Abstract
Early detection of SARS-CoV-2 infection is critical to reduce asymptomatic and pre-symptomatic spread of COVID-19, curb the spread of viral variants by travelers, and maximize efficacy of therapeutic treatments. We designed a study to evaluate the preferred test sensitivity and sample type (saliva and nasal swab) for detecting early infections of COVID-19. We performed a case-ascertained study to monitor household contacts of individuals recently diagnosed with a SARS-CoV-2 infection. From those individuals, we obtained twice-daily self-collected anterior-nares nasal swabs and saliva samples and quantified SARS-CoV-2 RNA viral loads in those samples using high-sensitivity RT-qPCR and RT-ddPCR assays. We found that SARS-CoV-2 RNA first appears in saliva and then in nasal-swab samples. A high-sensitivity (limit of detection of ~103 copies/mL) RNA test detected SARS-CoV-2 virus in saliva 1.5 to 4.5 days before the viral load in the paired nasal-swab samples exceeded the limit of detection of low-sensitivity tests. It was possible to observe a high (>107-108 copies/mL) viral load in saliva samples while the paired nasal swab was either negative or had low (~103 copies/mL) viral load. Our results indicate that both sampling site and test sensitivity must be considered to ensure early detection of SARS-CoV-2 infection: high-sensitivity tests that use saliva can detect SARS-CoV-2 infection days earlier than low-sensitivity tests that use nasal swabs. Furthermore, early in the infection, low-sensitivity tests that use nasal swabs may miss SARS-CoV-2-positive individuals with very high and potentially infectious viral loads in saliva.
Competing Interest Statement
The authors report grants from the Bill & Melinda Gates Foundation (to RFI), the Ronald and Maxine Linde Center for New Initiatives at the California Institute of Technology (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. 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.
Funding Statement
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. 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 Pre-doctoral Training Program (BLP) fellowships from the Donna and Benjamin M. Rosen Bioengineering Center (Caltech) (T32GM112592).
https://www.medrxiv.org/content/10.1101/2021.04.02.21254771v1
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