome Fund. F.M. was supported by the Bulgari Women & Science Fellowship in COVID-19 Research. C.G. was supported by the Robert S. Wennett Post-Doctoral Fellowship, in part by the National Center for Advancing Translational Sciences (National Institutes of Health Clinical and Translational Science Award program, grant UL1 TR001866), and by the Shapiro-Silverberg Fund for the Advancement of Translational Research. M.C.N. and P.D.B. are Howard Hughes Medical Institute Investigators. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS, NIAID or NIH.\n\nAuthor contributions: F.M., Y.W., C.O.B., F.S., M.C.N, P.J.B., T.H., and P.D.B., conceived the study and analyzed data. F.S. and J.D.S. generated spike plasmids. F.M., D.S.B., J.C.L and J.D.S. performed neutralization assays with natural SARS-CoV-2 variant and sarbecovirus HIV-1 pseudotypes. Y.W., F.S., and M.R. performed the selection and characterization of escape mutants using VSV/SARS-CoV-2 and HIV-1-pseudotypes. C.O.B. and K.H.T. performed protein purification and complex assembly. A.I.F. and C.O.B. performed crystallographic studies and analyzed structures. C.O.B., A.T.D., and A.I.F. performed cryo-EM studies and analyzed structures. S.H. and C.A.S. generated and performed analyses of homology models. Z.W., S.F., A.C., T.Y.O., M.C., K.G.M., V.R. and A.G. isolated and characterized monoclonal antibodies. C.G. and M.C. recruited participants and executed clinical protocols. F.M., Y.W., C.O.B., F.S., M.C.N, P.J.B., T.H. and P.D.B. wrote the paper with contributions from other authors. \n\nDeclaration of Interests: The Rockefeller University has filed provisional patent applications in connection with this work on which M.C.N. (US patent 63/021,387) and Y.W., F.S., T.H. and P.D.B. (US patent 63/036,124) are listed as inventors.\n\nSubmitted - 20210307-434227v1.full.pdf
", "abstract": "Antibodies elicited in response to infection undergo somatic mutation in germinal centers that can result in higher affinity for the cognate antigen. To determine the effects of somatic mutation on the properties of SARS-CoV-2 spike receptor-binding domain (RBD)-specific antibodies, we analyzed six independent antibody lineages. As well as increased neutralization potency, antibody evolution changed pathways for acquisition of resistance and, in some cases, restricted the range of neutralization escape options. For some antibodies, maturation apparently imposed a requirement for multiple spike mutations to enable escape. For certain antibody lineages, maturation enabled neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.", "date": "2021-03-08", "date_type": "published", "id_number": "CaltechAUTHORS:20210310-101010448", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210310-101010448", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Gordon and Betty Moore Foundation" }, { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-C76SF00515" }, { "agency": "NIH", "grant_number": "P41GM103393" }, { "agency": "NIH", "grant_number": "R37-AI64003" }, { "agency": "NIH", "grant_number": "R01AI78788" }, { "agency": "NIH", "grant_number": "P01-AI138938-S1" }, { "agency": "NIH", "grant_number": "K99 AI153465" }, { "agency": "NIH", "grant_number": "2U19AI111825" }, { "agency": "George Mason University" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-1745301" }, { "agency": "Caltech Merkin Institute for Translational Research" }, { "agency": "Howard Hughes Medical Institute (HHMI)" }, { "agency": "Burroughs Wellcome Fund" }, { "agency": "Bulgari Women and Science Fellowship" }, { "agency": "Robert S. Wennett Postdoctoral Fellowship" }, { "agency": "NIH", "grant_number": "UL1 TR001866" }, { "agency": "Shapiro-Silverberg Fund for the Advancement of Translational Research" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Richard-Merkin-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2021.03.07.434227", "pmcid": "PMC7987023", "primary_object": { "basename": "20210307-434227v1.full.pdf", "url": "https://authors.library.caltech.edu/records/0qq73-my993/files/20210307-434227v1.full.pdf" }, "pub_year": "2021", "author_list": "Muecksch, Frauke; Weisblum, Yiska; et al." }, { "id": "https://authors.library.caltech.edu/records/esqbh-pwd24", "eprint_id": 111336, "eprint_status": "archive", "datestamp": "2023-10-05 15:49:40", "lastmod": "2026-03-30 15:28:45", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rusch-Tessa", "name": { "family": "Rusch", "given": "Tessa" }, "orcid": "0000-0002-5445-6885" }, { "id": "Han-Yanting", "name": { "family": "Han", "given": "Yanting" }, "orcid": "0000-0003-3381-2059" }, { "id": "Liang-Dehua", "name": { "family": "Liang", "given": "Dehua" }, "orcid": "0000-0003-4794-0270" }, { "id": "Hopkins-Amber", "name": { "family": "Hopkins", "given": "Amber" }, "orcid": "0000-0002-8354-565X" }, { "id": "Lawrence-Caroline-V", "name": { "family": "Lawrence", "given": "Caroline V." } }, { "id": "Maoz-Uri-M", "name": { "family": "Maoz", "given": "Uri" }, "orcid": "0000-0002-7899-1241" }, { "id": "Paul-Lynn-K", "name": { "family": "Paul", "given": "Lynn K." }, "orcid": "0000-0002-3128-8313" }, { "id": "Stanlet-Damian-A", "name": { "family": "Stanley", "given": "Damian A." } } ] }, "title": "COVID-Dynamic: A large-scale multifaceted longitudinal study of socioemotional and behavioral change across the pandemic", "ispublished": "unpub", "full_text_status": "public", "note": "CC-By Attribution 4.0 International \n\nThis dataset is the result of a collaborative effort by the entire COVID-Dynamic team (in alphabetical order): Ralph Adolphs, R. Michael Alvarez, Ruby Basyouni, Isabella Camplison, Yanting Han, Denise Hien, Amber Hopkins, Jonathan Katz, Tian Lan, Caroline Lawrence, Dehua Liang, Chujun Lin, Teresa Lopez-Castro, Uri Maoz, Marie-Christine Nizzi, Lynn K. Paul, Allison Rabkin Golden, Tessa Rusch, Damian A. Stanley, Iman Wahle, and Gideon Yaffe. A detailed characterization of each team member's contribution is given in the contribution table (Figure 5). \n\nThis work was supported by grants from the National Institute of Mental Health (2P50MH094258), the Caltech Chen Neuroscience Institute, and the Caltech Merkin Institute (RA), by the Oscar M. Ruebhausen Fund at Yale Law School (GY), the Rutgers Center of Alcohol & Substance Use Studies (DH), the John Templeton Foundation and the Kay Family COVID-19 Rapid Response Research Awards at Chapman University (UM), and the Colin Powell School for Civic and Global Leadership, The City College of New York (TLC). The opinions expressed in this publication are those of the authors and do not necessarily reflect the views of the funding agencies.\n\nSubmitted - Manuscriptv6.pdf
", "abstract": "The COVID-19 pandemic is a catastrophe that has caused societal upheaval globally. In the US, 2 it triggered an economic shock and laid bare societal inequities. However, it also afforded a unique 3 opportunity to elucidate the dynamics of psychosocial processes during extreme and volatile 4 conditions. From April 2020 through January 2021, we conducted a within-participant longitudinal 5 study\u2014in 16 waves\u2014to capture the COVID-19 experiences of >1000 US residents, together with 6 curated, external data to contextualize participants' responses. Each hour-long wave combined 7 standard psychological assessments with surveys of emotion, social/political/moral attitudes, 8 COVID-19-related behaviors, and tasks assessing implicit attitudes and social decision-making. 9 Here we characterize the sample, assess data quality, and showcase examples to demonstrate 10 the promise of this dataset, which is intended to be a resource for researchers interested in a 11 multitude of psychological questions, as well as clinicians and policy makers looking to mitigate 12 the psychological effects of future calamities.", "date": "2021-03-07", "date_type": "published", "id_number": "CaltechAUTHORS:20211008-224631657", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20211008-224631657", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "2P50MH094258" }, { "agency": "Tianqiao and Chrissy Chen Institute for Neuroscience" }, { "agency": "Caltech Merkin Institute for Translational Research" }, { "agency": "Yale Law School" }, { "agency": "Rutgers Center of Alcohol & Substance Use Studies" }, { "agency": "John Templeton Foundation" }, { "agency": "Kay Family COVID-19 Rapid Response Research Awards" }, { "agency": "City College of New York" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Richard-Merkin-Institute" }, { "id": "Tianqiao-and-Chrissy-Chen-Institute-for-Neuroscience" } ] }, "doi": "10.31234/osf.io/75eyx", "primary_object": { "basename": "Manuscriptv6.pdf", "url": "https://authors.library.caltech.edu/records/esqbh-pwd24/files/Manuscriptv6.pdf" }, "pub_year": "2021", "author_list": "Rusch, Tessa; Han, Yanting; et al." }, { "id": "https://authors.library.caltech.edu/records/tehhm-n2q81", "eprint_id": 108034, "eprint_status": "archive", "datestamp": "2023-08-22 08:55:08", "lastmod": "2026-03-30 07:05:21", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yurk-Dominic", "name": { "family": "Yurk", "given": "Dominic" } }, { "id": "Abu-Mostafa-Y-S", "name": { "family": "Abu-Mostafa", "given": "Yaser" } } ] }, "title": "County-Specific, Real-Time Projection of the Effect of Business Closures on the COVID-19 Pandemic", "ispublished": "unpub", "full_text_status": "public", "keywords": "data-driven; model; COVID-19; policy; neural-net", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license. \n\nThis version posted February 12, 2021. \n\nWe thank Dr. Jeremy Goldhaber-Fiebert for providing us with early access to the SC-COSMO public health policy data\nset, which helped kick-start this research effort. \n\nOur overall COVID modeling research effort was supported by the Clinard Innovation Fund. \n\nAuthor Declarations: I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. \n\nYes. \n\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below: \n\nNone. \n\nAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. \n\nYes. \n\nI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). \n\nYes. \n\nI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. \n\nYes. \n\nData Availability: All data used are available through links referenced in the manuscript. \n\nCompeting Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: financial support from the Clinard Innovation Fund, which has no conflict of interest with this work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.\n\nSupplemental Material - 2021.02.10.21251533v1.full.pdf
", "abstract": "Public health policies such as business closures have been one of our most effective tools in slowing the spread of COVID-19, but they also impose costs. This has created demand from policy makers for models which can predict when and where such policies will be most effective to head off a surge and where they could safely be loosened. No current model combines data-driven, real-time policy effect predictions with county-level granularity. We present a neural net-based model for predicting the effect of business closures or re-openings on the COVID-19 time-varying reproduction number Rt in real time for every county in California. When trained on data from May through September the model accurately captured relative county dynamics during the October/November California COVID-19 surge (r2=0.76), indicating robust out-of-sample performance. To showcase the model's potential utility we present a case study of various counties in mid-October. Even when counties imposed similar restrictions at the time, our model successfully distinguished counties in need of drastic and immediate action to head off a surge from counties in less dire need of intervention. While this study focuses on business closures in California, the presented model architecture could be applied to other policies around world.", "date": "2021-02-12", "date_type": "published", "id_number": "CaltechAUTHORS:20210212-100829452", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210212-100829452", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Clinard Innovation Fund" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2021.02.10.21251533", "primary_object": { "basename": "2021.02.10.21251533v1.full.pdf", "url": "https://authors.library.caltech.edu/records/tehhm-n2q81/files/2021.02.10.21251533v1.full.pdf" }, "pub_year": "2021", "author_list": "Yurk, Dominic and Abu-Mostafa, Yaser" }, { "id": "https://authors.library.caltech.edu/records/mz3dd-zt163", "eprint_id": 107893, "eprint_status": "archive", "datestamp": "2023-08-20 01:46:46", "lastmod": "2026-03-30 14:11:30", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ghaffarizadeh-S-Aryan", "name": { "family": "Ghaffarizadeh", "given": "S. Aryan" } }, { "id": "Ghaffarizadeh-S-Arman", "name": { "family": "Ghaffarizadeh", "given": "S. Arman" }, "orcid": "0000-0002-6894-074X" }, { "id": "Behbahani-Amir-H", "name": { "family": "Behbahani", "given": "Amir H." }, "orcid": "0000-0001-5603-6887" }, { "id": "Mehdizadeh-Mohammad", "name": { "family": "Mehdizadeh", "given": "Mohammad" } }, { "id": "Olechowski-Alison", "name": { "family": "Olechowski", "given": "Alison" }, "orcid": "0000-0001-5557-654X" } ] }, "title": "Life and Work of Researchers Trapped in the COVID-19 Pandemic Vicious Cycle", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license. \n\nThis version posted February 3, 2021. \n\nAuthor contributions: S.Aryan.G, S.Arman.G, AHB, and MM, designed the survey under the supervision of AO. S.Aryan.G analyzed and interpreted results. S.Aryan.G and S.Arman.G wrote the initial draft of the manuscript and all authors revised and edited the manuscript. \n\nWe have no competing interest to declare.\n\nSubmitted - 2021.02.02.429476v1.full.pdf
Supplemental Material - media-1.pdf
", "abstract": "COVID-19 has disrupted researchers' work and posed challenges to their life routines. We have surveyed 740 researchers of which, 66% experienced a decrease in productivity, 50% indicated increased workload, and 66% reported they have been feeling internal pressure to make progress. Ones whose research required physical presence in a lab or the field experienced considerable disruption and productivity decrease. About 82% of this group will try to permanently reduce their work dependency on physical presence. Parents and those taking care of vulnerable members have been spending less time on research due to their role conflict. We also observed a gender gap in the overall disruption consequences; more female researchers have been experiencing a reduction in productivity and external pressure to make progress. The results of this study could help institution leaders and policymakers to better understand the challenges of the research community and take appropriate measures to instill long-term solutions.", "date": "2021-02-03", "date_type": "published", "id_number": "CaltechAUTHORS:20210203-144656191", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210203-144656191", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2021.02.02.429476", "primary_object": { "basename": "2021.02.02.429476v1.full.pdf", "url": "https://authors.library.caltech.edu/records/mz3dd-zt163/files/2021.02.02.429476v1.full.pdf" }, "related_objects": [ { "basename": "media-1.pdf", "url": "https://authors.library.caltech.edu/records/mz3dd-zt163/files/media-1.pdf" } ], "pub_year": "2021", "author_list": "Ghaffarizadeh, S. Aryan; Ghaffarizadeh, S. Arman; et al." }, { "id": "https://authors.library.caltech.edu/records/ad88j-vn708", "eprint_id": 118349, "eprint_status": "archive", "datestamp": "2023-08-20 01:46:57", "lastmod": "2026-03-29 19:53:32", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Harris-Lovett-Sasha", "name": { "family": "Harris-Lovett", "given": "Sasha" }, "orcid": "0000-0001-9006-6895" }, { "id": "Nelson-Kara-L", "name": { "family": "Nelson", "given": "Kara" }, "orcid": "0000-0001-8899-2662" }, { "id": "Beamer-Paloma", "name": { "family": "Beamer", "given": "Paloma" }, "orcid": "0000-0001-5287-2183" }, { "id": "Bischel-Heather-N", "name": { "family": "Bischel", "given": "Heather N." }, "orcid": "0000-0001-8335-0601" }, { "id": "Bivins-Aaron", "name": { "family": "Bivins", "given": "Aaron" }, "orcid": "0000-0001-9385-2138" }, { "id": "Bruder-Andrea", "name": { "family": "Bruder", "given": "Andrea" } }, { "id": "Butler-Caitlyn", "name": { "family": "Butler", "given": "Caitlyn" }, "orcid": "0000-0001-6887-3375" }, { "id": "Camenisch-Todd-D", "name": { "family": "Camenisch", "given": "Todd D." }, "orcid": "0000-0002-7797-9822" }, { "id": "De-Long-Susan-K", "name": { "family": "De Long", "given": "Susan K." }, "orcid": "0000-0002-3160-2392" }, { "id": "Karthikeyan-Smruthi", "name": { "family": "Karthikeyan", "given": "Smruthi" }, "orcid": "0000-0001-6226-4536" }, { "id": "Larsen-David-A", "name": { "family": "Larsen", "given": "David A." }, "orcid": "0000-0002-1876-6536" }, { "id": "Meierdiercks-Katherine", "name": { "family": "Meierdiercks", "given": "Katherine" }, "orcid": "0000-0003-3749-2785" }, { "id": "Mouser-Paula-J", "name": { "family": "Mouser", "given": "Paula" }, "orcid": "0000-0003-2316-0915" }, { "id": "Pagsuyoin-Sheree", "name": { "family": "Pagsuyoin", "given": "Sheree" }, "orcid": "0000-0001-7134-1679" }, { "id": "Prasek-Sarah-M", "name": { "family": "Prasek", "given": "Sarah" } }, { "id": "Radniecki-Tyler-S", "name": { "family": "Radniecki", "given": "Tyler S." }, "orcid": "0000-0002-5295-3562" }, { "id": "Ram-Jeffrey-L", "name": { "family": "Ram", "given": "Jeffrey L." }, "orcid": "0000-0002-1063-546X" }, { "id": "Roper-D-Keith", "name": { "family": "Roper", "given": "D. Keith" } }, { "id": "Safford-Hannah", "name": { "family": "Safford", "given": "Hannah" }, "orcid": "0000-0001-9283-2602" }, { "id": "Sherchan-Samendra-P", "name": { "family": "Sherchan", "given": "Samendra P." }, "orcid": "0000-0002-0092-7928" }, { "id": "Shuster-William", "name": { "family": "Shuster", "given": "William" }, "orcid": "0000-0001-7688-0110" }, { "id": "Stalder-Thibault", "name": { "family": "Stalder", "given": "Thibault" }, "orcid": "0000-0002-8368-1889" }, { "id": "Wheeler-Robert-T", "name": { "family": "Wheeler", "given": "Robert T." }, "orcid": "0000-0003-3223-7021" }, { "id": "Korfmacher-Katrina-S", "name": { "family": "Korfmacher", "given": "Katrina Smith" }, "orcid": "0000-0002-8926-4082" } ] }, "title": "Wastewater surveillance for SARS-CoV-2 on college campuses: Initial efforts, lessons learned and research needs", "ispublished": "unpub", "full_text_status": "public", "note": "The authors would like to thank these individuals for their important contributions to this research and information about their colleges' wastewater surveillance systems: Aaron Best, Walter Betancourt, Cindi K. Brinkman, Lifang Chiang, Erik R. Coats, David Freedman, Elmer Johnson, Rob Knight, Karl Korfmacher, Erin K. Lipp, Erin A. Mack, Christopher Maroney, Simona Matsoyan, Ian Pepper, Shalina Shahin, Lachlan Squair, Eva M. Top, and Rogelio Zuniga-Montanez. Dr. Korfmacher's work on this project was supported in part by the National Institute of Environmental Health Sciences grant P30 ES001247. Dr. Harris-Lovett's work on this project was supported in part by the Catena Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the views of contributors, interviewees, or institutions included in the study. \n\nThe authors declare they have no actual or potential competing financial interests.", "abstract": "Background: Wastewater surveillance for SARS-CoV-2 is an emerging approach to help identify the risk of a COVID-19 outbreak. This tool can contribute to public health surveillance at both community (wastewater treatment system) and institutional (e.g., colleges, prisons, nursing homes) scales. \n\nObjectives: This research aims to understand the successes, challenges, and lessons learned from initial wastewater surveillance efforts at colleges and university systems to inform future research, development and implementation.\n\nMethods:This paper presents the experiences of 25 college and university systems in the United States that monitored campus wastewater for SARS-CoV-2 during the fall 2020 academic period. We describe the broad range of approaches, findings, resource needs, and lessons learned from these initial efforts. These institutions range in size, social and political geographies, and include both public and private institutions.\n\nDiscussion: Our analysis suggests that wastewater monitoring at colleges requires consideration of information needs, local sewage infrastructure, resources for sampling and analysis, college and community dynamics, approaches to interpretation and communication of results, and follow-up actions. Most colleges reported that a learning process of experimentation, evaluation, and adaptation was key to progress. This process requires ongoing collaboration among diverse stakeholders including decision-makers, researchers, faculty, facilities staff, students, and community members.", "date": "2021-02-03", "date_type": "published", "id_number": "CaltechAUTHORS:20221215-540238000.11", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20221215-540238000.11", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "P30 ES001247" }, { "agency": "Catena Foundation" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2021.02.01.21250952", "pmcid": "PMC7872386", "pub_year": "2021", "author_list": "Harris-Lovett, Sasha; Nelson, Kara; et al." }, { "id": "https://authors.library.caltech.edu/records/ze84b-v1782", "eprint_id": 107036, "eprint_status": "archive", "datestamp": "2023-08-20 00:52:32", "lastmod": "2026-03-30 16:23:05", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Winnett-Alexander", "name": { "family": "Winnett", "given": "Alexander" }, "orcid": "0000-0002-7338-5605" }, { "id": "Cooper-Matthew-M", "name": { "family": "Cooper", "given": "Matthew M." }, "orcid": "0000-0002-5868-5159" }, { "id": "Shelby-Natasha", "name": { "family": "Shelby", "given": "Natasha" }, "orcid": "0000-0001-9097-3663" }, { "id": "Romano-Anna-E", "name": { "family": "Romano", "given": "Anna E." }, "orcid": "0000-0003-1871-1727" }, { "id": "Reyes-Jessica-A", "name": { "family": "Reyes", "given": "Jessica A." }, "orcid": "0000-0002-5507-7633" }, { "id": "Ji-Jenny", "name": { "family": "Ji", "given": "Jenny" }, "orcid": "0000-0002-7901-5605" }, { "id": "Porter-Michael-K", "name": { "family": "Porter", "given": "Michael K." }, "orcid": "0000-0002-0777-7563" }, { "id": "Savela-Emily-S", "name": { "family": "Savela", "given": "Emily S." }, "orcid": "0000-0001-9614-4276" }, { "id": "Barlow-Jacob-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Akana-Reid", "name": { "family": "Akana", "given": "Reid" }, "orcid": "0000-0003-4422-587X" }, { "id": "Tognazzini-Colten", "name": { "family": "Tognazzini", "given": "Colten" }, "orcid": "0000-0002-2754-3588" }, { "id": "Feaster-Matthew", "name": { "family": "Feaster", "given": "Matthew" }, "orcid": "0000-0001-9966-2845" }, { "id": "Goh-Ying-Ying", "name": { "family": "Goh", "given": "Ying-Ying" }, "orcid": "0000-0001-5136-7214" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "SARS-CoV-2 Viral Load in Saliva Rises Gradually and to Moderate Levels in Some Humans", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. \n\nThis version posted December 11, 2020. \n\nWe thank Lauriane Quenee, Junie Hildebrandt, Grace Fisher-Adams, RuthAnne Bevier, Chantal D'Apuzzo, Ralph Adolphs, Victor Rivera, Steve Chapman, Gary Waters, Leonard Edwards, and Shannon Yamashita for their assistance and advice on study implementation or administration. We thank Jessica Leong, Jessica Slagle, and Angel Navarro for volunteering their time to help with this study. We thank Kissler et al. for making their data publicly available to the community. We thank Maira Phelps, Lienna Chan, Lucy Li and Amy Kistler at the Chan Zuckerberg Biohub for performing SARS-CoV-2 sequencing. We thank Jennifer Fulcher, Debika Bhattacharya and Matthew Bidwell Goetz for their ideas on potential study populations and early study design. We thank Martin Hill, Alma Sanchez, Scott Kim, Debbie Noble, Nina Paddock, Whitney Harrison, and Stu Miller for their support with recruitment. We thank Allison Rhines, Karen Heichman, and Dan Wattendorf for valuable discussion and guidance. Finally, we thank all the Pasadena Public Health Department case investigators and contact tracers for their efforts in study recruitment and their work in the pandemic response. \n\nThis study is based on research funded in part by the Bill & Melinda Gates Foundation. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation. This work was also funded by the Jacobs Institute for Molecular Engineering for Medicine. AW is supported by an NIH NIGMS Predoctoral Training Grant (GM008042); MMC is supported by a Caltech Graduate Student Fellowship; and MP and JTB are each partially supported by National Institutes of Health Biotechnology Leadership Pre-doctoral Training Program (BLP) fellowships from Caltech's Donna and Benjamin M. Rosen Bioengineering Center (T32GM112592).\n\nData Availability: Raw Ct values and calculated viral loads are available at CaltechDATA, https://data.caltech.edu/records/1702. \n\nCompeting Interests Statement: The authors report grants from the Bill & Melinda Gates Foundation (to RFI) and the Jacobs Institute for Molecular Engineering for Medicine (to RFI), as well as a Caltech graduate fellowship (to MMC), two National Institutes of Health Biotechnology Leadership Pre-doctoral Training Program (BLP) fellowships (to MKP and JTB) from Caltech's Donna and Benjamin M. Rosen Bioengineering Center (T32GM112592), and a National Institutes of Health NIGMS Predoctoral Training Grant (GM008042) (to AW) during the course of the study. Dr. Ismagilov is a co-founder, consultant, and a director and has stock ownership and received personal fees from Talis Biomedical Corp., outside the submitted work. In addition, Dr. Ismagilov is an inventor on a series of patents licensed to Bio-Rad Laboratories Inc. in the context of ddPCR, with royalties paid. \n\nAuthor Declarations: I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. \n\nYes.\n\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:\n\nThis study was reviewed and approved by the Institutional Review Board of the California Institute of Technology, protocol #20-1026.\n\nAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.\n\nYes.\n\nI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).\n\nYes.\n\nI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.\n\nYes.\n\nSubmitted - 2020.12.09.20239467v1.full.pdf
Supplemental Material - media-1.pdf
Supplemental Material - media-2.pdf
", "abstract": "Transmission of SARS-CoV-2 in community settings often occurs before symptom onset, therefore testing strategies that can reliably detect people in the early phase of infection are urgently needed. Early detection of SARS-CoV-2 infection is especially critical to protect vulnerable populations who require frequent interactions with caretakers. Rapid COVID-19 tests have been proposed as an attractive strategy for surveillance, however a limitation of most rapid tests is their low sensitivity. Low-sensitivity tests are comparable to high sensitivity tests in detecting early infections when two assumptions are met: (1) viral load rises quickly (within hours) after infection and (2) viral load reaches and sustains high levels (>10\u2075 - 10\u2076 RNA copies/mL). However, there are no human data testing these assumptions. In this study, we document a case of presymptomatic household transmission from a healthy college student to his brother and father. Participants prospectively provided twice-daily saliva samples. Samples were analyzed by RT-qPCR and RT-ddPCR and we measured the complete viral load profiles throughout the course of infection of the brother and father. This study provides evidence that in at least some human cases of SARS-CoV-2, viral load rises slowly (over days, not hours) and not to such high levels to be detectable reliably by any low-sensitivity test. Additional viral load profiles from different samples types across a broad demographic must be obtained to describe the early phase of infection and determine which testing strategies will be most effective for identifying SARS-CoV-2 infection before transmission can occur.", "date": "2020-12-11", "date_type": "published", "id_number": "CaltechAUTHORS:20201211-113537700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201211-113537700", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Bill and Melinda Gates Foundation" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "GM008042" }, { "agency": "Donna and Benjamin M. Rosen Bioengineering Center" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32GM112592" } ] }, "local_group": { "items": [ { "id": "Rosen-Bioengineering-Center" }, { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "COVID-19" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2020.12.09.20239467", "pmcid": "PMC7743094", "primary_object": { "basename": "2020.12.09.20239467v1.full.pdf", "url": "https://authors.library.caltech.edu/records/ze84b-v1782/files/2020.12.09.20239467v1.full.pdf" }, "related_objects": [ { "basename": "media-1.pdf", "url": "https://authors.library.caltech.edu/records/ze84b-v1782/files/media-1.pdf" }, { "basename": "media-2.pdf", "url": "https://authors.library.caltech.edu/records/ze84b-v1782/files/media-2.pdf" } ], "pub_year": "2020", "author_list": "Winnett, Alexander; Cooper, Matthew M.; et al." }, { "id": "https://authors.library.caltech.edu/records/2z0dm-q9917", "eprint_id": 106792, "eprint_status": "archive", "datestamp": "2023-10-03 22:33:52", "lastmod": "2026-03-30 05:40:03", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Flynn-Michael-J", "name": { "family": "Flynn", "given": "Michael J." } }, { "id": "Snitser-Olga", "name": { "family": "Snitser", "given": "Olga" } }, { "id": "Flynn-James", "name": { "family": "Flynn", "given": "James" } }, { "id": "Green-Samantha", "name": { "family": "Green", "given": "Samantha" } }, { "id": "Yelin-Idan", "name": { "family": "Yelin", "given": "Idan" }, "orcid": "0000-0003-2515-4113" }, { "id": "Szwarcwort-Cohen-Moran", "name": { "family": "Szwarcwort-Cohen", "given": "Moran" } }, { "id": "Kishony-Roy", "name": { "family": "Kishony", "given": "Roy" } }, { "id": "Elowitz-M-B", "name": { "family": "Elowitz", "given": "Michael B." }, "orcid": "0000-0002-1221-0967" } ] }, "title": "A simple direct RT-LAMP SARS-CoV-2 saliva diagnostic", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. \n\nThis version posted November 22, 2020. \n\nThis project was supported by the Caltech Merkin Institute for Translational Research and the Israel Science Foundation (grant No. 3633/19) within the KillCorona Curbing Coronavirus Research Program. James Flynn provided his own funds to conduct the study at Catholic Medical Center. \n\nData Availability: All data from this study can be obtained by emailing the first author. \n\nThe authors have declared no competing interest. \n\nAuthor Declarations: \nI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. \n\nYes. \n\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below: \n\nThe IRB of the Technion at Israel Institute of Technology gave approval for Olga Snitser to collect anonymized SARS-CoV-2 swab samples and assay them with RT-qPCR and the RT-LAMP protocol developed in this paper. The IRB of Catholic Medical Center in Manchester, New Hampshire gave approval for James Flynn to collect patient saliva samples and assay them with the RT-LAMP diagnostic developed in this paper. \n\nAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. \n\nYes. \n\nI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). \n\nYes. \n\nI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. \n\nYes.\n\nSubmitted - 20201119-20234948v1full.pdf
", "abstract": "Widespread, frequent testing is essential for curbing the ongoing COVID-19 pandemic. Because its simplicity makes it ideal for widely distributed, high throughput testing, RT-LAMP provides an attractive alternative to RT-qPCR. However, most RT-LAMP protocols require the purification of RNA, a complex and low-throughput bottleneck that has often been subject to reagent supply shortages. Here, we report an optimized RT-LAMP-based SARS-CoV-2 diagnostic protocol for saliva and swab samples. In the protocol we replace RNA purification with a simple sample preparation step using a widely available chelating agent, as well as optimize key protocol parameters. When tested on clinical swab and saliva samples, this assay achieves a limit of detection of 105 viral genomes per ml, with sensitivity close to 90% and specificity close to 100%, and takes 45 minutes from sample collection to result, making it well suited for a COVID-19 surveillance program.", "date": "2020-11-22", "date_type": "published", "id_number": "CaltechAUTHORS:20201123-140413855", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201123-140413855", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Caltech Merkin Institute for Translational Research" }, { "agency": "Israel Science Foundation", "grant_number": "3633/19" }, { "agency": "James Flynn" } ] }, "local_group": { "items": [ { "id": "Richard-Merkin-Institute" }, { "id": "COVID-19" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2020.11.19.20234948", "primary_object": { "basename": "20201119-20234948v1full.pdf", "url": "https://authors.library.caltech.edu/records/2z0dm-q9917/files/20201119-20234948v1full.pdf" }, "pub_year": "2020", "author_list": "Flynn, Michael J.; Snitser, Olga; et al." }, { "id": "https://authors.library.caltech.edu/records/td5az-6c039", "eprint_id": 106734, "eprint_status": "archive", "datestamp": "2023-08-19 23:56:51", "lastmod": "2026-03-28 22:39:44", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Brogan-Daniel-J", "name": { "family": "Brogan", "given": "Daniel J." } }, { "id": "Chaverra-Rodriguez-D", "name": { "family": "Chaverra-Rodriguez", "given": "Duverney" }, "orcid": "0000-0001-8068-7436" }, { "id": "Lin-Calvin-P", "name": { "family": "Lin", "given": "Calvin P." } }, { "id": "Smidler-Andrea-L", "name": { "family": "Smidler", "given": "Andrea L." }, "orcid": "0000-0002-3281-1161" }, { "id": "Yang-Ting", "name": { "family": "Yang", "given": "Ting" } }, { "id": "Alcantara-Lenissa-M", "name": { "family": "Alcantara", "given": "Lenissa M." } }, { "id": "Antoshechkin-Igor-A", "name": { "family": "Antoshechkin", "given": "Igor" }, "orcid": "0000-0002-9934-3040" }, { "id": "Liu-Junru", "name": { "family": "Liu", "given": "Junru" }, "orcid": "0000-0002-6198-8150" }, { "id": "Raban-Robyn-R", "name": { "family": "Raban", "given": "Robyn R." }, "orcid": "0000-0002-5648-6770" }, { "id": "Belda-Ferre-Pedro", "name": { "family": "Belda-Ferre", "given": "Pedro" }, "orcid": "0000-0001-6532-1161" }, { "id": "Knight-Rob", "name": { "family": "Knight", "given": "Rob" }, "orcid": "0000-0002-0975-9019" }, { "id": "Komives-Elizabeth-A", "name": { "family": "Komives", "given": "Elizabeth A." }, "orcid": "0000-0001-5264-3866" }, { "id": "Akbari-Omar-S", "name": { "family": "Akbari", "given": "Omar S." }, "orcid": "0000-0002-6853-9884" } ] }, "title": "A Sensitive, Rapid, and Portable CasRx-based Diagnostic Assay for SARS-CoV-2", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license. \n\nThis version posted October 20, 2020. \n\nWe thank the SEARCH (San Diego Epidemiology And Research for COVID-19 Health) Alliance for providing clinical samples. This work was supported in part by UCSD Seed Funds for Emergent COVID-19 Related Research a Directors New Innovator award from NIH/NIAID (DP2 AI152071-01) and a DARPA Safe Genes Program Grant (HR0011-17-2-0047) awarded to O.S.A. and a Directors Pioneer award from NCCIH (DP1 AT010885) to R.K. and the UCSD Return to Learn program via the EXCITE (EXpedited COVID-19 IdenTification Environment) lab. \n\nData Availability: All data is available in the manuscript. \n\nCompeting Interest Statement: S.A. has a patent pending on this technology. All other authors declare no significant competing financial, professional, or personal interests that might have influenced the performance or presentation of the work described. \n\nAuthor Declarations: \nI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. \n\nYes. \n\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below: \n\nHuman samples from patients were collected under University of California San Diego Human Research Protection Program protocol number 200470 for negatives (PI: Lauge Farnaes) and under a waiver of consent from clinical samples from San Diego County for positives (PI: Kristian Andersen) as part of the SEARCH Alliance activities. Samples were de-identified as required by these protocols prior to testing and analysis under University of California San Diego Biological Use Authorization protocols R1806 and 2401. \n\nAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. \n\nYes. \n\nI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). \n\nYes. \n\nI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. \n\nYes.\n\nSubmitted - 2020.10.14.20212795v2.full.pdf
", "abstract": "Since its first emergence from China in late 2019, the SARS-CoV-2 virus has spread globally despite unprecedented containment efforts, resulting in a catastrophic worldwide pandemic. Successful identification and isolation of infected individuals can drastically curtail virus spread and limit outbreaks. However, during the early stages of global transmission, point-of-care diagnostics were largely unavailable and continue to remain difficult to procure, greatly inhibiting public health efforts to mitigate spread. Furthermore, the most prevalent testing kits rely on reagent- and time-intensive protocols to detect viral RNA, preventing rapid and cost-effective diagnosis. Therefore the development of an extensive toolkit for point-of-care diagnostics that is expeditiously adaptable to new emerging pathogens is of critical public health importance. Recently, a number of novel CRISPR-based diagnostics have been developed to detect COVID-19. Herein, we outline the development of a CRISPR-based nucleic acid molecular diagnostic utilizing a Cas13d ribonuclease derived from Ruminococcus flavefaciens (CasRx) to detect SARS-CoV-2, an approach we term SENSR (Sensitive Enzymatic Nucleic-acid Sequence Reporter). We demonstrate SENSR robustly detects SARS-CoV-2 sequences in both synthetic and patient-derived samples by lateral flow and fluorescence, thus expanding the available point-of-care diagnostics to combat current and future pandemics.", "date": "2020-10-20", "date_type": "published", "id_number": "CaltechAUTHORS:20201119-093121134", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201119-093121134", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "University of California, San Diego" }, { "agency": "NIH", "grant_number": "DP2 AI152071-01" }, { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-17-2-0047" }, { "agency": "NIH", "grant_number": "DP1 AT010885" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2020.10.14.20212795", "pmcid": "PMC7587836", "primary_object": { "basename": "2020.10.14.20212795v2.full.pdf", "url": "https://authors.library.caltech.edu/records/td5az-6c039/files/2020.10.14.20212795v2.full.pdf" }, "pub_year": "2020", "author_list": "Brogan, Daniel J.; Chaverra-Rodriguez, Duverney; et al." }, { "id": "https://authors.library.caltech.edu/records/d3exh-c5k72", "eprint_id": 110207, "eprint_status": "archive", "datestamp": "2023-08-19 23:17:49", "lastmod": "2025-02-01 18:44:11", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Green-Sydnee-A", "name": { "family": "Green", "given": "Sydnee A." } }, { "id": "Wigman-Benjamin", "name": { "family": "Wigman", "given": "Benjamin" } }, { "id": "Nistanaki-Stepand-K", "name": { "family": "Nistanaki", "given": "Sepand K." }, "orcid": "0000-0002-5252-803X" }, { "id": "Montgomery-Hayden-R", "name": { "family": "Montgomery", "given": "Hayden R." }, "orcid": "0000-0002-6750-0830" }, { "id": "Jones-Christopher-G", "name": { "family": "Jones", "given": "Christopher G." } }, { "id": "Nelson-H-M", "name": { "family": "Nelson", "given": "Hosea M." }, "orcid": "0000-0002-4666-2793" } ] }, "title": "Chemocatalytic Amplification Probes Enable Transcriptionally-Regulated Au(I)-Catalysis in E. coli and Sensitive Detection of SARS-CoV-2 RNA Fragments", "ispublished": "unpub", "full_text_status": "public", "note": "The content is available under CC BY NC ND 4.0 License. \n\nFinancial support for this work was generously provided by the David and Lucile Packard Foundation (to H.M.N.), the Pew Charitable Trusts (to H.M.N), Bristol Myers Squibb (to H.M.N.), the UCLA AIDS institute (to H.M.N.) and the National Science Foundation (DGE-1650604 to B.W. and C.G.J.). S.A.G. thanks the Department of Chemistry and Biochemistry UCLA Fellowship for funding. B.W. thanks the Christopher S. Foote Fellowship for funding. S.K.N. thanks the USPHS National Research Service Award (T32GM008496). The authors thank the UCLA Molecular Instrumentation Center for NMR and mass spectrometry instrumentation. This material is based on work supported by the National Institutes of Health under instrumentation (1S10OD016387-01). We would like to thank Dr. Mark Arbing for assistance and the UCLA-DOE Protein Expression Core for E. coli cell transformation and expression. We would like to thank Amir Nasajpour for assistance with cell imaging. We would like to acknowledge Professor F. Dean Toste (UC Berkeley) for useful discussions. \n\nAuthor Contributions. H.M.N. conceived of project and designed experiments. S.A.G., B.W., S.K.N., and H.R.M. designed and conducted experiments. C.G.J. performed statistical analyses. H.M.N., S.A.G., B.W., S.K.N., and C.G.J. prepared the manuscript. \n\nData Availability. Further fluorescence measurements, NMR spectra, cell images, and thermal stability measurements can be found in the SI Appendix.\n\nSupplemental Material - cc-covid-paper-si-final-1.pdf
", "abstract": "The union of transition metal catalysis with native biochemistry presents a powerful opportunity to perform abiotic reactions within complex biological systems. However, several chemical compatibility challenges associated with incorporating reactive metal centers into complex biological environments have hindered efforts in this area, despite the many opportunities it may present. More challenging than chemical compatibility is biocommunicative transition metal catalysis, where the reactivity of the metal species is regulated by native biological stimuli, akin to natural biocatalytic processes. Here we report a novel Au(I)-DNAzyme that is activated by short nucleic acids in a highly sequence-specific manner and that is compatible with complex biological matrices. The active Au(I)-DNAzyme catalyzes the formation of a fluorescent molecule with >10 turnovers. This functional allostery, resulting in chemocatalytic signal amplification, is competent in complex biological settings, including within recombinant E. coli cells, where the catalytic activity of the Au(I)-DNAzyme is regulated by transcription of an inducible plasmid. We further demonstrate the potential of this transition metal oligonucleotide complex as a highly sensitive and selective hybridization probe, permitting the detection of attomolar concentrations (ca. 60 molecules/ L) of SARS-CoV-2 RNA gene fragments in simulated biological matrices with \u226585% accuracy. Notably, this sensitive detection platform avoids expensive and poorly-scalable biochemical components (e.g. post-synthetically modified oligonucleotides or enzymes) and utilizes small molecule fluorophores, inexpensive Au salts and oligonucleotides composed of canonical bases. This discovery highlights promising opportunities to perform abiotic catalysis in complex biological settings under transcriptional regulation, as well as a chemocatalytic strategy for PCR-free, direct-detection of RNA and DNA.", "date": "2020-09-07", "date_type": "published", "id_number": "CaltechAUTHORS:20210811-225351023", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210811-225351023", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "David and Lucile Packard Foundation" }, { "agency": "Pew Charitable Trust" }, { "agency": "Bristol-Myers Squibb" }, { "agency": "UCLA" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-1650604" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32GM008496" }, { "agency": "NIH", "grant_number": "1S10OD016387-01" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.26434/chemrxiv.12915761.v2", "primary_object": { "basename": "cc-covid-paper-si-final-1.pdf", "url": "https://authors.library.caltech.edu/records/d3exh-c5k72/files/cc-covid-paper-si-final-1.pdf" }, "related_objects": [ { "basename": "chemocatalytic-amplification-probes-enable-transcriptionally-regulated-au-i-catalysis-in-e-coli-and-sensitive-detection-of-sars-co-v-2-rna-fragments.pdf", "url": "https://authors.library.caltech.edu/records/d3exh-c5k72/files/chemocatalytic-amplification-probes-enable-transcriptionally-regulated-au-i-catalysis-in-e-coli-and-sensitive-detection-of-sars-co-v-2-rna-fragments.pdf" } ], "pub_year": "2020", "author_list": "Green, Sydnee A.; Wigman, Benjamin; et al." }, { "id": "https://authors.library.caltech.edu/records/bnm3q-sbw29", "eprint_id": 105265, "eprint_status": "archive", "datestamp": "2023-09-25 22:37:59", "lastmod": "2026-03-30 05:35:55", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Barnes-Christopher-O", "name": { "family": "Barnes", "given": "Christopher O." }, "orcid": "0000-0003-2754-5951" }, { "id": "Jette-Claudia-A", "name": { "family": "Jette", "given": "Claudia A." }, "orcid": "0000-0002-5085-8027" }, { "id": "Abernathy-Morgan-E", "name": { "family": "Abernathy", "given": "Morgan E." } }, { "id": "Dam- Kim-Marie-A", "name": { "family": "Dam", "given": "Kim-Marie A." } }, { "id": "Esswein-Shannon-R", "name": { "family": "Esswein", "given": "Shannon R." }, "orcid": "0000-0002-5142-0190" }, { "id": "Gristick-Harry-B", "name": { "family": "Gristick", "given": "Harry B." }, "orcid": "0000-0002-1957-2821" }, { "id": "Malyutin-Andrey-G", "name": { "family": "Malyutin", "given": "Andrey G." } }, { "id": "Sharaf-Naima-G", "name": { "family": "Sharaf", "given": "Naima G." }, "orcid": "0000-0002-3662-9228" }, { "id": "Huey-Tubman-Kathryn-E", "name": { "family": "Huey-Tubman", "given": "Kathryn E." }, "orcid": "0000-0002-4683-8138" }, { "id": "Lee-Yu-E", "name": { "family": "Lee", "given": "Yu E." } }, { "id": "Robbiani-Davide-F", "name": { "family": "Robbiani", "given": "Davide F." }, "orcid": "0000-0001-7379-3484" }, { "id": "Nussenzweig-Michel-C", "name": { "family": "Nussenzweig", "given": "Michel C." }, "orcid": "0000-0003-0592-8564" }, { "id": "West-Anthony-P-Jr", "name": { "family": "West", "given": "Anthony P., Jr." } }, { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990" } ] }, "title": "Structural classification of neutralizing antibodies against the SARS-CoV-2 spike receptor-binding domain suggests vaccine and therapeutic strategies", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \n\nPosted August 30, 2020. \n\nWe thank Dr. Jost Vielmetter, Pauline Hoffman, and the Protein Expression Center in the Beckman Institute at Caltech for expression assistance, Drs. Jost Vielmetter and Jennifer Keeffe for setting up automated polyreactivity assays, Dr. Jennifer Keeffe for construct design, and Nicholas Koranda for help with cloning and protein purification. Electron microscopy was performed in the Caltech Beckman Institute Resource Center for Transmission Electron Microscopy with assistance from Dr. Songye Chen. We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support the Molecular Observatory (Dr. Jens Kaiser, director), and Drs. Silvia Russi, Aina Cohen, and Clyde Smith and the beamline staff at SSRL for data collection assistance. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-c76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and\nEnvironmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. This work was supported by NIH grant P01-AI138938-S1 (P.J.B. and M.C.N.), the Caltech Merkin Institute for Translational Research (P.J.B.), NIH grant P50 8 P50 AI150464-13 (P.J.B.), and a George Mason University Fast Grant (P.J.B.). C.O.B was supported by the Hanna Gray Fellowship Program from the Howard Hughes Medical Institute and the Postdoctoral Enrichment Program from the Burroughs Wellcome Fund. M.C.N. is a Howard Hughes Medical Institute Investigator. \n\nAuthor contributions: C.O.B., M.C.N., A.P.W., and P.J.B. conceived the study and analyzed data; D.F.R. and M.C.N. provided monoclonal antibody sequences and plasmids derived from COVID-19 convalescent donors. C.O.B. and K.H.T. performed protein purifications and C.O.B. assembled complexes for cryo-EM and X-ray crystallography studies. C.O.B. performed cryo-EM and interpreted structures with assistance from M.A.E., K.A.D, S.R.E., A.G.M., and N.G.S. C.A.J. and C.O.B. performed and analyzed crystallographic structures, with refinement assistance from M.A.E and K.M.D. Y.E.L. performed polyreactivity assays. H.B.G. performed and analyzed SPR experiments. A.P.W. analyzed antibody sequences. C.O.B., M.C.N., A.P.W., and P.J.B. wrote the paper with contributions from other authors. \n\nCompeting Interest Statement: The Rockefeller University has filed a provisional patent application for monoclonal antibodies described in this work, on which D.F.R. and M.C.N. are inventors. \n\nData availability: The cryo-EM maps and atomic models will be deposited at the EMDB and the PDB. Crystal structure data will be deposited in the PDB. Described materials will be available upon request, in some cases after completion of a materials transfer agreement.\n\nSubmitted - 2020.08.30.273920v1.full.pdf
", "abstract": "The COVID-19 pandemic presents an urgent health crisis. Human neutralizing antibodies (hNAbs) that target the host ACE2 receptor-binding domain (RBD) of the SARS-CoV-2 spike show therapeutic promise and are being evaluated clincally. To determine structural correlates of SARS-CoV-2 neutralization, we solved 8 new structures of distinct COVID-19 hNAbs in complex with SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed classification into categories: (1) VH3-53 hNAbs with short CDRH3s that block ACE2 and bind only to \"up\" RBDs, (2) ACE2-blocking hNAbs that bind both \"up\" and \"down\" RBDs and can contact adjacent RBDs, (3) hNAbs that bind outside the ACE2 site and recognize \"up\" and \"down\" RBDs, and (4) Previously-described antibodies that do not block ACE2 and bind only \"up\" RBDs. Class 2 comprised four hNAbs whose epitopes bridged RBDs, including a VH3-53 hNAb that used a long CDRH3 with a hydrophobic tip to bridge between adjacent \"down\" RBDs, thereby locking spike into a closed conformation. Epitope/paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally-occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects, suggesting combinations for clinical use, and providing insight into immune responses against SARS-CoV-2.", "date": "2020-08-30", "date_type": "published", "id_number": "CaltechAUTHORS:20200908-082702811", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200908-082702811", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Gordon and Betty Moore Foundation" }, { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-76SF00515" }, { "agency": "NIH", "grant_number": "P41GM103393" }, { "agency": "NIH", "grant_number": "P01-AI138938-S1" }, { "agency": "Caltech Merkin Institute for Translational Research" }, { "agency": "NIH", "grant_number": "P50 8 P50 AI150464-13" }, { "agency": "George Mason University" }, { "agency": "Howard Hughes Medical Institute (HHMI)" }, { "agency": "Burroughs Wellcome Fund" } ] }, "local_group": { "items": [ { "id": "Richard-Merkin-Institute" }, { "id": "COVID-19" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2020.08.30.273920", "primary_object": { "basename": "2020.08.30.273920v1.full.pdf", "url": "https://authors.library.caltech.edu/records/bnm3q-sbw29/files/2020.08.30.273920v1.full.pdf" }, "pub_year": "2020", "author_list": "Barnes, Christopher O.; Jette, Claudia A.; et al." }, { "id": "https://authors.library.caltech.edu/records/e5bfa-61p43", "eprint_id": 105083, "eprint_status": "archive", "datestamp": "2023-08-19 22:54:51", "lastmod": "2026-03-30 05:51:51", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Booeshaghi-A-Sina", "name": { "family": "Booeshaghi", "given": "A. Sina" }, "orcid": "0000-0002-6442-4502" }, { "id": "Tan-Fayth-Hui", "name": { "family": "Tan", "given": "Fayth" }, "orcid": "0000-0002-2160-5311" }, { "id": "Renton-Benjamin", "name": { "family": "Renton", "given": "Benjamin" } }, { "id": "Berger-Zackary", "name": { "family": "Berger", "given": "Zackary" }, "orcid": "0000-0002-5871-0342" }, { "id": "Pachter-L", "name": { "family": "Pachter", "given": "Lior" }, "orcid": "0000-0002-9164-6231" } ] }, "title": "Markedly heterogeneous COVID-19 testing plans among US colleges and universities", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. \n\nPosted August 11, 2020. \n\nThe authors have declared no competing interest. \n\nNo external funding was received in support of this project. \n\nAuthor Declarations: I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. \n\nYes. \n\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below: \n\nThis project did not require IRB approval. \n\nAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. \n\nYes. \n\nI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). \n\nYes. \n\nI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. \n\nYes. \n\nData Availability: The database of college and university testing plans is available as a Google Sheet. The code to generate all of the figures and results in the manuscript can be found on Github.\n\nSubmitted - 2020.08.09.20171223v1.full.pdf
", "abstract": "As the COVID-19 pandemic worsens in the United States, colleges that have invited students back for the fall are finalizing mitigation plans to lessen the spread of SARS-CoV-2. Even though students have largely been away from campuses over the summer, several outbreaks associated with colleges have already occurred, foreshadowing the scale of infection that could result from hundreds of thousands of students returning to college towns and cities. While many institutions have released return-to-campus plans designed to reduce viral spread and to rapidly identify outbreaks should they occur, in many cases communications by college administrators have been opaque. To contribute to an evaluation of university preparedness for the COVID-19 pandemic, we assessed a crucial element: COVID-19 on-campus testing. We examined testing plans at more than 500 colleges and universities throughout the US, and collated statistics, as well as narratives from publicly facing websites. We discovered a highly variable and muddled state of COVID-19 testing plans among US institutions of higher education that has been shaped by discrepancies between scientific studies and federal guidelines. We highlight cases of divergence between university testing plans and public health best practices, as well as potential bioethical issues.", "date": "2020-08-11", "date_type": "published", "id_number": "CaltechAUTHORS:20200824-142429940", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200824-142429940", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2020.08.09.20171223", "primary_object": { "basename": "2020.08.09.20171223v1.full.pdf", "url": "https://authors.library.caltech.edu/records/e5bfa-61p43/files/2020.08.09.20171223v1.full.pdf" }, "pub_year": "2020", "author_list": "Booeshaghi, A. Sina; Tan, Fayth; et al." }, { "id": "https://authors.library.caltech.edu/records/mxqck-kff92", "eprint_id": 106740, "eprint_status": "archive", "datestamp": "2023-08-19 22:31:00", "lastmod": "2026-03-29 18:53:23", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Xu-Rong", "name": { "family": "Xu", "given": "Rong" } }, { "id": "Lu-Renfei", "name": { "family": "Lu", "given": "Renfei" } }, { "id": "Zhang-Tao", "name": { "family": "Zhang", "given": "Tao" } }, { "id": "Wu-Qunfu", "name": { "family": "Wu", "given": "Qunfu" } }, { "id": "Cai-Weihua", "name": { "family": "Cai", "given": "Weihua" } }, { "id": "Han-Xudong", "name": { "family": "Han", "given": "Xudong" } }, { "id": "Wan-Zhenzhou", "name": { "family": "Wan", "given": "Zhenzhou" } }, { "id": "Jin-Xia", "name": { "family": "Jin", "given": "Xia" } }, { "id": "Zhang-Zhigang", "name": { "family": "Zhang", "given": "Zhigang" } }, { "id": "Zhang-Chiyu", "name": { "family": "Zhang", "given": "Chiyu" } } ] }, "title": "Temporal dynamics of human respiratory and gut microbiomes during the course of COVID-19 in adults", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \n\nThis version posted July 22, 2020. \n\nThis work was supported by grants from the National Key Research and Development Program of China (2017ZX10103009-002, 2019YFC1200603 and 2018YFC2000500), Special fund for COVID-19 diagnosis and treatment of Nantong Science and Technology Bureau (SFCDT3-2), the Second Tibetan Plateau Scientific Expedition and Research (STEP) program (2019QZKK0503), the Key Research Program of the Chinese Academy of Sciences (FZDSW-219), and the Chinese National Natural Science Foundation (31970571). \n\nData Availability: The raw data of 16S rRNA gene sequences are available at NCBI Sequence Read Archive (SRA) (https://www.ncbi.nlm.nih.gov/sra/) at BioProject ID PRJNA639286. \n\nhttps://www.ncbi.nlm.nih.gov/sra/ \n\n\nThe authors have declared no competing interest. \n\nAuthor Declarations. \nI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. \n\nYes. \n\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:\n\nThe study was approved by Nantong Third Hospital Ethics Committee (EL2020006: 28 February 2020). Written informed consents were obtained from each of the involved individuals. All experiments were performed in accordance with relevant guidelines and regulations. \n\nAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. \n\nYes. \n\nI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). \n\nYes. \n\nI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. \n\nYes.\n\nSupplemental Material - 2020.07.21.20158758-2.xlsx
Supplemental Material - 2020.07.21.20158758-3.xlsx
Supplemental Material - 2020.07.21.20158758-4.xlsx
Supplemental Material - 2020.07.21.20158758v1.full.pdf
", "abstract": "SARS-CoV-2 infects multiple organs including the respiratory tract and gut. Whether regional microbiomes are disturbed significantly to affect the disease progression of COVID-19 is largely unknown. To address this question, we performed cross-sectional and longitudinal analyses of throat and anal swabs from 35 COVID-19 adults and 15 controls by 16S rRNA gene sequencing. The results allowed a partitioning of patients into 3-4 categories (I-IV) with distinct microbial community types in both sites. Lower-diversity community types often appeared in the early phase of COVID-19, and synchronous fast restoration of both the respiratory and gut microbiomes from early dysbiosis towards late near-normal was observed in 6/8 mild COVID-19 adult patients despite they had a relatively slow clinical recovery. The synchronous shift of the community types was associated with significantly positive bacterial interactions between the respiratory tract and gut, possibly along the airway-gut axis. These findings reveal previously unknown interactions between respiratory and gut microbiomes, and suggest that modulations of regional microbiota might help to improve the recovery from COVID-19 in adult patients.", "date": "2020-07-22", "date_type": "published", "id_number": "CaltechAUTHORS:20201119-135010266", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201119-135010266", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Key Research and Development Program of China", "grant_number": "2017ZX10103009-002" }, { "agency": "National Key Research and Development Program of China", "grant_number": "2019YFC1200603" }, { "agency": "National Key Research and Development Program of China", "grant_number": "2018YFC2000500" }, { "agency": "Nantong Science and Technology Bureau", "grant_number": "SFCDT3-2" }, { "agency": "Second Tibetan Plateau Scientific Expedition and Research Program", "grant_number": "2019QZKK0503" }, { "agency": "Chinese Academy of Sciences", "grant_number": "FZDSW-219" }, { "agency": "National Natural Science Foundation of China", "grant_number": "31970571" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2020.07.21.20158758", "primary_object": { "basename": "2020.07.21.20158758v1.full.pdf", "url": "https://authors.library.caltech.edu/records/mxqck-kff92/files/2020.07.21.20158758v1.full.pdf" }, "related_objects": [ { "basename": "2020.07.21.20158758-2.xlsx", "url": "https://authors.library.caltech.edu/records/mxqck-kff92/files/2020.07.21.20158758-2.xlsx" }, { "basename": "2020.07.21.20158758-3.xlsx", "url": "https://authors.library.caltech.edu/records/mxqck-kff92/files/2020.07.21.20158758-3.xlsx" }, { "basename": "2020.07.21.20158758-4.xlsx", "url": "https://authors.library.caltech.edu/records/mxqck-kff92/files/2020.07.21.20158758-4.xlsx" } ], "pub_year": "2020", "author_list": "Xu, Rong; Lu, Renfei; et al." }, { "id": "https://authors.library.caltech.edu/records/bsd7r-k4525", "eprint_id": 109656, "eprint_status": "archive", "datestamp": "2023-08-22 05:42:05", "lastmod": "2026-03-30 22:45:51", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Garza-L\u00f3pez-Roberto-A", "name": { "family": "Garza-L\u00f3pez", "given": "Roberto A." }, "orcid": "0000-0002-9363-1842" }, { "id": "Kozak-John-J", "name": { "family": "Kozak", "given": "John J." } }, { "id": "Gray-H-B", "name": { "family": "Gray", "given": "Harry B." }, "orcid": "0000-0002-7937-7876" } ] }, "title": "Copper(II) Inhibition of the SARS-CoV-2 Main Protease", "ispublished": "unpub", "full_text_status": "public", "keywords": "SARS-CoV-2; Main Protease; Inhibition; Copper(II) ligands; Mpro; HIS 41; CYS 145; 6LU7; 6VXX; Homodimer; Schiff base; AutoDock Vina; Spike Protein; Spike glycoprotein", "note": "The content is available under CC BY NC ND 4.0 License.\n\nJul 21, 2020 Version 1.\n\nWork at Caltech was supported by the Arnold and Mabel Beckman Foundation. Support at\nPomona College was provided by the Howard Hughes Medical Institute Research Program and a\nSontag Research Fellowship Award. Molecular graphics and analyses performed with UCSF\nChimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the\nUniversity of California, San Francisco, with support from NIH P41-GM103311. Molecular\ngraphics and analyses performed with UCSF ChimeraX, developed by the Resource for\nBiocomputing, Visualization, and Informatics at the University of California, San Francisco,\nwith support from National Institutes of Health R01-GM129325 and the Office of Cyber\nInfrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases.\n\nThe author(s) have declared they have no conflict of interest with regard to this content.\n\nThe author(s) have declared ethics committee/IRB approval is not relevant to this content.\n\nSubmitted - copper-ii-inhibition-of-the-sars-co-v-2-main-protease.pdf
", "abstract": "In an analysis of the structural stability of the coronavirus main protease (Mpro), we identified regions of the protein that could be disabled by cobalt(III)-cation binding to histidines and cysteines [1]. Here we have extended our work to include copper(II) chelates, which we have docked to HIS 41 and CYS 145 in the Mpro active-site region. We have found stable docked structures where Cu(II) could readily bond to the CYS 145 thiolate, which would be lethal to the enzyme. We also started studying the Spike Protein, PDB ID: 6VXX and the region around the D614G mutant.", "date": "2020-07-21", "date_type": "published", "publisher": "American Chemical Society", "id_number": "CaltechAUTHORS:20210629-204239084", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210629-204239084", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "Howard Hughes Medical Institute (HHMI)" }, { "agency": "Sontag Foundation" }, { "agency": "NIH", "grant_number": "P41-GM103311" }, { "agency": "NIH", "grant_number": "R01-GM129325" }, { "agency": "National Institute of Allergy and Infectious Diseases" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Division-of-Chemistry-and-Chemical-Engineering" } ] }, "doi": "10.26434/chemrxiv.12673436.v1", "pmcid": "PMC7668746", "primary_object": { "basename": "copper-ii-inhibition-of-the-sars-co-v-2-main-protease.pdf", "url": "https://authors.library.caltech.edu/records/bsd7r-k4525/files/copper-ii-inhibition-of-the-sars-co-v-2-main-protease.pdf" }, "pub_year": "2020", "author_list": "Garza-L\u00f3pez, Roberto A.; Kozak, John J.; et al." }, { "id": "https://authors.library.caltech.edu/records/vxg86-ydj89", "eprint_id": 103463, "eprint_status": "archive", "datestamp": "2023-08-19 21:32:25", "lastmod": "2025-02-01 18:03:06", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Cohen-Bruce-N", "name": { "family": "Cohen", "given": "Bruce N." } }, { "id": "Nichols-Aaron-L", "name": { "family": "Nichols", "given": "Aaron L." }, "orcid": "0000-0001-9341-0049" }, { "id": "Grant-Stephen", "name": { "family": "Grant", "given": "Stephen" }, "orcid": "0000-0003-0923-8886" }, { "id": "Blumenfeld-Zachary", "name": { "family": "Blumenfeld", "given": "Zach" }, "orcid": "0000-0002-4627-5582" }, { "id": "Dougherty-D-A", "name": { "family": "Dougherty", "given": "Dennis A." }, "orcid": "0000-0003-1464-2461" }, { "id": "Alvarez-R-M", "name": { "family": "Alvarez", "given": "R. Michael" }, "orcid": "0000-0002-8113-4451" }, { "id": "Ritz-Beate", "name": { "family": "Ritz", "given": "Beate" }, "orcid": "0000-0001-6976-7339" }, { "id": "Lester-H-A", "name": { "family": "Lester", "given": "Henry A." }, "orcid": "0000-0002-5470-5255" } ] }, "title": "Successful Cessation Programs that Reduce Comorbidity May Explain Surprisingly Low Smoking Rates Among Hospitalized COVID-19 Patients", "ispublished": "unpub", "full_text_status": "public", "note": "Open Access | CC-BY\n\nWe thank Michael H. Kanter (Kaiser Permanente Medical School) and Nora Volkow (NIDA) for comments and suggestions.\n\nSubmitted - Causality_vs_Correlation_Smoking_in_COVID19_v10.5_BNC_5_22_2020.pdf
", "abstract": "A recent, non-peer-reviewed meta-analysis suggests that smoking may reduce the risk of hospitalization with COVID-19 because the prevalence of smoking among hospitalized COVID-19 is less than that of the general population. However, there are alternative explanations for this phenomena based on (1) the failure to report, or accurately record, smoking history during emergency hospital admissions and (2) a pre-disposition to avoid smoking among COVID-19 patients with tobacco-related comorbidities (a type of \"reverse\" causation). For example, urine testing of hospitalized patients in Australia for cotinine showed that smokers were under-counted by 37% because incoming patients failed to inform staff about their smoking behavior. Face-to-face interviews can introduce bias into the responses to attitudinal and behavioral questions not present in the self-completion interviews typically used to measure smoking prevalence in the general population. Subjects in face-to-face interviews may be unwilling to admit socially undesirable behavior and attitudes under direct questioning. Reverse causation may also contribute to the difference between smoking prevalence in the COVID-19 and general population. Patients hospitalized with COVID-19 may be simply less prone to use tobacco than the general population. A potentially robust \"reverse causation\" hypothesis for reduced prevalence of smokers in the COVID-19 population is the enrichment of patients in that population with serious comorbidities that motivates them to quit smoking. We judge that this \"smoking cessation\" mechanism may account for a significant fraction of the reduced prevalence of smokers in the COVID-19 population. Testing this hypothesis will require a focused research program.", "date": "2020-05-26", "date_type": "published", "id_number": "CaltechAUTHORS:20200526-135356434", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200526-135356434", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.32388/WURFH0", "primary_object": { "basename": "Causality_vs_Correlation_Smoking_in_COVID19_v10.5_BNC_5_22_2020.pdf", "url": "https://authors.library.caltech.edu/records/vxg86-ydj89/files/Causality_vs_Correlation_Smoking_in_COVID19_v10.5_BNC_5_22_2020.pdf" }, "pub_year": "2020", "author_list": "Cohen, Bruce N.; Nichols, Aaron L.; et al." }, { "id": "https://authors.library.caltech.edu/records/wpsjb-te013", "eprint_id": 106749, "eprint_status": "archive", "datestamp": "2023-08-19 21:24:42", "lastmod": "2026-03-29 20:20:37", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chour-William", "name": { "family": "Chour", "given": "William" }, "orcid": "0000-0003-1817-0123" }, { "id": "Xu-Alexander-M", "name": { "family": "Xu", "given": "Alexander M." }, "orcid": "0000-0003-4877-4358" }, { "id": "Ng-Alphonsus-H-C", "name": { "family": "Ng", "given": "Alphonsus H. C." }, "orcid": "0000-0003-0074-4598" }, { "id": "Choi-Jongchan", "name": { "family": "Choi", "given": "Jongchan" } }, { "id": "Xie-Jingyi", "name": { "family": "Xie", "given": "Jingyi" } }, { "id": "Yuan-Dan", "name": { "family": "Yuan", "given": "Dan" } }, { "id": "Delucia-Diane-C", "name": { "family": "Delucia", "given": "Diane C." } }, { "id": "Edmark-Rick-A", "name": { "family": "Edmark", "given": "Rick A." } }, { "id": "Jones-Lesley-C", "name": { "family": "Jones", "given": "Lesley C." } }, { "id": "Schmitt-Thomas-M", "name": { "family": "Schmitt", "given": "Thomas M." } }, { "id": "Chaffee-Mary-E", "name": { "family": "Chaffee", "given": "Mary E." } }, { "id": "Duvvuri-Venkata-R", "name": { "family": "Duvvuri", "given": "Venkata R." } }, { "id": "Murray-Kim-M", "name": { "family": "Murray", "given": "Kim M." } }, { "id": "Peng-Songming", "name": { "family": "Peng", "given": "Songming" }, "orcid": "0000-0002-2742-6584" }, { "id": "Wallick-Julie", "name": { "family": "Wallick", "given": "Julie" } }, { "id": "Algren-Heather-A", "name": { "family": "Algren", "given": "Heather A." } }, { "id": "Berrington-William-R", "name": { "family": "Berrington", "given": "William R." } }, { "id": "O'Mahoney-D-Shane", "name": { "family": "O'Mahoney", "given": "D. Shane" } }, { "id": "Lee-John-K", "name": { "family": "Lee", "given": "John K." }, "orcid": "0000-0003-4077-0395" }, { "id": "Greenberg-Philip-D", "name": { "family": "Greenberg", "given": "Philip D." } }, { "id": "Goldman-Jason-D", "name": { "family": "Goldman", "given": "Jason D." }, "orcid": "0000-0002-3825-6832" }, { "id": "Heath-J-R", "name": { "family": "Heath", "given": "James R." }, "orcid": "0000-0001-5356-4385" } ] }, "title": "Shared Antigen-specific CD8\u207a T cell Responses Against the SARS-COV-2 Spike Protein in HLA A*02:01 COVID-19 Participants", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \n\nThis version posted May 8, 2020. \n\nWe acknowledge the Parker Institute for Cancer Immunotherapy, the WA State Andy Hill CARE Foundation, the Wilke Foundation, the M.J. Murdock Charitable Trust, and the Swedish Foundation for generous support of this work. \n\nData Availability: Please contact the ISB data manager for release of data. \n\nCompeting Interest Statement: JRH is a founder and board member of PACT Pharma, which is seeking to commercialize certain of the technologies described here. \n\nAuthor Declarations: \nAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. \n\nYes. \n\nAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. \n\nYes. \n\nI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). \n\nYes. \n\nI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. \n\nYes.\n\nSubmitted - 2020.05.04.20085779v1.full.pdf
Supplemental Material - 2020.05.04.20085779-1.pdf
", "abstract": "We report here on antigens from the SARS-CoV-2 virus spike protein, that when presented by Class I MHC, can lead to cytotoxic CD8\u207a T cell anti-viral responses in COVID-19 patients. We present a method in which the SARS-CoV-2 spike protein is converted into a library of peptide antigen-Major Histocompatibility Complexes (pMHCs) as single chain trimers that contain the peptide antigen, the MHC HLA allele, and the \u03b2-2 microglobulin sub-unit. That library is used to detect the evolution of virus-specific T cell populations from two COVID-19 patients, at two time points over the course of infection. Both patients exhibit similar virus-specific T cell populations, but very different time-trajectories of those populations. These results can be used to track those virus-specific T cell populations over the course of an infection, thus providing deep insight into the variations in immune system trajectories observed in different COVID-19 patients.", "date": "2020-05-08", "date_type": "published", "id_number": "CaltechAUTHORS:20201120-071520503", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201120-071520503", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Parker Institute for Cancer Immunotherapy" }, { "agency": "Washington State Andy Hill CARE Foundation" }, { "agency": "Wilke Family Foundation" }, { "agency": "M. J. Murdock Charitable Trust" }, { "agency": "Swedish Foundation" } ] }, "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2020.05.04.20085779", "primary_object": { "basename": "2020.05.04.20085779-1.pdf", "url": "https://authors.library.caltech.edu/records/wpsjb-te013/files/2020.05.04.20085779-1.pdf" }, "related_objects": [ { "basename": "2020.05.04.20085779v1.full.pdf", "url": "https://authors.library.caltech.edu/records/wpsjb-te013/files/2020.05.04.20085779v1.full.pdf" } ], "pub_year": "2020", "author_list": "Chour, William; Xu, Alexander M.; et al." }, { "id": "https://authors.library.caltech.edu/records/msp7x-hgx37", "eprint_id": 103294, "eprint_status": "archive", "datestamp": "2023-08-19 21:21:24", "lastmod": "2026-03-30 05:36:44", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Jue-Erik", "name": { "family": "Jue", "given": "Erik" }, "orcid": "0000-0001-7585-3794" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Commercial stocks of SARS-CoV-2 RNA may report low concentration values, leading to artificially increased apparent sensitivity of diagnostic assays", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. \n\nThis version posted May 4, 2020. \n\nData Availability: All data will be made available at CaltechDATA upon publication. \n\nCompeting Interest Statement: R.F.I. receives droplet digital PCR patent royalties from Bio-Rad and has a financial interest in Talis Biomedical Corp. \n\nThis work was funded in part by an Innovation in Regulatory Science Award (IRSA) from the Burroughs Wellcome Fund, a grant from the Jacobs Institute for Molecular Engineering for Medicine (Caltech) and NSF Graduate Research Fellowship DGE-144469 (to E.J.). \n\nAuthor Declarations: All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.\n\nSubmitted - 2020.04.28.20077602v1.full.pdf
", "abstract": "In response to the rapidly evolving COVID-19 pandemic, the U.S. Food and Drug Administration (FDA) has rapidly issued 49 emergency use authorizations (EUAs) for SARS-CoV-2 in vitro diagnostic test-kits. A critical metric in the performance evaluation for a diagnostic test kit is the analytical sensitivity, which is measured by the limit of detection (LOD). Commercial RNA stocks with known titers are used to determine LOD. We identified a problem with the titer reported for the commercial stocks when examining the analytical sensitivity of the reverse transcription quantitative PCR (RT-qPCR) protocol that is recommended by the Centers for Disease Control and Prevention (CDC) using plasmid DNA from Integrated DNA Technologies (IDT), synthetic RNA from BEI Resources (BEI), and extracted genomic RNA from BEI. We detected 3/3 positives for reactions containing synthetic RNA at a concentration of 0.1 copies/reaction (based on the supplier's label concentration). The apparent better-than-single-molecule performance is a statistically highly unlikely event, indicating a potential inaccuracy in the supplier's quantification of the stock material. Using an ultrasensitive and precise assay, reverse transcription digital PCR (RT-dPCR), we independently quantified concentrations of commercial SARS-CoV-2 plasmid DNA and SARS-CoV-2 RNA stocks. For plasmid DNA, the actual concentration measured by RT-dPCR was 11% of the nominal label concentration. For synthetic RNA, the actual concentration measured by RT-dPCR for one lot was 770% of the label concentration and for a different lot was 57% of the label concentration. For genomic RNA, the concentration measured by RT-dPCR for one lot was 240% of the label concentration and for a different lot it was 300% of the label concentration. This SARS-CoV-2 genomic RNA from BEI Resources has been used in at least 11 approved FDA Emergency Use Authorizations as of April 27, 2020. Such deviations of reported RNA or DNA stock concentrations from true concentrations can result in inaccurate quantification and calculation of LOD. Precise and accurate reporting of DNA and RNA stock concentrations by commercial suppliers will enable accurate quantification of assay performance, which is urgently needed to improve evaluation of different assays by diagnostic developers and regulatory bodies.", "date": "2020-05-04", "date_type": "published", "id_number": "CaltechAUTHORS:20200519-071416134", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200519-071416134", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Burroughs Wellcome Fund" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-144469" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "COVID-19" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2020.04.28.20077602", "primary_object": { "basename": "2020.04.28.20077602v1.full.pdf", "url": "https://authors.library.caltech.edu/records/msp7x-hgx37/files/2020.04.28.20077602v1.full.pdf" }, "pub_year": "2020", "author_list": "Jue, Erik and Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/2mzma-1yx77", "eprint_id": 106742, "eprint_status": "archive", "datestamp": "2023-08-19 21:00:12", "lastmod": "2026-03-30 06:40:10", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nazeeri-Albert-I", "name": { "family": "Nazeeri", "given": "Albert I." } }, { "id": "Hilburn-Isaac-A", "name": { "family": "Hilburn", "given": "Isaac A." }, "orcid": "0000-0002-5189-3414" }, { "id": "Wu-Daw-An", "name": { "family": "Wu", "given": "Daw-An" }, "orcid": "0000-0003-4296-3369" }, { "id": "Mohammed-Kabir-A", "name": { "family": "Mohammed", "given": "Kabir A." }, "orcid": "0000-0001-8903-6920" }, { "id": "Badal-D-Yovan", "name": { "family": "Badal", "given": "D. Yovan" }, "orcid": "0000-0001-9754-9531" }, { "id": "Chan-Moses-H-W", "name": { "family": "Chan", "given": "Moses H. W." }, "orcid": "0000-0002-9582-527X" }, { "id": "Kirschvink-J-L", "name": { "family": "Kirschvink", "given": "Joseph L." }, "orcid": "0000-0001-9486-6689" } ] }, "title": "Ethanol-Drying Regeneration of N95 Respirators", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \n\nThis version posted July 3, 2020. \n\nFunding Statement: No external funding. \n\nData Availability: All data are available upon request. \n\nThe authors have declared no competing interest. \n\nAuthor Declarations: \nAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. \n\nYes. \n\nAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. \n\nYes. \n\nI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). \n\nYes. \n\nI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. \n\nYes.\n\nSubmitted - 2020.04.12.20059709v1.full.pdf
Submitted - 2020.04.12.20059709v2.full.pdf
", "abstract": "A critical shortage of respirators, masks and other personal protective equipment (PPE) exists due to the COVID-19 pandemic. Of particular need are N95 respirators, which use meltblown microfibers of charged polypropylene. An intensive search is underway to find reliable methods to lengthen the useful life of these normally disposable units. Recent experiments on respirators cleaned with ethanol solutions found drastic post-treatment drops infiltration efficiency (>40%). This has been attributed to a mechanism whereby ethanol disrupts the charges in the microfibers, reducing their ability to trap particles. The CDC/NIOSH has issued guidance directing clinicians and researchers to pursue other methods of decontamination. In our experiments, we replicated the drop in efficiency after 70% ethanol treatment, but we found that the efficiency rose again after more effective drying, which we achieved with a vacuum chamber. After drying at pressures of < ~6 mbar (0.6 kPa), the measured filtering efficiency rose to within 2% of the pre-washing value, and we found that this was sustained for 5 cleaning-drying cycles in three models of N95 masks. We stress that our tests are not meant to certify that the respirators are safe for use, which would require further, standardized, testing under NIOSH protocols. The tests presented here are used to understand basic mechanisms by which treatments can decrease or increase filtration efficiency. The main mechanism underlying the loss and recovery of filter efficiency seems to be the deposition and removal of water molecules adsorbed on the fiber surfaces, a hypothesis which is supported by several observations: (A) the filtering efficiency increases non-linearly with the weight loss during drying. (B) filtration efficiency shows an abrupt recovery as the vacuum pressure drops from 13 to 6 mbar, the range physically attributable to the removal of adsorbed water. (C) Optical microscopy of the microfiber layer reveals surface wetting of the fibers, which is most resistant to drying in dense regions of the fiber network. These observations indicate that losses in filter efficiency may be caused by the wicking of water into the dense fiber networks, reducing the available surface area for filtration. Such a degradation mechanism has two implications: (A) Ethanol and other aqueous decontamination methods may be more viable than previously assumed. Investigations of such methods should specify drying methods in their protocols. We employ vacuum chambers in this study, but other methods of removing adsorbed water could be equivalent. (B) This mechanism presents the possibility that mask filtration performance may be subject to degradation by other sources of moisture, and that the mask would continue to be compromised even if it appears dry. Further research is needed to determine the conditions under which such risks apply, and whether drying should be a routine practice for respirators undergoing extended use. This study introduces a number of methods which could be developed and validated for use in resource-limited settings. As the pandemic continues to spread in rural areas and developing nations, these would allow for local efforts to decontaminate, restore, and test medical masks.", "date": "2020-04-16", "date_type": "published", "id_number": "CaltechAUTHORS:20201119-142640062", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201119-142640062", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "COVID-19" } ] }, "doi": "10.1101/2020.04.12.20059709", "primary_object": { "basename": "2020.04.12.20059709v1.full.pdf", "url": "https://authors.library.caltech.edu/records/2mzma-1yx77/files/2020.04.12.20059709v1.full.pdf" }, "related_objects": [ { "basename": "2020.04.12.20059709v2.full.pdf", "url": "https://authors.library.caltech.edu/records/2mzma-1yx77/files/2020.04.12.20059709v2.full.pdf" } ], "pub_year": "2020", "author_list": "Nazeeri, Albert I.; Hilburn, Isaac A.; et al." }, { "id": "https://authors.library.caltech.edu/records/38zqx-kg397", "eprint_id": 102345, "eprint_status": "archive", "datestamp": "2023-08-19 20:53:33", "lastmod": "2026-03-30 07:10:02", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Booeshaghi-A-Sina", "name": { "family": "Booeshaghi", "given": "A. Sina" }, "orcid": "0000-0002-6442-4502" }, { "id": "Pachter-L", "name": { "family": "Pachter", "given": "Lior" }, "orcid": "0000-0002-9164-6231" } ] }, "title": "Decrease in ACE2 mRNA expression in aged mouse lung", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. \n\nPosted April 05, 2020. \n\nData availability: Raw FASTQ files can be obtained from GSE124872.\n\nSubmitted - 2020.04.02.021451v1.full.pdf
Supplemental Material - media-1.pdf
", "abstract": "Angiotensin-converting enzyme 2 (ACE2) has been identified as a critical receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This has led to extensive speculation on the role of ACE2 in disease severity, and in particular, whether variation in its expression can explain higher mortality in older individuals. We examine this question in mouse lung and show that 24-month old mice have significantly reduced ACE2 mRNA expression relative to 3-month old mice. The differences appear to be localized to ciliated cells.", "date": "2020-04-05", "date_type": "published", "id_number": "CaltechAUTHORS:20200406-101324270", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200406-101324270", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2020.04.02.021451", "primary_object": { "basename": "2020.04.02.021451v1.full.pdf", "url": "https://authors.library.caltech.edu/records/38zqx-kg397/files/2020.04.02.021451v1.full.pdf" }, "related_objects": [ { "basename": "media-1.pdf", "url": "https://authors.library.caltech.edu/records/38zqx-kg397/files/media-1.pdf" } ], "pub_year": "2020", "author_list": "Booeshaghi, A. Sina and Pachter, Lior" } ]