Intranasal M2SR (M2-Deficient Single Replication) H3N2 Influenza Vaccine Provides Enhanced Mucosal and Serum Antibodies in Adults

BACKGROUND: We previously demonstrated that an intranasal dose of 10(8) 50% tissue culture infectious dose (TCID(50)) M2-deficient single replication (M2SR) influenza vaccine protected against highly drifted H3N2 influenza challenge in a subset of subjects who demonstrated ≥2-fold increase in microneutralization (MN) antibodies to Belgium2015 (the challenge strain) after vaccination. Here, we describe a phase 1b, observer-blinded, dose-escalation study demonstrating an increased proportion of responders with this signal of immune protection. METHODS: Serosusceptible subjects aged 18–49 years were randomized to receive 2 doses (10(8)–10(9) TCID(50)) of M2SR or placebo administered 28 days apart. Clinical specimens were collected before and after each dose. The primary objective was to demonstrate safety of M2SR vaccines. RESULTS: The vaccine was well tolerated at all dose levels. Against Belgium2015, ≥ 2-fold increases in MN antibodies were noted among 40% (95% confidence interval [CI], 24.9%–56.7%) of subjects following a single 10(8) TCID(50) M2SR dose and among 80.6% (95% CI, 61.4%–92.3%) after 10(9) dose (P < .001). A single 10(9) TCID(50) dose of M2SR generated ≥4-fold hemagglutination inhibition antibody seroconversion against the vaccine strain in 71% (95% CI, 52.0%–85.8%) of recipients. Mucosal and cellular immune responses were also induced. CONCLUSIONS: These results indicate that M2SR may provide substantial protection against infection with highly drifted strains of H3N2 influenza. CLINICAL TRIALS REGISTRATION: NCT03999554.