Omicron COVID-19 immune correlates analysis of a third dose of mRNA-1273 in the COVE trial

Abstract

In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint.

Fig. 1. Distributions of BD1 and of BD29 neutralizing antibody (nAb) and binding antibody (bAb) marker levels, stratified by Omicron COVID-19 case vs. non-case status and by SARS-CoV-2 naive vs. non-naive status.

a–d nAb titer against Spike (BA.1 strain) pseudovirus; e–h IgG bAb concentration against Spike (BA.1 strain). Points are from per-protocol boosted participants in the original-vaccine (filled triangles) or crossover-vaccine (open circles) arm with lines (gray: original-vaccine arm; red: crossover-vaccine arm) connecting the BD1 and BD29 data points for an individual participant (a, e: n = 79; b, f: n = 84; c, g: 32; d, h: n = 23). The violin plots contain interior box plots with upper and lower horizontal edges representing the 25th and 75th percentiles of antibody level and middle line representing the 50th percentile. The vertical bars represent the distance from the 25th (or 75th) percentile of antibody level and the minimum (or maximum) antibody level within the 25th (or 75th) percentile of antibody level minus (or plus) 1.5 times the interquartile range. Each side shows a rotated probability density (estimated by a kernel density estimator with a default Gaussian kernel) of the data. Positive response rates were computed with inverse probability of sampling weighting. LLOQ, lower limit of quantification. AU/ml, arbitrary units/ml. LLOQ = 8 AU/ml for nAb BA.1 and 102 AU/ml for Spike IgG BA.1. Positive (quantifiable) response for BA.1 nAb at a given timepoint was defined by value ≥LLOQ at that timepoint. Positive response for Spike IgG-BA.1 bAb at a given timepoint was defined by value ≥LLOQ at that timepoint. Omicron Case = COVID-19 endpoint in the interval [≥7 days post BD29 AND ≥December 1, 2021 to April 5, 2022 (data cutoff date)]. Non-case = Did not acquire COVID-19 (of any strain) in the interval [BD1 to April 5, 2022]. SARS-CoV-2 naive = No evidence of SARS-CoV-2 infection from enrollment through to BD1; Non-naive = Any evidence of SARS-CoV-2 infection in the interval [≥14 days after the first two doses of mRNA-1273, BD1].

Fig. 2. Analyses of BD29 and of Fold-Rise (BD29/BD1) BA.1 strain neutralizing antibody (nAb) titer and Spike IgG-BA.1 strain binding antibody (bAb) concentration as a correlate of risk of Omicron COVID-19.

Curves show cumulative incidence of Omicron COVID-19, estimated using a Cox model (purple) or a nonparametric method (blue), in per-protocol boosted (a, b) SARS-CoV-2 naive participants (N = 14,047) and (c, d) non-naive participants (N = 204) by 92 days post BD29 by BD29 antibody marker level. The solid lines indicate the mean cumulative incidences. The dotted lines and shadings in between indicate bootstrap pointwise 95% CIs. The distribution of the marker in the respective analysis population, calculated by kernel density estimation, is plotted in light green. e Hazard ratios of Omicron COVID-19 per 10-fold increase in each BD29 and fold-rise (BD29/BD1) BA.1 marker in per-protocol boosted SARS-CoV-2 naive participants or non-naive participants. Baseline covariates adjusted for: baseline risk score, at risk status, community of color status, BD1 marker level (paired to the BD29 marker studied). P values are based on the Wald test and are 2-sided.

Fig. 3. Correlate of booster relative efficacy curves against Omicron COVID-19 among SARS-CoV-2 naive participants (N = 2464) as a function of predicted-at-exposure immune marker level.

a Neutralizing antibody (nAb) titer against Spike (BA.1 strain) pseudovirus; (b) IgG binding antibody (bAb) concentration against Spike (BA.1 strain). The curves show the relative efficacy of three-dose mRNA-1273 vs. two-dose mRNA-1273. The dashed black lines are 95% confidence intervals. The green histograms are an estimate of the density of predicted-at-exposure antibody marker level in per-protocol boosted SARS-CoV-2 naive participants. The gray shadings indicate the middle 90% (5th percentile to 95th percentile) of this marker distribution.

Fig. 4. Matched neutralizing antibody, COVID-19 vaccine efficacy curves for Ancestral and Omicron eras.

The curves show vaccine efficacy among SARS-CoV-2 naive participants (a, N = 1615; b, c, N = 2464). a The solid curve graphs two-dose vs. placebo vaccine efficacy against Ancestral COVID-19 by D57 (28 days post dose 2) Ancestral strain neutralizing antibody (nAb) titer in International Units (IU50/ml). The blue histogram shows the distribution of post dose 2 Ancestral nAb titer. The light blue shading indicates the middle 90% (5th percentile to 95th percentile) of the marker distribution. b The solid curve graphs three-dose vs. two-dose booster relative efficacy against Omicron COVID-19 by BD29 (28 days post dose 3) BA.1 nAb titer in imputed IU50/ml (see Methods). In (a) and (b), solid lines are point estimates and dashed lines are 95% confidence intervals. c The two dashed lines are the most and least conservative estimates of extrapolated booster vaccine efficacy against Omicron (BA.1) COVID-19 by BD29 (28 days post dose 3) BA.1 nAb titer in imputed IU50/ml for a 3-dose group vs an unvaccinated group. The curves are based on inferring an unvaccinated group using observational cohort data reported in eTable 2 in ref. , namely that by 13 months post dose 2, VE (versus an unvaccinated control) against infection and hospitalization waned to 34% and 62%, respectively. In (b) and (c), the green histogram shows the distribution of post dose 3 BA.1 nAb titer. The light green shadings indicate the middle 90% (5th percentile to 95th percentile) of the marker distribution.