A Study Deciphers the Factors that Influence the Protective Efficacy of the RTS,S Malaria Candidate Vaccine

 ISGlobal participated in an international study that used state-of-the-art genome sequencing technology to help explain the protective effects of RTS,S, the world's most advanced malaria vaccine candidate. They found that genetic variants of the parasite protein targeted by the vaccine influence its capacity to protect small children against the disease. The study, led by the Broad Institue, the Harvard School of Public Health and the Fred Hutchinson Cancer Research Institute and with the participation of 11 African institutions involved in the phase 3 clinical trial for RTS,S, was published in the  New England Journal of Medicine.

 The RTS,S vaccine, that offers partial protection against malaria, is designed to induce immunity against a parasite-specific protein known as circumsporozoite (CSP), expressed at the surface of the parasite's infectious form. The CSP protein is genetically diverse, although the RTS,S contains only one version (or allele) of it.  "The parasite surely developed such variability as a strategy to evade the host's immune system" explains Dr. Carlota Dobaño, researcher at ISGlobal and co-author of the study. Therefore, the present study sought to determine whether the vaccine's effectiveness depends on whether the infecting parasite is of the same strain, in other words expresses the same allele, than that used in the vaccine.

Thanks to an international collaboration, researchers could analyse  blood samples from more than 5.000 children that participated in the phase 3 clinical trial of the vaccine, between 2009 and 2013. Using advanced genomic and statistical technologies, the authors found that the vaccine-mediated protection in children between 5 and 17 months of age was higher when the CSP alleles were identical to those of the vaccine (50%) than when they were different (33%).    In other words, the vaccine is more effective in children infected with parasites carrying the same alleles than in those carrying different alleles. 

These results reveal fundamental aspects of the malaria immunity conferred by RTS,S. a non-specific component offers protection regardless of the parasite strain, whereas a strain-specific component provides additional protection if the parasite's CSP is identical to the one used in the vaccine. The authors conclude that vaccine efficacy will greatly depend on the proportion of identical alleles within the local parasite population. 

However, Dr. Dobaño, that leads a research Project at ISGlobal on the mechanisms of malaria immunity, adds: "Apart from this, that helps explain the partial efficacy of the RTS,S vaccine, we are currently investigating additional factors we believe may also influence the children's response to the vaccine, with the hope of improving it."  

In any case, the approach used in this collaboration which involved more than 15 countries and 25 institutions, can be of great relevance to the design of multivalent vaccines (i.e. that contain more than one allele or antigenic variant) against other infectious diseases caused by highly variable pathogens.  

Reference:

Neafsey DE, Juraska M, Bedford T, Benkeser D, Valim C, et al.Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine. N Engl J Med. 2015 Oct 21.