Prime-boost vaccination with recombinant protein and adenovirus-vector expressing Plasmodium vivax circumsporozoite protein (CSP) partially protects mice against Pb/Pv sporozoite challenge

Abstract

Vaccine development against Plasmodium vivax malaria lags behind that for Plasmodium falciparum. To narrow this gap, we administered recombinant antigens based on P. vivax circumsporozoite protein (CSP) to mice. We expressed in Pichia pastoris two chimeric proteins by merging the three central repeat regions of different CSP alleles (VK210, VK247, and P. vivax-like). The first construct (yPvCSP-AllFL) contained the fused repeat regions flanked by N- and C-terminal regions. The second construct (yPvCSP-AllCT) contained the fused repeat regions and the C-terminal domain, plus RI region. Mice were vaccinated with three doses of yPvCSP in adjuvants Poly (I:C) or Montanide ISA720. We also used replication-defective adenovirus vectors expressing CSP of human serotype 5 (AdHu5) and chimpanzee serotype 68 (AdC68) for priming mice which were subsequently boosted twice with yPvCSP proteins in Poly (I:C) adjuvant. Regardless of the regime used, immunized mice generated high IgG titres specific to all CSP alleles. After challenge with P. berghei ANKA transgenic parasites expressing Pb/PvVK210 or Pb/PvVK247 sporozoites, significant time delays for parasitemia were observed in all vaccinated mice. These vaccine formulations should be clinically tried for their potential as protective universal vaccine against P. vivax malaria.

Protective Malaria Vaccine in Mice Based on the Plasmodium vivax Circumsporozoite Protein Fused with the Mumps Nucleocapsid Protein

“…By eliciting an inflammatory Th1-like response in mice and humans, it was hypothesized that such a response could contribute to protection [50]. Previously, our research group showed that Poly (I:C) was responsible to enhance not only the immunogenicity of PvCSP recombinant proteins upon vaccination [21,33] but also protection after a parasitic challenge [22,41]. In this study, the NLP-CSP R vaccine formulation induced a predominance of IgG2c over IgG1.…”

“…One of the most effective ways to analyze vaccine efficacy is through a challenge test. This approach has been used previously and has proven effective at demonstrating vaccine-induced protection [21,22,41]. However, P. vivax does not infect rodents.…”

Protective Immunity in Mice Immunized With P. vivax MSP119-Based Formulations and Challenged With P. berghei Expressing PvMSP119

“…Malaria elimination based on vaccines will require the development of a vaccine not only against P. falciparum, but also against P. vivax. Many research groups in Brazil and abroad are working on the development of a P. vivax vaccine based on the PvCSP antigen (9)(10)(11). However, it is reasonable to foresee, based on the results obtained with the clinical trials of RTS,S/AS01, that a P. vivax vaccine based only on the PvCSP may not be fully effective by itself.…”

“…The lack of a continuous P. vivax laboratory culture has so far thwarted efficacy tests of these available vaccine formulations in pre-clinical studies, which is an obvious obstacle to progress with these formulations to clinical tests in humans. The mouse-infecting P. berghei has been used for efficacy tests of PvCSP-based formulations (10,11). These studies used P. berghei hybrid mutant lines expressing the PvCSP to challenge mice immunized with formulations based on the P. vivax antigen.…”

Assessing Malaria Vaccine Efficacy

“…With the renewed interest in malaria eradication, the development of an effective malaria vaccine is high on the agenda. Diverse strategies are being proposed to develop better vaccines: identification of new vaccine candidate [116], combinations of different antigens targeting the same stage or different stages [117]; new delivery systems and prime-boost strategies using different modalities [118]; and new adjuvants to induce stronger and longer lasting efficient immune responses [119][120][121][122]. However, for all vaccine types described, the absence of validated surrogates of protection to help select and prioritize different vaccine formulations is a major roadblock, which should be given priority to accelerate vaccine testing.…”