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.

Immune Correlates Analysis of a Single Ad26.COV2.S Dose in the ENSEMBLE COVID-19 Vaccine Efficacy Clinical Trial

“…Whereas in ENSEMBLE evidence was strongest for the nAb ID50 marker as a correlate, in COVE the three antibody markers had similar evidence levels as correlates, all passing the pre-specified multiplicity correction bar. Furthermore, similar vaccine efficacy by nAb ID50 curves were observed in ENSEMBLE-US and COVE, and in both trials the vast majority of circulating strains were similar to the reference strain 1,2,31 (which was used in the nAb assay). This generates the hypothesis that the most transportable correlate across vaccine platforms may involve assessing nAbs against circulating strains, which can be evaluated in the future based on additional data from ENSEMBLE and from other COVID-19 vaccine efficacy trials.…”

SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: A randomized trial

“…The MMRM model included data from all visits until EOT with the following covariates: treatment, visit, baseline value (log10 copies per mL), risk factor (high risk yes/no), center, and treatment by visit interaction; unstructured covariance matrix were used thus allowing adjustment for correlations between the time points within subjects. 11 …”

Anti-nucleocapsid antibodies following SARS-CoV-2 infection in the blinded phase of the mRNA-1273 Covid-19 vaccine efficacy clinical trial

“…Anti-N seropositivity correlated with illness visit SARS-CoV-2 viral copy number, with each log increase in viral copy number nearly doubling the odds of anti-N seropositivity at the PDV. As the viral copy number on the day of the illness visit in mRNA-1273 vaccinated Covid-19 cases has been shown to be 100-fold lower than that in placebo recipient Covid-19 cases, 9 the lower anti-N seropositivity in the mRNA-1273 recipients could be partly explained by their reduced exposure to N-antigen. However, strong vaccine effects remain; at 2.0 log 10 copies/ml the predicted probability of seroconversion was 0.15 for vaccinated Covid-19-cases compared to 0.71 for placebo recipient Covid-19 cases.…”

“…In Covid-19 cases, viral copy number was assessed at the illness visits Day 1, 3, 5, 7, 9, 14, 21, and 28 by SARS-CoV-2 RT–qPCR and conversion of cycle-threshold (Ct) values to viral genome copy number. 9 Illness visit day 1 was by swab and other illness days by saliva.…”