Prime-Boost Immunization Strategies against Chikungunya Virus

Abstract

Chikungunya virus (CHIKV) is a reemerging mosquito-borne alphavirus that causes debilitating arthralgia in humans. Here we describe the development and testing of novel DNA replicon and protein CHIKV vaccine candidates and evaluate their abilities to induce antigen-specific immune responses against CHIKV. We also describe homologous and heterologous prime-boost immunization strategies using novel and previously developed CHIKV vaccine candidates. Immunogenicity and efficacy were studied in a mouse model of CHIKV infection and showed that the DNA replicon and protein antigen were potent vaccine candidates, particularly when used for priming and boosting, respectively. Several prime-boost immunization strategies eliciting unmatched humoral and cellular immune responses were identified. Further characterization by antibody epitope mapping revealed differences in the qualitative immune responses induced by the different vaccine candidates and immunization strategies. Most vaccine modalities resulted in complete protection against wild-type CHIKV infection; however, we did identify circumstances under which certain immunization regimens may lead to enhancement of inflammation upon challenge. These results should help guide the design of CHIKV vaccine studies and will form the basis for further preclinical and clinical evaluation of these vaccine candidates. IMPORTANCE As of today, there is no licensed vaccine to prevent CHIKV infection. In considering potential new vaccine candidates, a vaccinethat could raise long-term protective immunity after a single immunization would be preferable. While humoral immunity seems to be central for protection against CHIKV infection, we do not yet fully understand the correlates of protection. Therefore, in the absence of a functional vaccine, there is a need to evaluate a number of different candidates, assessing their merits when they are used either in a single immunization or in a homologous or heterologous prime-boost modality. Here we show that while single immunization with various vaccine candidates results in potent responses, combined approaches significantly enhance responses, suggesting that such approaches need to be considered in the further development of an efficacious CHIKV vaccine.

Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus

“…which a large portion (180 nucleotides) of the nsP3 replicase gene region has been deleted (9,10). We have shown that this deletion is stable and does not revert (9), and results in this study have extended and corroborated these findings.…”

“…Accordingly, we infected a separate group of 6 naive cynomolgus macaques ( Figure 1; Δ5nsP3-B) with a dose of the Δ5 virus corresponding to that used for vaccination (1 × 10 5 plaque-forming units, PFU). The s.c. route of injection in the upper back (s.c., n = 4) was chosen to mimic the route used for vaccination and challenge, while the route of inoculation s.c. at the back of the wrist (i.w., n = 2) was used to allow monitoring of possible localized joint swelling as it was done in mouse models (8)(9)(10). Within the first days after infection, viremia could readily be detected in all animals ( Figure 6B).…”

“…Animals receiving the Δ5 virus were immunized only once on day 42 (group A), whereas the other animals were primed with D on day 0 and further boosted with either D (DD regimen) or M (DM regimen) on day 42. Our previous findings that a DM prime-boost gives very strong immune responses (10,11,14) prompted us to choose to evaluate this heterologous combination instead of testing M alone. A fourth control group of animals received saline only on days 0 and 42.…”

“…The third candidate vaccine is a recombinant modified vaccinia Ankara virus, MVA-CE (hereafter M) that expresses the full-length CHIKV C-E3-E2-6K-E1 polyprotein (8,10).…”

“…We recently developed a number of CHIKV vaccine candidates based on the La Reunion (LR-CHIKV) strain of East Central South African (ECSA) genotype. These were able to induce protective immunity against CHIKV infection in mice (8)(9)(10)(11). Here, we have evaluated the safety, immunogenicity, and efficacy of 3 of those candidates in nonhuman primates.…”