Memory B-Cell and Antibody Responses Induced by Plasmodium falciparum Sporozoite Immunization

Abstract

BackgroundImmunization of healthy volunteers during receipt of chemoprophylaxis with Plasmodium falciparum sporozoites (CPS-immunization) induces sterile protection from malaria. Antibody responses have long been known to contribute to naturally acquired immunity against malaria, but their association with sterile protection after whole sporozoite immunization is not well established. We therefore studied the induction and kinetics of malaria parasite antigen-specific antibodies and memory B-cells (MBCs) during CPS-immunization and their correlation with protection from challenge infection.MethodsWe assessed humoral reactivity to 9 antigens representing different stages of the life cycle of P. falciparum by performing standardized MBC enzyme-linked immunospot and enzyme-linked immunosorbent assays on peripheral blood mononuclear cells and plasma samples from 38 Dutch volunteers enrolled in 2 randomized controlled clinical trials.ResultsMBCs and antibodies recognizing pre-erythrocytic and cross-stage antigens were gradually acquired during CPS-immunization. The magnitude of these humoral responses did not correlate with protection but directly reflected parasite exposure in CPS-immunization and challenge.ConclusionsHumoral responses to the malarial antigens circumsporozoite protein, liver-stage antigen-1, apical membrane antigen-1, and merozoite surface protein-1 do not to predict protection from challenge infection but can be used as sensitive marker of recent parasite exposure.Clinical Trials RegistrationNCT01236612 and NCT01218893.

Impact of Malaria Preexposure on Antiparasite Cellular and Humoral Immune Responses after Controlled Human Malaria Infection

“…Reactivity to the CSP sporozoite antigen is expected after PfSPZ inoculation and consistent with previous findings (38,39). Increased antibody responses against P. falciparum lysate and EXP-1 likely reflect cross-stage reactivity between late-liver-stage and blood-stage merozoites, while exposure to developing liver stages (LSA-1) in naive volunteers appears insufficient to induce a detectable antibody response.…”

“…Increased antibody responses against P. falciparum lysate and EXP-1 likely reflect cross-stage reactivity between late-liver-stage and blood-stage merozoites, while exposure to developing liver stages (LSA-1) in naive volunteers appears insufficient to induce a detectable antibody response. Similarly, limited exposure to blood-stage-expressed AMA-1, due to early curative treatment, appears to prevent induction of detectable titers in naive volunteers, which is consistent with results even after multiple CHMIs (39). Consistent with preexposure, Tanzanians showed on the group level a greater increase in titers for P. falciparum lysate, AMA-1, and LSA-1 than the previously malaria-naive Dutch.…”

Pre-Erythrocytic Vaccine Candidates in Malaria

“…However, when volunteers were challenged with infection, the volunteers who responded to LS"-1 were not protected from malaria [55]. Further, in malaria-naive volunteers immunized by exposure to bites from infected mosquitoes while receiving chloroquine, 7 % of the volunteers produced antibodies to LS"-1 however, the humoral response did not provide sterile protection from malaria [175].…”

“…In vitro, antibodies to TR"P can block binding of sporozoites to human hepatocytes, and it has been postulated that antibodies could help to prevent infection of the liver [201]. In a study using malaria-naive volunteers infected with P. falciparum while receiving chloroquine to provide sterile immunity, volunteers did not produce antibodies to TR"P or detectable memory " cells [175]. " recent study, using malaria-naive volunteers vaccinated with irradiated sporozoites and subsequently challenged with the homologous strain of P. falciparum (3D7 clone of NF5 ) correlated the magnitude of the antibody response to TR"P with sterile protective immunity [5 ].…”

An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

“…Anti-CSP antibody titers have correlated with protection in some clinical trials [43], but they have also been negatively correlated in one other trial [46]. This is likely because the presence of large amounts of antibodies against a single sporozoite antigen does not necessarily imply the ability of these antibodies to functionally block sporozoites.…”