Initial analysis of viral dynamics and circulating viral variants during the mRNA-1273 Phase 3 COVE trial

Abstract

The mRNA-1273 vaccine for coronavirus disease 2019 (COVID-19) demonstrated 93.2% efficacy in reduction of symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the blinded portion of the Phase 3 Coronavirus Efficacy (COVE) trial. While mRNA-1273 demonstrated high efficacy in prevention of COVID-19, including severe disease, its effect on the viral dynamics of SARS-CoV-2 infections is not understood. Here, in exploratory analyses, we assessed the impact of mRNA-1273 vaccination in the ongoing COVE trial (number NCT04470427) on SARS-CoV-2 copy number and shedding, burden of disease and infection, and viral variants. Viral variants were sequenced in all COVID-19 and adjudicated COVID-19 cases (n = 832), from July 2020 in the blinded part A of the study to May 2021 of the open-label part B of the study, in which participants in the placebo arm started to receive the mRNA-1273 vaccine after US Food and Drug Administration emergency use authorization of mRNA-1273 in December 2020. mRNA-1273 vaccination significantly reduced SARS-CoV-2 viral copy number (95% confidence interval) by 100-fold on the day of diagnosis compared with placebo (4.1 (3.4-4.8) versus 6.2 (6.0-6.4) log10 copies per ml). Median times to undetectable viral copies were 4 days for mRNA-1273 and 7 days for placebo. Vaccination also substantially reduced the burden of disease and infection scores. Vaccine efficacies (95% confidence interval) against SARS-CoV-2 variants circulating in the United States during the trial assessed in this post hoc analysis were 82.4% (40.4-94.8%) for variants Epsilon and Gamma and 81.2% (36.1-94.5%) for Epsilon. The detection of other, non-SARS-CoV-2, respiratory viruses during the trial was similar between groups. While additional study is needed, these data show that in SARS-CoV-2-infected individuals, vaccination reduced both the viral copy number and duration of detectable viral RNA, which may be markers for the risk of virus transmission.

Conflict of interest statement

L.R.B. reports grants from NIH/NIAID for the conduct of this study. H.M.E.S. reports grants from NIH during the conduct of the study. I.F. reports receiving research grants from Janssen Pharmaceuticals and Sanofi. E.K. is an employee and founder of Altitude Clinical Consulting and former employee of Crisor LLC, and has consulted, served on advisory boards or received travel reimbursement from Amphastar, AstraZeneca, Boehringer Ingelheim, Chiesi, Connect Biopharma, GlaxoSmithKline, Mylan, Novartis, Sunovion and Theravance. B.E., D.D. and K.M.M. declare no competing interests. R.P., Y.D.P., B.G., G.D., X.Z., B.D., W.D., H.Z. and B.L. report being employees of Moderna, Inc. and may hold stock/stock options in that company. K.K., J.E.T. and F.S. are Moderna consultants.

© 2022. The Author(s).

Figures

Fig. 1. Viral copy and shedding analysis population.

Included in the analysis were participants in the PP population who were SARS-CoV-2 negative by both binding antibody against NP (ROCHE Elecsys) and RT–PCR at baseline and day 29, and negative for binding antibody against NP (ROCHE Elecsys) at day 57 (ref. ). The analysis was limited to adjudicated COVID-19 cases in the blinded portion of the study—that is, before unblinding or the data cutoff date of 26 March 2021, based on a database lock on 4 May 2021.

Fig. 2. Reduction in SARS-CoV-2 viral copy number for mRNA-1273 compared with placebo.

a,b, The number of viral copies (a) and reduction in number of viral copies (b) was assessed on the basis of SARS-CoV-2 RT–PCR Ct values converted to viral copy number (Methods). MMRM analysis was performed comparing absolute and change from baseline log10 viral copy between vaccinated and placebo participants, based on data from nasopharyngeal swabs at day 1 of illness and saliva samples at days 3, 5, 7, 9, 14, 21 and 28 of illness. Adjudicated cases in the blinded portion of the study were included. mRNA participants (n = 36) comprised 29 with first illness visits and 7 with second illness visits. Placebo participants (n = 595) included 527 cases from first illness visits and 61, 5 and 2 for second, third and fourth illness visits, respectively. a, Solid lines represent placebo (red) and mRNA-1273 (blue) and dotted lines correspondingly denote 95% CIs. b, Difference between mRNA-1273 and placebo participants in viral copies (log10, black solid line) and 95% CI (dotted lines).

Fig. 3. Spike-sequence-associated lineages found among COVE trial participants.

a–c, Summary of selected spike-sequence-associated lineages found among COVE trial participants (regardless of symptoms) between July 2020 and May 2021. a, Number of sequences in the clinical dataset. b, Percentage of assigned lineages in the clinical dataset. c, Percentage of lineages circulating in the United States over the same period (time-matched sequence set) obtained from GISAID,.

Fig. 4. Respiratory pathogens detected in the COVE study, by month.

a,b, Respiratory pathogen sequences detected from August 2020 to June 2021 in samples from all participant illness visits. a, Number of positive samples. b, Percentage of pathogens detected.

Extended Data Fig. 1. Viral copy number by age groups.

Viral copy number (log10) in participants ≥18-<65 years (a) and ≥65 years (b) at the indicated illness day visits for placebo and mRNA-1273. Summary of log10 viral copies and mean and standard errors of the mean (SEM) for a and b plots (c).

Extended Data Fig. 2. Time to undetectable SARS-CoV-2 viral copies.

Survival probability of time to undetectable SARS-CoV-2 log10 viral copies for participants in placebo and mRNA-1273 groups (a). Dotted lines represent medians (days) for placebo (7) and mRNA-1273 (4). Tick marks indicate censored data. Nasopharyngeal swabs at day 1 of illness and saliva samples at days 3, 5, 7, 9, 14, 21, and 28 of illness. Lower limit of quantitation: <2.9 log10 copies/ml for saliva samples. Medians of time (days) to undetectable SARS-CoV-2 viral copies in (b).

Extended Data Fig. 3. Viral copy number of variants first detected in California.

Mean viral copy number (log10) of variants detected in participants over illness visit days (a) and summary of the means and standard errors of the mean (SEM) (b).