A Randomized Phase 1/2 Study of a Respiratory Syncytial Virus Prefusion F Vaccine

Abstract

Background: Protection against human respiratory syncytial virus (RSV) remains an unmet need potentially addressable by maternal immunization. This phase 1/2 study evaluated a bivalent prefusion F vaccine (RSVpreF) with antigens from RSV subgroups A and B.

Methods: Adults 18-49 years old (N = 618) were randomized to receive placebo or 60, 120, or 240 µg RSVpreF with or without Al(OH)3. Safety and immunogenicity were evaluated.

Results: RSVpreF recipients more frequently reported local reactions and systemic events than placebo recipients; these were mostly mild or moderate. No vaccine-related serious adverse events occurred through 12 months postvaccination. All RSVpreF formulations induced 1-month postvaccination virus-neutralizing titers higher than those associated with protection of high-risk infants by palivizumab, the only prophylactic currently available for RSV. Geometric mean fold rises (GMFRs) across RSVpreF doses/formulations were 10.6-16.9 for RSV A and 10.3-19.8 for RSV B at 1 month postvaccination, greater than those historically elicited by postfusion F vaccines. GMFRs were 3.9-5.2 and 3.7-5.1, respectively, at 12 months postvaccination.

Conclusions: RSVpreF formulations were safe, well tolerated, and induced robust neutralizing responses in adults. These findings support development of RSVpreF, which is being evaluated in a pivotal phase 3 study for maternal immunization.

Clinical trials registration: NCT03529773.

Keywords: F protein; immunogenicity; maternal vaccination; neutralizing responses; respiratory syncytial virus; safety; vaccine.

Figure 1.

Study design. Expanded cohort groups included in this report are highlighted in yellow. Abbreviations: RSVpreF, bivalent respiratory syncytial virus prefusion F vaccine; SIIV, seasonal inactivated influenza vaccine.

Figure 2.

Disposition of participants 18–49 years old in the (A) sentinel and (B) expanded cohorts. Expanded cohort groups included in this report are highlighted in yellow. Participants who did not receive SIIV concomitantly with the RSV vaccine received it 1 month later. Abbreviations: Cmplt’d, completed; f/u, follow-up; PV1, postvaccination 1; rec’d, received; RSV, respiratory syncytial virus; RSVpreF, bivalent RSV prefusion F vaccine; SIIV, seasonal inactivated influenza vaccine.

Figure 3.

Percentages of participants 18–49 years old in the sentinel and expanded cohorts combined reporting individual (A) local reactions or (B) systemic events by severity within 14 days postvaccination 1. Total number of participants (n) = 52–54 per group. Abbreviations: 60, 60 µg RSVpreF; 60A, 60 µg RSVpreF + AI(OH)₃; 120, 120 µg RSVpreF; 120A, 120 µg RSVpreF + AI(OH)₃; 240, 240 µg RSVpreF; 240A, 240 µg RSVpreF + AI(OH)₃; P, placebo; RSVpreF, bivalent respiratory syncytial virus prefusion F vaccine.

Figure 4.

RSV neutralizing GMTs through 12 months postvaccination 1 and corresponding GMFRs compared with baseline for (A) RSV subgroup A and (B) RSV subgroup B in participants 18–49 years old in the sentinel and expanded cohorts combined. Data are shown separately by dose level for ease of viewing. Abbreviations: GMFR, geometric mean fold rise; GMT, geometric mean titer; RSV, respiratory syncytial virus; RSVpreF, bivalent RSV prefusion F vaccine.

Figure 5.

Vaccine-elicited RSV A/B neutralizing titer fold rise as a function of prevaccination RSV A/B neutralizing titers. For each individual, the prevaccination titer is the combined A/B 50% neutralizing titer, calculated as the geometric mean of the RSV A and B neutralizing titers. The combined A/B 50% neutralizing titer fold rise is the geometric mean of the fold rises of 50% neutralizing titers against RSV A and RSV B from prevaccination to 1 month postvaccination. The correlation across all data was calculated at −0.61. Data are shown for participants 18–49 years old in the sentinel and expanded cohorts combined. Abbreviations: GMFR, geometric mean fold rise; RSV, respiratory syncytial virus; RSVpreF, bivalent RSV prefusion F vaccine.