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Malaria Vaccine Efficacy Could Rely on Parasite's Genotype

NEW YORK (GenomeWeb) – A malaria vaccine may be more effective against parasites whose genotype matches that of the vaccine itself, according to researchers from Harvard University and the Fred Hutchinson Cancer Research Center.

Reporting this week in the New England Journal of Medicine, researchers evaluated malarial genotypes of individuals enrolled in a phase III trial of GlaxoSmithKline's vaccine, RTS,S/ASO1.

The vaccine was previously evaluated in a large phase III trial in Africa in more than 15,000 children and was found to confer "moderate protective efficacy against clinical disease and severe malaria that wanes over time," according to the study authors.

The mechanism by which the vaccine confers protection is incompletely understood, although it is known to target a specific protein produced by the Plasmodium falciparum malaria parasite called circumsporozoite protein. However, the circumsporozoite protein contains regions where polymorphisms can occur, including a conserved tandem repeat with a length polymorphism between 37 and 44 repeat unit, and numerous polymorphisms within the C-terminal region of protein.

Researchers hypothesized the vaccine might be less effective against malaria parasites with polymorphisms in those regions.

To test this theory, they used PCR and next-generation sequencing on both Illumina's MiSeq instrument and Pacific Biosciences' RS II. The researchers targeted and sequenced the circumsporozoite protein C-terminal and as well as a control region with the MiSeq from children enrolled in the clinical trial who had become infected with malaria. They used the PacBio system to sequence the longer repeat region.

Over 4,000 samples were sequenced on the MiSeq and over 3,000 on the PacBio. Samples included patients at multiple time points after they received the vaccine.

Genetic data of the malaria parasite was evaluated from 1,181 kids between the ages of five and 17 months who received the RTS,S vaccine and 909 who received a control vaccine, all of whom had developed clinically confirmed malaria.

Over two-thirds of patents had "complex infections," defined as being founded by two or more distinct parasite lineages, the authors reported. Patients that received the RTS,S vaccine were more likely to have complex infections — 71 percent had complex infections compared to 61 percent of patients who received the control vaccine.

Looking at the relationship between polymorphisms to the C-terminal region and vaccine efficacy, the researchers found that one-year post vaccination, the C-terminal region in the malaria parasite matched that of the vaccine in 139 individuals, but was a mismatch in 1,951 individuals. Thus, cumulative vaccine efficacy against malaria with a perfect genotype match at the C-terminal site was 50.3 percent. For those without a perfect match, efficacy was 33.4 percent.

In addition, efficacy was higher immediately after receiving the vaccine. Through six months post vaccination, efficacy was 70.2 percent in individuals with a matched genotype and 56.3 percent in those with mismatched genotypes.

Looking at the relationship between the number of repeats and vaccine efficacy, the researchers found a non-significant effect with increasing repeats and vaccine efficacy.

The results suggest that among children between the ages of five and 17 months the RTS,S vaccine "has greater activity against malaria parasites with matched circumsporozoite protein allele than against mismatched malaria," the authors concluded, and overall vaccine efficacy will depend on the genotype of the local parasite population.

In addition, the authors noted, "Genetic surveillance of circumsporozoite protein sequences in parasite populations could inform the development of future vaccine candidates targeting polymorphic malaria proteins."

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