Abstract
BackgroundThe Plasmodium protein Cell-traversal protein for ookinetes and sporozoites (CelTOS) plays an important role in cell traversal of host cells in both, mosquito and vertebrates, and is required for successful malaria infections. CelTOS is highly conserved among the Plasmodium species, suggesting an important functional role across all species. Therefore, targeting the immune response to this highly conserved protein and thus potentially interfering with its biological function may result in protection against infection even by heterologous species of Plasmodium.Methodology/Principal FindingsTo test this hypothesis, we developed a recombinant codon-harmonized P. falciparum CelTOS protein that can be produced to high yields in the E. coli expression system. Inbred Balb/c and outbred CD-1 mice were immunized with various doses of the recombinant protein adjuvanted with Montanide ISA 720 and characterized using in vitro and in vivo analyses.Conclusions/SignificanceImmunization with PfCelTOS resulted in potent humoral and cellular immune responses and most importantly induced sterile protection against a heterologous challenge with P. berghei sporozoites in a proportion of both inbred and outbred mice. The biological activity of CelTOS-specific antibodies against the malaria parasite is likely linked to the impairment of sporozoite motility and hepatocyte infectivity. The results underscore the potential of this antigen as a pre-erythrocytic vaccine candidate and demonstrate for the first time a malaria vaccine that is cross-protective between species.
Highlights
Malaria remains a significant disease in most tropical countries and despite prophylactic efforts in the form of bed nets and the development of novel anti-malarial drugs, the disease is still a major threat to global health and the survival of children under the age of five
To determine whether Cell-traversal protein for ookinetes and sporozoites (CelTOS) is a protective antigen against heterologous challenge, Balb/c and CD-1 mice were immunized with different doses of P. falciparum CelTOS recombinant protein (PfCelTOS) (Purification profile Figure S1) adjuvanted with Montanide ISA 720 and challenged subcutaneously with P. berghei sporozoites two weeks after the last immunization
CelTOS has been shown to play a pivotal role in the cell traversal of host cells by malaria parasites [8]
Summary
Malaria remains a significant disease in most tropical countries and despite prophylactic efforts in the form of bed nets and the development of novel anti-malarial drugs, the disease is still a major threat to global health and the survival of children under the age of five. The results from RTS,S vaccination are encouraging, there remains a need to increase the observed vaccine efficacy of pre-erythrocytic vaccine candidates and this may be achieved by either modifying the adjuvant partners, changing the vaccine delivery platform or by the addition of new antigens. These approaches have primarily focused on the circumsporozoite protein (CSP) (reviewed in [3]) as the target antigen and as such it is not clear whether other pre-erythrocytic antigens can substitute for CSP or can act in combination with a CSP-based vaccine to achieve the required increase in vaccine efficacy.
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