Live-attenuated respiratory syncytial virus vaccine with M2-2 deletion and with SH non-coding region is highly immunogenic in children.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and vaccines are needed. Live RSV vaccine D46/NS2/N/DeltaM2-2-HindIII, attenuated by deletion of the RSV RNA regulatory protein M2-2, is based on previous candidate LID/DeltaM2-2, but incorporates prominent differences versus MEDI/DeltaM2-2 which was more restricted in replication in Phase 1. METHODS: RSV-seronegative children ages 6-24 months received one intranasal dose [105 plaque forming units (PFU)] of D46/NS2/N/DeltaM2-2-HindIII (n=21) or placebo (n=11) (NCT03102034/NCT03099291) and were monitored for vaccine shedding, reactogenicity, RSV-antibody responses and RSV-associated medically-attended acute respiratory illness (RSV-MAARI) and antibody responses during the following RSV season. RESULTS: All 21 vaccinees were infected with vaccine; 20 (95%) shed vaccine [median peak titers: 3.5 log10 PFU/mL (immunoplaque assay); 6.1 log10 copies/mL (PCR)]. Serum RSV-neutralizing antibodies and anti-RSV F IgG increased >/=4-fold in 95% and 100%, respectively. Mild upper respiratory symptoms and/or fever occurred in vaccinees (76%) and placebo recipients (18%). Over the RSV season, RSV-MAARI occurred in 2 vaccinees and 4 placebo recipients. Three vaccinees had >/=4-fold increases in serum RSV-neutralizing antibody titers after the RSV season without RSV-MAARI. CONCLUSION: D46/NS2/N/DeltaM2-2-HindIII had excellent infectivity and immunogenicity, and primed for anamnestic responses, encouraging further evaluation of this attenuation strategy.