Immune correlates analysis of mRNA-1345 RSV vaccine efficacy clinical trial

Abstract

Identifying an immunologic marker as a correlate of protection (CoP) for RSV vaccination is important. In the pivotal phase 3 trial, the mRNA-1345 vaccine demonstrated efficacy against RSV in older adults (NCT05127434). Here, we evaluate neutralizing antibodies (nAb) against RSV-A and -B, and IgG binding antibodies (bAb) to RSV fusion antigens as correlates of risk (CoR) and CoP against the pivotal trial's efficacy endpoints of RSV lower respiratory tract disease with ≥2 or ≥3 signs/symptoms (RSV-LRTD-2+ and -3 + ) and acute respiratory disease (RSV-ARD). Day 29 RSV nAb and prefusion (preF) IgG demonstrate consistent inverse correlates with RSV endpoint occurrence. Day 29 point estimates (95% CIs) of the hazard ratio of each endpoint (RSV-LRTD-2 + , RSV-LRTD-3 + , RSV-ARD) per 10-fold increase in RSV-A nAb are 0.44 (0.30-0.65), 0.41 (0.20-0.84), and 0.45 (0.28-0.71), respectively, similar to RSV-B nAb and preF IgG. These results demonstrate Day 29 RSV nAb and preF IgG are CoRs and support their role as CoPs against RSV endpoints.

Fig. 1. Analysis of efficacy through 8.6 months of follow-up: cumulative incidence of RSV-LRTD and RSV-ARD in PPE set.

Shown are the a cumulative incidence of RSV-LRTD-2+ symptoms, b cumulative incidence of RSV-LRTD-3+ symptoms, and c cumulative incidence of RSV-ARD. Only the first episodes occurring between 14 days and 12 months postinjection were included in the analysis (PPE set). All participants who had been randomly assigned, received the vaccine or placebo, completed ≥1 visit or surveillance contact 14 days after injection, and had no major protocol deviation that would affect the efficacy outcomes were included. In each panel, the arrow indicates when the injection was administered (Day 1). The cumulative incidence is based on the Kaplan–Meier method, and the incidence rate was defined as the number of participants with a case, divided by the number of participants at risk, with adjustment for person-years. Tick marks indicate censored data. ARD acute respiratory disease, LRTD lower respiratory tract disease, PPE per-protocol efficacy, RSV respiratory syncytial virus.

Fig. 2. Day 29 RSV nAb (IU/mL) and IgG bAb (AU/mL) by RSV-LRTD-2+ case status and by vaccine and placebo in the Day 29 case-cohort set.

a RSV-A nAb. b RSV-B nAb. c RSV preF IgG bAb. d RSV postF IgG bAb. The violin-box plot is composed of an interior box plot and rotated probability density plots (estimated by a default Gaussian kernel density estimator) of the antibody marker data on each side. In the box plot, the middle line and the lower and upper horizonal edges represent the 50th, 25th, and 75th percentile of antibody titers or concentrations, and the vertical whiskers represent the distance from the 25th (or 75th) percentiles of antibody titers or concentrations and the minimum (or maximum) antibody titers or concentrations within the 25th (or 75th) percentile of antibody level minus (or plus) 1.5 times the interquartile range. The GMT or GMC level and the corresponding 95% confidence interval are adjusted by the IPS-weight. ARD acute respiratory disease, bAb binding antibody, GMC geometric mean concentration, GMT geometric mean titer, IgG immunoglobulin G, IPS inverse probability of sampling, LLOQ lower limit of quantification, LRTD lower respiratory tract disease, nAb neutralizing antibody, postF postfusion, preF prefusion, RSV respiratory syncytial virus, ULOQ upper limit of quantification.

Fig. 3. RSV-LRTD-2+ risk by placebo and antibody marker level in vaccine recipients in the Day 29 case-cohort set.

Covariate-adjusted instantaneous hazard rate and cumulative incidence of RSV-LRTD-2+ by placebo and by low, medium, and high tertile of Day 29 RSV nAb or IgG bAb marker level in vaccine recipients. (a) and (c) for Day 29 RSV-A nAb. (b) and (d) for Day 29 RSV preF IgG bAb. e Day 29 RSV-A and RSV-B nAb and RSV preF and postF IgG bAb. Baseline risk factors are adjusted in the univariable (qualitative) IPS-weighted Cox PH regression model, including the actual stratification factors age and LRTD at-risk and baseline risk score. bAb binding antibody, FWER family-wise error rate, IgG immunoglobulin G, IPS inverse probability of sampling, LRTD lower respiratory tract disease, nAb neutralizing antibody, PH proportional hazard, point est. point estimate, postF postfusion, preF prefusion, RSV respiratory syncytial virus.

Fig. 4. Further CoR/CoP analysis for RSV-LRTD-2+ by Day 29 RSV-A nAb and Day 29 RSV preF IgG bAb, respectively.

a and d Solid red and blue curves demonstrate point estimates of the covariate-adjusted cumulative incidence of RSV-LRTD-2+ during the study period for vaccine and placebo recipients across a range of assigned antibody titers or concentration levels (within 0.5th–99.5th percentiles of observed antibody values in vaccine and placebo groups). Dashed red and blue curves, along with the shades, represent the bootstrap pointwise 95% CIs. Solid and dashed horizontal gray lines represent the point estimates and 95% CIs of the average covariate-adjusted cumulative incidence of RSV-LRTD-2+ in vaccine and placebo recipients. b and e Solid black curve shows the point estimate of controlled VE across a range of assigned antibody titers or concentration levels (within 0.5th–99.5th percentiles of observed antibody values in vaccine and placebo groups), dashed black curves demonstrate the bootstrap pointwise 95% CIs. Rug lines below and above represent RSV-LRTD-2+ cases and non-cases by vaccination status, respectively. The shaded gray area between dashed curves highlights the VE above the median of the antibody level in placebo recipients. Solid and dashed horizontal gray lines are point estimates and 95% CIs of clinical VE in the additional analysis. c and f Red curve along the blue area represents the reverse cumulative density function values for the observed antibody marker values in vaccine recipients. The black curve is the covariate-adjusted cumulative incidence of RSV-LRTD-2+ during the study period above a range of antibody marker levels (below the 97.5th percentile of observed antibody values in the vaccine group). The shadowed gray area is the bootstrap pointwise 95% CIs. The stacked histogram of the observed antibody marker titers or concentration levels by vaccination status overlayed on the bottom of cumulative incidence plots (a, d) and VE plots (b, e). Baseline covariates of age, LRTD at-Risk, and baseline risk score are adjusted in the IPS-weighted Cox regression model. bAb binding antibody, CDF cumulative distribution function, CI confidence interval, CoP correlate of protection, CoR correlate of risk, IgG immunoglobulin G, IPS inverse probability of sampling, LRTD lower respiratory tract disease, nAb neutralizing antibody, postF postfusion, preF prefusion, RSV respiratory syncytial virus, VE vaccine efficacy.