J Virol. 2014 Jul 9. pii: JVI.00810-14. [Epub ahead of print]
Virus-like Particle Secretion and Genotype-dependent Immunogenicity of Dengue Virus Serotype 2 DNA Vaccine.
Dengue virus (DENV), composed of four distinct serotypes, is the most important and fast emerging arthropod-borne pathogen imposing a great deal of economic and public health burden. We constructed five genotypes of dengue virus serotype 2 (DENV-2) DNA vaccine candidates and evaluated immunogenicity, neutralizing (Nt) activity of elicited antibodies and the protective efficacy elicited in mice immunized with the vaccine candidates. We observed a significant correlation between the level of in vitro VLP secretion, the elicited antibody response and protective efficacy by different genotypic DNA vaccines in immunized mice. However, higher total IgG antibodies did not always translate into higher Nt antibodies against homologous and heterologous viruses. We also found that in contrast to previous reports, more than fifty percent of the total IgG are targeting EDIII of E protein and a substantial fraction of this population are interdomain antibodies that are highly neutralizing flavivirus sub-group cross-reactive, such as monoclonal antibody 1B7-5. In addition, the lack of critical epitope(s) in sylvatic virus recognized by interdomain antibodies, could be the major cause of poor protection of pVD2-Asian 1 genotype vaccinated mice from the lethal challenge of sylvatic virus. In conclusion, although pVD2-Asian 1 is immunogenic, elicits sufficient Nt antibody titers against all DENV-2 genotypes, and provides 100% protection against homologous Asian 1 and heterologous Cosmopolitan genotype virus challenge, it is critical to monitor the potential emergence of sylvatic genotype viruses since current vaccine candidates under development may not protect vaccinated humans from these viruses.
Five genotype-specific dengue virus serotype 2 (DENV-2) DNA vaccine candidates were evaluated for their immunogenicity, homologous and heterologous neutralizing (Nt) antibody titers and cross-genotype protection in murine model. Protective immunity elicited by our prototype vaccine candidate (Asian 1, strain 16681) in mice was protective against other genotype viruses but not against the sylvatic genotype virus, whose emergence and potential risk after introduction into human population have previously been demonstrated. The underlying mechanism of lack of protection elicited by the prototype vaccine may at least be contributed by the absence of a flavivirus sub-group cross-reactive, highly neutralizing 1B7-5-like epitope in the sylvatic DENV-2. DENV DNA vaccine directs the synthesis and assembly of virus-like particles (VLP), induces immune responses similar to live-attenuated vaccines; and its flexibility permits the fast deployment of vaccine to combat emerging viruses such as sylvatic genotype viruses. Enhanced VLP secretion by the replacement of EDI-II of pVD2-Cosmopolitan with Asian 1 EDI-II has elicited significantly higher total IgG and Nt antibodies and suggests a novel approach to enhance immunogenicity of DNA vaccine. A DENV vaccine capable of eliciting protective immunity against existing and emerging genotype viruses should be the focus of future DENV vaccine development.
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