An international team led by researchers from the Broad Institute of MIT and Harvard, the Harvard T.H. Chan School of Public Health, and Fred Hutchinson Cancer Research Center have used genomic methods to uncover key biological insights that help explain the protective effects of the malaria vaccine candidate, RTS,S/AS01 (RTS,S).
Applying highly sensitive sequencing technology to more patient samples than previously tested, the team was able to determine that genetic variation in the protein targeted by RTS,S influences the vaccine’s ability to ward off malaria in young children. The work, which was published online October 21st by the New England Journal of Medicine (NEJM), could inform future vaccine development.
RTS,S is designed to target a fragment of a specific protein, circumsporozoite (CS), that sits on the surface of the Plasmodium falciparum parasite. The CS protein is capable of provoking an immune response that can prevent parasites from infecting the liver, where they typically mature and reproduce before dispersing and invading red blood cells, leading to symptomatic malaria. RTS,S aims to trigger that response as a way to protect against the disease. However, the CS protein is genetically diverse – perhaps due to its evolutionary role in the immune response – and RTS,S includes only one version (or “allele”) of the protein. The current study sought to test whether alleles of CS that matched the one targeted by RTS,S were linked with better vaccine protection.
Through a collaboration with the vaccine division of the healthcare company GlaxoSmithKline, researchers from Harvard and the Broad obtained blood samples from over 5,000 of the approximately 15,000 infants and children who participated in the vaccine’s phase 3 trial across 11 study sites in Africa between 2009 and 2013. The researchers were sent samples when the first symptomatic cases appeared in those vaccinated, as well as samples from all participants at month 14 and month 20 following vaccination. By sequencing those samples, the team determined that, while RTS,S provided at least partial protection against all strains of the parasite, it was significantly more effective at preventing malaria in children with matched allele parasites than in preventing malaria with mismatched allele parasites. The same effect was not noted in infants.
Previous studies during the RTS,S’s phase 2 trials had not detected an allele-specific effect for this vaccine candidate. However, the current study benefited from a larger sample size and technological advances that made it possible to read the genetic samples with much greater sensitivity that, for instance, allowed for the detection of rare alleles and multiple parasite infections.
This approach can now be applied not only to malaria but also to other major infectious diseases that involve highly variable vaccine targets. It is already being applied in HIV vaccine trials. Furthermore, the work underscores how a full and comprehensive catalogue of the genetic diversity of key pathogens could inform the design of vaccines.
RTS,S is the first malaria vaccine candidate to complete phase 3 trials. Originally designed by scientists at GlaxoSmithKline (GSK) in 1987, development of the vaccine is now being advanced by a public-private partnership between GSK and PATH Malaria Vaccine Initiative.