Rationale: Needle-free intranasal vaccines offer major potential advantages, especially against pathogens entering via mucosal surfaces. As yet, there is no effective vaccine against respiratory syncytial virus (RSV), a ubiquitous pathogen of global importance that preferentially infects respiratory epithelial cells; new strategies are urgently required.Objectives: Here, we report the safety and immunogenicity of a novel mucosal RSV F protein vaccine linked to an immunostimulatory bacterium-like particle (BLP).Methods: In this phase I, randomized, double-blind, placebo-controlled trial, 48 healthy volunteers, aged 18-49 years, were randomly assigned to receive placebo or SynGEM (low or high dose) intranasally by prime-boost administration. The primary outcome was safety and tolerability, with secondary objectives assessing virus-specific immunogenicity.Measurements and Main Results: There were no significant differences in adverse events between placebo and vaccinated groups. SynGEM induced systemic plasmablast responses and significant, durable increases in RSV-specific serum antibody in healthy, seropositive adults. Volunteers given low-dose SynGEM (140 μg F, 2 mg BLP) required a boost at Day 28 to achieve plateau responses with a maximum fold change of 2.4, whereas high-dose recipients (350 μg F, 5 mg BLP) achieved plateau responses with a fold change of 1.5 after first vaccination that remained elevated up to 180 days after vaccination, irrespective of further boosting. Palivizumab-like antibodies were consistently induced, but F protein site ∅-specific antibodies were not detected, and virus-specific nasal IgA responses were heterogeneous, with the strongest responses in individuals with lower pre-existing antibody levels.Conclusions: SynGEM is thus the first nonreplicating intranasal RSV subunit vaccine to induce persistent antibody responses in human volunteers.Clinical trials registered with www.clinicaltrials.gov (NCT02958540).
Keywords: clinical trial; immunology; mucosal; respiratory; virus.