Vaccination with chemically attenuated Plasmodium falciparum asexual blood-stage parasites induces parasite-specific cellular immune responses in malaria-naïve volunteers: a pilot study

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.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1173-9) contains supplementary material, which is available to authorized users.

The Case for Exploiting Cross-Species Epitopes in Malaria Vaccine Design

“…There are few reports of species-transcending T-cells in humans. The most definitive study showed that T-cells isolated from volunteers immunized with attenuated blood stage P. falciparum parasites proliferated in vitro in response to P. knowlesi iRBCs (54). Whether these T-cells have functional activity to protect against heterologous challenge is not known.…”

A genetically hmgb2 attenuated blood stage P. berghei induces crossed-long live protection

“…Several reports of Good' team showed that cellular immune responses and protection were induced by different chemically attenuated parasites in various murine models [16,23] and in humans [6,26]. Actually, a long-lasting cellular immune response was observed in a small number of human volunteers induced by chemically attenuated P. falciparum followed by a drug treatment [7]. However, no parasite challenge was analysed thereafter and need further work to establish if this reactive immune response will be cross protective in humans.…”

“…As for the living red blood cell (RBC) vaccines, the first report [6] showed that a low amount as low as 30-300 P. falciparum parasitized RBC (iRBC) infected with the 3D7 Plasmodium live parasites when injected four times to five volunteers followed by an anti-malarial treatment triggered a some protection against an homologous challenge. Thereafter, several trials were achieved with living parasites followed by antimalarial treatment [7,8] as well as with chemically attenuated P. falciparum [7]. In addition, several genetically attenuated parasites with defects in replication capacity have been shown to lead to self-resolving infections leading possibly to potent and long-lasting protection in various murine models against both erythrocytic [9,10,11] and pre-erythrocytic [4,12,13,14] challenges.…”

“…However, these studies provided only limited information regarding the immunological mechanisms that confer protection except a recent study which provided a detailed characterization of the immune mechanisms underlying the long-lasting protective immunity provided by the HRF-deficient PbNK65 parasites [15]. These immunological changes produced by living parasites that might potentially trigger long lasting protection was also studied in human after P. falciparum infection [16,7].…”

A step forward for an attenuated blood-stage malaria vaccine

“…Stanisic et al [ 14 ] present a pilot study evaluating the safety and immunogenicity of a chemically attenuated Plasmodium falciparum asexual blood-stage vaccine in malaria-naïve human subjects. This is the first clinical study of its kind.…”