RESUMO
Clinical trials are an essential step in evaluation of safety and efficacy of malaria vaccines, and human experimental malaria infections have been used for evaluation of protective immunity of Plasmodium falciparum malaria. In this study, a quantitative real-time polymerase chain reaction was used to measure P. falciparum malaria parasitemia in non-immune volunteers who had been experimentally infected by mosquito bites. Based on a remarkably small variation in the kinetics of parasitemia, a statistical model was developed that provides detailed estimates of pre-patent periods and parasite multiplication of blood stages. Using this model, we could predict results on vaccine efficacy for 1) pre-erythrocytic vaccines in the asymptomatic incubation period and 2) asexual stage vaccines after a limited number of multiplication cycles. The model shows that stage-specific vaccines even with limited efficacy can be highly efficacious when used in combination. This P. falciparum challenge method significantly adds to the potential to evaluate efficacy of candidate malaria vaccines before going into field trials.
Assuntos
Vacinas Antimaláricas , Malária Falciparum/prevenção & controle , Modelos Biológicos , Parasitemia/parasitologia , Plasmodium falciparum/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , Adolescente , Adulto , Animais , Anopheles/parasitologia , Sangue/parasitologia , Ensaios Clínicos Fase II como Assunto , Humanos , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Plasmodium falciparum/crescimento & desenvolvimento , Projetos de PesquisaRESUMO
The glutamate-rich protein (GLURP) of P. falciparum is the target of cytophilic antibodies which are significantly associated with protection against clinical malaria. A phase 1 clinical trial was conducted in healthy adult volunteers with the long synthetic peptide (LSP) GLURP(85-213) combined with either Aluminum Hydroxide (Alum, 18 volunteers) or Montanide ISA 720 (ISA, 18 volunteers) as adjuvants. Immunizations with 10, 30 or 100 microg GLURP(85-213) were administered subcutaneously at days 0, 30, and 120. Adverse events occurred more frequently with increasing dosage of GLURP(85-213) LSP and were more prevalent in the ISA group. Serious vaccine-related adverse events were not observed. The vaccine induced dose-dependent cellular and humoral immune responses, with high levels of (mainly cytophilic IgG1) antibodies that recognize parasites by immunofluorescence (IFA). Plasma samples collected 30 days after the last immunization induced a dose-dependent inhibition of parasite growth in vitro in the presence of monocytes. In conclusion, immunizations with GLURP(85-213) LSP formulations induce adverse events but can be administered safely, generating antibodies with capacity to mediate growth-inhibitory activity against P. falciparum in vitro.