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Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial.

ABSTRACT: In the coronavirus efficacy (COVE) phase 3 clinical trial, vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. These immune markers were measured at the time of second vaccination and 4 weeks later, with values reported in standardized World Health Organization international units. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. Vaccine recipients with postvaccination 50% neutralization titers 10, 100, and 1000 had estimated vaccine efficacies of 78% (95% confidence interval, 54 to 89%), 91% (87 to 94%), and 96% (94 to 98%), respectively. These results help define immune marker correlates of protection and may guide approval decisions for messenger RNA (mRNA) COVID-19 vaccines and other COVID-19 vaccines.

SUBMITTER: Gilbert PB

PROVIDER: S-EPMC9017870 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial.

Gilbert Peter B PB Montefiori David C DC McDermott Adrian B AB Fong Youyi Y Benkeser David D Deng Weiping W Zhou Honghong H Houchens Christopher R CR Martins Karen K Jayashankar Lakshmi L Castellino Flora F Flach Britta B Lin Bob C BC O'Connell Sarah S McDanal Charlene C Eaton Amanda A Sarzotti-Kelsoe Marcella M Lu Yiwen Y Yu Chenchen C Borate Bhavesh B van der Laan Lars W P LWP Hejazi Nima S NS Huynh Chuong C Miller Jacqueline J El Sahly Hana M HM Baden Lindsey R LR Baron Mira M De La Cruz Luis L Gay Cynthia C Kalams Spyros S Kelley Colleen F CF Andrasik Michele P MP Kublin James G JG Corey Lawrence L Neuzil Kathleen M KM Carpp Lindsay N LN Pajon Rolando R Follmann Dean D Donis Ruben O RO Koup Richard A RA

Science (New York, N.Y.) 20211123 6576

In the coronavirus efficacy (COVE) phase 3 clinical trial, vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. These immune markers were measured at the time of second vaccination and 4 weeks later, with values reported in standardized World Health Organization international units. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. Vaccine recipien ...[more]

PMID: 34812653

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Project description:BackgroundIn the Coronavirus Efficacy (COVE) trial, estimated mRNA-1273 vaccine efficacy against coronavirus disease-19 (COVID-19) was 94%. SARS-CoV-2 antibody measurements were assessed as correlates of COVID-19 risk and as correlates of protection.MethodsThrough case-cohort sampling, participants were selected for measurement of four serum antibody markers at Day 1 (first dose), Day 29 (second dose), and Day 57: IgG binding antibodies (bAbs) to Spike, bAbs to Spike receptor-binding domain (RBD), and 50% and 80% inhibitory dilution pseudovirus neutralizing antibody titers calibrated to the WHO International Standard (cID50 and cID80). Participants with no evidence of previous SARS-CoV-2 infection were included. Cox regression assessed in vaccine recipients the association of each Day 29 or 57 serologic marker with COVID-19 through 126 or 100 days of follow-up, respectively, adjusting for risk factors.ResultsDay 57 Spike IgG, RBD IgG, cID50, and cID80 neutralization levels were each inversely correlated with risk of COVID-19: hazard ratios 0.66 (95% CI 0.50, 0.88; p=0.005); 0.57 (0.40, 0.82; p=0.002); 0.42 (0.27, 0.65; p<0.001); 0.35 (0.20, 0.61; p<0.001) per 10-fold increase in marker level, respectively, multiplicity adjusted P-values 0.003-0.010. Results were similar for Day 29 markers (multiplicity adjusted P-values <0.001-0.003). For vaccine recipients with Day 57 reciprocal cID50 neutralization titers that were undetectable (<2.42), 100, or 1000, respectively, cumulative incidence of COVID-19 through 100 days post Day 57 was 0.030 (0.010, 0.093), 0.0056 (0.0039, 0.0080), and 0.0023 (0.0013, 0.0036). For vaccine recipients at these titer levels, respectively, vaccine efficacy was 50.8% (-51.2, 83.0%), 90.7% (86.7, 93.6%), and 96.1% (94.0, 97.8%). Causal mediation analysis estimated that the proportion of vaccine efficacy mediated through Day 29 cID50 titer was 68.5% (58.5, 78.4%).ConclusionsBinding and neutralizing antibodies correlated with COVID-19 risk and vaccine efficacy and likely have utility in predicting mRNA-1273 vaccine efficacy against COVID-19.Trial registration numberCOVE ClinicalTrials.gov number, NCT04470427.

Project description:BackgroundImmunoassays for determining past SARS-CoV-2 infection have not been systematically evaluated in vaccinated persons in comparison with unvaccinated persons.ObjectiveTo evaluate antinucleocapsid antibody (anti-N Ab) seropositivity in mRNA-1273 (Moderna) vaccinees with breakthrough SARS-CoV-2 infection.DesignNested substudy of a phase 3 randomized, double-blind, placebo-controlled vaccine efficacy trial. (ClinicalTrials.gov: NCT04470427).Setting99 sites in the United States, July 2020 through March 2021.ParticipantsParticipants were aged 18 years or older, had no known history of SARS-CoV-2 infection, and were at risk for SARS-CoV-2 infection or severe COVID-19. Substudy participants were diagnosed with SARS-CoV-2 infection during the trial's blinded phase.Intervention2 mRNA-1273 or placebo injections 28 days apart.MeasurementsNasopharyngeal swabs from days 1 and 29 (vaccination days) and from symptom-prompted illness visits were tested for SARS-CoV-2 via polymerase chain reaction (PCR). Serum samples from days 1, 29, and 57 and the participant decision visit (PDV, when participants were informed of treatment assignment; median day 149) were tested for anti-N Abs by the Elecsys immunoassay.ResultsAmong 700 participants with PCR-confirmed COVID-19 illness during the blinded phase of the trial (through March 2021), seroconversion to anti-N Abs (median of 53 days after diagnosis) occurred in 21 of 52 mRNA-1273 vaccinees (40% [95% CI, 27% to 54%]) versus 605 of 648 placebo recipients (93% [CI, 92% to 95%]). Each 1-log increase in SARS-CoV-2 viral copies at diagnosis was associated with 90% higher odds of anti-N Ab seroconversion (odds ratio, 1.90 [CI, 1.59 to 2.28]).LimitationThe scope was restricted to mRNA-1273 vaccinees and the Elecsys assay, the sample size was small, data on Delta and Omicron infections were lacking, and the analysis did not address a prespecified objective of the trial.ConclusionVaccination status should be considered when interpreting seroprevalence and seropositivity data based solely on anti-N Ab testing. Primary Funding source: National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

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Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial.

Publications

Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial.

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