Humoral Immunogenicity of the mRNA-1273 Vaccine in the Phase 3 Coronavirus Efficacy (COVE) Trial

Abstract

Background: Messenger RNA (mRNA)-1273 vaccine demonstrated 93.2% efficacy against coronavirus disease 2019 (COVID-19) in the Coronavirus Efficacy (COVE) trial. The humoral immunogenicity results are now reported.

Methods: Participants received 2 mRNA-1273 (100 µg) or placebo injections, 28 days apart. Immune responses were evaluated in a prespecified, randomly selected per-protocol immunogenicity population (n = 272 placebo; n = 1185 mRNA-1273). Serum binding antibodies (bAbs) and neutralizing antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-spike protein were assessed at days 1, 29, and 57 by baseline SARS-CoV-2-negative (n = 1197) and SARS-CoV-2-positive (n = 260) status, age, and sex.

Results: SARS-CoV-2-negative vaccinees had bAb geometric mean AU/mL levels of 35 753 at day 29 that increased to 316 448 at day 57 and nAb inhibitory dilution 50% titers of 55 at day 29 that rose to 1081 at day 57. In SARS-CoV-2-positive vacinees, the first mRNA-1273 injection elicited bAb and nAb levels that were 11-fold (410 049) and 27-fold (1479) higher than in SARS-CoV-2-negative vaccinees, respectively, and were comparable to levels after 2 injections in uninfected participants. Findings were generally consistent by age and sex.

Conclusions: mRNA-1273 elicited robust serologic immune responses across age, sex, and SARS-CoV-2 status, consistent with its high COVID-19 efficacy. Higher immune responses in those previously infected support a booster-type effect. Clinical Trials Registration. NCT04470427.

Keywords: COVE trial; COVID-19; SARS-CoV-2; immunogenicity; mRNA-1273; pseudovirus neutralizing antibody assay; spike-binding antibody assay.

Figure 1.

Trial profile immunogenicity analysis population. The per-protocol subcohort for immunogenicity analysis consisted of participants in the full analysis set (FAS) who were sampled into the random subcohort and received both planned doses (ie, received assigned treatment) with dose 2 received within 21–41 days after dose 1, and no major protocol deviations that impacted critical or key data. ^aStratified random sampling criteria were FAS participants with nonmissing information on strata, based on per-protocol rules consistent with those used for efficacy and those with immunogenicity data at days 1, 29, and 57, all adjudicated coronavirus disease 2019 cases (Supplementary Table 1). Samples from people living with human immunodeficiency virus were excluded due to a known interference of antiretroviral medications with pseudovirus neutralizing antibody assay [41]. Data cutoff: 26 March 2021. Abbreviations: FAS, full analysis set; HIV, human immunodeficiency virus; mRNA, messenger RNA; PP, per-protocol; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2.

Spike binding and neutralizing antibody titers by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) baseline status and age. Geometric mean (GM) concentrations of SARS-CoV-2–specific spike (S) binding antibodies assessed by Meso-Scale Discovery Multiplex assay (MSD) (A) and neutralizing antibody GM titers by pseudovirus neutralizing antibody assay (PsVNA) ID₅₀ (inhibitory dilution 50%, defined as the serum dilution at which SARS-CoV-2 infection is reduced by 50% in PsVNA) (B) at the corresponding visit days (days 1, 29, and 57) and baseline SARS-CoV-2 status and age groups. The lower limit of quantitation (LLOQ) and upper limit of quantitation (ULOQ) were, respectively, 200 and 1 128 439 AU/mL for MSD and 19 and 4404 GM ID₅₀ for PsVNA assays. Antibody values <LLOQ were replaced by 0.5 × LLOQ and those >ULOQ were converted to the ULOQ if actual values were not reported and where available are reported. The 95% confidence intervals (CIs) were calculated based on the t-distribution of the log-transformed values for GM levels and GM ID₅₀ titers, then back-transformed to the original scale for presentation. *Responses in participants who received placebo (Pbo) averaged across days, study vaccine, and age group for SARS-CoV-2–negative and –positive cohorts. ^aSeroresponses at participant levels defined as a ≥4-fold increase in GM levels and titers from baseline ≥4 × LLOQ for those with baseline antibody levels <LLOQ, or a 4 times or higher-level ratio in participants with baseline antibody level ≥LLOQ. Human convalescent sera (Conv) collected from coronavirus disease 2019 patients tested by MSD (n = 84) and PsVNA (n = 165; 34 asymptomatic [A], 71 symptomatic [S], and 60 hospitalized [H]) assays served as reference control titers. For conversion of binding antibody AU/mL to binding antibody units, multiply AU units by 0.009 for MSD spike (S2-P) protein, and for conversion to international units by 0.242 for PsVNA ID₅₀ titers [3]. Data cutoff: 26 March 2021.

Figure 3.

Distribution of binding and neutralizing antibody responses by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) status and age. Reciprocal endpoint geometric mean (GM) spike (S) binding antibody log₁₀ levels by Meso-Scale Discovery Multiplex assay (MSD; A), and neutralizing antibody titers by S-pseudovirus neutralizing antibody assay (PsVNA) (inhibitory dilution 50%, defined as the serum dilution at which SARS-CoV-2 infection is reduced by 50% in PsVNA; ID₅₀ log₁₀) (B) at the corresponding visit days (days 1, 29, and 57), and baseline SARS-CoV-2 status and age groups. The lower limit of quantitation (LLOQ) and upper limit of quantitation (ULOQ), respectively, were log₁₀ 2.3 and 6.1 for MSD and log₁₀ 1.3 and 3.6 for PsVNA ID₅₀ assays. Antibody values reported as below the LLOQ were replaced by 0.5 × LLOQ. Values greater than the ULOQ are replaced by the ULOQ if actual values were not available and where available are reported. Human convalescent sera (Conv) collected from coronavirus disease 2019 patients tested by MSD (n = 84) and PsVNA (n = 165; 34 asymptomatic [A], 71 symptomatic [S], and 60 hospitalized [H]) assays served as reference control titers. Boxes and horizontal bars denote interquartile (IQR) ranges and median endpoint titers; whisker endpoints are the maximum and minimum values below or above the median ± 1.5 times the IQR. Data cutoff: 26 March 2021.