Distinct mechanisms of neutralization by antibodies targeting a conserved pneumovirus F epitope.

UNLABELLED: Pneumoviruses cause seasonal outbreaks leading to hospitalizations of vulnerable populations such as infants and the elderly. Cross-neutralizing antibodies targeting viral fusion have been isolated from infected individuals, but their elicitation and mechanisms of action remain understudied. Here, we describe two vaccine-elicited antibody classes, LOR24 and LOR69, that bind an overlapping epitope, and identify the somatic mutations that endow their breadth and potency, respectively. Cryo-electron microscopy structures of both antibodies bound to the HRSV fusion (F) protein show binding modes distinct from each other and from the previously described cross-neutralizing antibody MPE8, yet they all use similar motifs for binding. Complementary in vitro and electron microscopy experiments show that these antibodies either lock prefusion F as a trimer, arrest F in a monomeric or intermediate state, or promote the transition to the postfusion conformation. This work sheds light on mechanisms of pneumovirus neutralization and the elicitation of cross-neutralizing antibody responses.

ETOC BLURB: Cross-reactive antibodies are elicited against conserved sites on pneumovirus fusion glycoproteins. Ols, Arcoverde Cerveira, Borst, Bermúdez-Méndez et al. characterized three distinct antibody classes that converge on antigenic site III, use different binding poses, and block infection at distinct steps of the fusion process, including premature triggering of the postfusion conformation.

HIGHLIGHTS: - A minimal set of mutations imparts potency and breadth to antibody LOR24- CryoEM structures of two distinct site III antibody classes, LOR24 and LOR69- Site III antibodies, including MPE8, use similar binding motifs- LOR24 destabilizes prefusion HRSV-F and triggers its postfusion transition.