Deciphering the protective role of adaptive immunity to CHIKV/IRES a novel candidate vaccine against Chikungunya in the A129 mouse model

Abstract

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, recently re-emerged in Africa and spread to islands in the Indian Ocean, the Indian subcontinent, and to South East Asia. Viremic travelers have also imported CHIKV to the Western hemisphere highlighting the importance of CHIKV in public health. In addition to the great burden of arthralgic disease, which can persist for months or years, epidemiologic studies have estimated case-fatality rates of ~0.1%, principally from neurologic disease in older patients. There are no licensed vaccines or effective therapies to prevent or treat human CHIKV infections. We have developed a live CHIKV vaccine (CHIKV/IRES) that is highly attenuated yet immunogenic in mouse models, and is incapable of replicating in mosquito cells. In this study we sought to decipher the role of adaptive immunity elicited by CHIKV/IRES in protection against wild-type CHIKV infection. A single dose of vaccine effectively activated T cells with an expansion peak on day 10 post immunization and elicited memory CD4+ and CD8+ T cells that produced IFN-γ, TNF-α and IL-2 upon restimulation with CHIKV/IRES. Adoptive transfer of CHIKV/IRES-immune CD4+ or CD8+ T cells did not confer protection against wtCHIKV-LR challenge. By contrast, passive immunization with anti-CHIKV/IRES immune serum provided protection, and a correlate of a minimum protective neutralizing antibody titer was established. Overall, our findings demonstrate the immunogenic potential of the CHIKV/IRES vaccine and highlight the important role that neutralizing antibodies play in protection against an acute CHIKV infection.

Prime-Boost Immunization Strategies against Chikungunya Virus

“…Some of these observations, however, have been made under in vitro conditions. Here and in our previous work (12), observations have suggested that ADE may occur in CHIKV infection in mice with low IgG titers, below 10 4 . This important observation reveals the need for further work to provide indications on how to avoid ADE induced by vaccination.…”

“…We and others have demonstrated a clear correlation between antibodies and protection against CHIKV infection in both mice (10,12,49) and humans (50), highlighting the importance of antibody responses for immunity against CHIKV. This was also observed here: high anti-CHIKV antibody levels correlated inversely with viremia and foot swelling after challenge.…”

“…Undoubtedly, this study has reemphasized the importance of these identified epitopes in generating CHIKV-neutralizing antibodies, and such information would serve well for future anti-CHIKV vaccine formulations. Although T cells cannot prevent CHIKV infection, as evidenced by adoptive transfer studies (T cells and antibodies) on mice (10), T cells are essential for clearing infected cells in the formation of functional and long-lived immunity, including T helper cells (10,49,60). The combination of priming with DREPEnv and boosting with p62-E1 protein or MVA-CHIKV generated unmatched T cell immune responses, with a mean well over 10 4 SFU/10 6 splenocytes.…”

“…Several CHIKV vaccine candidates are under development (9), including attenuated (10)(11)(12)(13)(14)(15)(16) or inactivated (17)(18)(19) CHIKV, alphavirus chimeras (20)(21)(22), and subunit (23)(24)(25)(26)(27) and genetic (21,(28)(29)(30)(31) vaccines. Moreover, we have reported previously on the construction and preclinical evaluation of novel CHIKV vaccine candidates, based on attenuated CHIKV (12) or recombinant modified vaccinia virus Ankara (MVA) expressing CHIKV antigens (MVA-CHIKV) (29), that were able to induce strong immunogenicity and efficacy in a mouse model.…”

Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus

“…Thus, it was of importance to assess the individual merits of new CHIKV vaccine platforms in a more stringent animal model that more closely resembles a clinical setting. Antibody responses are known to correlate with protection against CHIKV (29)(30)(31)(32)(33)(34)(35)(36), but CD4 T cell responses may also be important (37)(38)(39). Thus, it was of importance to determine the potential immunological differences that our vaccine candidate might display.…”