Antibodies to variant
surface antigen have been implicated as mediators of
malaria immunity in studies measuring
immunoglobulin G (
IgG) binding to infected erythrocytes.
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is an important target for these
antibodies, but no study has directly linked the presence of PfEMP1
antibodies in children to protection. We measured plasma
IgG levels to the
cysteine-rich interdomain region 1alpha (CIDR1alpha) of VAR4 (VAR4-CIDR1alpha), a member of a semiconserved PfEMP1 subfamily, by
enzyme-linked
immunosorbent assay in 561 Tanzanian individuals, who were monitored clinically for 7 months. The participants resided in Mkokola (a high-transmission village where
malaria is holoendemic) or Kwamasimba (a moderate-transmission village). For comparison, plasma
IgG levels to two
merozoite surface protein 1 (
MSP1) constructs, MSP1-19 and
MSP1 block 2, and a control CIDR1 domain were measured. VAR4-CIDR1alpha
antibodies were acquired at an earlier age in Mkokola than in Kwamasimba, but after the age of 10 years the levels were comparable in the two villages. After controlling for age and other covariates, the risk of having
anemia at enrollment was reduced in VAR4-CIDR1alpha responders for Mkokola (adjusted odds ratio [AOR], 0.49; 95% confidence interval [CI], 0.29 to 0.88; P = 0.016) and Kwamasimba (AOR, 0.33; 95% CI, 0.16 to 0.68; P = 0.003) villages. The risk of developing
malaria fever was reduced among individuals with a measurable VAR4-CIDR1alpha response from Mkokola village (AOR, 0.51; 95% CI, 0.29 to 0.89; P = 0.018) but not in Kwamasimba. Antibody levels to the
MSP1 constructs and the control CIDR1alpha domain were not associated with morbidity protection. These data strengthen the concept of developing
vaccines based on PfEMP1.