An open-label phase 1/2a trial of a genetically modified rodent malaria parasite for immunization against Plasmodium falciparum malaria

Abstract

For some diseases, successful vaccines have been developed using a nonpathogenic counterpart of the causative microorganism of choice. The nonpathogenicity of the rodent Plasmodium berghei (Pb) parasite in humans prompted us to evaluate its potential as a platform for vaccination against human infection by Plasmodium falciparum (Pf), a causative agent of malaria. We hypothesized that the genetic insertion of a leading protein target for clinical development of a malaria vaccine, Pf circumsporozoite protein (CSP), in its natural pre-erythrocytic environment, would enhance Pb’s capacity to induce protective immunity against Pf infection. Hence, we recently generated a transgenic Pb sporozoite immunization platform expressing PfCSP (PbVac), and we now report the clinical evaluation of its biological activity against controlled human malaria infection (CHMI). This first-in-human trial shows that PbVac is safe and well tolerated, when administered by a total of ~300 PbVac-infected mosquitoes per volunteer. Although protective efficacy evaluated by CHMI showed no sterile protection at the tested dose, significant delays in patency (2.2 days, P = 0.03) and decreased parasite density were observed after immunization, corresponding to an estimated 95% reduction in Pf liver parasite burden (confidence interval, 56 to 99%; P = 0.010). PbVac elicits dose-dependent cross-species cellular immune responses and functional PfCSP-dependent antibody responses that efficiently block Pf sporozoite invasion of liver cells in vitro. This study demonstrates that PbVac immunization elicits a marked biological effect, inhibiting a subsequent infection by the human Pf parasite, and establishes the clinical validation of a new paradigm in malaria vaccination.

Generation of a Genetically Modified Chimeric Plasmodium falciparum Parasite Expressing Plasmodium vivax Circumsporozoite Protein for Malaria Vaccine Development

“…It has been shown that viable and infectious rodent P. berghei sporozoites can be engineered to express CSP proteins from two different Plasmodium species. These chimeric sporozoites were generated by introducing a P. falciparum csp gene as an additional copy into the P. berghei genome (Mendes et al, 2018a;Mendes et al, 2018b;Reuling et al, 2020). Based on this observation we aimed at generating chimeric P. falciparum sporozoites expressing both PfCSP and an chimeric PvCSP protein (PvCSP-chi).…”

“…To develop chimeric P. falciparum sporozoites expressing PvCSP, we therefore aimed at generating a chimeric P. falciparum line expressing both the endogenous PfCSP and an engineered PvCSP. It has been shown that introducing the P. falciparum csp gene as an additional copy into the genome of the rodent parasite P. berghei (Pb) results in development of viable and infective sporozoites, expressing both PbCSP and PfCSP in pre-erythrocytic stages (Mendes et al, 2018a;Mendes et al, 2018b;Reuling et al, 2020). We used CRISPR/Cas9 gene editing to introduce a chimeric Pvcsp gene, containing repeats of both the VK210 and VK247 alleles, into the Pfp47 locus of the P. falciparum NF54 genome.…”

Dissection-independent production of a protective whole-sporozoite malaria vaccine

“…For basic sciences, this stepwise process will be an important step towards single cell -omic studies that require large amounts of highly pure sporozoites, free of the mosquito-associated contaminants that often limit our ability to draw conclusions from these studies [65][66][67]. Concurrently, application of this technology to a vaccine development pipeline, including genetically attenuated sporozoites [68,69], offers the tantalizing opportunity to develop and manufacture pure, viable, immunogenic wholeparasite sporozoite vaccines at a dramatically increased scale when compared to current methods.…”

A guide to investigating immune responses elicited by whole‐sporozoite pre‐erythrocytic vaccines against malaria

“…Therefore, the purification of immunoglobulins (Igs) from serum/plasma samples by affinity chromatography may be considered in order to reduce non-specific background activity [27]. Although Protein G or HiTrap Protein G HP columns are most commonly employed for this purpose in the context of Wsp PE vaccine candidate clinical trials [18,[28][29][30][31], one study concluded that polyethylene glycol purification of human serum/plasma samples is optimal for recovering functional antigen-specific antibodies [27].…”