A prefusion-stabilized RSV F subunit vaccine elicits B cell responses with greater breadth and potency than a postfusion F vaccine

There is currently no licensed vaccine for respiratory syncytial virus (RSV). Here, we assess the effect of RSV fusion protein (F) conformation on B cell responses in a post hoc comparison of samples from the DS-Cav1 [prefusion (pre-F)] and MEDI7510 [postfusion (post-F)] vaccine clinical trials. We compared the magnitude and quality of the serological and B cell responses across time points and vaccines. We measured RSV A and B neutralization, F-binding immunoglobulin G titers, and competition assays at week 0 (before vaccination) and week 4 (after vaccination) to evaluate antibody specificity and potency. To compare B cell specificity and activation, we used pre-F and post-F probes in tandem with a 17-color immunophenotyping flow cytometry panel at week 0 (before vaccination) and week 1 (after vaccination). Our data demonstrate that both DS-Cav1 and MEDI7510 vaccination robustly elicit F-specific antibodies and B cells, but DS-Cav1 elicited antibodies that more potently neutralized both RSV A and B. The superior potency was mediated by antibodies that bind antigenic sites on the apex of pre-F that are not present on post-F. In the memory (CD27+) B cell compartment, vaccination with DS-Cav1 or MEDI7510 elicited B cells with different epitope specificities. B cells preferentially binding the pre-F probe were activated in DS-Cav1–vaccinated participants but not in MEDI7510-vaccinated participants. Our findings emphasize the importance of using pre-F as an immunogen in humans because of its deterministic role in eliciting highly potent neutralizing antibodies and memory B cells. Description A respiratory syncytial virus prefusion subunit vaccine elicited higher potency neutralizing antibodies than a postfusion subunit vaccine in humans. Function follows form Function follows form Respiratory syncytial virus (RSV) can cause severe infection in infants and older adults; however, no vaccine for RSV is currently approved. Candidate vaccines that target the RSV fusion (F) protein have been developed. Older vaccines use the postfusion, or Post-F, version of the protein, whereas new vaccines employ a prefusion stabilized, or Pre-F, immunogen. Here, Chang and Phung et al. directly compared immune responses elicited by a Post-F vaccine, MEDI7510, and a Pre-F vaccine, DS-Cav1. The authors found that DS-Cav1 elicited antibodies that more potently neutralized RSV A and B than MEDI7510. This enhanced response was mediated by the presence of antibodies that could bind sites on the F protein that were only present in the Pre-F state. Together, these data highlight the value of structure-based vaccine design. -CM