Genomics of Human Respiratory Syncytial Virus Vaccine Attenuation

ABSTRACTThe human orthopneumovirus (HRSV) is a major cause of lower respiratory tract infection in children worldwide. Despite decades of efforts, no vaccine is available. In this work, we report mutations that are frequent in vaccine candidates and rare in wild-type genomes, taking into account all the publicly available HRSV sequence data. These mutations are different from the ones already known to attenuate the virus, and thus may contribute to the effort towards producing a live attenuated vaccine against HRSV.

Safety and Immunogenicity of the Respiratory Syncytial Virus Vaccine RSV/ΔNS2/Δ1313/I1314L in RSV-Seronegative Children

Background Respiratory syncytial virus (RSV) is the leading global cause of severe pediatric acute respiratory tract illness, and a vaccine is needed. RSV/ΔNS2/Δ1313/I1314L contains 2 attenuating elements: (1) deletion of the interferon antagonist NS2 gene and (2) deletion of codon 1313 of the RSV polymerase gene and the stabilizing missense mutation I1314L. This live vaccine candidate was temperature-sensitive, genetically stable, replication restricted, and immunogenic in nonhuman primates. Methods A single intranasal dose of RSV/ΔNS2/Δ1313/I1314L was evaluated in a double-blind, placebo-controlled trial (vaccine-placebo ratio, 2:1) at 106 plaque-forming units (PFU) in 15 RSV-seropositive children and at 105 and 106 PFU in 21 and 30 RSV-seronegative children, respectively. Results In RSV-seronegative children, the 105 PFU dose was overattenuated, but the 106 PFU dose was well tolerated, infectious (RSV/ΔNS2/Δ1313/I1314L replication detected in 90% of vaccinees), and immunogenic (geometric mean serum RSV plaque-reduction neutralizing antibody titer, 1:64). After the RSV season, 9 of 20 vaccinees had increases in the RSV titer that were significantly greater than those in 8 of 10 placebo recipients (1:955 vs 1:69, respectively), indicating that the vaccine primed for anamnestic responses after natural RSV exposure. Conclusion Rational design yielded a genetically stable candidate RSV vaccine that is attenuated yet immunogenic in RSV-seronegative children, warranting further evaluation. Clinical Trials Registration NCT01893554.