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Sharpening the focus of anti-RSV antibodies
Respiratory syncytial virus (RSV) is a paramyxovirus that infects lung epithelial cells causing potentially severe infections in young children, the elderly, and the immunocompromised. Although an effective RSV vaccine remains a major unmet medical need, previous work has identified a stabilized pre-F conformation of the RSV fusion (F) protein as a preferred immunogen for eliciting neutralizing antibodies. Swanson et al. constructed a multimeric vaccine featuring a central ferritin core connected to eight trimeric pre-F spikes bearing engineered glycans that mask poorly neutralizing epitopes. This self-assembling nanoparticle vaccine induced stronger neutralizing antibody responses than pre-F trimers in both mice and nonhuman primates. These studies pave the way toward initiating clinical trials to test this vaccine’s ability to protect vulnerable human populations from RSV-associated disease.
Abstract
A stabilized form of the respiratory syncytial virus (RSV) fusion (F) protein has been explored as a vaccine to prevent viral infection because it presents several potent neutralizing epitopes. Here, we used a structure-based rational design to optimize antigen presentation and focus antibody (Ab) responses to key epitopes on the pre-fusion (pre-F) protein. This protein was fused to ferritin nanoparticles (pre-F-NP) and modified with glycans to mask nonneutralizing or poorly neutralizing epitopes to further focus the Ab response. The multimeric pre-F-NP elicited durable pre-F–specific Abs in nonhuman primates (NHPs) after >150 days and elicited potent neutralizing Ab (NAb) responses in mice and NHPs in vivo, as well as in human cells evaluated in the in vitro MIMIC system. This optimized pre-F-NP stimulated a more potent Ab response than a representative pre-F trimer, DS-Cav1. Collectively, this pre-F vaccine increased the generation of NAbs targeting the desired pre-F conformation, an attribute that facilitates the development of an effective RSV vaccine.
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