Live-attenuated vaccines of human respiratory syncytial virus for infants and young children: Progress and prospects of an old yet promising platform.

Human respiratory syncytial virus (RSV) remains a leading cause of lower respiratory tract illness (LRTI) in infants, young children, and the elderly. Although long-acting monoclonal antibodies, subunit, and messenger ribonucleic acid (mRNA) vaccines can protect vulnerable populations (infants < 6 months old and older adults) via passive and active immunization, respectively, a conspicuous protection gap remains for RSV-seronegative infants and young children aged 6 to 60 months, leaving this vulnerable pediatric cohort largely unprotected. For these RSV-seronegative pediatric populations, intranasal live-attenuated vaccines (LAVs) have emerged as promising formulations owing to the key advantage of lacking vaccine-associated enhanced respiratory disease (VAERD) following natural RSV infection in vaccine recipients. Furthermore, intranasal RSV LAVs can induce the full spectrum of protective immune responses against the virus systemically and locally, including neutralizing antibodies, secretory IgA (SIgA), and tissue-resident memory CD8+ T (TRM) cells. Despite the suboptimal Phase 3 efficacy of Sanofi's RSVt candidate (RSV/ΔNS2/Δ1313/I1314L), alternative RSV LAVs featuring the M2-2 gene deletions have shown enhanced efficacy in clinical studies, alongside emerging strategies designed to rationally augment the immunogenicity of RSV LAVs. Due to the sustained efforts over the past five decades on RSV LAVs, significant advances have been made both in the technology to generate RSV LAVs-most notably reverse genetics-and in our understanding of pivotal benchmarks, including attenuation design, evaluation criteria for attenuation and immune efficacy, as well as the stepwise strategy for clinical research in RSV-seronegative children. Concurrently, this review provides a comprehensive synthesis of these historical and ongoing efforts, while highlighting future directions to prevent RSV disease in RSV-seronegative pediatric populations.