Evaluation of Plasmodium vivax Cell-Traversal Protein for Ookinetes and Sporozoites as a Preerythrocytic P. vivax Vaccine

Abstract

Four different vaccine platforms, each targeting the human malaria parasite Plasmodium vivax cell-traversal protein for ookinetes and sporozoites (PvCelTOS), were generated and assessed for protective efficacy. These platforms consisted of a recombinant chimpanzee adenoviral vector 63 (ChAd63) expressing PvCelTOS (Ad), a recombinant modified vaccinia virus Ankara expressing PvCelTOS (MVA), PvCelTOS conjugated to bacteriophage Qβ virus-like particles (VLPs), and a recombinant PvCelTOS protein expressed in eukaryotic HEK293T cells (protein). Inbred BALB/c mice and outbred CD-1 mice were immunized using the following prime-boost regimens: Ad-MVA, Ad-VLPs, and Ad-protein. Protective efficacy against sporozoite challenge was assessed after immunization using a novel chimeric rodent Plasmodium berghei parasite (Pb-PvCelTOS). This chimeric parasite expresses P. vivax CelTOS in place of the endogenous P. berghei CelTOS and produces fully infectious sporozoites. A single Ad immunization in BALB/c and CD-1 mice induced anti-PvCelTOS antibodies which were boosted efficiently using MVA, VLP, or protein immunization. PvCelTOS-specific gamma interferon- and tumor necrosis factor alpha-producing CD8+ T cells were induced at high frequencies by all prime-boost regimens in BALB/c mice but not in CD-1 mice; in CD-1 mice, they were only marginally increased after boosting with MVA. Despite the induction of anti-PvCelTOS antibodies and PvCelTOS-specific CD8+ T-cell responses, only low levels of protective efficacy against challenge with Pb-PvCelTOS sporozoites were obtained using any immunization strategy. In BALB/c mice, no immunization regimens provided significant protection against a Pb-PvCelTOS chimeric sporozoite challenge. In CD-1 mice, modest protective efficacy against challenge with chimeric P. berghei sporozoites expressing either PvCelTOS or P. falciparum CelTOS was observed using the Ad-protein vaccination regimen.

Extensive Transcriptional and Translational Regulation Occur During the Maturation of Malaria Parasite Sporozoites

“…Two of these gene products are both UIS mRNAs and UIS proteins in both species: CelTOS and SPELD. While less is known about SPELD, which is found on the sporozoite surface and is essential for liver stage development, CelTOS has been the focus of substantial study and is a promising target for therapeutic interventions 41, 52 . As above, we anticipate that the uncharacterized gene products identified here will play similar roles to those that have already been studied, and deserve prioritization in future work.…”

Structural Features of Apicomplexan Pore-Forming Proteins and Their Roles in Parasite Cell Traversal and Egress

“…Finally, despite having a similar ability to form PVs in a HEPG2 cell line, ∆ celtos sporozoites have much lower cell wounding activity. Taken together, these experiments highlight the importance of CelTOS in both ookinete and sporozoite cell traversal, rendering this protein a potential vaccine target for preventing liver infection [ 31 , 32 ].…”

Identification of highly-protective combinations of Plasmodium vivax recombinant proteins for vaccine development

“…The moderate success of the P. falciparum RTS,S vaccine has also made P. vivax CSP a main vaccine candidate ( Mueller et al, 2015 ; Salman et al, 2017 ; Bennett et al, 2016 ). The potential of novel, pre-erythrocytic candidate antigens, including P. vivax cell-traversal protein for ookinetes (CelTOS) and thrombospondin-related anonymous protein (TRAP) is being investigated in animal models ( Mueller et al, 2015 ; Alves et al, 2017 ; Bauza et al, 2014 ).…”