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Quantitative SARS-CoV-2 Viral-Load Curves in Paired Saliva Samples and Nasal Swabs Inform Appropriate Respiratory Sampling Site and Analytical Test Sensitivity Required for Earliest Viral Detection

Savela, Emily S. and Winnett, Alexander Viloria and Romano, Anna E. and Porter, Michael K. and Shelby, Natasha and Akana, Reid and Ji, Jenny and Cooper, Matthew M. and Schlenker, Noah W. and Reyes, Jessica A. and Carter, Alyssa M. and Barlow, Jacob T. and Tognazzini, Colten and Feaster, Matthew and Goh, Ying-Ying and Ismagilov, Rustem F. (2022) Quantitative SARS-CoV-2 Viral-Load Curves in Paired Saliva Samples and Nasal Swabs Inform Appropriate Respiratory Sampling Site and Analytical Test Sensitivity Required for Earliest Viral Detection. Journal of Clinical Microbiology, 60 (2). Art. No. e01785-21. ISSN 0095-1137. PMCID PMC8849374; PMC8043477. doi:10.1128/JCM.01785-21.

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Early detection of SARS-CoV-2 infection is critical to reduce asymptomatic and presymptomatic transmission, curb the spread of variants, and maximize treatment efficacy. Low-analytical-sensitivity nasal-swab testing is commonly used for surveillance and symptomatic testing, but the ability of these tests to detect the earliest stages of infection has not been established. In this study, conducted between September 2020 and June 2021 in the greater Los Angeles County, California, area, initially SARS-CoV-2-negative household contacts of individuals diagnosed with COVID-19 prospectively self-collected paired anterior-nares nasal-swab and saliva samples twice daily for viral-load quantification by high-sensitivity reverse-transcription quantitative PCR (RT-qPCR) and digital-RT-PCR assays. We captured viral-load profiles from the incidence of infection for seven individuals and compared diagnostic sensitivities between respiratory sites. Among unvaccinated persons, testing saliva with a high-analytical-sensitivity assay detected infection up to 4.5 days before viral loads in nasal swabs reached concentrations detectable by low-analytical-sensitivity nasal-swab tests. For most participants, nasal swabs reached higher peak viral loads than saliva but were undetectable or at lower loads during the first few days of infection. High-analytical-sensitivity saliva testing was most reliable for earliest detection. Our study illustrates the value of acquiring early (within hours after a negative high-sensitivity test) viral-load profiles to guide the appropriate analytical sensitivity and respiratory site for detecting earliest infections. Such data are challenging to acquire but critical to designing optimal testing strategies with emerging variants in the current pandemic and to respond to future viral pandemics.

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URLURL TypeDescription Paper CentralArticle CentralDiscussion Paper ItemData
Savela, Emily S.0000-0001-9614-4276
Winnett, Alexander Viloria0000-0002-7338-5605
Romano, Anna E.0000-0003-1871-1727
Porter, Michael K.0000-0002-0777-7563
Shelby, Natasha0000-0001-9097-3663
Akana, Reid0000-0003-4422-587X
Ji, Jenny0000-0002-7901-5605
Cooper, Matthew M.0000-0002-5868-5159
Schlenker, Noah W.0000-0002-8581-4403
Reyes, Jessica A.0000-0002-5507-7633
Carter, Alyssa M.0000-0002-2776-9421
Barlow, Jacob T.0000-0002-1842-4835
Feaster, Matthew0000-0001-9966-2845
Goh, Ying-Ying0000-0001-5136-7214
Ismagilov, Rustem F.0000-0002-3680-4399
Alternate Title:SARS-CoV-2 is detectable using sensitive RNA saliva testing days before viral load reaches detection range of low-sensitivity nasal swab tests
Additional Information:© 2022 Savela et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Received 24 August 2021; Returned for modification 21 September 2021; Accepted 10 December 2021; Accepted manuscript posted online 15 December 2021; Published 16 February 2022. We thank Lauriane Quenee, Junie Hildebrandt, Grace Fisher-Adams, 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, Jessica Slagle, Mika Walton, Angel Navarro, Daniel Brenner, and Ojas Pradhan for volunteering their time to help with this study, Si Hyung Jin for helping with a literature review, and Mary Arrastia for providing biosafety support. We thank Maira Phelps, Lienna Chan, Lucy Li, Dan Lu, and Amy Kistler at the Chan Zuckerberg Biohub for performing SARS-CoV-2 sequencing. We thank Angie Cheng, Susan Magdaleno, Christian Kis, Monica Herrera, and Zaina Lemeir for technical discussions regarding saliva extraction and ddPCR detection. We thank Jennifer Fulcher, Debika Bhattacharya, and Matthew Bidwell Goetz for their ideas on potential study populations and early study design. We thank Omai Garner and David Beenhouwer for providing materials for initial nasal-swab validation. We thank Martin Hill, Alma Sanchez, Scott Kim, Debbie Noble, Nina Paddock, Whitney Harrison, Emily Holman, Isaac Turner, Vivek Desai, Luke Wade, Tom Mayell, Stu Miller, and Jennifer Howes for their support with recruitment. We thank Allison Rhines, Karen Heichman, and Dan Wattendorf for valuable discussions. Finally, we thank all the case investigators and contact tracers at the Pasadena Public Health Department and the City of Long Beach Department of Health & Human Services for their efforts in study recruitment and their work in the pandemic response. R.F.I. is a cofounder, consultant, and a director and has stock ownership of Talis Biomedical Corp. In addition, R.F.I. is an inventor on a series of patents licensed by the University of Chicago to Bio-Rad Laboratories, Inc., in the context of ddPCR. This 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. A.V.W. is supported by a National Institutes of Health NIGMS predoctoral training grant (GM008042) and a UCLA DGSOM Geffen fellowship; M.M.C. is supported by a Caltech graduate student fellowship, and M.K.P. and J.T.B. are each partially supported by a National Institutes of Health Biotechnology Leadership Predoctoral Training Program (BLP) fellowship from Caltech’s Donna and Benjamin M. Rosen Bioengineering Center (T32GM112592).
Group:COVID-19, Rosen Bioengineering Center, Jacobs Institute for Molecular Engineering for Medicine
Funding AgencyGrant Number
Bill and Melinda Gates FoundationINV-023124
Ronald and Maxine Linde Center for New InitiativesUNSPECIFIED
Jacobs Institute for Molecular Engineering for MedicineUNSPECIFIED
NIH Predoctoral FellowshipGM008042
Donna and Benjamin M. Rosen Bioengineering CenterUNSPECIFIED
NIH Predoctoral FellowshipT32GM112592
Subject Keywords:RT-qPCR, COVID-19, case-ascertained, diagnostics, household study, longitudinal sampling, nasal swab, presymptomatic, saliva, surveillance, transmission
Issue or Number:2
PubMed Central ID:PMC8849374; PMC8043477
Record Number:CaltechAUTHORS:20210407-080559241
Persistent URL:
Official Citation:Savela ES, Viloria Winnett A, Romano AE, Porter MK, Shelby N, Akana R, Ji J, Cooper MM, Schlenker NW, Reyes JA, Carter AM, Barlow JT, Tognazzini C, Feaster M, Goh YY, Ismagilov RF. Quantitative SARS-CoV-2 Viral-Load Curves in Paired Saliva Samples and Nasal Swabs Inform Appropriate Respiratory Sampling Site and Analytical Test Sensitivity Required for Earliest Viral Detection. J Clin Microbiol. 2022 Feb 16;60(2):e0178521. doi: 10.1128/JCM.01785-21.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108641
Deposited By: Tony Diaz
Deposited On:08 Apr 2021 22:13
Last Modified:31 May 2022 18:49

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