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Malaria infection during pregnancy, caused by the sequestering of  Plasmodium falciparum  parasites in the placenta, leads to high infant mortality and maternal morbidity. The parasite-placenta adherence mechanism is mediated by the VAR2CSA protein, a target for natural occurring immunity. Currently, vaccine development is based on its ID1-DBL2Xb domain however little is known about the global genetic diversity of the encoding  var2csa  gene, which could influence vaccine efficacy. In a comprehensive analysis of the  var2csa gene  in >2,000  P. falciparum  field isolates across 23 countries, we found that  var2csa  is duplicated in high prevalence (>25%), African and Oceanian populations harbour a much higher diversity than other regions, and that insertions/deletions are abundant leading to an underestimation of the diversity of the locus. Further, ID1-DBL2Xb haplotypes associated with adverse birth outcomes are present globally, and African-specific haplotypes exist, which should be incorporated into vaccine design.

Global genetic diversity of var2csa in Plasmodium falciparum with implications for malaria in pregnancy and vaccine development