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ABSTRACTProtective immunity to Plasmodium falciparummalaria acquired after natural exposure is largely antibody mediated. IgG-specific P. falciparumEMP1 (PfEMP1) proteins on the infected erythrocyte surface are particularly important. The transient antibody responses and the slowly acquired protective immunity probably reflect the clonal antigenic variation and allelic polymorphism of PfEMP1. However, it is likely that other immune-evasive mechanisms are also involved, such as interference with formation and maintenance of immunological memory. We measured PfEMP1-specific antibody levels by enzyme-linked immunosorbent assay (ELISA) and memory B-cell frequencies by enzyme-linked immunosorbent spot (ELISPOT) assay in a cohort of P. falciparum-exposed nonpregnant Ghanaian women. The antigens used were a VAR2CSA-type PfEMP1 (IT4VAR04) with expression restricted to parasites infecting the placenta, as well as two commonly recognized PfEMP1 proteins (HB3VAR06 and IT4VAR60) implicated in rosetting and not pregnancy restricted. This enabled, for the first time, a direct comparison in the same individuals of immune responses specific for a clinically important parasite antigen expressed only during well-defined periods (pregnancy) to responses specific for comparable antigens expressed independent of pregnancy. Our data indicate that PfEMP1-specific B-cell memory is adequately acquired even when antigen exposure is infrequent (e.g., VAR2CSA-type PfEMP1). Furthermore, immunological memory specific for VAR2CSA-type PfEMP1 can be maintained for many years without antigen reexposure and after circulating antigen-specific IgG has disappeared. The study provides evidence that natural exposure to P. falciparumleads to formation of durable B-cell immunity to clinically important PfEMP1 antigens. This has encouraging implications for current efforts to develop PfEMP1-based vaccines.

ABSTRACTPlacenta-sequestering Plasmodium falciparumparasites causing pregnancy-associated malaria express pregnancy-specific variant surface antigens (VSAPAM). We report here that VSAPAM-expressing patient isolates adhere strongly to the choriocarcinoma cell line BeWo and that the BeWo line can be used to efficiently select for VSAPAMexpression in vitro.

In areas of intense Plasmodium falciparum transmission, protective immunity is acquired during childhood in parallel with acquisition of agglutinating antibodies to parasite-encoded variant surface antigens (VSA) expressed on parasitized red blood cells. In a semi-immune child in such an area, clinical disease is caused mainly by parasites expressing VSA not recognized by preexisting VSA-specific antibodies in that child. Such malaria episodes are known to cause an increase in agglutinating antibodies specifically recognizing VSA expressed by the parasite isolate causing the illness, whereas antibody responses to other parasite isolates are relatively unaffected. However, the detailed kinetics of this VSA antibody acquisition are unknown and hence were the aim of this study. We show that P. falciparum malaria in Ghanaian children generally caused a rapid and sustained increase in variant-specific VSA antibody levels, while more transient and limited increases in levels of antibodies to VSA expressed by other parasite isolates were also seen. Plasma VSA antibody levels were positively correlated with the age of the healthy plasma donors but negatively correlated with the age of the parasite donors (the malaria patient). The data from this first detailed longitudinal study of acquisition of VSA antibodies support the hypothesis that naturally acquired protective immunity to P. falciparum malaria is mediated, at least in part, by VSA-specific antibodies.

ABSTRACTIn areas of intense Plasmodium falciparumtransmission, protective immunity is acquired during childhood in parallel with acquisition of agglutinating antibodies to parasite-encoded variant surface antigens (VSA) expressed on parasitized red blood cells. In a semi-immune child in such an area, clinical disease is caused mainly by parasites expressing VSA not recognized by preexisting VSA-specific antibodies in that child. Such malaria episodes are known to cause an increase in agglutinating antibodies specifically recognizing VSA expressed by the parasite isolate causing the illness, whereas antibody responses to other parasite isolates are relatively unaffected. However, the detailed kinetics of this VSA antibody acquisition are unknown and hence were the aim of this study. We show that P. falciparummalaria in Ghanaian children generally caused a rapid and sustained increase in variant-specific VSA antibody levels, while more transient and limited increases in levels of antibodies to VSA expressed by other parasite isolates were also seen. Plasma VSA antibody levels were positively correlated with the age of the healthy plasma donors but negatively correlated with the age of the parasite donors (the malaria patient). The data from this first detailed longitudinal study of acquisition of VSA antibodies support the hypothesis that naturally acquired protective immunity to P. falciparummalaria is mediated, at least in part, by VSA-specific antibodies.

ABSTRACTPlacenta-sequestered Plasmodium falciparumparasites that cause pregnancy-associated malaria (PAM) in otherwise clinically immune women express distinct variant surface antigens (VSAPAM) not expressed by parasites in nonpregnant individuals. We report here that parasites from the peripheral blood of clinically immune pregnant women also express VSAPAM, making them a convenient source of VSAPAMexpressors for PAM vaccine research.

Plasmodium falciparumerythrocyte membrane protein 1 (PfEMP1) is an important malaria virulence factor. The protein family can be divided into clinically relevant subfamilies. ICAM-1-binding group A PfEMP1 proteins also bind endothelial protein C receptor and have been associated with cerebral malaria in children. IgG to these PfEMP1 proteins is acquired later in life than that to group A PfEMP1 not binding ICAM-1.

ABSTRACTCerebral malaria (CM) is a potentially deadly outcome of Plasmodium falciparummalaria that is precipitated by sequestration of infected erythrocytes (IEs) in the brain. The adhesion of IEs to brain endothelial cells is mediated by a subtype of parasite-encoded erythrocyte membrane protein 1 (PfEMP1) that facilitates dual binding to host intercellular adhesion molecule 1 (ICAM-1) and endothelial protein receptor C (EPCR). The PfEMP1 subtype is characterized by the presence of a particular motif (DBLβ_motif) in the constituent ICAM-1-binding DBLβ domain. The rate of natural acquisition of DBLβ_motif-specific IgG antibodies and the ability to induce such antibodies by vaccination are unknown, and the aim of this study was to provide such data. We used an enzyme-linked immunosorbent assay (ELISA) to measure DBLβ-specific IgG in plasma from Ghanaian children with malaria. The ability of human immune plasma and DBLβ-specific rat antisera to inhibit the interaction between ICAM-1 and DBLβ was assessed using ELISA and in vitroassays of IE adhesion under flow. The acquisition of DBLβ_motif-specific IgG coincided with age-specific susceptibility to CM. Broadly cross-reactive antibodies inhibiting the interaction between ICAM-1 and DBLβ_motif domains were detectable in immune plasma and in sera of rats immunized with specific DBLβ_motif antigens. Importantly, antibodies against the DBLβ_motif inhibited ICAM-1-specific in vitroadhesion of erythrocytes infected by four of five P. falciparumisolates from cerebral malaria patients. We conclude that natural exposure to P. falciparumas well as immunization with specific DBLβ_motif antigens can induce cross-reactive antibodies that inhibit the interaction between ICAM-1 and a broad range of DBLβ_motif domains. These findings raise hope that a vaccine designed specifically to prevent CM is feasible.