The case for PfEMP1-based vaccines to protect pregnant women againstPlasmodium falciparummalaria

Abstract

Vaccines are very cost-effective tools in combating infectious disease mortality and morbidity. Unfortunately, vaccines efficiently protecting against infection with malaria parasites are not available and are not likely to appear in the near future. An alternative strategy would be vaccines protecting against the disease and its consequences rather than against infection per se, by accelerating the development of the protective immunity that is normally acquired after years of exposure to malaria parasites in areas of stable transmission. This latter strategy is being energetically pursued to develop a vaccine protecting pregnant women and their offspring against mortality and morbidity caused by the accumulation of Plasmodium falciparum-infected erythrocytes in the placenta. It is based on a detailed understanding of the parasite antigen and the host receptor involved in this accumulation, as well as knowledge regarding the protective immune response that is acquired in response to placental P. falciparum infection. Nevertheless, it remains controversial in some quarters whether such a vaccine would have the desired impact, or indeed whether the strategy is meaningful. This article critically examines the relevance of several perceived obstacles to development of a vaccine against placental malaria.

B-Cell Responses to Pregnancy-Restricted and -Unrestricted Plasmodium falciparum Erythrocyte Membrane Protein 1 Antigens in Ghanaian Women Naturally Exposed to Malaria Parasites

“…7), although the proportion of women with FV2-specific memory B-cell frequencies above the negative cutoff did increase with parity [P(r s ϭ 0.86) Ͻ 0.001]. The sustained presence of FV2-specific memory B cells many years after the last pregnancy implies that maintenance of PfEMP1-specific immunological memory does not require regular exposure to antigen, given that essentially all available evidence indicates that expression of VAR2CSA-type PfEMP1 proteins is restricted to pregnancy (29). Furthermore, the finding that the frequency of FV2-specific memory B cells did not depend on parity suggests that exposure to VAR2CSA-type PfEMP1 proteins over the course of a single pregnancy may be sufficient to induce affinity maturation, class switching, and induction of long-term sustainable immunological memory.…”

“…7) above the negative cutoff were detected in about half of these women. This was unexpected given the strong evidence that expression of VAR2CSA-type PfEMP1 is restricted to pregnancy (29). Apart from the trivial explanation of unrecognized or unremembered (unsuccessful) pregnancies mentioned above, it remains a possibility that VAR2CSA-specific immunity can occasionally appear independent of pregnancy.…”

Kinetics of B Cell Responses to Plasmodium falciparum Erythrocyte Membrane Protein 1 in Ghanaian Women Naturally Exposed to Malaria Parasites

“…Expression of VAR2CSA-type PfEMP1 proteins appears restricted to pregnancy, which explains why primigravidae living in areas of stable transmission of P. falciparum parasites are fully susceptible to placental malaria despite enjoying substantial protection from P. falciparum malaria in general, acquired during childhood and adolescence (reviewed in Refs. 28,35). In such areas, susceptibility to placental malaria declines in subsequent pregnancies, reflecting acquisition of specific immunity against the placentasequestering parasites.…”

“…Second, they show that pregnancy is associated with a marked IgG response to VAR2CSA-type PfEMP1 (reviewed in Ref. 28). Third, the levels of these latter Abs decline fairly rapidly postdelivery, when pregnancy-restricted P. falciparum Ags are no longer present (23,29,30).…”

Placental Cytokine and Chemokine Profiles Reflect Pregnancy Outcomes in Women Exposed to Plasmodium falciparum Infection

“…PAM can lead to severe complications for both the mother and the child. During pregnancy, a new organ appears in the maternal body, namely, the placenta, which displays new receptors, such as chondroitin sulfate A (CSA), mediating adherence of P. falciparum-infected erythrocytes (Pf-Es) (4). The sequestration of Pf-Es, accompanied by the infiltration of monocytes into the placenta, is associated with various outcomes, including low birth weight due to fetal growth restriction and preterm delivery, as well as maternal anemia, with substantial rates of morbidity and mortality (5).…”