A Novel MVA Vectored Chikungunya Virus Vaccine Elicits Protective Immunity in Mice

Abstract

BackgroundChikungunya virus (CHIKV) is a re-emerging arbovirus associated with febrile illness often accompanied by rash and arthralgia that may persist for several years. Outbreaks are associated with high morbidity and create a public health challenge for countries affected. Recent outbreaks have occurred in both Europe and the Americas, suggesting CHIKV may continue to spread. Despite the sustained threat of the virus, there is no approved vaccine or antiviral therapy against CHIKV. Therefore, it is critical to develop a vaccine that is both well tolerated and highly protective.Methodology/Principal FindingsIn this study, we describe the construction and characterization of a modified Vaccinia virus Ankara (MVA) virus expressing CHIKV E3 and E2 proteins (MVA-CHIK) that protected several mouse models from challenge with CHIKV. In particular, BALB/c mice were completely protected against viremia upon challenge with CHIKV after two doses of MVA-CHIK. Additionally, A129 mice (deficient in IFNα/β) were protected from viremia, footpad swelling, and mortality. While high anti-virus antibodies were elicited, low or undetectable levels of neutralizing antibodies were produced in both mouse models. However, passive transfer of MVA-CHIK immune serum to naïve mice did not protect against mortality, suggesting that antibodies may not be the main effectors of protection afforded by MVA-CHIK. Furthermore, depletion of CD4+, but not CD8+ T-cells from vaccinated mice resulted in 100% mortality, implicating the indispensable role of CD4+ T-cells in the protection afforded by MVA-CHIK.Conclusions/SignificanceThe results presented herein demonstrate the potential of MVA to effectively express CHIKV E3-E2 proteins and generate protective immune responses. Our findings challenge the assumption that only neutralizing antibodies are effective in providing protection against CHIKV, and provides a framework for the development of novel, more effective vaccine strategies to combat CHIKV.

The Evolution of Poxvirus Vaccines

“…HBs clinical [321] 30 CTL and 16 HTL epitopes preclinical [322] Hepatitis C NS3, NS4 and NS5B (genotype 1b) preclinical and clinical [323,324] E1 and E2 (genotype 1b) preclinical [325] C, E1 and E2, p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B (genotype 1a) preclinical [326] Chikungunya C, E3, E2, 6K and E1 preclinical [327] E3 and E2 preclinical [328] E3-E2, 6K-E1 or E3-E2-6K-E1 preclinical [329] Dengue Envelope (Dengue type 2 virus) preclinical [330] Envelope (Dengue type 3 virus) preclinical [331] Ebola GP (Zaire and Sudan strains) preclinical [332] CCHF GP preclinical [333] SARS Spike protein preclinical [334][335][336][337] Spike or nucleocapsid proteins preclinical [338] Nucleocapsid preclinical [339] MERS Spike protein preclinical [340] RSV F or G glycoprotein preclinical [342][343][344] Rift valley fever Gn/Gc GP preclinical [345,346] Rabies Glycoprotein preclinical [347] JEV Membrane (prM) and envelope (E) proteins (Korean strain) preclinical [348][349][350] B cell, CTL and Th multiple linear epitopes (SA14 strain) preclinical [351] Measles HA preclinical [352] F and HA preclinical [94,353] CMV Soluble GP B (gB) preclinical [354] UL55 (surface glycoprotein), UL83 (tegument protein) and UL123/e4 (nuclear protein) preclinical [355] pp65 (tegument protein) and CMV immediate early gene IE1 preclinical [356] pp65-2, gB and IE1 (Rhesus CMV) preclinical…”

Chikungunya Virus Vaccines: Viral Vector–Based Approaches: Table 1.

“…In addition, the passive transfer of sera from immunized mice did not protect against lethal challenge in A129 mice. However, CD4 + T cells were critical in protecting mice against challenge [22]. Together, these 2 independent studies clearly demonstrate that neutralizing antibodies can confer protection against CHIKV infections; however, a role for cellular responses cannot be ruled out.…”

Dissecting the Role of E2 Protein Domains in Alphavirus Pathogenicity

“…Ifnar1 Ϫ/Ϫ mice have previously been shown to be a useful vaccine and pathogenicity model for CHIKV, producing similar pathology (with similar cell tropism) and high viremia, which are characteristic of CHIKV disease in humans (49,50). When given either 10 2 PFU or 10 4.5 PFU in the footpad, CHIK-GFP and SFV-GFP were uniformly lethal in this model ( Fig.…”