Acquisition of Growth-Inhibitory Antibodies against Blood-Stage Plasmodium falciparum

Abstract

BackgroundAntibodies that inhibit the growth of blood-stage Plasmodium falciparum may play an important role in acquired and vaccine-induced immunity in humans. However, the acquisition and activity of these antibodies is not well understood.MethodsWe tested dialysed serum and purified immunoglobulins from Kenyan children and adults for inhibition of P. falciparum blood-stage growth in vitro using different parasite lines. Serum antibodies were measured by ELISA to blood-stage parasite antigens, extracted from P. falciparum schizonts, and to recombinant merozoite surface protein 1 (42 kDa C-terminal fragment, MSP1-42).ResultsAntibodies to blood-stage antigens present in schizont protein extract and to recombinant MSP1-42 significantly increased with age and were highly correlated. In contrast, growth-inhibitory activity was not strongly associated with age and tended to decline marginally with increasing age and exposure, with young children demonstrating the highest inhibitory activity. Comparison of growth-inhibitory activity among samples collected from the same population at different time points suggested that malaria transmission intensity influenced the level of growth-inhibitory antibodies. Antibodies to recombinant MSP1-42 were not associated with growth inhibition and high immunoglobulin G levels were poorly predictive of inhibitory activity. The level of inhibitory activity against different isolates varied.ConclusionsChildren can acquire growth-inhibitory antibodies at a young age, but once they are acquired they do not appear to be boosted by on-going exposure. Inhibitory antibodies may play a role in protection from early childhood malaria.

Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

“…While a measure of antibody function would be valuable, the lack of robust assays has limited the inclusion of functional antibody measures to assess the contribution of antibody quality to immunity. The growth inhibition assay has yielded inconsistent results with respect to the role of growth inhibitory antibodies in protection (11,55,56). More recently, opsonic phagocytosis assays (14) and neutrophil-based antibody-dependent respiratory burst assays (13) have been developed and applied to a limited number of cohort studies with results suggesting that these assays may function as correlates of immunity.…”

“…Past experiments involving the passive transfer of immunoglobulin from immune adults into P. falciparum-infected individuals provided strong evidence that antibodies (Abs) play an important role in mediating immunity and target the blood stages of infection (4-6). Targets of antibodies include antigens expressed by the merozoite stage of the parasite, and these antibodies function by inhibiting merozoite invasion of red blood cells and by opsonizing merozoites for uptake by phagocytes and antibody-dependent cellular inhibition (7)(8)(9)(10)(11)(12)(13)(14).An important approach for identifying antigens as targets of protective immunity in humans is to assess the acquisition of antibodies and the association between antigen-specific responses and protection from symptomatic malaria in malariaexposed populations (3), particularly in longitudinal cohort studies that prospectively examine the relationship between antibody responses and different malaria-based outcomes over time (15). Studies examining the protective associations for antibodies to merozoite antigens have reported various results (15-24).…”

“…Past experiments involving the passive transfer of immunoglobulin from immune adults into P. falciparum-infected individuals provided strong evidence that antibodies (Abs) play an important role in mediating immunity and target the blood stages of infection (4-6). Targets of antibodies include antigens expressed by the merozoite stage of the parasite, and these antibodies function by inhibiting merozoite invasion of red blood cells and by opsonizing merozoites for uptake by phagocytes and antibody-dependent cellular inhibition (7)(8)(9)(10)(11)(12)(13)(14).…”

Merozoite Surface Protein 1 from Plasmodium falciparum Is a Major Target of Opsonizing Antibodies in Individuals with Acquired Immunity against Malaria

“…Most studies to date have analyzed the direct growth inhibitory potential of MSP-1-specific antibodies in vitro, although a correlation between this mechanism and protective immunity remains elusive. Furthermore, it is controversial whether and under what circumstances MSP-1 contributes to direct growth inhibition of Plasmodium blood stages, since some publications reported MSP-1-specific GI activity (50, 51, 56, 71-75) and others presented contradicting data (17,63,(76)(77)(78). The different results regarding MSP-1-specific GI activity both in previous studies and in our study could have several explanations, i.e., (i) there may be different IgG isotypes or affinities of MSP-1 antibodies that partly inhibit the growth of P. falciparum in vitro, (ii) antibodies may target various MSP-1 epitopes and only some are growth inhibitory, and (iii) the MSP-1 antibody titer may be too low for detectable GI activity in the in vitro assay.…”

PATH Malaria Vaccine Initiative (MVI): Perspectives on the status of malaria vaccine development

“…Unlike P. vivax merozoites, which primarily invade erythrocytes via an association with the Duffy antigen, P. falciparum utilizes a complex network of different proteins from the erythrocyte binding protein (EBA) and reticulocytes binding protein (Rh) families. 42,43 A multi-antigen vaccine containing the critical invasion ligands of P. falciparum, possibly in combination with a partially effective pre-erythrocytic vaccine to reduce initial blood stage parasite levels, may have significant potential.…”