Immune correlates analysis of a phase 3 trial of the AZD1222 (ChAdOx1 nCoV-19) vaccine

Abstract

In the phase 3 trial of the AZD1222 (ChAdOx1 nCoV-19) vaccine conducted in the U.S., Chile, and Peru, anti-spike binding IgG concentration (spike IgG) and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured four weeks after two doses were assessed as correlates of risk and protection against PCR-confirmed symptomatic SARS-CoV-2 infection (COVID-19). These analyses of SARS-CoV-2 negative participants were based on case-cohort sampling of vaccine recipients (33 COVID-19 cases by 4 months post dose two, 463 non-cases). The adjusted hazard ratio of COVID-19 was 0.32 (95% CI: 0.14, 0.76) per 10-fold increase in spike IgG concentration and 0.28 (0.10, 0.77) per 10-fold increase in nAb ID50 titer. At nAb ID50 below the limit of detection (< 2.612 IU50/ml), 10, 100, and 270 IU50/ml, vaccine efficacy was -5.8% (-651%, 75.6%), 64.9% (56.4%, 86.9%), 90.0% (55.8%, 97.6%) and 94.2% (69.4%, 99.1%). These findings provide further evidence towards defining an immune marker correlate of protection to help guide regulatory/approval decisions for COVID-19 vaccines.

Fig. 1. D57 antibody marker level by COVID-19 outcome status in baseline SARS-CoV-2 negative vaccine recipients.

a Anti-spike IgG concentration and b pseudovirus (PsV) neutralization ID50 titer. The violin plots contain interior box plots with upper and lower horizontal edges the 25th and 75th percentiles of antibody level and middle line the 50th percentile, and vertical bars 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. At both sides of the box, a rotated probability density curve estimated by a kernel density estimator with a default Gaussian kernel is plotted. Frequencies of participants with positive spike IgG/detectable nAb ID50 responses were computed with inverse probability of sampling weighting (reported at the top of the plots as “Rate”). Pos.Cut, Positivity cut-off for spike IgG defined by IgG >10.8424 BAU/ml, the assay positivity cut-off. ULoQ = 6934 BAU/ml for spike IgG. Seroresponse for ID50 was defined by a detectable value >limit of detection (LOD) (2.612 IU50/ml). ULoQ = 8319.938 IU50/ml. Post Day 57 cases experienced the primary COVID-19 endpoint starting 7 days post D57 visit through to the data cut (March 5, 2021). Non-cases are sampled into the immunogenicity subcohort with no evidence of SARS-CoV-2 infection (i.e., never tested RT-PCR positive) up to the end of the correlates study period (the data cut-off date March 5, 2021).

Fig. 2. Scatterplot of D57 spike IgG vs. D57 pseudovirus (PsV)-nAb ID50 values for baseline SARS-CoV-2 negative vaccine recipients in the immunogenicity subcohort.

Corr, Spearman rank correlation.

Fig. 3. COVID-19 risk by D57 antibody marker level in baseline SARS-CoV-2 negative vaccine recipients.

Cumulative incidence of COVID-19 by Low, Medium, High tertile of D57 antibody marker level. a, c Anti-spike IgG concentration; b, c pseudovirus (PsV) neutralization ID50 titer. The overall P-value is from a generalized Wald-test p-value of the null hypothesis that the hazard rate is constant across the Low, Medium, and High tertile groups. The total number of cases across the Low, Medium, and High tertiles (N = 45) for each antibody marker differs from the numbers in Table 1 and Fig. 1 (N = 33, 22 for spike IgG, PsV-nAb ID50, respectively) because the 45 includes all vaccine breakthrough cases including those without D57 antibody marker data.

Fig. 4. Analyses of D57 antibody markers as a correlate of risk in baseline SARS-CoV-2 negative vaccine recipients.

a, b Age and baseline risk score-adjusted cumulative incidence of COVID-19 by 92 days post D57 by D57 (A) anti-spike IgG or (b) pseudovirus (PsV)-nAb ID50 titer, estimated using a marginalized Cox model. The dotted black lines indicate bootstrap pointwise 95% CIs. The upper and lower horizontal gray lines are the overall cumulative incidence of COVID-19 from 7 to 92 days post D57 in placebo and vaccine recipients, respectively. Curves are plotted over the antibody marker range from the 2.5th percentile to the 97.5th percentile: 21.3 to 1088 BAU/ml for spike IgG and 1.31 to 270 IU50/ml for PsV-nAb ID50. c, d Age and baseline risk score-adjusted cumulative incidence of COVID-19 by 92 days post D57 by D57 (c) anti-spike IgG or (d) PsV-nAb ID50 titer above a threshold. The blue dots are point estimates at each COVID-19 primary endpoint linearly interpolated by solid black lines; the gray shaded area is pointwise 95% confidence intervals (CIs). The estimates and CIs assume a non-increasing threshold-response function. The upper boundary of the green shaded area is the estimate of the reverse cumulative distribution function (CDF) of D57 antibody marker level. The vertical red dashed line is the D57 antibody marker threshold above which no COVID-19 endpoints occurred (in the time frame of 7 days post D57 through to the data cut-off date March 5, 2021). PsV, pseudovirus.

Fig. 5. Vaccine efficacy by D57 antibody marker level in baseline SARS-CoV-2 negative vaccine recipients.

Curves shown are for D57 (a) anti-spike IgG concentration or (b) pseudovirus (PsV)-nAb ID50 titer. The dotted black lines indicate bootstrap pointwise 95% confidence intervals. The green histogram is an estimate of the density of D57 antibody marker level and the horizontal gray line is the overall vaccine efficacy from 7 to 92 days post D35, with the dotted gray lines indicating the 95% confidence intervals. Analyses adjusted for age and baseline risk score. Curves are plotted over the antibody marker range from the 2.5th percentile to the 97.5th percentile: 21.3 to 1088 BAU/ml for anti-spike IgG and 1.31 to 270 IU50/ml for PsV-nAb ID50.

Fig. 6. Vaccine efficacy (solid lines) in baseline SARS-CoV-2 negative participants by post-vaccination antibody marker level in five randomized, placebo-controlled COVID-19 vaccine efficacy trials.

Vaccine efficacy was estimated using the marginalized Cox proportional hazards implementation of Gilbert et al.. Vaccine efficacy (VE) estimates are shown by (a) anti-spike IgG concentration [D57 in COVE, D29 in ENSEMBLE-United States sites (ENSEMBLE-US), D35 in PREVENT-19, D57 in COV002] or (b) pseudovirus (PsV)-nAb ID50 titer (D57 in COVE, D29 in ENSEMBLE-US, D57 in AZD1222, D35 in PREVENT-19, D56 in COV002). The dashed lines indicate bootstrap point-wise 95% confidence intervals. The follow-up periods for the VE assessment were: COVE (doses D1, D29), 7 to 100 days post D57; ENSEMBLE-US (one dose, D1), 1 to 53 days post D29; PREVENT-19 (doses D0, D21), 7–59 days post D35; AZD1222 (doses D1, D29), 7 to 92 days post D57; COV002 (doses D1, D29; 7 to ~150 days post D57). The histograms are an estimate of antibody marker density in baseline SARS-CoV-2 negative vaccine recipients. Curves are plotted over the following antibody marker ranges: (a) COVE: 2.5th percentile to 97.5th percentile of marker, ENSEMBLE-US: 2.5th percentile to 97.5th percentile, PREVENT-19: 2.5th percentile to 97.5th percentile, COV002: 29 to 899 BAU/ml; (b) COVE: 10 IU50/ml to 97.5th percentile of marker, ENSEMBLE-US: 2.5th percentile to 97.5th percentile, PREVENT-19: 2.5th percentile to 97.5th percentile, AZD1222: 2.5th percentile to 97.5th percentile, COV002: 3 to 140 IU50/ml. Baseline covariates adjusted for were: COVE: baseline risk score, comorbidity status, and Community of color status; ENSEMBLE-US, baseline risk score; PREVENT-19: baseline risk score; AZD1222: age, baseline risk score; COV002: baseline risk score.