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.
Naturally acquired immunity to malaria is robust and protective against all strains of the same species of Plasmodium. This develops as a result of repeated natural infection, taking several years to develop.
j Plasmodium falciparum is the most virulent human malaria parasite because of its ability to cytoadhere in the microvasculature. Nonhuman primate studies demonstrated relationships among knob expression, cytoadherence, and infectivity. This has not been examined in humans. Cultured clinical-grade P. falciparum parasites (NF54, 7G8, and 3D7B) and ex vivo-derived cell banks were characterized. Knob and knob-associated histidine-rich protein expression, CD36 adhesion, and antibody recognition of parasitized erythrocytes (PEs) were evaluated. Parasites from the cell banks were administered to malaria-naive human volunteers to explore infectivity. For the NF54 and 3D7B cell banks, blood was collected from the study participants for in vitro characterization. All parasites were infective in vivo. However, infectivity of NF54 was dramatically reduced. In vitro characterization revealed that unlike other cell bank parasites, NF54 PEs lacked knobs and did not cytoadhere. Recognition of NF54 PEs by immune sera was observed, suggesting P. falciparum erythrocyte membrane protein 1 expression. Subsequent recovery of knob expression and CD36-mediated adhesion were observed in PEs derived from participants infected with NF54. Knobless cell bank parasites have a dramatic reduction in infectivity and the ability to adhere to CD36. Subsequent infection of malaria-naive volunteers restored knob expression and CD36-mediated cytoadherence, thereby showing that the human environment can modulate virulence. P lasmodium falciparum is the most virulent of the six Plasmodium sp. parasites that infect humans. Its ability to cytoadhere and sequester itself in the microvasculature can result in obstruction of blood flow and organ dysfunction, and these are key processes in the development of severe falciparum malaria (1).Parasite cytoadherence and sequestration are facilitated by parasite-encoded knoblike structures that first appear on early trophozoite-stage parasites and are formed beneath the plasma membrane of parasitized erythrocytes (PEs) (2). Cytoadherence to receptors in the deep vasculature prevents removal and destruction of the parasite by the mononuclear phagocytic system, especially the spleen. Higher knob densities have been reported on PEs collected directly from patients than on cultured PEs infected in vitro (3). Following in vitro cultivation of P. falciparum, knob formation on PEs varies in an isolate-dependent manner (3-5), ranging from a mild reduction in density to complete ablation. The major structural protein in knobs is the knob-associated histidinerich protein (KAHRP) (2, 6, 7). Deletion of the gene encoding KAHRP results in the loss of knobs (8, 9).P. falciparum isolates can lose the ability to adhere to tissue receptors in vitro (10). Loss of adherence is isolate dependent and can occur independently of whether the knob phenotype is retained (10). Cytoadherence involves an interaction between parasite ligands and tissue receptors, including CD36, on the vascular endothelium (11, 12). The principal parasite adh...
An assessment of current antenatal care practices and identification of modifiable risk factors for prematurity and low birth weight infants in pregnancy in Solomon Islands Rural and Remote Health 15: 3230. (Online) 2015
Kirakira continues to have a very high perinatal mortality rate that has not changed over the last 6 years. The rate is double that reported for Solomon Islands in current World Health Organization data. This discrepancy is likely due to an absence of clinical data outside of the National Referral Hospital in Honiara. This paper identifies clinical indicators that could be targeted to help lower the perinatal mortality rate in this remote and impoverished community.
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