A DNA Vaccine against Chikungunya Virus Is Protective in Mice and Induces Neutralizing Antibodies in Mice and Nonhuman Primates

Abstract

Chikungunya virus (CHIKV) is an emerging mosquito-borne alphavirus indigenous to tropical Africa and Asia. Acute illness is characterized by fever, arthralgias, conjunctivitis, rash, and sometimes arthritis. Relatively little is known about the antigenic targets for immunity, and no licensed vaccines or therapeutics are currently available for the pathogen. While the Aedes aegypti mosquito is its primary vector, recent evidence suggests that other carriers can transmit CHIKV thus raising concerns about its spread outside of natural endemic areas to new countries including the U.S. and Europe. Considering the potential for pandemic spread, understanding the development of immunity is paramount to the development of effective counter measures against CHIKV. In this study, we isolated a new CHIKV virus from an acutely infected human patient and developed a defined viral challenge stock in mice that allowed us to study viral pathogenesis and develop a viral neutralization assay. We then constructed a synthetic DNA vaccine delivered by in vivo electroporation (EP) that expresses a component of the CHIKV envelope glycoprotein and used this model to evaluate its efficacy. Vaccination induced robust antigen-specific cellular and humoral immune responses, which individually were capable of providing protection against CHIKV challenge in mice. Furthermore, vaccine studies in rhesus macaques demonstrated induction of nAb responses, which mimicked those induced in convalescent human patient sera. These data suggest a protective role for nAb against CHIKV disease and support further study of envelope-based CHIKV DNA vaccines.

Non-contact helium-based plasma for delivery of DNA vaccines

“…The experimental immunization schedule and specimen collection time points were selected based on other intradermal EP-delivered vaccines reported in the literature using mouse models as well as guinea pig models. 9,[24][25][26][27][28][29] ELISA and ELISpot analysis. To measure antibody titers, an indirect ELISA was performed as described previously.…”

Serological correlates of immune protection conferred by Chikungunya virus infection

“…The cytokines Il-1, Il-6, and Il-10 have been identified as pro-inflammatory markers in the acute phase, and mCP-1, Il-6, Il-8, mIP-1α, mIP-1β, and Th-1 activation with viral persistence in macrophages were identified as markers in the chronic phase of the disease with severe clinical symptoms (2,8,9). In population studies of ChIKV disease, antibody titers have been estimated by IgG and Igm antibody elISA (2,10,11) and neutralizing antibodies by the hemagglutination-inhibition test (hIt), complement-fixation test and by serum microneutralization (SNt) tests (12,13). The 50% plaque reduction neutralization test (PRNt 50 ) was used in clinical evaluation of ChIKV vaccine in a Phase II study (14).…”

“…The 50% plaque reduction neutralization test (PRNt 50 ) was used in clinical evaluation of ChIKV vaccine in a Phase II study (14). Pre-clinical vaccine studies have relied on the estimation of neutralizing antibodies by either PRNt 50 (15) or by SNt and hIt as a measure of protective efficacy of the vaccine (13,16). Recently, a ChIKV-pseudotyped lentiviral vector using the structural proteins of ChIKV and luciferase as reporter gene has been developed as a safe alternative for the use of virus in neutralization assays (17).…”

“…There is compelling evidence that pre-existing immunity to ChIKV is associated with low infection rates in the community, and is protective both in clinical setting as well as in the animal models of infection (13,16,18). A reference serum panel of ChIKV convalescent subjects was used to derive comparative titers of neutralizing antibodies by different methods.…”

Current research and clinical trials for a vaccine against Chikungunya virus

“…Induction of hemagglutination inhibition antibodies, virus neutralizing antibodies, and interferon-γ was observed in Rhesus macaques. 123 A new formulation using noninfectious virus-like particles in vitro was explored against CHIKV infection by Akahata et al in 2010. 124 The virus-like particle vaccines have already been approved by the US Food and Drug Administration for hepatitis B virus and human papillomavirus.…”