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M2SR (M2-deficient single replication) is an investigational live intranasal vaccine that protects against multiple influenza A subtypes in influenza-naïve and previously infected ferrets. We conducted a phase 1, first-in-human, randomized, dose-escalation, placebo-controlled study of M2SR safety and immunogenicity. Adult subjects received a single intranasal administration with either placebo or one of three M2SR dose levels (106, 107 or 108 tissue culture infectious dose (TCID50)) expressing hemagglutinin and neuraminidase from A/Brisbane/10/2007 (H3N2) (24 subjects per group). Subjects were evaluated for virus replication, local and systemic reactions, adverse events (AE), and immune responses post-vaccination. Infectious virus was not detected in nasal swabs from vaccinated subjects. At least one AE (most commonly mild nasal rhinorrhea/congestion) was reported among 29%, 58%, and 83% of M2SR subjects administered a low, medium or high dose, respectively, and among 46% of placebo subjects. No subject had fever or a severe reaction to the vaccine. Influenza-specific serum and mucosal antibody responses and B- and T-cell responses were significantly more frequent among vaccinated subjects vs. placebo recipients. The M2SR vaccine was safe and well tolerated and generated dose-dependent durable serum antibody responses against diverse H3N2 influenza strains. M2SR demonstrated a multi-faceted immune response in seronegative and seropositive subjects. [ABSTRACT FROM AUTHOR]

Background Demonstration of protection by a M2SR (M2 deficient Single Replication) monovalent H3N2 vaccine was assessed in a phase 2a clinical trial in which the challenge virus was substantially drifted from the vaccine. M2SR is an investigational, live virus vaccine containing hemagglutinin (HA) and neuraminidase (NA) selected from targeted Type A influenza strains. M2SR undergoes only a single round of infection in the respiratory epithelium but evokes an immune response profile similar to wild-type influenza virus and protects ferrets against both homologous and heterologous influenza variants. Methods A blinded, randomized, placebo-controlled human challenge study (EudraCT #: 2017-004971-30) was conducted with M2SR containing HA and NA from A/Brisbane/10/2007 (H3N2). 18–55-year-old subjects received 1 IN dose of saline or 108 TCID50 of vaccine. 4 weeks later, 99 subjects were challenged IN with 106 TCID50 H3N2 A/Belgium/4217/2015 (Figures 1 and 2). Results Adverse events (AE) were similar between placebo (N = 51) and M2SR recipients (N = 48) during the 28 days after immunization. After challenge with A/Belgium/4217/2015, 35% of M2SR recipients experienced influenza infection and illness, compared with 49% of placebo subjects (Figure 3). An 18% reduction in viral load was noted after challenge for M2SR subjects. Serum microneutralization response to vaccine was detected in 54% of M2SR subjects (vs. 0/51 placebo subjects), and among these subjects a 34% reduction in viral load and 51% reduction in symptom scores was noted after challenge vs placebo. Among the 29% of subjects with post-vaccine response to both vaccine and challenge strains, a 62% reduction in viral load and 56% reduction in symptom scores was noted after challenge with highly drifted H3N2 (Figure 4). Conclusion One dose of M2SR protected healthy adults against influenza infection and illness with a highly drifted challenge strain. This is believed to be the first study to demonstrate protection against challenge with an influenza strain substantially different from the vaccine and indicates potential for improved breadth of protection by M2SR compared with current vaccines. The mild vaccine AE profile supports clinical trials of additional dose levels and regimens to enhance drifted strain protection by M2SR. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]