Covid-19 in the Phase 3 Trial of mRNA-1273 During the Delta-variant Surge

Baden, L. R.; ElSahly, H. M.; Essink, B.; Follman, D.; Neuzil, K. M.; August, A.; Clouting, H.; Fortier, G.; Deng, W.; Han, S.; Zhao, X.; Leav, B.; Talarico, C.; Girard, B.; Paila, Y.; Tomassini, J. E.; Schodel, F.; Pajon, R.; Zhou, H.; Das, R.; Miller, J.

Abstract Background: Following emergency use authorization in December 2020, the Coronavirus Efficacy (COVE) trial was amended to an open-label phase, where participants were unblinded and those randomized to placebo were offered vaccination. Emergence of the delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with increased incidences of coronavirus disease 2019 (Covid-19) among unvaccinated and vaccinated persons. This exploratory analysis evaluated the incidence and genetic sequences of Covid-19 cases in the ongoing COVE trial during the open-label phase from July-August 2021, when delta-variants surged in the US. Methods: Covid-19 cases identified between July 1, 2021-Aug 27, 2021 in participants initially randomized to mRNA-1273 (vaccinated from July-December 2020) and those initially randomized to the placebo (vaccinated December 2020-April 2021) who received at least one dose and were SARS-CoV-2-negative at baseline in the modified-intent-to treat population were analyzed. Included were Covid-19 cases occurring after 26-Mar-2021 with positive RT-PCR results in nasopharyngeal samples (central lab test) and reported Covid-19 symptoms. Genetic sequencing of Covid-19 cases was also performed. Results: There were 14,746 participants in the earlier mRNA-1273 (mRNA-1273e) group and 11,431 in the later placebo-mRNA1273 (mRNA-1273p) group. Covid-19 cases increased from the start of the open-label phase to July-August 2021. During July and August, 162 Covid-19 cases occurred in the mRNA-1273e group and 88 in the mRNA-1273p group. Of the cases sequenced, 144/149 [97.0%]) in the mRNA-1273 and 86/88 (99%) in the mRNA-1273p groups were attributed to delta. The incidence rate of Covid-19 was lower for the mRNA-1273p (49.0/1000 person-years) versus mRNA-1273e (77.1/1000 person-years) group with a 36.4% (95% CI 17.1%-51.5%) reduction in the observed incidence rates. There were fewer severe Covid-19 cases in the mRNA-1273p (6; 6.2/1000 person-years) than mRNA-1273e (13; 3.3/1000 person-years) groups with an estimated 46.0% (95% CI -52.4%-83.2%) reduction of the observed incidence rate for later versus earlier vaccinations during July-August. Three Covid-19 related hospitalizations occurred with two resulting deaths in the mRNA-1273e group. Conclusion: Incidence rates of Covid-19 and severe Covid-19 were lower during the months when delta was the dominant variant (July/August 2021) among COVE participants vaccinated more recently. Analysis of COVID-19 cases from the open-label phase of the COVE study is ongoing.