IgM, IgG, and IgG Subclass Antibody Responses to Plasmodium falciparum Proteins in Naïve, Malaria-Vaccinated and Semi-Immune Volunteers after Controlled Human Malaria Infection

The immune response to malaria vaccines is generally stronger in malaria-naive individuals than in those with lifelong exposure. The immunological basis for this is unclear. IgM, total IgG, and IgG subclass (IgG1, IgG2, IgG3, and IgG4) antibody responses against 21 pre-erythrocytic and erythrocytic Plasmodium falciparum proteins before and after controlled human malaria infection (CHMI) via the direct venous inoculation of 3,200 P. falciparum sporozoites (PfSPZ) were compared in three groups of volunteers: 1) malaria-naïve (n = 22); 2) malaria-naïve immunized with a PfSPZ chemoattenuated vaccine (PfSPZ-CVac) (n = 27); and 3) lifelong malaria-exposed individuals from Africa (n = 20), including those with normal hemoglobin (n = 11) or sickle cell trait (n = 9). Before and after CHMI, PfSPZ-CVac-immunized individuals exhibited higher levels of IgM and IgG to CSP and SSP-2/TRAP than the other two groups. Malaria-experienced Africans exhibited more intense and broader antibody responses to blood-stage (BS) antigens than naïve and vaccinated individuals, longer pre-patent periods (PPPs), and fewer symptoms. Among confirmed malaria cases, cytophilic IgG1 and IgG3 antibodies to BS antigens were positively associated with longer PPPs, whereas IgG2, IgG4, and IgM were not. IgG2 and IgG4 (noncytophilic) P. falciparum-specific antibodies were higher in the semi-immune group, including elevated anti-CSP IgG4 (regulatory) levels. The IgM response in African volunteers post-CHMI was stronger than that in malaria-naïve and vaccinated individuals and had the hallmark of a secondary memory response. Cytophilic immunoglobulins controlled parasitaemia better than noncytophilic immunoglobulins. However, elevation of the latter in lifelong malaria-exposed individuals could be associated with regulatory responses and hamper vaccine efficacy.