Humoral Immunogenicity of mRNA-1345 RSV Vaccine in Older Adults

Abstract

Background: The mRNA-1345 vaccine demonstrated efficacy against respiratory syncytial virus (RSV) disease with acceptable safety in adults aged ≥60 years in the ConquerRSV trial. Here, humoral immunogenicity results from the trial are presented.

Methods: This phase 2/3 trial randomly assigned adults (≥60 years) to mRNA-1345 50-µg encoding prefusion F (preF) glycoprotein (n = 17 793) vaccine or placebo (n = 17 748). RSV-A and RSV-B neutralizing antibody (nAb) and preF binding antibody (bAb) levels at baseline and day 29 postvaccination were assessed in a per-protocol immunogenicity subset (PPIS; mRNA-1345, n = 1515; placebo, n = 333).

Results: Day 29 nAb geometric mean titers (GMTs) increased 8.4-fold against RSV-A and 5.1-fold against RSV-B from baseline. Seroresponses (4-fold rise from baseline) in the mRNA-1345 groups were 74.2% and 56.5% for RSV-A and RSV-B, respectively. Baseline GMTs were lower among participants who met the seroresponse criteria than those who did not. mRNA-1345 induced preF bAbs at day 29, with a pattern similar to nAbs. Day 29 antibody responses across demographic and risk subgroups were generally consistent with the overall PPIS.

Conclusions: mRNA-1345 enhanced RSV-A and RSV-B nAbs and preF bAbs in adults (≥60 years) across various subgroups, including those at risk for severe disease, consistent with its demonstrated efficacy in the prevention of RSV disease.

Clinical trials registration: NCT05127434.

Keywords: RSV; binding antibody; immunogenicity; mRNA-1345; neutralizing antibody.

Figure 1.

Summary of stratification for random immunogenicity subcohort (Supplementary Table 1). ^aRandom sampling stratified by age (60–74 y and ≥75 y), lower respiratory tract disease (LRTD) risk factor (absent/present), and region (Northern/Southern Hemisphere). ^bPer-protocol immunogenicity set: participants in the random immunogenicity subcohort who received the assigned vaccine dose according to protocol and had respiratory syncytial virus (RSV) immunogenicity titer results at baseline, ≥1 valid result after vaccine administration, and no major protocol deviations affecting the primary immunogenicity outcomes; participants identified with an event of RSV acute respiratory disease or RSV-LRTD postbaseline were not excluded. Abbreviations: FAS, full analysis set; PPIS, per-protocol immunogenicity set.

Figure 2.

Neutralizing antibody geometric mean titers (GMTs) were assessed in the per-protocol immunogenicity set (PPIS). GMTs (IU/mL) of neutralizing antibodies for respiratory syncytial virus (RSV) subtypes A and B in participants in the PPIS were determined via microneutralization assays. Geometric mean fold rises (GMFRs) were determined for GMTs at day 29 vs baseline. The 95% confidence intervals (CIs) were calculated based on the t-distribution of the log-transformed values or the difference in the log-transformed values for geometric mean value and GMFR, respectively, then back-transformed to the original scale for presentation. Brackets represent GMFRs from baseline determined for GMTs at day 29 vs baseline; “n” indicates number of participants with nonmissing data at the visit (baseline or postbaseline).

Figure 3.

Neutralizing antibody geometric mean titers (GMTs) were assessed in the per-protocol immunogenicity set. Geometric mean fold rises (GMFRs) were determined for GMTs at day 29 vs baseline. The 95% confidence intervals (CIs) were calculated based on the t-distribution of the log-transformed values or the difference in the log-transformed values for geometric mean concentration and GMFR, respectively, then back-transformed to the original scale for presentation. Dotted lines represent the overall GMFR for respiratory syncytial virus (RSV) subtypes A and B; “n” indicates number of participants with nonmissing data at the visit (baseline or postbaseline). Age and risk factors were collected on electronic case report forms. Baseline values for Edmonton Frail Scale total score were defined as the most recent nonmissing measurement (scheduled or unscheduled) collected on or before the date of injection of mRNA-1345 or placebo. “Other” race group includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, other, or multiple races. Comorbidities include chronic obstructive pulmonary disease (COPD), asthma, chronic respiratory disease, diabetes, congestive heart failure (CHF), advanced liver disease, or advanced renal disease. The GMTs for the subgroups are provided in Supplementary Tables 4 and 5.

Figure 4.

The geometric mean concentrations (GMCs; arbitrary units [AU]/mL) of binding antibodies to respiratory syncytial virus (RSV) prefusion F (preF) antigen were determined in a quantitative multiplex bead-based Luminex assay. Antibody values reported as below the lower limit of quantification (LLOQ; 35 for preF) are replaced by 0.5× LLOQ. Values greater than the upper limit of quantification (ULOQ; 580 553 for preF) are replaced by the ULOQ. The 95% confidence intervals (CIs) were calculated based on the t-distribution of the log-transformed values or the difference in the log-transformed values for GMC and geometric mean fold rise (GMFR), respectively, then back-transformed to the original scale for presentation. Brackets represent GMFRs from baseline determined for GMC at day 29 vs baseline; “n” indicates number of participants with nonmissing data at the visit (baseline or postbaseline).

Figure 5.

Prefusion F (PreF) binding antibody geometric mean concentrations (GMCs) were assessed in the per-protocol immunogenicity set (PPIS). GMCs (AU/mL) of binding antibodies for respiratory syncytial virus (RSV) preF in participants in the PPIS were determined in a quantitative multiplex bead-based Luminex assay. Geometric mean fold rises (GMFRs) were determined for GMCs at day 29 vs baseline. The 95% confidence intervals (CIs) were calculated based on the t-distribution of the log-transformed values or the difference in the log-transformed values for GMC and GMFR, respectively, then back-transformed to the original scale for presentation. Dotted line represents the overall GMFR for RSV preF; “n” indicates number of participants with nonmissing data at the visit (baseline or postbaseline). Age and risk factors were collected on electronic case report forms. Assignment to vaccination groups was stratified by age (60–74 y vs ≥75 y) and risk factors for lower respiratory tract disease (present vs absent). Baseline values for Edmonton Frail Scale total score were defined as the most recent nonmissing measurement (scheduled or unscheduled) collected on or before the date of injection of mRNA-1345 or placebo. “Other” race group includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, other, or multiple races. Comorbidities include chronic obstructive pulmonary disease (COPD), asthma, chronic respiratory disease, diabetes, congestive heart failure (CHF), advanced liver disease, or advanced renal disease.