Long-Term Clinical Protection from Falciparum Malaria Is Strongly Associated with IgG3 Antibodies to Merozoite Surface Protein 3

Abstract

BackgroundSurrogate markers of protective immunity to malaria in humans are needed to rationalize malaria vaccine discovery and development. In an effort to identify such markers, and thereby provide a clue to the complex equation malaria vaccine development is facing, we investigated the relationship between protection acquired through exposure in the field with naturally occurring immune responses (i.e., induced by the parasite) to molecules that are considered as valuable vaccine candidates.Methods and FindingsWe analyzed, under comparative conditions, the antibody responses of each of six isotypes to five leading malaria vaccine candidates in relation to protection acquired by exposure to natural challenges in 217 of the 247 inhabitants of the African village of Dielmo, Senegal (96 children and 121 older adolescents and adults). The status of susceptibility or resistance to malaria was determined by active case detection performed daily by medical doctors over 6 y from a unique follow-up study of this village. Of the 30 immune responses measured, only one, antibodies of the IgG3 isotype directed to merozoite surface protein 3 (MSP3), was strongly associated with clinical protection against malaria in all age groups, i.e., independently of age. This immunological parameter had a higher statistical significance than the sickle cell trait, the strongest factor of protection known against Plasmodium falciparum. A single determination of antibody was significantly associated with the clinical outcome over six consecutive years in children submitted to massive natural parasite challenges by mosquitoes (over three parasite inoculations per week). Finally, the target epitopes of these antibodies were found to be fully conserved.ConclusionsSince anti-MSP3 IgG3 antibodies can naturally develop along with protection against P. falciparum infection in young children, our results provide the encouraging indication that these antibodies should be possible to elicit by vaccination early in life. Since these antibodies have been found to achieve parasite killing under in vitro and in vivo conditions, and since they can be readily elicited by immunisation in naïve volunteers, our immunoepidemiological findings support the further development of MSP3-based vaccine formulations.

Isolation and expression of UB05, a Plasmodium falciparum antigen recognised by antibodies from semi-immune adults in a high transmission endemic area of the Cameroonian rainforest

“…Furthermore, the absence of fever in parasitised subjects with high concentrations of anti-UB05 antibodies suggests a role for UB05 in limiting clinical malaria. The correlation between higher concentrations of antibodies against malaria with reduced parasitaemia and morbidity has been shown for a number of vaccine candidates including the serine rich antigen (SERA) and MSP3 (38,39). The direct mechanism of action of these specific antibodies in reducing fever, even in the presence of malaria parasites, remains to be determined.…”

Evidence That the Erythrocyte Invasion Ligand PfRh2 is a Target of Protective Immunity against Plasmodium falciparum Malaria

“…Prior studies suggested that IgG1 and IgG3 are the predominant subclasses that respond to merozoite Ags (35,45,46,47); however, to the best of our knowledge, no study has examined IgG subclass responses to any PfRh protein. IgG1 and IgG3 are cytophilic Abs with a high potential to activate complement and with high affinity for FcgRs, thus having the ability to activate T cell-mediated cytotoxicity and Ab-dependent phagocytosis.…”

Chemokine levels and parasite- and allergen-specific antibody responses in children and adults with severe or uncomplicatedPlasmodium falciparummalaria

“…During the fi rst months of life, maternal antibodies may mediate partial protection against P. falciparum infection [4,5], while naturally acquired protective immunity against malaria is slow to develop, remains incomplete, and requires repeated exposure to infection which will generate memory B cells, which produce specifi c IgG subclasses able to neutralize the blood developmental stages of the parasite [6][7][8][9][10]. The secretion of cytokines and chemokines by T cells, monocytes, and NK cells is another essential prerequisite for the regulation of cellular effector mechanisms against P. falciparum blood-stage parasites [11], but infl ammatory cytokines and chemokines may also exacerbate disease manifestation and organ-specifi c pathogenesis [12].…”