Abstract
BackgroundThe continuing morbidity and mortality associated with infection with malaria parasites highlights the urgent need for a vaccine. The efficacy of sub-unit vaccines tested in clinical trials in malaria-endemic areas has thus far been disappointing, sparking renewed interest in the whole parasite vaccine approach. We previously showed that a chemically attenuated whole parasite asexual blood-stage vaccine induced CD4+ T cell-dependent protection against challenge with homologous and heterologous parasites in rodent models of malaria.MethodsIn this current study, we evaluated the immunogenicity and safety of chemically attenuated asexual blood-stage Plasmodium falciparum (Pf) parasites in eight malaria-naïve human volunteers. Study participants received a single dose of 3 × 107 Pf pRBC that had been treated in vitro with the cyclopropylpyrolloindole analogue, tafuramycin-A.ResultsWe demonstrate that Pf asexual blood-stage parasites that are completely attenuated are immunogenic, safe and well tolerated in malaria-naïve volunteers. Following vaccination with a single dose, species and strain transcending Plasmodium-specific T cell responses were induced in recipients. This included induction of Plasmodium-specific lymphoproliferative responses, T cells secreting the parasiticidal cytokines, IFN-γ and TNF, and CD3+CD45RO+ memory T cells. Pf-specific IgG was not detected.ConclusionsThis is the first clinical study evaluating a whole parasite blood-stage malaria vaccine. Following administration of a single dose of completely attenuated Pf asexual blood-stage parasites, Plasmodium-specific T cell responses were induced while Pf-specific antibodies were not detected. These results support further evaluation of this chemically attenuated vaccine in humans.Trial registrationTrial registration: ACTRN12614000228684. Registered 4 March 2014.
Highlights
The continuing morbidity and mortality associated with infection with malaria parasites highlights the urgent need for a vaccine
Plasmodium spp. parasites cause more than 200 million clinical cases of malaria and 438,000 deaths per year, with the majority of deaths occurring in children < 5 years of age [1]
The fundamental rationale for a whole parasite vaccine is that by maximising the number of antigens presented to the immune system, including those that are conserved between different parasite strains, the impact of antigenic polymorphism will be diminished
Summary
The continuing morbidity and mortality associated with infection with malaria parasites highlights the urgent need for a vaccine. The efficacy of sub-unit vaccines tested in clinical trials in malaria-endemic areas has far been disappointing, sparking renewed interest in the whole parasite vaccine approach. Disappointing results following the testing of sub-unit vaccines in clinical trials [2,3,4,5] have highlighted some of the limitations of sub-unit vaccines that need to be addressed, including antigenic polymorphism in critical epitopes. The limited protection induced by sub-unit vaccine candidates has resulted in renewed interest in the whole organism vaccine approach. CHMI with whole blood-stage parasites is used for the in vivo assessment of malaria vaccine and drug candidate efficacy (reviewed in [12]). There have been no published clinical studies of whole parasite blood-stage malaria vaccines [15]
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