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Neutralizing epitopes of RSV and palivizumab resistance in Japan.

ABSTRACT: Respiratory Syncytial Virus (RSV) is one of the most important viral pathogen related to acute lower respiratory infection in young children. The virus surface envelope contains the G, F, and SH proteins as spike proteins. The F protein is considered to be a major antigenic target for the neutralizing (NT) epitope as only the F protein is essential for cell infection among the three viral envelope proteins, and it is more highly conserved than the G protein. Recently, four antigenic targets related to NT activity have been reported;site I, site II, site IV, and site zero (0). Site II is the target for palivizumab used throughout the world to suppress severe RSV infection as passive immunity in high-risk children since 1998. Under the recent conditions in which indications for palivizumab administered subjects are being expanded, palivizumab-resistant mutations have been confirmed overseas in children with RSV infection, although they remain infrequent. Therefore, continuous genetic analysis of the palivizumab-binding region of the F protein is necessary. In addition, as vaccine development progresses, RSV infection control is expected to improve greatly over the next decade.

SUBMITTER: Hashimoto K

PROVIDER: S-EPMC5792496 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Neutralizing epitopes of RSV and palivizumab resistance in Japan.

Hashimoto Koichi K Hosoya Mitsuaki M

Fukushima journal of medical science 20170901 3

Respiratory Syncytial Virus (RSV) is one of the most important viral pathogen related to acute lower respiratory infection in young children. The virus surface envelope contains the G, F, and SH proteins as spike proteins. The F protein is considered to be a major antigenic target for the neutralizing (NT) epitope as only the F protein is essential for cell infection among the three viral envelope proteins, and it is more highly conserved than the G protein. Recently, four antigenic targets rela ...[more]

PMID: 28867684

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Project description:Human respiratory syncytial virus (RSV) is a cause of lower respiratory tract infection in infants, young children, and older adults. There is no licensed vaccine and prophylactic treatment options are limited. The RSV fusion (F) glycoprotein is a target of host immunity and thus a focus for vaccine development. F-trimers are metastable and undergo significant rearrangements from the prefusion to a stable postfusion structure with neutralizing epitopes on intermediate structures. We hypothesize that vaccine strategies that recapitulate the breathable F quaternary structure, and provide accessibility of B-cells to epitopes on intermediate conformations, may collectively contribute to protective immunity, while rigid prefusion F structures restrict access to key protective epitopes. To test this hypothesis, we used the near full-length prefusogenic F as a backbone to construct three prefusion F variants with substitutions in the hydrophobic head cavity: (1) disulfide bond mutant (DS), (2) space filling hydrophobic amino acid substitutions (Cav1), and (3) DS, Cav1 double mutant (DS-Cav1). In this study, we compared the immunogenicity of prefusogenic F to prefusion F variants in two animal models. Native prefusogenic F was significantly more immunogenic, producing high titer antibodies to prefusogenic, prefusion, and postfusion F structures, while animals immunized with DS or DS-Cav1 produced antibodies to prefusion F. Importantly, prefusogenic F elicited antibodies that target neutralizing epitopes including prefusion-specific site zero (Ø) and V and conformation-independent neutralizing sites II and IV. Immunization with DS or DS-Cav1 elicited antibodies primarily to prefusion-specific sites Ø and V with little or no antibodies to other key neutralizing sites. Animals immunized with prefusogenic F also had significantly higher levels of antibodies that cross-neutralized RSV A and B subtypes, while immunization with DS or DS-Cav1 produced antibodies primarily to the A subtype. We conclude that breathable trimeric vaccines that closely mimic the native F-structure, and incorporate strategies for B-cell accessibility to protective epitopes, are important considerations for vaccine design. F structures locked in a single conformation restrict access to neutralizing epitopes that may collectively contribute to destabilizing F-trimers important for broad protection. These results also have implications for vaccine strategies targeting other type 1 integral membrane proteins.

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Neutralizing epitopes of RSV and palivizumab resistance in Japan.

Publications

Neutralizing epitopes of RSV and palivizumab resistance in Japan.

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