key: cord-0985894-1c5qn3pu
authors: 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.
title: Covid-19 in the Phase 3 Trial of mRNA-1273 During the Delta-variant Surge
date: 2021-09-22
journal: medRxiv : the preprint server for health sciences
DOI: 10.1101/2021.09.17.21263624
sha: 8591b4a4d4ae68d740751c2d10d7f80bd14cc308
doc_id: 985894
cord_uid: 1c5qn3pu

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.

Lindsey R. Baden*, M.D., 1 Hana M. El Sahly*, M.D., 2 Brandon Essink, M.D., 3 Dean Follmann, Ph.D., 4 Kathleen M. Neuzil, M.D., 5 Allison August, M.D., 6 Heather Clouting, MSc., 6 Gabrielle Fortier, MPH., 6 Weiping Deng, Ph.D., 6 Following emergency use authorization (EUA) of the mRNA-1273 Covid-19 vaccine on 18-Dec-2020, the observer-blind, pivotal Coronavirus Efficacy (COVE) trial was amended to an openlabel phase, where participants were unblinded and those randomized to placebo were offered vaccination. 1, 2 The surveillance of Covid-19 through the protocol-defined illness visits remained unchanged through the open label phase. The emergence of the delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the US was associated with increased incidence of Covid-19 in the community among unvaccinated as well as vaccinated persons. [3] [4] [5] Herein we describe Covid-19 incidences during a portion of the open-label phase 01July through 27-August-2021, in participants initially randomized to the mRNA-1273 group (vaccinated from July-December 2020) and those initially randomized to the placebo group (vaccinated December 2020-April 2021) in the modified-intent-to treat (mITT) population. Included in this analysis were 14,746 participants in the earlier mRNA-1273 (mRNA-1273e) group and 11,431 in the later placebo-mRNA-1273 (mRNA-1273p) group. The baseline characteristics of the participants were similar between the groups except for the fraction of participants ≥65 years of age, and healthcare workers (Table S1 ). Median follow-up times from the first dose were 13 months in the mRNA-1273e (including double-blind and open-label phases) and 7.9 months in the mRNA-1273p (only open-label phase) groups.

Covid-19 cases from the beginning of the open-label phase through June 2021 were low with an increase observed in July and August 2021 (Fig. S1 ). The greatest numbers of cases were observed in Texas, Florida and California (Table S2) . While an increased number of breakthrough cases occurred during the open-label period, the incidence rates of Covid-19 starting after the second dose of mRNA-1273 in the trial were overall low for the mRNA-1273e (19.6) cases/1000 person-year, and much lower than the placebo group during the blinded study phase (134) ( Table S3 ). During July and August, 162 Covid-19 cases occurred in the mRNA-1273e group and 88 in the mRNA-1273p group (Table 1 and Fig. S2 ). Of the cases sequenced, 144/149 (97%) in the mRNA-1273e and 86/87 (99%) in the mRNA-1273p groups were caused by the delta variant (Table S4 ). The incidence rate of Covid-19 was lower among the mRNA-1273p (49.0/1000 person-years) group than the mRNA-1273e (77.1/1000 person-years) group with a 36.4% (95% CI 17.1%-51.5%) reduction in the observed incidence rates. Incidence rates reductions were more pronounced in the younger than the older age groups. Similar results were seen using an adjusted Cox proportional model (Table S5 ). All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. There were 13 protocol-specified severe Covid-19 cases in the mRNA-1273e (6.2/1000 person-years) and 6 (3.3/1000 person-years) in the mRNA-1273p groups with an estimated 46.0% (95% CI -52.4%-83.2%) reduction of the observed incidence rate for later compared with earlier vaccinations during July-August (Table 1 ). There were three Covid-19 related hospitalizations all in the mRNA-1273e group, two of which resulted in death, both in men ≥70 years of age with medical comorbidities more than 10 months after vaccination (Table S6) .

Overall, lower incidence rates of Covid-19 and fewer severe Covid-19 cases were 

This is an exploratory analysis of the previously reported phase 3, randomized, observerblind, placebo-controlled Coronavirus Efficacy (COVE) trial that enrolled medically stable adults at 99 US sites (clintrials.gov NCT04470427). 1,2 Eligible participants included adults 18 years or older with no known history of SARS-CoV-2 infection, whose circumstances put them at appreciable risk for SARS-CoV-2 infection and/or high risk of severe Covid-19. Participants

The primary endpoint was vaccine efficacy of mRNA-1273 at preventing a first occurrence of symptomatic preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Limitations of this analysis include a differential distribution between the mRNA-1273e and mRNA-1273p groups due to the amended study from a blinded to open-label phase and cross-over of placebo participants, and lack of randomization. While there also exists a potential for bias attributed to differences in the risk of those remaining on the study; the demographics suggest a general balance in group characteristics between the groups. Although the findings are based on an analysis of incidence rates, findings in the Cox proportional analysis, adjusted by the original risk stratification of the study showed similar results. Additionally, the analysis is limited to a short 2-month duration of July to August and with a longer follow-up times the result and differences between the groups may change. Please note the Covid-19 cases in this analysis are pending adjudication by the endpoint adjudication committee.

All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

As the trial is ongoing, access to patient-level data and supporting clinical documents with qualified external researchers may be available upon request and subject to review once the trial is complete.

All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. mRNA-1273e =mRNA-1273 earlier and includes participants who were originally randomized and received mRNA-1273 in the blinded phase (vaccinated from 27 July 2020 to 16 Dec 2020). mRNA-1273p= placebo-mRNA-1273 treated and includes participants who were originally randomized to placebo in the blinded phase and receiving mRNA-1273 in the open-label phase (vaccinated from 29 Dec 2020 to 30 Apr 2021 post-EUA). Yr=years; CI=confidence interval. N denotes the number of participants with negative SARS-CoV-2 status at study entry (modified intent-to treat) who were at risk pre-vaccination. For this analysis, participants at risk at the start of the analysis period (01-Jul-21 to 27-Aug-21) were included and person-years was calculated for this analysis period. Incidence rate was defined as the number of Covid-19 cases divided by the number of participants at risk at the beginning of the time period (July 1, 2021) and adjusted by person-years in each group. To assess the difference in incidence rates of Covid-19 between the mRNA-1273 group and the placebo-mRNA-1273 group, the 1-ratio of incidence rate was calculated and provided with the 95% confidence intervals calculated using the exact method (Poisson distribution) adjusting for person-years.*Placebo-mRNA-1273 participants not considered at risk in the open-label phase were excluded from this analysis: those who (i) were COVID-19 or SARS-CoV-2 infection during the blinded phase, (ii) did not enter open-label or received off-study COVID-19 vaccine, or (iii) became a case prior to 1st dose of mRNA in the open-label phase. †Covid-19 cases starting 14 days after dose 2.

All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted September 22, 2021. ; https://doi.org/10.1101/2021.09.17.21263624 doi: medRxiv preprint

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