Allele Specificity of Gamma Interferon Responses to the Carboxyl-Terminal Region of Plasmodium falciparum Merozoite Surface Protein 1 by Kenyan Adults with Naturally Acquired Immunity to Malaria

Abstract

Cross-sectional seroepidemiological studies of populations naturally exposed to Plasmodium falciparum suggest an association between protection from malaria and circulating antibodies to the carboxyl terminus of merozoite surface protein 1 (MSP1) Infection with Plasmodium spp., the protozoan parasites responsible for malaria, results in an estimated 350 to 500 million infections per year with an ensuing 1 to 2 million deaths, the majority of which are caused by Plasmodium falciparum (45). Adults who have maintained lifelong residence in areas where malaria transmission is stable and of high intensity gradually develop naturally acquired immunity, an age-related phenomenon marked by a reduced frequency and severity of clinical malaria and high-density blood stage parasitemia relative to that of infants and children. Maintaining naturally acquired immunity is thought to require continuing exposure to malaria blood stage antigens mediated through asymptomatic low-density blood stage infection. A malaria vaccine that would accelerate the development of naturally acquired immunity during infancy and childhood has been a high priority for many years. The recent success of vector interventions, such as insecticidetreated bed nets, in decreasing transmission of P. falciparum in sub-Saharan Africa suggests that a blood stage vaccine would also be desirable in order to maintain the strength and duration of naturally acquired immunity among adults (17)..Merozoite surface protein 1 (MSP1) is one of several candidates that have been considered for a blood stage vaccine. The primary ϳ195-kDa MSP1 protein is expressed during schizogony and is processed initially to form a 42-kDa carboxyl-terminal fragment (MSP1 42 ) that remains attached to the merozoite surface. A second proteolytic cleavage results in the shedding of a 33-kDa fragment (MSP1 33 ) with formation of a 19-kDa carboxyl-terminal fragment (MSP1 19 ) anchored to the merozoite surface during invasion of the red blood cell (RBC) (4, 5). The 19-kDa fragment of MSP1 contains the major B-cell epitopes (18), the recognition of which is enhanced by T-helper epitopes in the 33-kDa fragment (1). Antibodies to MSP1 19

Humoral and Cellular Immunity to Plasmodium falciparum Merozoite Surface Protein 1 and Protection From Infection With Blood-Stage Parasites

“…Natural malaria infections in endemic areas display significant genetic heterogeneity and antigenic diversity [46], which complicate the correlation of antigen-specific immunity with strain-specific protection from infection. Studies of strain-specific immunity to MSP1 42 are further challenged by the fact that major T-cell and B-cell epitopes are encoded in segments of msp1 that have undergone recombination, leading to different haplotypes that are not easily sequenced from mixed-strain infections [29,33]. Using disparate yet region-specific genotyping methods for msp1, we observed allele-specific immunologic correlations of protection for antibodies to MSP1 19 [33] but apparently only for children, not adults.…”

“…Enzyme-linked immunosorbent spot assays (ELISPOT) and enzyme-linked immunosorbent assays (ELISAs) were performed as previously described [28,29] by incubating PBMCs for 84 hours with 5 µg/mL MSP1 42 3D7, MSP1 42 FVO, or M2 3D7 peptide. IFN-γ and IL-10 ELISA responses were considered positive if the culture supernatant contained ≥20 pg/mL following stimulation with malaria antigen.…”

Age-Related Differences in Naturally Acquired T Cell Memory to Plasmodium falciparum Merozoite Surface Protein 1

“…Although our study is limited by the small samples size, results show that the overall frequency of antigen-specific CD4 and CD8 T-cells that produced IFN-γ in response to MSP1 42 were low and did not appear to differ according to parasitemia or ages ranging from 0.5 to 5 years and ≥18 years but there was a shift in hierarchy among various T-cell subsets responsive to MSP1 42 such that the T EM subset was the dominant cell type in adults in contrast to children who had more phenotypically naïve-like, T N cells. These shifts were observed not only for IFN-γ producing CD4 cells, which might be anticipated based on the presumed importance of CD4 helper T-cells in generating and maintaining antibody mediated responses by B-cells, but also for CD8 T-cells, which are thought to be important in generating immunity to pre-erythrocytic rather than blood stage malaria antigens [31], [32]. Categorizing samples based on the presence of parasitemia or parasite density did not appear to influence IFN-γ responses T-cell subset dominance, however most of our study participants were aparasitemic and asymptomatic.…”

Inhibitory Humoral Responses to the Plasmodium falciparum Vaccine Candidate EBA-175 Are Independent of the Erythrocyte Invasion Pathway

“…In the face of such a challenge, there has been a recent renewed interest in developing blood-stage vaccines for malaria, specifically strain-transcending vaccines based on a combination of blood-stage antigens (24,38,42). Although a recombinant EBA-175 vaccine is currently in phase I clinical trials (43), few other blood-stage vaccine candidates have progressed beyond phase I clinical trials, largely due to low levels of protection and allele-specific immunity (42,(44)(45)(46)(47)(48).…”