A universal vaccine candidate against Plasmodium vivax malaria confers protective immunity against the three PvCSP alleles

Abstract

Malaria is a highly prevalent parasitic disease in regions with tropical and subtropical climates worldwide. Among the species of Plasmodium causing human malaria, P. vivax is the second most prevalent and the most geographically widespread species. A major target of a pre-erythrocytic vaccine is the P. vivax circumsporozoite protein (PvCSP). In previous studies, we fused two recombinant proteins representing three allelic variants of PvCSP (VK210, VK247 and P. vivax-like) to the mumps virus nucleocapsid protein to enhance immune responses against PvCSP. The objective of the present study was to evaluate the protective efficacy of these recombinants in mice challenged with transgenic P. berghei parasites expressing PvCSP allelic variants. Formulations containing Poly (I:C) or Montanide ISA720 as adjuvants elicited high and long-lasting IgG antibody titers specific to each PvCSP allelic variant. Immunized mice were challenged with two existing chimeric P. berghei parasite lines expressing PvCSP-VK210 and PvCSP-VK247. We also developed a novel chimeric line expressing the third allelic variant, PvCSP-P. vivax-like, as a new murine immunization-challenge model. Our formulations conferred partial protection (significant delay in the time to reach 1% parasitemia) against challenge with the three chimeric parasites. Our results provide insights into the development of a vaccine targeting multiple strains of P. vivax.

Immune System Modulation by the Adjuvants Poly (I:C) and Montanide ISA 720

“…In agreement, Montanide triggered higher cytophilic-type IgG titers (IgG2b) and was able to generate antibodies with higher avidity than those elicited by Poly (I:C). These differences could explain the higher partial protection against the challenge that Montanide conferred when administered with a PvCSP-based antigen ( 10 ). However, the protection achieved was not sterile.…”

“…One of them, Poly (I:C), elicited high antibodies titers conferring partial protection to immunized mice ( 6 , 8 , 9 ). Another adjuvant tested in our formulations was Montanide ISA 720, which generated even higher IgG titers and promoted a greater decline in parasite burden during the challenge test when compared to Poly (I:C)- adjuvanted formulations ( 10 ).…”

“…Thus, the different patterns in the immunological response generated by the effect of the adjuvants could directly influence the protective effect of each formulation, mainly because they have different mechanisms of action ( 10 ). Poly (I:C) is a synthetic double-stranded RNA (dsRNA) designed to act like a natural ligand of TLR3 receptor, and known to elicit long-lived antibodies with strong Th1 responses against P. falciparum antigen ( 11 ).…”

A genetically modified Plasmodium berghei parasite as a surrogate for whole-sporozoite vaccination against P. vivax malaria

“…Thus, although VK210 is the most common variant of PvCSP 22 , the expression of only this sequence on the Pb platform may represent a limitation of PbviVac. In fact, a recombinant protein including the repeats of both PvCSP VK210 and VK247, as well as of P. vivax-like CSP, has recently been generated and shown to elicit the production of high titers of antibodies against each of the variants following immunization of a mouse model 45 . Accordingly, and since previous studies demonstrated the absence of significant cross-reactivity among the different PvCSP alleles in animals immunized with individual recombinant proteins (VK210, VK247 and P. vivax-like) 46 , the Pb platform may in the future be engineered to simultaneously express of the most common alleles of CSP, potentially eliciting protective immune responses against a wider range of Pv strains.…”

Peptide emulsions in incomplete Freund’s adjuvant create effective nurseries promoting egress of systemic CD4+and CD8+T cells for immunotherapy of cancer

“…Immunization with recombinant CS protein in Montanide ISA-720 induced high and long-lasting antibody responses and partial protection against challenge with parasites in mice. 64 Immunization with recombinant CS protein in Montanide ISA-51 is tested in malaria-naïve and semi-immune volunteers in an ongoing trial (NCT04739917, Table 1).…”