Genetic determinants of the immune response to malaria

People living in malaria-endemic regions acquire some level of protective immunity against the disease as they get older. Although the immunity is only partial, it reduces the amount of illness and death caused by malaria, and one of the main goals of vaccine developers is to achieve a similar level of immunity in young children. Unfortunately, we still lack a good understanding of how protective immunity against malaria works, despite decades of scientific effort to dissect the molecular mechanisms.

To better understand why people differ in their immune response to the parasite, and how this affects their level of resistance to the disease, we:

• Worked with partner studies in a number of geographical locations to collected serum samples, DNA and epidemiological data from 17,000 people
• Developed a standardised, scalable antibody-detection assay for known malarial antigens to allow an integrated analysis across study sites
• Completed measurements of IgG antibody levels against the P. falciparum vaccine candidate antigens MSP1, MSP2, CSP and AMA1, and total IgE levels
• Genotyped 200 single nucleotide polymorphisms (SNPs) across candidate genes and published malaria-associated SNPs

We then used the resulting data to investigate two basic questions:

1. Across multiple study sites, do SNPs in immune response genes correlate with antimalarial antibody levels?
2. Within individual sites, do both SNPs in immune response genes and antimalarial antibody levels correlate with key clinical phenotypic variables, for example disease severity?

This project began shortly after MalariaGEN was formed in 2005, and has greatly influenced our approach to collaborative science.