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Hepatitis E vaccine candidate harboring a non-particulate immunogen of E2 fused with CRM197 fragment A.

Antiviral Res; 164: 154-161, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30802475
The Hepatitis E vaccine (Hecolin, licensed in China) harbors a potent particulate immunogen, p239, designed from a 26-aa N-terminal extension of its poorly immunogenic parental protein, E2. Although an effective vaccine, we sought to design a fusion protein in a non-particulate form that could improve the delivery and immunogenicity of E2 epitopes. The non-toxic mutant of diphtheria toxin, CRM197 (Cross-Reacting Material 197) has been successfully used as a carrier protein for conjugated vaccines to enhance the immunogenicity of polysaccharides. Here, we designed a fusion non-particulate protein of E2 and the catalytic domain (fragment A) of CRM197 and evaluated its antigenicity, immunogenicity and disease prevention efficacy in primates. This fusion protein, named CRM197(A)-E2, was bacterially expressed and purified by chromatography. CRM197(A)-E2 presented as a homodimer in solution, similar to its parental E2 protein, and exhibited excellent antigenicity against representative neutralizing monoclonal antibodies, like E2 and p239. However, CRM197(A)-E2 manifested higher immunogenicity in mice compared with that achieved by the particulate p239, as indicated by the 10-times lower ED50 value and 2-log higher HEV-specific antibody level that could persist for at least 28 weeks. In addition, both the 1 µg and 10 µg doses of CRM197(A)-E2 adjuvanted with aluminum could protect vaccinated monkeys against HEV challenge, matching that achieved with only the higher (10 µg) dose of the p239 vaccine. These results suggest that the CRM197 fragment A alone serves as an intra-molecular adjuvant to remarkably enhance the immunogenicity of the target of interest in a non-particulate form. These findings may pave the way for rational vaccine design, especially in cases where particulates are not accessible.