Malaria-Induced Acquisition of Antibodies toPlasmodium falciparumVariant Surface Antigens

Abstract

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.Plasmodium falciparum malaria remains one of the leading health problems of the world. In areas where malaria is endemic, substantial clinical protection is acquired during the first decade of life and the majority of malaria-related morbidity and mortality are concentrated in young children (reviewed in reference 27). This acquisition of protective immunity is paralleled by increases in levels of antibodies capable of agglutinating red blood cells (RBC) infected by late developmental stages of malaria parasites (20,21). The agglutination is mediated by antibodies recognizing variant surface antigens (VSA) inserted by the parasites into the RBC membrane (22,31). The best characterized of these VSA is P. falciparum erythrocyte membrane protein 1, which mediates adhesion of parasitized RBC to a number of specific receptors in the host vasculature (3,4,7,(23)(24)(25)(28)(29)(30). This in vivo adhesion, termed sequestration, is thought to be an important parasite survival strategy and a key element in the pathogenesis of P. falciparum malaria (18). Previous studies have shown that P. falciparum parasites causing clinical disease in semi-immune children express VSA not recognized by preexisting variantspecific antibodies and that malaria episodes cause an increase in antibodies specifically recognizing VSA expressed by the parasite isolate causing illness (10,15,20). However, the detailed kinetics of changes in VSA antibody levels in relation to clinical episodes are not known, particularly during the period shortly after the clinical episode, and the aim of the present ...

Plasmodium falciparum Variant Surface Antigen Expression Varies Between Isolates Causing Severe and Nonsevere Malaria and Is Modified by Acquired Immunity

“…Although the culture time needed to obtain sufficient parasite material varied between isolates, there was no significant correlation between time in culture, age, or category of parasite donor and recognition of the isolates by plasma Abs (data not shown). Our rate of success in adapting the clinical P. falciparum isolates to in vitro culture in this study is comparable to that obtained in similar studies (6,7).…”

Virulence in malaria: an evolutionary viewpoint

“…This variability is afforded by the multiple copies in the genome of their coding gene, denoted var (Baruch et al 1995;Smith et al 1995;Su et al 1995). These antigens are recognized by the immune system in a highly variantspecific way (Marsh & Howard 1986;Forsyth et al 1989;Newbold et al 1992;Iqbal et al 1993;Reeder et al 1994;Giha et al 1998;Bull et al 1999;Giha et al 1999;Nielsen et al 2002;Ofori et al 2002) although there appears to be some cross-reactivity between variants (Aguiar et al 1992;Chattopadhyay et al 2003). Low titres (Marsh et al 1989) and lack of recognition by antibody to the variant expressed by the infecting type has been associated with disease severity in field studies (Bull et al 1998(Bull et al , 2000Giha et al 2000;Nielsen et al 2002).…”

Plasmodium berghei sporozoite challenge of vaccinated BALB/c mice leads to the induction of humoral immunity and improved function of CD8+ memory T cells

“…People in endemic areas develop after repeated infections a nonsterile immunity against malaria [2] that is supposed to be based on antibodies against blood-stage antigens and IFN-γ made by CD4 + T cells [5,6]. Antibodies to sporozoites are also present in people living in endemic areas but at very low titers and after years of repeated exposure [37].…”

“…In contrast, the acquisition of anti-parasite immunity takes years to decades, although transmigrant studies show that adults may acquire immunity more rapidly than children [3,4]. It is supposed that anti-parasite immunity is based mainly on antibodies recognising variant surface antigens on the membranes of infected erythrocytes whereas immune responses against preerythrocytic forms seem to play a minor role [5,6]. Naturally acquired immunity is never sterile but enables adults in endemic areas to be infected without clinical symptoms and with low parasite densities.…”

“…With regard to our results one explanation could be that anti-sporozoite antibodies support the maintenance of CSP-specific memory T cells but also facilitate the activation of these memory T cells in case of reinfection with Plasmodium sporozoites. This issue needs to be further investigated.People in endemic areas develop after repeated infections a nonsterile immunity against malaria [2] that is supposed to be based on antibodies against blood-stage antigens and IFN-γ made by CD4 + T cells [5,6]. Antibodies to sporozoites are also present in people living in endemic areas but at very low titers and after years of repeated exposure [37].…”