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. 2024 May 1;7(5):e2412835.
doi: 10.1001/jamanetworkopen.2024.12835.

SARS-CoV-2 Viral Load in the Nasopharynx at Time of First Infection Among Unvaccinated Individuals: A Secondary Cross-Protocol Analysis of 4 Randomized Trials

Leigh H Fisher  1 , Jia Jin Kee  1 , Albert Liu  2 , Claudia M Espinosa  3 , April K Randhawa  1 , James Ludwig  1 , Craig A Magaret  1 , Samuel T Robinson  1 , Peter B Gilbert  1 , Ollivier Hyrien  1 , James G Kublin  1 , Nadine Rouphael  4 , Ann R Falsey  5 , Magdalena E Sobieszczyk  6 , Hana M El Sahly  7 , Beatriz Grinsztejn  8 , Glenda E Gray  9 , Karen L Kotloff  10 , Cynthia L Gay  11 , Brett Leav  12 , Ian Hirsch  13 , Frank Struyf  14 , Lisa M Dunkle  15 , Kathleen M Neuzil  16 , Lawrence Corey  1 , Yunda Huang  1 , Paul A Goepfert  17 , Stephen R Walsh  18 , Lindsey R Baden  18 , Holly Janes  1 ; COVID-19 Prevention Network (CoVPN)
Collaborators, Affiliations

SARS-CoV-2 Viral Load in the Nasopharynx at Time of First Infection Among Unvaccinated Individuals: A Secondary Cross-Protocol Analysis of 4 Randomized Trials

Leigh H Fisher et al. JAMA Netw Open. .

Abstract

Importance: SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity.

Objective: To characterize VL at COVID-19 diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease.

Design, setting, and participants: This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax. Participants were SARS-CoV-2 negative at baseline and acquired COVID-19 during the blinded phase of the trials. The setting included the US, Brazil, South Africa, Colombia, Argentina, Peru, Chile, and Mexico; start dates were July 27, 2020, to December 27, 2020; data cutoff dates were March 26, 2021, to July 30, 2021. Statistical analysis was performed from November 2022 to June 2023.

Main outcomes and measures: Linear regression was used to assess the association of demographic and clinical characteristics, viral variant, and trial with polymerase chain reaction-measured log10 VL in nasal and/or nasopharyngeal swabs taken at the time of COVID-19 diagnosis.

Results: Among 1667 participants studied (886 [53.1%] male; 995 [59.7%] enrolled in the US; mean [SD] age, 46.7 [14.7] years; 204 [12.2%] aged 65 years or older; 196 [11.8%] American Indian or Alaska Native, 150 [9%] Black or African American, 1112 [66.7%] White; 762 [45.7%] Hispanic or Latino), median (IQR) log10 VL at diagnosis was 6.18 (4.66-7.12) log10 copies/mL. Participant characteristics and viral variant explained only 5.9% of the variability in VL. The independent factor with the highest observed differences was trial: Janssen participants had 0.54 log10 copies/mL lower mean VL vs Moderna participants (95% CI, 0.20 to 0.87 log10 copies/mL lower). In the Janssen study, which captured the largest number of COVID-19 events and variants and used the most intensive post-COVID surveillance, neither VL at diagnosis nor averaged over days 1 to 28 post diagnosis was associated with COVID-19 severity.

Conclusions and relevance: In this study of placebo recipients from 4 randomized phase 3 trials, high variability was observed in SARS-CoV-2 VL at the time of COVID-19 diagnosis, and only a fraction was explained by individual participant characteristics or viral variant. These results suggest challenges for future studies of interventions seeking to influence VL and elevates the importance of standardized methods for specimen collection and viral load quantitation.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Liu reported grants from Gilead Sciences and Viiv Healthcare to his institution, and from Gilead Sciences Study drug donation for studies outside the submitted work. Dr Espinosa reported grants from Moderna and Novavax outside the submitted work. Dr Robinson reported grants from NIH to his institution during the conduct of the study. Dr Rouphael reported personal fees from advisory boards of Sanofi, Moderna, Seqirus, and Pfizer; grants from Sanofi, Merck, Pfizer, and VaxCo; and personal fees from ICON, CyanVac and EMMES for serving as a safety consultant during the conduct of the study. Dr Falsey reported grants from NIH during the conduct of the study; grants from Janssen, Pfizer, Merck, BioFire Diagnostics, VaxCo, CyanVac, and Moderna; received travel compensation from GSK, personal fees from Sanofi Pasteur Advisory Board, and personal fees from ADMA Scientific Board outside the submitted work. Dr Sobieszczyk reported grants from Merck Sharpe, Dohme, Sanofi, Gilead, and Gates Foundation to the institution outside of the submitted work. Dr El Sahly reported grants from NIAID during the conduct of the study. Dr Kotloff reported grants from NIAID to her institution during the conduct of the study; grants from Novavax to her institution outside the submitted work. Dr Gay reported grants from the University of North Carolina at Chapel Hill during the conduct of the study. Dr Leav reported employment from Moderna during the conduct of the study and outside the submitted work. Dr Hirsch employment and stock ownership from AstraZeneca during the conduct of the study. Dr Struyf reported employment and stock ownership from Johnson & Johnson during the conduct of the study; other from GlaxoSmithKline stock ownership outside the submitted work; and funding by BARDA and support from NIH/NIAID for the trials discussed in the manuscript (please see the corresponding author for details). Dr Dunkle reported personal fees from Novavax (employee) during the conduct of the study. Dr Neuzil reported grants from NIH during the conduct of the study. Dr Goepfert reported a patent for COVID-19 monoclonal antibody issued by Aridis. Dr Walsh reported grants from NIH/NIAID, nonfinancial support from Sanofi Pasteur, grants from Moderna, grants from Sanofi Pasteur, and grants from Janssen Vaccines during the conduct of the study; personal fees from BioNTech (IDMC member), personal fees from Janssen Vaccines (IDMC chair), grants from Pfizer, grants from Worcester HIV Vaccine, and grants from VIR Biotechnology outside the submitted work; and spouse holds stock and stock options in Regeneron Pharmaceuticals. Dr Baden reported grants from NIH funding during the conduct of the study; and Dr Baden is involved in HIV and COVID-19 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network (HVTN), COVID Vaccine Prevention Network (CoVPN), International AIDS Vaccine Initiative (IAVI), Crucell/Janssen, Moderna, Military HIV Research Program (MHRP), Gates Foundation, and the Ragon Institute. Dr Janes reported grants from NIH during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Overview of Study and Analysis Cohorts
The study cohort consisted of participants randomized to the placebo group of each of the 4 US government–sponsored, phase 3 vaccine efficacy trials who were SARS-CoV-2 negative at baseline and went on to have a primary end point COVID-19 infection. Those participants with viral load data from diagnosis (ie, the first illness-associated polymerase chain reaction [PCR] test) were included in the analysis cohort, including those with negative PCR swabs. CoVPN indicates COVID Vaccine Prevention Network.
Figure 2.
Figure 2.. Protocol-Specific Individual-Level SARS-CoV-2 Viral Load Data Over Illness Visits
Blue dots denote individual viral load values based on nasal and/or nasopharyngeal (NP) swabs; gray lines connect results from the same participant. Orange curves are smooth estimates using locally estimated scatterplot smoothing and summarize viral load trends based on nasal and/or NP swabs. Moderna collected saliva swabs post–COVID-19 onset, which are not shown given the focus on viral load based on nasal/NP swabs. aCOVID-19 onset was defined in each parent protocol: the date of first positive polymerase chain reaction (PCR) test (AstraZeneca), symptom onset (Janssen), the earlier of the 2 (Novavax), or the later of the 2 (Moderna). Thus, for Janssen and Moderna some PCR-positive tests prior to COVID-19 onset were observed.
Figure 3.
Figure 3.. SARS-CoV-2 Viral Load in Nasopharyngeal Swab at COVID-19 Diagnosis by Trial, COVID-19 Severity, SARS-CoV-2 Variant, and Days Since COVID-19 Onset
At the bottom of each panel, the number and percentage of participants with detectable viral load (>0 copies/mL) at diagnosis are provided. In panel C, colors indicate the highest level of World Health Organization designation: dark blue for the ancestral variant, red for variants of concern, light blue for variants of interest, and gray for those missing sequence. In panel D, COVID-19 onset was defined in each parent protocol: the date of first positive polymerase chain reaction (PCR) test (AstraZeneca), symptom onset (Janssen), the earlier of the 2 (Novavax), or the later of the 2 (Moderna). Thus, for Janssen and Moderna there were some PCR-positive tests prior to COVID-19 onset.
Figure 4.
Figure 4.. Estimated Mean Differences in SARS-CoV-2 Viral Load in Nasal and/or Nasopharyngeal (NP) Swabs at COVID-19 Diagnosis, Based on Multivariate Model
Forest plot illustrating estimated mean difference in log10 copies/mL SARS-CoV-2 viral load between groups defined by participant or COVID-19 characteristics; 95% CIs and Holm-adjusted P values are provided.
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