Novel Attenuated Chikungunya Vaccine Candidates Elicit Protective Immunity in C57BL/6 mice

Abstract

Chikungunya virus (CHIKV) is a reemerging mosquito-borne alphavirus that has caused severe epidemics in Africa and Asia and occasionally in Europe. As of today, there is no licensed vaccine available to prevent CHIKV infection. Here we describe the development and evaluation of novel CHIKV vaccine candidates that were attenuated by deleting a large part of the gene encoding nsP3 or the entire gene encoding 6K and were administered as viral particles or infectious genomes launched by DNA. The resulting attenuated mutants were genetically stable and elicited high magnitudes of binding and neutralizing antibodies as well as strong T cell responses after a single immunization in C57BL/6 mice. Subsequent challenge with a high dose of CHIKV demonstrated that the induced antibody responses protected the animals from viremia and joint swelling. The protective antibody response was long-lived, and a second homologous immunization further enhanced immune responses. In summary, this report demonstrates a straightforward means of constructing stable and efficient attenuated CHIKV vaccine candidates that can be administered either as viral particles or as infectious genomes launched by DNA. IMPORTANCESimilar to other infectious diseases, the best means of preventing CHIKV infection would be by vaccination using an attenuated vaccine platform which preferably raises protective immunity after a single immunization. However, the attenuated CHIKV vaccine candidates developed to date rely on a small number of attenuating point mutations and are at risk of being unstable or even sensitive to reversion. We report here the construction and preclinical evaluation of novel CHIKV vaccine candidates that have been attenuated by introducing large deletions. The resulting mutants proved to be genetically stable, attenuated, highly immunogenic, and able to confer durable immunity after a single immunization. Moreover, these mutants can be administered either as viral particles or as DNA-launched infectious genomes, enabling evaluation of the most feasible vaccine modality for a certain setting. These CHIKV mutants could represent stable and efficient vaccine candidates against CHIKV.

Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus

“…In this study ,we evaluated 3 different CHIKV vaccine candidates and regimens in nonhuman primates ( Figure 1A). The first vaccine candidate, Δ5nsP3 (hereafter Δ5), is an attenuated virus in , an infectious attenuated virus carrying a 60 amino acid-long deletion in the nsP3 replicase protein (9). Middle, the DREP-E (D) replicon DNA vaccine (9).…”

“…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.…”

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

“…We apologize to all whose work could not be referenced because of formatting and length restrictions. Other live-attenuated CHIKV vaccine strategies include deletions in viral genes (187,188), modification of glycosaminoglycan binding (138), alphavirus chimeras (189,190), and codon alteration (191). As reversion is a major safety concern with live-attenuated vaccines, a CHIKV vaccine containing a combination of attenuation strategies could diminish reversion and pathogenicity.…”

Chikungunya

“…There are currently no vaccines available for chikungunya virus, although some are in development. 1,2,5 …”