Abstract
Chikungunya virus (CHIKV) infection can result in chronic and debilitating arthralgia affecting humans in tropical and subtropical regions around the world, yet there are no licensed vaccines to prevent infection. DNA launched virus like particle (VLP) vaccines represent a potentially safer alternative to traditional live-attenuated vaccines; however, fully characterized immunocompetent mouse models which appropriately include both male and female animals for preclinical evaluation of these, and other, vaccine platforms are lacking. Utilizing virus stocks engineered to express mutations reported to enhance CHIKV virulence in mice, infection of male and female immunocompetent mice was evaluated, and the resulting model utilized to assess the efficacy of candidate DNA launched CHIKV VLP vaccines. Results demonstrate the potential utility of DNA launched VLP vaccines in comparison to a live attenuated CHIKV vaccine and identify gender differences in viral RNA loads that impact interpretation of vaccine efficacy and may have important implications for future CHIKV vaccine development.
Highlights
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that is most predominantly associated with an acute febrile illness in humans
CHIKV has been associated with multiple outbreaks globally since its reemergence in Kenya in 2004 and new variants with increased fitness for the mosquito vector and atypical symptomology have emerged [5,6,7,8,9,10,11], yet the extent of CHIKV infections is underreported because the symptomology is similar to that of dengue virus (DENV) and Zika virus (ZIKV) which are transmitted by the same vectors and circulate in the same areas [12]
To evaluate clinical endpoints to be used for efficacy studies, a CHIKV clone engineered to express mutations reported to enhance virus infection in mice was compared to the parental AF15561 strain by challenging equal numbers of male and female C57BL/6J mice at doses of 1 × 102, 1 × 104 or 1 × 106 copies of viral RNA
Summary
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus (family Togaviridae) that is most predominantly associated with an acute febrile illness in humans. Vaccination to prevent CHIKV infection may be necessary to protect against virus induced arthralgia and several different vaccine strategies have been evaluated including liveattenuated, subunit, virus-like particle (VLP), and DNA vaccines [13,14,15]. Subunit vaccines and VLP vaccines which express the viral structural proteins in non-native and native forms, respectively, are considerably safer than the live-attenuated vaccines but elicit a predominantly humoral immune response that is insufficient to protect against intracellular pathogens such as CHIKV. An important limitation of DNA vaccines is that the number of cells that are transfected following immunization is limited which in turn limits the number of antigen-producing and, more importantly, antigen presenting cells [18] While this is less critical for developing a humoral response, this significantly limits the development of a strong cell mediated immune response
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