Abstract:The induction of protective humoral immune responses against sporozoite surface proteins of the human parasite Plasmodium falciparum (Pf) is a prime goal in the development of a preerythrocytic malaria vaccine. The most promising antibody target is circumsporozoite protein (CSP). Although PfCSP induces strong humoral immune responses upon vaccination, vaccine efficacy is overall limited and not durable. Here, we review recent efforts to gain a better molecular and cellular understanding of anti-PfCSP B cell re… Show more
“…In terms of a vaccine design strategy, whether the development of homotypic interactions in an immune response is advantageous or not for both vaccine efficacy and durability remains to be determined. The current working hypothesis in the field posits that highly avid binding to extended NANP repeats, potentially afforded by homotypic interactions, induces strong B-cell activation but limits affinity maturation in germinal centers, which ultimately suppresses the development of antibodies with high affinity to the core NPNA epitope (Cockburn & Seder, 2018; Wahl & Wardemann, 2022). This would account for the robust antibody response to CSP, but also the difficulty in generating long-lived immunity and the generally low levels of somatic hypermutation observed in anti-NANP antibodies (Aye et al, 2020; McNamara et al, 2020; Murugan et al, 2018).…”
The generation of high-quality antibody responses to PfCSP, the primary surface antigen of Plasmodium falciparum sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the IGHV3-33 germline gene, which is among the most prevalent and potent antibody families induced in the anti-CSP immune response and targets the NANP repeat region. Cryo-EM reveals a remarkable spectrum of helical Fab-CSP structures stabilized by homotypic interactions between tightly packed Fabs, many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to CSP and in protection from P. falciparum malaria infection. These data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies, advance our understanding of the mechanism(s) of antibody-mediated protection, and inform next generation CSP vaccine design.
“…In terms of a vaccine design strategy, whether the development of homotypic interactions in an immune response is advantageous or not for both vaccine efficacy and durability remains to be determined. The current working hypothesis in the field posits that highly avid binding to extended NANP repeats, potentially afforded by homotypic interactions, induces strong B-cell activation but limits affinity maturation in germinal centers, which ultimately suppresses the development of antibodies with high affinity to the core NPNA epitope (Cockburn & Seder, 2018; Wahl & Wardemann, 2022). This would account for the robust antibody response to CSP, but also the difficulty in generating long-lived immunity and the generally low levels of somatic hypermutation observed in anti-NANP antibodies (Aye et al, 2020; McNamara et al, 2020; Murugan et al, 2018).…”
The generation of high-quality antibody responses to PfCSP, the primary surface antigen of Plasmodium falciparum sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the IGHV3-33 germline gene, which is among the most prevalent and potent antibody families induced in the anti-CSP immune response and targets the NANP repeat region. Cryo-EM reveals a remarkable spectrum of helical Fab-CSP structures stabilized by homotypic interactions between tightly packed Fabs, many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to CSP and in protection from P. falciparum malaria infection. These data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies, advance our understanding of the mechanism(s) of antibody-mediated protection, and inform next generation CSP vaccine design.
“…The liver phase process where merozoites are formed from sporozoites is called exoerythrocytic schizogony, which takes seven to ten days. 19 The blood phase involves merozoites from the liver that enter circulation and transform into trophozoites and then schizonts that are composed of many merozoites. 20 The schizonts burst, releasing merozoites into the bloodstream that subsequently invade more red blood cells.…”
Section: The P Falciparum -Life Cycle and Vaccine Targetsmentioning
confidence: 99%
“…The liver phase process where merozoites are formed from sporozoites is called exoerythrocytic schizogony, which takes seven to ten days. 19 Figure 1 The P. falciparum life cycle and vaccine specific targets. Mosquito bite injects sporozoites into the circulation ( A ).…”
Section: Introductionmentioning
confidence: 99%
“…NPDP (green), NANP, and NVDP (dark blue) are the main motifs targeted by the antibodies. Used with permission of Rockefeller University Press, from How to induce protective humoral immunity against Plasmodium falciparum circumsporozoite protein, Wahl I, Wardemann H, volume 219/ edition 2, 2022; permission conveyed through Copyright Clearance Center, Inc. 19 ( B ). The RTS, S vaccine; makes use of complete Pfcsp 3D7 C-terminal domain and 18 NANP repeats.…”
Section: Introductionmentioning
confidence: 99%
“…The RTS, S vaccine contains epitopes designed to stimulate both the cell-mediated and humoral adaptive immune systems to produce an optimal immune response against Pf. 19 The “R” stands for the central repeat region of Plasmodium (P.) falciparum circumsporozoite protein (CSP); the “T” for the T-cell epitopes of the CSP; and the ‘S’ for hepatitis B surface antigen (HBsAg). 27 The molecular structure of the vaccine antigen is made up of 19 NANP central tandem repeats and the N-terminus of the amino acids in the hepatitis B surface antigen attached to the C-terminus of the CSP.…”
Malaria vaccines targeting the circumsporozoite protein (CSP) of the
P
.
falciparum
parasite have been overall relatively promising. RTS, S is a pre-erythrocytic recombinant protein-based malaria vaccine that targets CSP. RTS, S effectiveness shows some limited success regardless of its 58% efficacy for severe disease.
P
.
falciparum
circumsporozoite protein (Pfcsp) has stood to be the main candidate protein for most pre-erythrocytic stage vaccines. Studies on the structural and biophysical characteristics of antibodies specific to CSP (anti-CSP) are underway to achieve fine specificity with the CSP polymorphic regions. More recent studies have proposed the use of different kinds of monoclonal antibodies, the use of appropriate adjuvants, ideal vaccination dose and frequency, and improved targeting of particular epitopes for the robust production of functional antibodies and high complement-fixing activity as other potential methods for achieving long-lasting RTS, S. This review highlights recent findings regarding humoral immune responses to CSP elicited by RTS, S vaccine.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
