RESUMO
We report the first safety and immunogenicity trial of the Plasmodium falciparum malaria blood stage vaccine candidate, FMP1/AS02A consisting of the FMP1 antigen, an Escherichia coli-expressed His-tagged fusion protein from the 42 kDa C-terminal fragment from the 3D7 clone of the merozoite surface protein 1 formulated in the AS02A adjuvant. An open label, prospective, single-center Phase I dose escalation trial of FMP1/AS02A was conducted in 15 adult malaria-naïve human volunteers to assess safety, reactogenicity, and immunogenicity. The vaccine was safe and well-tolerated and no serious adverse events were observed. The vaccine induced high-titer ELISA and IFA responses in all volunteers. Proliferative and ELISPOT responses were induced to vaccine antigen. Biologically active antibodies were induced as measured by GIA. This study establishes the foundation to further evaluate and measure the vaccine's ability to reduce morbidity and mortality in target populations directly affected by P. falciparum malaria.
Assuntos
Lipídeo A/análogos & derivados , Vacinas Antimaláricas/imunologia , Proteína 1 de Superfície de Merozoito/imunologia , Plasmodium falciparum/imunologia , Saponinas/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Adolescente , Adulto , Animais , Anticorpos Antiprotozoários/sangue , Combinação de Medicamentos , Ensaio de Imunoadsorção Enzimática , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Interferon gama/biossíntese , L-Lactato Desidrogenase/análise , Lipídeo A/administração & dosagem , Lipídeo A/farmacologia , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/crescimento & desenvolvimento , Saponinas/administração & dosagem , Linfócitos T/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologiaRESUMO
Malaria vaccine RTS,S combined with thrombospondin-related anonymous protein (TRAP) and formulated with AS02A (RTS,S+TRAP/AS02A) is safe and immunogenic in adult humans and rhesus monkeys (Macaca mulatta). Here, RTS,S+TRAP/AS02A was administered on a 0-, 1-, and 3-month schedule to three cohorts of infant monkeys, along with adult comparators. Cohort 1 evaluated 1/5, 1/2, and full adult doses, with the first dose administration at one month of age; cohort 2 monkeys received full adult doses, with the first dose administration at one versus three months of age; and, cohort 3 compared infants gestated in mothers with or without previous RTS,S/AS02A immunization. Immunization site reactogenicity was mild. Some infants, including the phosphate-buffered saline only recipient, developed transient iron-deficiency anemia, which is considered a result of repeated phlebotomies. All RTS,S+TRAP/AS02A regimens induced vigorous antibody responses that persisted through 12 weeks after the last vaccine dose. Modest lymphoproliferative and ELISPOT (interferon-gamma and interleukin-5) responses, particularly to TRAP, approximated adult comparators. RTS,S+TRAP/AS02A was safe and well tolerated. Vigorous antibody production and modest, selective cell-mediated immune responses suggest that RTS,S+TRAP/AS02A may be immunogenic in human infants.