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1.
PLoS One ; 6(10): e24586, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22003383

RESUMO

BACKGROUND: Models of immunity to malaria indicate the importance of CD8+ T cell responses for targeting intrahepatic stages and antibodies for targeting sporozoite and blood stages. We designed a multistage adenovirus 5 (Ad5)-vectored Plasmodium falciparum malaria vaccine, aiming to induce both types of responses in humans, that was tested for safety and immunogenicity in a Phase 1 dose escalation trial in Ad5-seronegative volunteers. METHODOLOGY/PRINCIPAL FINDINGS: The NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). Group 1 (n = 6) healthy volunteers received one intramuscular injection of 2×10∧10 particle units (1×10∧10 each construct) and Group 2 (n = 6) a five-fold higher dose. Transient, mild to moderate adverse events were more pronounced with the higher dose. ELISpot responses to CSP and AMA1 peaked at 1 month, were higher in the low dose (geomean CSP = 422, AMA1 = 862 spot forming cells/million) than in the high dose (CSP = 154, p = 0.049, AMA1 = 423, p = 0.045) group and were still positive at 12 months in a number of volunteers. ELISpot depletion assays identified dependence on CD4+ or on both CD4+ and CD8+ T cells, with few responses dependent only on CD8+ T cells. Intracellular cytokine staining detected stronger CD8+ than CD4+ T cell IFN-γ responses (CSP p = 0.0001, AMA1 p = 0.003), but similar frequencies of multifunctional CD4+ and CD8+ T cells secreting two or more of IFN-γ, TNF-α or IL-2. Median fluorescence intensities were 7-10 fold higher in triple than single secreting cells. Antibody responses were low but trended higher in the high dose group and did not inhibit growth of cultured P. falciparum blood stage parasites. SIGNIFICANCE: As found in other trials, adenovectored vaccines appeared safe and well-tolerated at doses up to 1×10∧11 particle units. This is the first demonstration in humans of a malaria vaccine eliciting strong CD8+ T cell IFN-γ responses. TRIAL REGISTRATION: ClinicalTrials.govNCT00392015.


Assuntos
Adenoviridae/genética , Antígenos de Protozoários/efeitos adversos , Antígenos de Protozoários/imunologia , Vetores Genéticos/genética , Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/imunologia , Plasmodium falciparum/imunologia , Adolescente , Adulto , Antígenos de Protozoários/química , Antígenos de Protozoários/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Relação Dose-Resposta Imunológica , Feminino , Expressão Gênica , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Interferon gama/metabolismo , Vacinas Antimaláricas/química , Vacinas Antimaláricas/genética , Masculino , Proteínas de Membrana/efeitos adversos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Fragmentos de Peptídeos/imunologia , Proteínas de Protozoários/efeitos adversos , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia , Adulto Jovem
2.
PLoS One ; 6(10): e25868, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22003411

RESUMO

BACKGROUND: A protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge. METHODOLOGY/PRINCIPAL FINDINGS: NMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at 1 x 1010 particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected. SIGNIFICANCE: The NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection. TRIAL REGISTRATION: ClinicalTrials.gov NCT00392015.


Assuntos
Adenoviridae/genética , Vetores Genéticos/genética , Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/efeitos adversos , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Antígenos de Protozoários/efeitos adversos , Antígenos de Protozoários/genética , Antígenos de Protozoários/imunologia , Relação Dose-Resposta Imunológica , Feminino , Expressão Gênica , Humanos , Vacinas Antimaláricas/genética , Masculino , Proteínas de Membrana/efeitos adversos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Plasmodium falciparum/citologia , Proteínas de Protozoários/genética , Esporozoítos/imunologia , Adulto Jovem
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