Suptavumab for the Prevention of Medically Attended Respiratory Syncytial Virus Infection in Preterm Infants

Abstract

Background: Respiratory syncytial virus (RSV) is a major cause of childhood medically attended respiratory infection (MARI).

Methods: We conducted a randomized, double-blind, placebo-controlled phase 3 trial in 1154 preterm infants of 1 or 2 doses of suptavumab, a human monoclonal antibody that can bind and block a conserved epitope on RSV A and B subtypes, for the prevention of RSV MARI. The primary endpoint was proportion of subjects with RSV-confirmed hospitalizations or outpatient lower respiratory tract infection (LRTI).

Results: There were no significant differences between primary endpoint rates (8.1%, placebo; 7.7%, 1-dose; 9.3%, 2-dose). Suptavumab prevented RSV A infections (relative risks, .38; 95% confidence interval [CI], .14-1.05 in the 1-dose group and .39 [95% CI, .14-1.07] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .0499), while increasing the rate of RSV B infections (relative risk 1.36 [95% CI, .73-2.56] in the 1-dose group and 1.69 [95% CI, .92-3.08] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .12). Sequenced RSV isolates demonstrated no suptavumab epitope changes in RSV A isolates, while all RSV B isolates had 2-amino acid substitution in the suptavumab epitope that led to loss of neutralization activity. Treatment emergent adverse events were balanced across treatment groups.

Conclusions: Suptavumab did not reduce overall RSV hospitalizations or outpatient LRTI because of a newly circulating mutant strain of RSV B. Genetic variation in circulating RSV strains will continue to challenge prevention efforts.

Clinical trials registration: NCT02325791.

Keywords: efficacy; infants; respiratory syncytial virus; safety.

Figure 1.

Randomization, trial assignment, and follow-up. ^aOne subject eligible for the trial was not randomized but was dosed. Note: The full analysis set (all infants randomized and dosed with study drug) is used for analysis. Abbreviation: AE, adverse events.

Figure 2.

Cumulative incidence of (A) overall RSV primary endpoint (RSV hospitalization or outpatient LRTI) over time, by treatment group, and (B) by RSV-A and RSV-B subtype primary endpoint, by treatment group. Subjects who had no event during the 150-day efficacy assessment period were censored at the last time point when their primary endpoint was assessed, ie, day 150 visit (day 150 ± 5 days) for completers of that visit, or the last visit (scheduled or unscheduled) completed by a subject up to day 150 for noncompleters of the day 150 visit. Abbreviations: LRTI, lower respiratory tract infection; RSV, respiratory syncytial virus.

Figure 3.

Neutralization assay indicating that suptavumab is able to neutralize RSV-A clinical isolates from trial participants but not RSV-B isolates. A neutralization assay using the indicated RSV strain was performed using suptavumab or palivizumab. To determine neutralization ability, each antibody was incubated with clinical trial sample subtype A (MOI: .02) or subtype B (MOI: .05) for 2 hours (37°C, 5% CO₂). Virus-free and antibody-free controls were included. Postincubation, the antibody–virus mixture was added to the HEp-2 cells and the infection was maintained for 3 days. The degree of infection was determined by enzyme-linked immunosorbent assay. Luminescence values were analyzed by a 3-parameter logistic equation over an 11-point response curve (GraphPad Prism). Abbreviations: MOI, multiplicity of infection; RSV, respiratory syncytial virus.