Long‐lived Plasmodium falciparum specific memory B cells in naturally exposed Swedish travelers

Abstract

Antibodies (Abs) are critical for immunity to malaria. However, Plasmodium falciparum specific Abs decline rapidly in absence of reinfection, suggesting impaired immunological memory. This study determines whether residents of Sweden that were treated for malaria following international travel maintained long‐lasting malaria‐specific Abs and memory B cells (MBCs). We compared levels of malaria‐specific Abs and MBCs between 47 travelers who had been admitted with malaria at the Karolinska University Hospital between 1 and 16 years previously, eight malaria‐naïve adult Swedes without histories of travel, and 14 malaria‐immune adult Kenyans. Plasmodium falciparum‐lysate‐specific Ab levels were above naïve control levels in 30% of the travelers, whereas AMA‐1, merozoite surface protein‐142, and merozoite surface protein‐3‐specific Ab levels were similar. In contrast, 78% of travelers had IgG‐MBCs specific for at least one malaria antigen (59, 45, and 28% for apical merozoite antigen‐1, merozoite surface protein‐1, and merozoite surface protein‐3, respectively) suggesting that malaria‐specific MBCs are maintained for longer than the cognate serum Abs in the absence of re‐exposure to parasites. Five travelers maintained malaria antigen‐specific MBC responses for up to 16 years since the diagnosis of the index episode (and had not traveled to malaria‐endemic regions in the intervening time). Thus P. falciparum can induce long‐lasting MBCs, maintained for up to 16 years without reexposure.

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

“…This suggests that robust immunological memory can result even when antigen exposure is infrequent (as is the case for VAR2CSA). This conclusion is supported by data on acquisition of immunity in settings with a low level of endemicity, in travelers, and in experimentally infected mice (17,59,71). The finding that FV2-specific memory B-cell frequencies did not depend on time since last pregnancy (Fig.…”

“…It has been suggested that this could explain the paradoxical inverse relationship between parasite exposure and acquired immunity observed in some studies (58,59). However, the antigen specificity of phenotypically identified "atypical"/"exhausted" memory B cells observed in these papers was not estab- lished, and other recent studies did not find evidence that B-cell memory for P. falciparum antigens is deficient (16,17) or that "atypical" P. falciparum-specific B cells are dysfunctional (18). Careful studies of the phenotype-function relationships among B-cell subsets with known antigen specificity are clearly warranted.…”

“…Thus, it has been speculated that continuous or regular exposure to P. falciparum antigens is required to maintain B-cell memory, but also that formation of B-cell memory is compromised in areas of intense parasite transmission (58,59). Several recent reports indicating the formation of durable B-cell memory following natural exposure to P. falciparum antigens add to the ambiguity (15)(16)(17)(18). If immunological memory to malaria were indeed defective, it could undermine the sustainability of recent reductions in parasite transmission, as it might leave formerly protected individuals vulnerable if transmission should reappear (60,61).…”

“…The evidence supporting the hypothesis of a fragile or dysfunctional immunological memory to P. falciparum includes the often transient IgG responses in children with malaria (5-9), apparent interference with antigen presentation (10,11), "masking" of surface-exposed IgG epitopes (12), and expansion of "atypical" or "exhausted" B cells after prolonged exposure to P. falciparum antigens (13,14). Conversely, the hypothesis is challenged by recent evidence that P. falciparum-specific B-cell memory can be acquired efficiently and maintained for extended periods in the absence of exposure (15)(16)(17) and by data suggesting that "atypical" P. falciparum-specific memory B cells are not functionally "exhausted" (18).…”

Immunoprofiling of the Tryptophan-Rich Antigen Family in Plasmodium vivax

“…However, several studies have demonstrated stable antibody responses to PfMSP1-19, P. falciparum merozoite surface protein 2 (PfMSP2), and PfAMA1 antigens (31,33,34). Moreover, longlived antibody and memory B-cell responses to P. falciparum (PfMSP1-19, PfMSP2, PfCSP, and PvAMA1) and P. vivax (PvMSP1-19, PvAMA1, and PvDBP) were identified recently (35,36). Here, we also observed that antibodies against several PvTRAgs (TRAg_13, TRAg_15, and TRAg_29) and PvMSP1-19 were detected in individuals from Jiangsu Province, China (where malaria is not recently endemic), who had had a vivax malaria episode 5 or 12 years before.…”