A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite

Abstract

Development of a highly effective vaccine or antibodies for prevention and ultimately elimination of malaria is urgently needed. Here, we report the isolation of a number of human monoclonal antibodies (mAbs) directed against the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) from several subjects immunized with an attenuated whole sporozoite (SPZ) vaccine (Sanaria® PfSPZ Vaccine). Passive transfer of one of these antibodies, mAb CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. Stoichiometry and affinity of mAb CIS43 for PfCSP indicate two sequential multivalent binding events to six sites: the first 7-fold higher affinity binding event is to a unique “junctional” epitope positioned between the N-terminus and the central repeat domain of PfCSP. Moreover, mAb CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Crystal structures of the CIS43 fragment antigen binding (Fab) in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope’s conformational flexibility, and defined NPN as the structural repeat motif. The demonstration that mAb CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next generation rational vaccine design.

Down‐selecting circumsporozoite protein‐based malaria vaccine: A comparison of malaria sporozoite challenge model

“…All truncated PfCSPs in Imject® Alum conferred high protection (60%‐70%), indicating that all regions contribute to this protection. This result is consistent with other studies identifying protective human mAbs that potently bind to the “junctional” epitope between the N‐terminus and the central repeat of PfCSP . The present study demonstrated that PfCSP‐C immunization conferred protection and anti‐PfCSP‐C Abs reacted with the sporozoites.…”

“…Consistently, the present study revealed that anti‐repeat Abs had higher neutralizing activity in vitro than those of other regions. The superior action of anti‐repeat Abs may be attributable to their multivalent interactions and higher affinity of the repeat region . Therefore, the induction of the Ab titres by the repeat boost is the most potent and effective among the other truncated PfCSP‐boost immunizations against challenge by iv sporozoite injection.…”

“…However, in early studies, a NANP repeat‐based peptide‐in‐adjuvant vaccine failed to induce protective efficacy in field studies . Recently, Kisalu et al reported that a human monoclonal antibody (mAb) that recognizes a unique “junctional” epitope positioned between the N‐terminus and the central repeat region of PfCSP provided sterile protection against the bites of infected mosquitoes in a rodent malaria model. They suggested that this mAb inhibits not only sporozoite motility in the skin but also their invasion of hepatocytes by interfering with the cleavage of PfCSP.…”

Immunoglobulin M, more than just an early responder to malaria

“…Antibodies capable of neutralizing the pre‐erythrocytic sporozoite independent of complement can also prevent malaria infection in vitro and in vivo . For instance, one such antibody binds to and prevents the cleavage of the circumsporozoite protein, which is required for sporozoite infection of hepatocytes …”

Plasmodium falciparum pre-erythrocytic stage vaccine development

“…Recent studies have described mAbs CIS23, CIS34, CIS42 and CIS43 isolated from P. falciparum CSPspecific memory B-cells from volunteers who had been immunized with the PfSPZ vaccine [41][42][43]. CIS43 and MGG4 mAb had cross-reactivity with NPDP, NVDP and NANP repeat regions and the CTD fragment, thereby enabling them to bind to this protein and alter its cleavage after processing to limit hepatocyte invasion in an animal model [42][43][44]. The next step will involve clinical trials being run by PATH's Malaria Vaccine Initiative for determining whether mAbs can induce protection against P. falciparum infection.…”