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Quantitative SARS-CoV-2 viral-load curves in paired saliva and nasal swabs inform appropriate respiratory sampling site and analytical test sensitivity required for earliest viral detection

Savela, Emily S. and Winnett, Alexander 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. (2021) Quantitative SARS-CoV-2 viral-load curves in paired saliva and nasal swabs inform appropriate respiratory sampling site and analytical test sensitivity required for earliest viral detection. . (Unpublished)

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Early detection of SARS-CoV-2 infection is critical to reduce asymptomatic and pre-symptomatic transmission, curb the spread of variants by travelers, and maximize treatment efficacy. Low-sensitivity nasal-swab testing (antigen and some nucleic-acid-amplification tests) is commonly used for surveillance and symptomatic testing, but the ability of low-sensitivity nasal-swab tests to detect the earliest stages of infection has not been established. In this case-ascertained study, 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 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, high-sensitivity saliva testing detected infection up to 4.5 days before viral loads in nasal swabs reached the limit of detection of low-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-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 design optimal testing strategies in the current pandemic and will be required for responding to future viral pandemics. As new variants and viruses emerge, up-to-date data on viral kinetics are necessary to adjust testing strategies for reliable early detection of infections.

Item Type:Report or Paper (Discussion Paper)
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URLURL TypeDescription Paper ItemData
Savela, Emily S.0000-0001-9614-4276
Winnett, Alexander0000-0002-7338-5605
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
Carter, Alyssa M.0000-0002-2776-9421
Barlow, Jacob T.0000-0002-1842-4835
Feaster, Matthew0000-0001-9966-2845
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: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. Version 1 - April 7, 2021; Version 2 - August 26, 2021. 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 discussion and guidance. 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. 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. AW 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 MP and JTB are each partially supported by National Institutes of Health Biotechnology Leadership Predoctoral Training Program (BLP) fellowship from Caltech’s Donna and Benjamin M. Rosen Bioengineering Center (T32GM112592). Data Availability: Data are available on CaltechDATA at Author Declarations: I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes. The details of the IRB/oversight body that provided approval or exemption for the research described are given below: California Institute of Technology IRB All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes. I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as 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). Yes. I 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. Yes. Competing Interests Statement: RFI is a co-founder, consultant, and a director and has stock ownership of Talis Biomedical Corp. In addition, RFI is an inventor on a series of patents licensed by the University of Chicago to Bio-Rad Laboratories Inc. in the context of ddPCR.
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:COVID-19; Saliva; Nasal swab; Diagnostics; Pre-Symptomatic; Surveillance; RT-qPCR; Longitudinal sampling; Case-ascertained; Household study; Transmission
Record Number:CaltechAUTHORS:20210407-080559241
Persistent URL:
Official Citation:Quantitative SARS-CoV-2 viral-load curves in paired saliva and nasal swabs inform appropriate respiratory sampling site and analytical test sensitivity required for earliest viral detection. Emily S. Savela, Alexander Winnett, Anna E. Romano, Michael K. Porter, Natasha Shelby, Reid Akana, Jenny Ji, Matthew M. Cooper, Noah W. Schlenker, Jessica A. Reyes, Alyssa M. Carter, Jacob T. Barlow, Colten Tognazzini, Matthew Feaster, Ying-Ying Goh, Rustem F. Ismagilov. medRxiv 2021.04.02.21254771; doi:
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:30 Aug 2021 22:41

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