Live-Attenuated Respiratory Syncytial Virus Vaccine With M2-2 Deletion and With Small Hydrophobic Noncoding 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/Delta M2-2-HindIII, attenuated by deletion of the RSV RNA regulatory protein M2-2, is based on previous candidate LID/Delta M2-2 but incorporates prominent differences from MEDI/Delta M2-2, which was more restricted in replication in phase 1. Methods. RSV-seronegative children aged 6-24 months received 1 intranasal dose (10(5) plaque-forming units [PFUs] of D46/NS2/N/Delta M2-2-HindII [n = 211 or placebo [n = 111) 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 titer, 3.5 log(10) PFUs/mL with immunoplaque assay and 6.1 log(10) copies/ml, with polymerase chain reaction). Serum RSV-neutralizing antibodies and anti-RSV fusion immunoglobulin G increased >= 4-fold in 95% and 100% of vaccines, respectively. Mild upper respiratory tract 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. Conclusions. D46/NS2/N/Delta M2-2-HindIII had excellent infectivity and immunogenicity and primed vaccine recipients for anamnestic responses, encouraging further evaluation of this attenuation strategy.