Immunization of Aotus monkeys with a functional domain of the Plasmodium falciparum variant antigen induces protection against a lethal parasite line

Abstract

Immunity to Plasmodium falciparum in African children has been correlated with antibodies to the P. falciparum erythrocyte membrane protein 1 (PfEMP1) variant gene family expressed on the surface of infected red cells. We immunized Aotus monkeys with a subregion of the Malayan Camp variant antigen (MCvar1) that mediates adhesion to the host receptor CD36 on the endothelial surface and present data that PfEMP1 is an important target for vaccine development. The immunization induced a high level of protection against the homologous strain. Protection correlated with the titer of agglutinating antibodies and occurred despite the expression of variant copies of the gene during recurrent waves of parasitemia. A second challenge with a different P. falciparum strain, to which there was no agglutinating activity, showed no protection but boosted the immune response to this region during the infection. The level of protection and the evidence of boosting during infection encourage further exploration of this concept for malaria vaccine development.

Figure 1

Parasitemia in control and immunized monkeys challenged with MC R+ P. falciparum parasites. (A) yPyCSP/FA formulation (control); (B) y179/FA formulation; (C) yPyCSP/MF59 formulation (control); (D) y179/MF59 formulation. Parasitemia are given as PEs/μl on a log scale. Drug treatments for high parasitemia are indicated by down arrows, and appearances of secondary peak recrudescence are marked by arrowheads. ‡, Died during trial.

Figure 2

Parasitemia and agglutination results with PEs taken from various peaks during the MC R+ challenge. (A) Agglutination scores of various isolates depicted at 1:25 sera dilution. Agglutination was scored as described (23). (B) Parasitemia courses in monkeys from the Freund's adjuvant groups (immunized and control) tested in A. Arrows indicate the day of challenge PEs were taken. (C) Parasitemia courses in monkeys from the MF59 adjuvant groups (immunized and control) tested in A. Arrows indicate the day of challenge PEs were taken.

Figure 3

Agglutination titers of y179 immunized monkeys with MC R+ parasites on day of MC R+ challenge. (A) y179/FA immunized monkeys; (B) y179/MF59 immunized monkeys.