Human Challenge Trial of a Nucleoside-Modified Messenger Ribonucleic Acid Influenza Vaccine

Human challenge trials evaluate protection from influenza exposure following vaccination but have not been reported for nucleoside-modified messenger ribonucleic acid (modRNA) influenza vaccines.

This phase 2a, double-blind trial randomly assigned healthy adults 18-55 years of age in a 1:1 ratio to receive either a modRNA or quadrivalent influenza vaccine (QIV) 30 days before an influenza A/H1N1 challenge. Control group participants from a separate trial were exposed to the same virus but were not vaccinated. Four primary efficacy end points were used to evaluate events from day 1 to 8 postchallenge. Two end points were the percentage of participants with laboratory-confirmed symptomatic influenza (grade 2 or higher) and the percentage with febrile influenza (with a temperature of at least 37.9°C). Influenza end points were compared between vaccine and control groups to calculate vaccine efficacy (VE [1 minus relative risk]). Two end points were the median differences between the vaccine and control groups for the area under the viral load (VL)-time curve (VL-AUC) and for peak VL. Vaccine safety end points were examined.

The per-protocol cohort included 55, 48, and 52 participants in the modRNA, QIV, and control groups, respectively. Symptomatic influenza occurred in 0%, 4.2%, and 26.9% of participants in the modRNA, QIV, and control groups, respectively, with a VE of 100.0% (95% confidence interval [CI], 75.2% to 100.0%) for the modRNA vaccine and 84.5% (95% CI, 43.4% to 96.0%) for the QIV. Febrile influenza occurred in 0%, 0%, and 17.3% of participants in the modRNA, QIV, and control groups, respectively, with a VE of 100.0% (95% CI, 61.2% to 100.0%) for the modRNA vaccine and 100.0% (95% CI, 55.9% to 100.0%) for the QIV. The median differences in the VL-AUC between the vaccine and control groups were -88.66 for the modRNA (95% CI, -261.95 to -1.35) and -67.01 for the QIV (95% CI, -254.13 to -0.97). The median differences in peak VL between the vaccine and control groups were -4.52 for the modRNA vaccine (95% CI, -5.29 to 0.00) and -1.49 for the QIV (95% CI, -5.25 to 0.00). No serious adverse events were reported.

Following an influenza challenge, the modRNA vaccine was associated with greater VE and reduced VL compared with the control, without any serious adverse events. (Funded by hVIVO and Pfizer; clinical trial registration number, ISRCTN13789612.).