Differing rates of antibody acquisition to merozoite antigens in malaria: implications for immunity and surveillance

Abstract

Antibodies play a key role in acquired human immunity to (Pf) malaria and target merozoites to reduce or prevent blood-stage replication and the development of disease. Merozoites present a complex array of antigens to the immune system, and currently, there is only a partial understanding of the targets of protective antibodies and how responses to different antigens are acquired and boosted. We hypothesized that there would be differences in the rate of acquisition of antibodies to different antigens and how well they are boosted by infection, which impacts the acquisition of immunity. We examined responses to a range of merozoite antigens in 2 different cohorts of children and adults with different age structures and levels of malaria exposure. Overall, antibodies were associated with age, exposure, and active infection, and the repertoire of responses increased with age and active infection. However, rates of antibody acquisition varied between antigens and different regions within an antigen following exposure to malaria, supporting our hypothesis. Antigen-specific responses could be broadly classified into early response types in which antibodies were acquired early in childhood exposure and late response types that appear to require substantially more exposure for the development of substantial levels. We identified antigen-specific responses that were effectively boosted after recent infection, whereas other responses were not. These findings advance our understanding of the acquisition of human immunity to malaria and are relevant to the development of malaria vaccines targeting merozoite antigens and the selection of antigens for use in malaria surveillance.

Dichotomous miR expression and immune responses following primary blood-stage malaria

“…Interestingly, correlations are primarily for antigen MSP2 (and for 1 of 2 MSP1 proteins), but not for the other antigens MSP3, MSP4, MSP5, or MSP6. It is known that MSP1 and MSP2 are more prominent components of the initial response to malaria infection, and are generated after low levels of exposure, whereas other antigens require more exposure (28). An alternative explanation may be that MSP2 responses, particularly MSP2-specific IgG responses, are due to germinal center responses, rather than extrafollicular response of the other IgM responses against the other MSP antigens (29).…”

Evaluating antidisease immunity to malaria and implications for vaccine design

“…42,43 Overall, in light of this evidence, it may be difficult to determine the right combinations for a multi-component erythrocytic stage vaccine because humoral responses to various components will differ in magnitude and kinetics, and vary based on the level of exposure. 81 Furthermore, relatively high antibody levels do not necessarily protect children from symptomatic malaria, although they are associated with reduced parasitaemia at clinical presentation. Therefore, other mechanisms, besides humoral responses, may preclude symptomatic malaria in children exposed to perennial parasite transmission.…”

Moderately Neutralizing Epitopes in Nonfunctional Regions Dominate the Antibody Response to Plasmodium falciparum EBA-140

“…One such family of proteins is the erythrocyte binding-like (EBL) family of proteins that are involved in tight junction formation, including erythrocyte-binding antigen 140 (EBA-140) (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), EBA-175 (15)(16)(17)(18)(19)(20)(21)(22), EBA-181 (8,10,(23)(24)(25)(26), EBL1 (27), and Duffy-binding protein (DBP) (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). EBL family proteins share a similar domain structure ( Fig.…”

“…Antibodies to EBA-140 are correlated with acquired immunity and protection in individuals in regions where malaria is endemic (8,9,11,14). This acquired immunity is age and antibody response dependent (8,9,11,14). Individuals with higher antibody titers to EBA-140 show greater protection against infection than those with low titers (9).…”

“…Individuals with higher antibody titers to EBA-140 show greater protection against infection than those with low titers (9). IgG responses are higher for the RII domain of EBA-140 and EBA-175, although responses to RIII to RV are also correlated with protection (9,14). Polysera from individuals from different continents and countries show reactivity to EBA-140, suggesting EBA-140 is a conserved target of protective immunity and therefore a viable vaccine candidate (8,9,11,13,14).…”