Chikungunya Virus Vaccine Candidate Incorporating Synergistic Mutations Is Attenuated and Protects Against Virulent Virus Challenge

Incorporating previously described attenuating mutations into a single chikungunya virus live-attenuated vaccine candidate synergistically improves safety without compromising immunogenicity in a mouse model of disease. These mutations serve as components of a vaccine toolkit that can enhance rational vaccine development. Background Chikungunya virus (CHIKV) is an arbovirus that periodically emerges to cause large epidemics of arthritic disease. Although the robust immunity elicited by live-attenuated virus (LAV) vaccine candidates makes them attractive, CHIKV vaccine development has been hampered by a high threshold for acceptable adverse events. Methods We evaluated the vaccine potential of a recently described LAV, skeletal muscle-restricted virus (SKE), that exhibits diminished replication in skeletal muscle due to insertion of target sequences for skeletal muscle-specific miR-206. We also evaluated whether these target sequences could augment safety of an LAV encoding a known attenuating mutation, E2 G82R. Attenuation of viruses containing these mutations was compared with a double mutant, SKE G82R. Results SKE was attenuated in both immunodeficient and immunocompetent mice and induced a robust neutralizing antibody response, indicating its vaccine potential. However, only SKE G82R elicited diminished swelling in immunocompetent mice at early time points postinoculation, indicating that these mutations synergistically enhance safety of the vaccine candidate. Conclusions These data suggest that restriction of LAV replication in skeletal muscle enhances tolerability of reactogenic vaccine candidates and may improve the rational design of CHIKV vaccines.

Automated summary

Incorporating attenuating mutations into a chikungunya virus vaccine candidate improves safety without compromising immunogenicity, showing promise for rational vaccine design.