Respiratory syncytial virus (RSV) continues to circulate at high levels despite the introduction of new monoclonal antibodies (mAbs) and vaccines targeting the prefusion F (pre-F) protein. We analyzed the viral genome sequences of 133 RSV clinical samples collected during the 2022-2023 and 2023-2024 seasons, and selected representative isolates for phenotypic testing. We selected four RSV A and four RSV B replication-competent, sequence-verified stocks that were assessed for replication kinetics in vitro and neutralization sensitivity by a panel of F-targeting mAbs and polyclonal sera using a rabbit vaccination model. Isolates retained sensitivity to all mAbs tested. We detected no mutations in mAb binding sites in the isolates tested. RSV-A isolates were slightly less susceptible to multiple mAbs than RSV-B isolates. Antigenic cartography revealed a separation of antibody responses by subtype: RSV-A isolates clustered together and aligned with lower neutralization by antibodies such as MPE8 and 101F, whereas RSV-B isolates formed a distinct cluster associated with higher mAb susceptibility. In a rabbit vaccination model, RSV-A-only sera efficiently neutralized all RSV-A isolates and the RSV-B1 reference strain but showed diminished activity against contemporary RSV-B isolates. RSV-B-only sera displayed balanced neutralization across both subtypes. Combined RSV-A+B immunization produced uniformly strong responses to all isolates, suggesting that multivalent exposure may overcome subtype-specific antibody polarization. Collectively, our results demonstrate consistent antigenic divergence of RSV subtypes and underscore the importance of considering genetic and phenotypic divergence for F-directed immunoprophylaxis.
Silva Marinho, P., Ghimire, D., Tsai Silva, J. V., Devlin, J., Kwon, S., Adams, G., Jorquera, P., Luban, J., Lemieux, J. E.
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