A Randomized, Controlled, Observer-Blinded Phase 1 Study of the Safety and Immunogenicity of a Respiratory Syncytial Virus Vaccine With or Without Alum Adjuvant

Abstract

Background: Respiratory syncytial virus (RSV) is a leading cause of childhood bronchiolitis and pneumonia, particularly in early infancy. Immunization of pregnant women could boost preexisting immune responses, providing passive protection to newborns through placental transfer of anti-RSV antibody.

Methods: In this first-in-humans clinical trial of a purified recombinant RSV protein F vaccine engineered to preferentially maintain prefusion conformation (RSV-PreF), 128 healthy men 18-44 years old were randomized to one dose of a RSV-PreF vaccine containing 10, 30, or 60 µg of RSV-PreF antigen, with or without alum adjuvant, or control, and followed for one year for safety and immunogenicity outcomes.

Results: Injection site pain was the most common adverse event, reported by up to 81.3% of participants. The highest RSV neutralizing antibody responses were in the 30 µg RSV-PreF/alum, 60 µg RSV-PreF/alum, and 60 µg RSV-PreF/nonadjuvant groups. Responses were evident on day 7, and 30 days after vaccination these participants had RSV-A neutralizing antibody titers of ≥1:512, and >70% had titers of 1:1024, with titers increasing by 3.2-4.9 fold. Responses remained high on day 60 but waned on days 180 and 360.

Conclusions: The RSV-PreF vaccine elicited rapid RSV neutralizing antibody responses in healthy young men, with an acceptable adverse event profile.

Keywords: maternal immunization; respiratory syncytial virus; vaccine; vaccine safety and immunogenicity.

Figure 1.

Flow of participants. Abbreviations: ATP, according to protocol; LSV, last study visit; n, number of participants; RSV-PreF, respiratory syncytial virus engineered to preferentially maintain a prefusion conformation.

Figure 2.

Solicited injection site adverse events (A) and general adverse events (B) during the 7 days after vaccination—total vaccinated cohort. Grade 3 (severe) pain was defined as pain that is significant at rest and prevents normal everyday activities. Redness and/or swelling were considered present if the greatest surface diameter of each was >100 mm. A grade 3 (severe) systemic adverse event was defined as an event that prevents normal everyday activities. Saccharose NaCl served as the control. Error bars depict 95% confidence intervals. Abbreviation: RSV-PreF, respiratory syncytial virus engineered to preferentially maintain a prefusion conformation.

Figure 3.

Geometric mean concentrations (GMCs) of anti–respiratory syncytial virus prefusion (RSV-PreF) antibodies before vaccination and on days 30, 60, 180, and 360 after vaccination, by study vaccine group—adapted according-to-protocol (ATP) cohort for immunogenicity. The adapted ATP cohort is as follows: the analysis on the time points up to day 60 comprised the ATP cohort for immunogenicity (n = 119), and the analysis on day 180 and day 360 comprised the ATP cohort for persistence (n = 114). Saccharose NaCl served as the control. Error bars depict 95% confidence intervals (CIs).

Figure 4.

Anti–respiratory syncytial virus A (RSV-A) and anti–RSV-B neutralizing antibody (nAb) geometric mean titers (GMTs), by study group. Abbreviation: CI, confidence interval.

Figure 5.

Palivizumab competing antibody (PCA) geometric mean concentration (GMC) days 0–360, by study group. Abbreviation: RSV-PreF, respiratory syncytial virus engineered to preferentially maintain a prefusion conformation.