Abstract
Respiratory syncytial virus (RSV) is a global public health burden for which no licensed vaccine exists. To aid vaccine development via increased understanding of the protective antibody response to RSV prefusion glycoprotein F (PreF), we performed structural and functional studies using the human neutralizing antibody (nAb) RSB1. The crystal structure of PreF complexed with RSB1 reveals a conformational, pre-fusion specific site V epitope with a unique cross-protomer binding mechanism. We identify shared structural features between nAbs RSB1 and CR9501, elucidating for the first time how diverse germlines obtained from different subjects can develop convergent molecular mechanisms for recognition of the same PreF site of vulnerability. Importantly, RSB1-like nAbs were induced upon immunization with PreF in naturally-primed cattle. Together, this work reveals new details underlying the immunogenicity of site V and further supports PreF-based vaccine development efforts.
Highlights
Human respiratory syncytial virus (RSV) is a highly contagious member of the Pneumoviridae family of negative-sense, enveloped, RNA viruses
We identify shared structural features between neutralizing antibody (nAb) RSB1 and CR9501, elucidating for the first time how diverse germlines obtained from different subjects can develop convergent molecular mechanisms for recognition of the same prefusion glycoprotein F (PreF) site of vulnerability
RSB1 was previously selected from a naturally infected donor in a memory B cell screening assay that identified a panel of PreF-specific neutralizing antibodies against RSV A, and based on binding competition, was grouped along with site Ø binding antibodies such as D25[35]
Summary
Human respiratory syncytial virus (RSV) is a highly contagious member of the Pneumoviridae family of negative-sense, enveloped, RNA viruses. Over 80% of the population is exposed by the age of 2 years, making RSV among the most common causes of acute lower respiratory tract illness leading to hospitalization in children under 5 years of age [1, 2]. The disease severity and risk of hospitalization is further amplified in very young infants below the age of 6 months [3]. Due to its moderate effectiveness, high cost and the need for monthly intramuscular injections [5], its use is restricted to high-risk infants. There remains an important unmet medical need for an effective vaccine against RSV to protect all vulnerable populations [6,7,8]. Several RSV vaccine programs have begun clinical development in the last decade [9], to date there is no approved vaccine [10, 11]
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