A Novel ChimericPlasmodium vivaxCircumsporozoite Protein Induces Biologically Functional Antibodies That Recognize both VK210 and VK247 Sporozoites

Abstract

A successful vaccine against Plasmodium vivax malaria would significantly improve the health and quality of the lives of more than 1 billion people around the world. A subunit vaccine is the only option in the absence of long-term culture of P. vivax parasites. The circumsporozoite protein that covers the surface of Plasmodium sporozoites is one of the best-studied malarial antigens and the most promising vaccine in clinical trials. We report here the development of a novel "immunologically optimal" recombinant vaccine expressed in Escherichia coli that encodes a chimeric CS protein encompassing repeats from the two major alleles, VK210 and VK247. This molecule is widely recognized by sera from patients naturally exposed to P. vivax infection and induces a highly potent immune response in genetically disparate strains of mice. Antibodies from immunized animals recognize both VK210 and VK247 sporozoites. Furthermore, these antibodies appear to be protective in nature since they cause the agglutination of live sporozoites, an in vitro surrogate of sporozoite infectivity. These results strongly suggest that recombinant CS is biologically active and highly immunogenic across major histocompatibility complex strains and raises the prospect that in humans this vaccine may induce protective immune responses.Outside of sub-Saharan Africa, Plasmodium vivax is the most prevalent of all human malarias. In addition to being present in tropical and subtropical regions, the ability of the parasite to complete its mosquito cycle at temperatures as low as 15°C has also allowed it to be spread in temperate climates. A unique feature of P. vivax is that some strains are capable of causing delayed infection by remaining latent for several months in the liver before emerging into the circulation to manifest clinical symptoms. Such individuals have been known to maintain transmission of malaria in areas where it is no longer naturally transmitted (41). Although P. vivax is usually not fatal, it is responsible for ca. 50% of all malaria cases worldwide (20). The large number of clinical cases and the severe morbidity this type of malaria causes contributes to a serious economic impact in developing countries. Recently, reports of severe forms of malaria caused by P. vivax infection have begun to appear (42). However, due to the fact that the disease caused by P. vivax is less lethal than P. falciparum, investments made to develop a vaccine against this parasite are lagging far behind. There is a need for concerted efforts toward developing vaccines to control the global transmission of P. vivax infections.Malaria parasites, while developing within hepatocytes, do not cause clinical illness and therefore are ideal targets for designing vaccines to protect children and malaria-naive adults against infection. Immunization with irradiation-attenuated malaria sporozoites has long been shown to induce protection against experimental sporozoite challenge in animal models and in humans (13,25), and currently efforts are ongoing to develop go...

Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand T fh cells and promote germinal center induction

“…In addition to these quantitative effects on the antibody response, VMP001-ICMV immunization also changed the qualitative nature of the antibody response, promoting a more balanced Th1/Th2 response (both in terms of T-cell cytokine production and antibody isotypes) and broadening the antibody targets within VMP001, including epitopes implicated in protection against Plasmodium (5). We previously reported that immunization with Freund's adjuvant, a very strong but toxic adjuvant for small-animal experimental immunization, could elicit responses against multiple epitopes within VMP001 (5). Here we have made the important advance of achieving broad antibody responses using clinically relevant adjuvant materials.…”

“…VMP001 was prepared as previously described (5,6). Synthesis of ICMVs was performed as described previously with slight modifications (10).…”

“…To date, however, there have been limited attempts to advance vaccines for P. vivax. We recently developed VMP001, a recombinant protein antigen composed of CSP core sequences derived from two widespread isolates of P. vivax (5,6). Although VMP001 mixed with either alum or Montanide elicits antigen-specific antibody responses (5,6), adjuvants capable of eliciting high-affinity antibodies against protective regions within CSP, which may lead to opsonization of sporozoites (7) or inhibition of their entry into hepatocytes (8), are of great interest.…”

PATH Malaria Vaccine Initiative (MVI): Perspectives on the status of malaria vaccine development

“…44,45 A leading PvCSP approach involves a chimeric circumsporozoite construct, expressed in E. coli, that contains major CS repeats from the two major alleles (VK210 and VK247). 46 Antibodies from immunized mice recognized both VK210 and VK247 sporozoites and cause agglutination of live sporozoites, an in vitro surrogate of sporozoite infectivity. 46 A leading PvRII antigen, also produced in E. coli, has been demonstrated to elicit relevant antibodies, using an in vitro binding inhibition assay, following immunization of Rhesus macaques with PvRII formulated with when administered with either Alhydrogel, Montanide ISA720 or AS02 adjuvant.…”

“…46 Antibodies from immunized mice recognized both VK210 and VK247 sporozoites and cause agglutination of live sporozoites, an in vitro surrogate of sporozoite infectivity. 46 A leading PvRII antigen, also produced in E. coli, has been demonstrated to elicit relevant antibodies, using an in vitro binding inhibition assay, following immunization of Rhesus macaques with PvRII formulated with when administered with either Alhydrogel, Montanide ISA720 or AS02 adjuvant. 47 Looking ahead, a multi-antigen, multistage approach, which would necessitate the two antigens, CSP and PvRII, being combined and formulated with a common adjuvant, may offer the best opportunity for success.…”