A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

Abstract

There is a need to develop a single and highly effective vaccine against the emerging chikungunya virus (CHIKV), which causes a severe disease in humans. Here, we have generated and characterized the immunogenicity profile and the efficacy of a novel CHIKV vaccine candidate based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). MVA-CHIKV was stable in cell culture, expressed the CHIKV structural proteins, and triggered the cytoplasmic accumulation of Golgi apparatus-derived membranes in infected human cells. Furthermore, MVA-CHIKV elicited robust innate immune responses in human macrophages and monocyte-derived dendritic cells, with production of beta interferon (IFN-␤), proinflammatory cytokines, and chemokines. After immunization of C57BL/6 mice with a homologous protocol (MVA-CHIKV/MVA-CHIKV), strong, broad, polyfunctional, and durable CHIKVspecific CD8؉ T cell responses were elicited. The CHIKV-specific CD8 ؉ T cells were preferentially directed against E1 and E2 proteins and, to a lesser extent, against C protein. CHIKV-specific CD8؉ memory T cells of a mainly effector memory phenotype were also induced. The humoral arm of the immune system was significantly induced, as MVA-CHIKV elicited high titers of neutralizing antibodies against CHIKV. Remarkably, a single dose of MVA-CHIKV protected all mice after a high-dose challenge with CHIKV. In summary, MVA-CHIKV is an effective vaccine against chikungunya virus infection that induced strong, broad, highly polyfunctional, and long-lasting CHIKV-specific CD8 ؉ T cell responses, together with neutralizing antibodies against CHIKV. These results support the consideration of MVA-CHIKV as a potential vaccine candidate against CHIKV. IMPORTANCEWe have developed a novel vaccine candidate against chikungunya virus (CHIKV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). Our findings revealed that MVA-CHIKV is a highly effective vaccine against chikungunya virus, with a single dose of the vaccine protecting all mice after a high-dose challenge with CHIKV. Furthermore, MVA-CHIKV is highly immunogenic, inducing strong innate responses: high, broad, polyfunctional, and long-lasting CHIKV-specific CD8 ؉ T cell responses, together with neutralizing antibodies against CHIKV. This work provides a potential vaccine candidate against CHIKV.

Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus

“…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).…”

“…Middle, the DREP-E (D) replicon DNA vaccine (9). Bottom, the recombinant modified vaccinia virus Ankara MVA-CE (M) vaccine (8) has a cDNA copy of the CHIKV structural gene cassette (C-E3-E2-6K-E1) inserted into the MVA genome and is expressed under the control of the MVA sE/L promoter. (B) Immunization schedule of cynomolgus macaques.…”

“…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).…”

“…The Δ5, D, and M vaccine candidates have been described (8)(9)(10). The stability of the 180 nucleotides long deletion in Δ5 was originally determined after 5 passages in Vero cells (9), and herein, the analysis was extended to include 10 passages.…”

“…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.…”