Vaccines for emerging infections: Chikungunya vaccine

Background: Chikungunya virus (CHIKV) infection is a febrile illness that is rarely fatal, but causes incapacitating arthralgia that persists in convalescence. Unusual clinical presentations with high morbidity are reported in the recent epidemics. The virus genome is under selective pressure to adapt to arthropod and human hosts to sustain transmission. Vaccination is the most feasible and cost-effective option to block virus transmission during epidemics. However, in the absence of data from deployment of CHIKV vaccine, and lack of reference reagents, the challenge was to qualify a field isolate as vaccine strain, and to define a correlate of protective immunity for clinical development. Methods & Materials: Phylogenetic reconstruction of CHIKV sequences was performed in MEGA5. Selection was inferred by Codon-based Maximum Likelihood estimates in HyPhy. Genome sequencing and adventitious agents testing were performed by Next Generation Sequencing (NGS). Neutralizing antibodies were estimated by 50% Plaque Reduction Neutralization Test (PRNT50) in CHIKV convalescent sera, vaccine antisera and in cross neutralization studies. Antibody isotypes and avidity were estimated by ELISA. GMP vaccine production was established, and pre-clinical toxicity studies were outsourced to a GLP laboratory. Results: The study identified a novel E1-K211E mutation under significant positive selection in 2009-2010 isolates which formed a distinct clade within the ECSA (East, Central, and South African) genotype. Vaccine antisera and CHIKV convalescent sera from 2006-2013, cross neutralized Asian and ECSA heterotypic variants from 1963 to 2010. Vaccine virus banks were certified free of adventitious agents by sensitive NGS technology. High immunogenicity was established by iterative inactivation methods and animal testing. The candidate vaccine elicited neutralizing antibodies in animals comparable to the levels in convalescent subjects (GMT, 1021 by PRNT50) (95%CI 763, 1366). Spearman-Karber estimates of median effective and protective doses were established in animal challenge studies. Neutralizing IgG3 isotype and antibodies with high avidity were elicited by the vaccine. In GLP pre-clinical toxicity studies, the vaccine elicited no adverse and arthritogenic effect in animals. Conclusion: The indigenously developed Chikungunya vaccine using a field isolate of the virus, provides a scientific basis for developing safe, immunogenic and cost-effective vaccine for emerging infections, and to address an unmet healthcare need in developing countries.