Introduction

Consortial Project 2 studied the human genetic factors suspected to influence the antibody response to malaria parasite antigens, with a particular focus on antigens that are being strongly considered for vaccine development.

Objectives & Coordination

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.

Sampling locations

Burkina Faso, Kenya, Mali, Senegal, Sri Lanka, Sudan, Tanzania.

Partner studies

Each partner study conducted epidemiological surveys to measure the immune response to malaria, in order to investigate any correlation between levels of infection and clinical illness.

The partner studies differed in their epidemiological study design and in the precise variables that are measured, but what all had in common is that they have provided samples of serum and DNA to a central repository. This allowed all partner studies to share genetic data and anti-malarial antibody measurements made in a reference laboratory using a common set of laboratory protocols.

Publications

• Host genetic polymorphisms and serological response against malaria in a selected population in Sri Lanka
  Dewasurendra RL, Jeffreys A, Gunawardena SA, Chandrasekharan NV, Rockett K, Kwiatkowski D, & Karunaweera ND
  Malaria Journal, 2018; 17 473
  10.1186/s12936-018-2622-9
• Genetic determinants of anti-malarial acquired immunity in a large multi-centre study
  Shelton et al.
  Malaria Journal, 2015; 14 333
  10.1186/s12936-015-0833-x
• Novel Insights Into the Protective Role of Hemoglobin S and C Against Plasmodium falciparum Parasitemia
  Mangano et al.
  Journal of Infectious Diseases, 2015; 212(4) 626-34
  10.1093/infdis/jiv098
• G6PD gene variants and its association with malaria in a Sri Lankan population
  Dewasurendra et al.
  Malaria Journal, 2015; 14 93
  10.1186/s12936-015-0603-9
• Glucose-6-phosphate dehydrogenase polymorphisms and susceptibility to mild malaria in Dogon and Fulani, Mali
  Maiga et al.
  Malaria Journal, 2014; 13 270
  10.1186/1475-2875-13-270
• Human candidate polymorphisms in sympatric ethnic groups differing in malaria susceptibility in Mali
  Maiga et al.
  PLoS One, 2013; 8(10) e75675
  10.1371/journal.pone.0075675
• Genetic polymorphisms associated with anti-malarial antibody levels in a low and unstable malaria transmission area in southern Sri Lanka
  Dewasurendra et al.
  Malaria Journal, 2012; 11 281
  doi:10.1186/1475-2875-11-281
• A global network for investigating the genomic epidemiology of malaria
  Malaria Genomic Epidemiology Network
  Nature, 2008; 456(7223) 732-7
  10.1038/nature07632