Functional human IgA targets a conserved site on malaria sporozoites

Abstract

Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as Plasmodium falciparum, is poorly characterized, despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to P. falciparum sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the P. falciparum circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies.

Human antibodies against noncircumsporozoite proteins block Plasmodium falciparum parasite development in hepatocytes

“…Mass spectrometry or microarrays can be used to identify mAb targets, while their functionality will have to be tested with hepatic cell lines and in in vivo models. The identified mAbs may further support structure-based vaccine identification, design, and clinical development as previously shown for CSP and RH5 vaccines ( 34 , 35 ).…”

Protective effects of combining monoclonal antibodies and vaccines against the Plasmodium falciparum circumsporozoite protein

“…Since the SPZ binding of repeat mAbs is antagonized by other repeat mAbs (Fig 6B -6D) but not N-or C-CSP mAbs (Figs 5C and 6E and S4B), we next determined how a polyclonal PfCSP antibody response would affect the SPZ binding of repeat mAbs. The Pb-PfCSP-SPZ binding of A750-labeled CIS43, L9, or 317 were assessed in the presence of serum pooled from ten naïve mice immunized three times with R21 (virus-like particles composed of 19 NANP repeats and C-CSP fused to a single hepatitis B surface antigen [39]), fifteen naïve US adults immunized three times with irradiated PfSPZ [51], and ten children or adults with the highest FL-rCSP titers from a cohort of 758 Malian volunteers naturally exposed to malaria [52]. Serum from a malaria-naïve US adult was included as a negative control.…”

“…Clinical specimens (i.e., peripheral blood mononuclear cells and serum) were derived from malaria-naïve, healthy adults in the VRC 314 clinical trial (https://clinicaltrials.gov/; NCT02015091), a multi-institution, phase 1, open-label, dose-escalation trial with controlled human malaria infection designed to assess the safety, immunogenicity, and protective efficacy of the Sanaria PfSPZ Vaccine administered by intravenous or intramuscular injection [51]. Serum was also collected from a cohort study conducted in the rural village of Kalifabougou, Mali [52,58].…”

Atypical B cells upregulate co-stimulatory molecules during malaria and secrete antibodies with T follicular helper cell support

“…CD21/CD27 staining (bottom panels) within total (left) and Pf + (right) CD10 -IgD -B cells, with gating to identify actBCs, MBCs and atBCs. (B) Percentages of atBCs, MBCs and actBCs within the total, Pf + and HA + IgD -CD10 -B cell populations in children(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) years; n=34) at baseline (filled circles) and 7 days after febrile malaria (empty squares), Malian adults (n=20) and malaria-naïve U.S. adults (n=15) at their baseline. Each dot indicates an individual, connected lines show paired samples, bars show means.…”