Bivalent RSVpreF Vaccine in Adults 18 to <60 Years Old With High-Risk Conditions

Abstract

Background: Older individuals and adults with certain chronic or immunocompromising health conditions are at increased risk of severe respiratory syncytial virus (RSV) disease.

Methods: In this phase 3 randomized trial of RSVpreF safety and immunogenicity in 18-59-year-olds at high risk of severe RSV disease, participants were randomized 2:1 to 1 RSVpreF (120 µg) or placebo dose. Primary safety endpoints included reactogenicity events and adverse events (AEs) through 7 days and 1 month after vaccination, respectively, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) throughout the study. In primary analyses, immunogenicity elicited 1 month after RSVpreF was bridged to a randomly selected subset of ≥60-year-olds receiving RSVpreF from the immunogenicity subset in the pivotal phase 3 RENOIR trial, which demonstrated RSVpreF efficacy. Noninferiority was declared if 95% confidence interval (CI) lower bounds were >.667 (neutralizing titer adjusted geometric mean ratios) and >-10% (seroresponse rate differences) for RSV-A and RSV-B.

Results: Overall, 678 participants received RSVpreF (n = 453) or placebo (n = 225). Most reactogenicity events were mild/moderate; severe events occurred in ≤2.0% of participants overall. AE frequencies were similar in RSVpreF (7.1%) and placebo recipients (7.6%). No vaccine-related SAEs or NDCMCs were reported. One month after RSVpreF administration, noninferiority criteria were met in 18-59-year-olds versus ≥60-year-olds for RSV-A and RSV-B neutralizing titers and seroresponse rates.

Conclusions: RSVpreF was well tolerated with no safety concerns and demonstrated immunobridging to efficacy in 18-59-year-olds at high risk of severe RSV disease versus ≥60-year-olds in whom efficacy was previously demonstrated, supporting use of RSVpreF to prevent RSV-associated disease in this population. NCT05842967.

Keywords: RSV; RSVpreF; immunogenicity; safety; vaccine.

Figure 1.

Enrollment, randomization, vaccine and placebo administration, and follow-up. The evaluable immunogenicity population is defined in Supplementary Table 1.

Figure 2.

RSV-A and RSV-B neutralization titer (A) and seroresponse results (B) at 1 m after RSVpreF vaccination in participants 18–59 y of age versus adults ≥60 y of age. Results are for the evaluable immunogenicity population (Supplementary Table 1). Participants ≥60 y of age are a subset of participants who received RSVpreF in the pivotal RENOIR study. The LLOQ values were 242 for RSV-A and 99 for RSV-B neutralizing titers. Assay results below the LLOQ were set to 0.5 × LLOQ. GMTs and GMRs and associated 2-sided CIs were calculated by exponentiating the LS means or the mean difference, respectively, and the corresponding CIs based on analysis of log-transformed titers using a regression model with 18–59 y of age and ≥60 y of age groups, baseline log-transformed titers, and sex as covariates. Seroresponse was defined as achieving a ≥4-fold rise from baseline (before vaccination) or a postvaccination assay result ≥4 × LLOQ if the baseline measurement was <LLOQ. Seroresponses are presented with Clopper-Pearson exact 2-sided 95% CIs. Difference in seroresponse is expressed as a percentage with Miettinen-Nurminen 95% CIs. The dotted lines represent the prespecified noninferiority criteria. Abbreviations: ANCOVA, analysis of covariance; CI, confidence interval; GMR, geometric mean ratio; GMT, geometric mean titer; LLOQ, lower limit of quantitation; LS, least square; RSV, respiratory syncytial virus.

Figure 3.

RSV neutralizing titer GMTs and GMFRs with 95% CIs (A) overall and by demographic subgroup for (B) RSV-A, and (C) RSV-B. Data are for the evaluable immunogenicity population (Supplementary Table 1). LLOQ values were 242 for RSV-A and 99 for RSV-B neutralizing titers. Assay results below the LLOQ were set to 0.5 × LLOQ for all GMT and GMFR calculations, except when the prevaccination assay result was <LLOQ and the postvaccination result was ≥LLOQ, in which case the prevaccination value was set to LLOQ when calculating GMFRs. GMTs and GMFRs were calculated by exponentiating the mean logarithm of the titers or the mean logarithm of the fold rises, respectively, with corresponding CIs based on the Student t distribution. Panels B and C include subgroups with ≥3 participants. Abbreviations: CI, confidence interval; GMFR, geometric mean fold rise; GMT, geometric mean titer; LLOQ, lower limit of quantitation; N, number of participants with valid and determinate assay results; RSV, respiratory syncytial virus.

Figure 4.

Local reactions and systemic events reported within 7 d after administration of RSVpreF or placebo. Panel A shows local reactions, and panel B shows systemic events in RSVpreF (n = 451) and placebo recipients (n = 225) who received study intervention and who had ≥1 d of electronic data transferred. Severity scales are summarized in Supplementary Table 5. The numbers above the bars show the percentage of participants in each group with the specified local reaction or systemic event. Error bars are 95% CIs. Severe swelling was reported by 1 participant (0.2%) in the RSVpreF group; severe fatigue in 4 participants (0.9%) in the RSVpreF group and 1 participant (0.4%) in the placebo group; severe headache in 1 participant (0.2%) in the RSVpreF group; severe joint pain in 1 participant (0.2%) in the RSVpreF group; severe nausea in 1 participant (0.4%) in the placebo group; and severe diarrhea in 3 participants (0.7%) in the RSVpreF group and 2 participants (0.9%) in the placebo group. Abbreviation: CI, confidence interval.

Figure 5.

Adverse events. Data are for the safety population (defined in Supplementary Table 1). Related events were as determined by the investigator. Abbreviations: AE, adverse event; AESI, adverse event of special interest; NDCMC, newly diagnosed chronic medical condition.