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Hum Vaccin Immunother ; 8(11): 1564-84, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23151451

RESUMO

When introduced in the 1990s, immunization with DNA plasmids was considered potentially revolutionary for vaccine development, particularly for vaccines intended to induce protective CD8 T cell responses against multiple antigens. We conducted, in 1997-1998, the first clinical trial in healthy humans of a DNA vaccine, a single plasmid encoding Plasmodium falciparum circumsporozoite protein (PfCSP), as an initial step toward developing a multi-antigen malaria vaccine targeting the liver stages of the parasite. As the next step, we conducted in 2000-2001 a clinical trial of a five-plasmid mixture called MuStDO5 encoding pre-erythrocytic antigens PfCSP, PfSSP2/TRAP, PfEXP1, PfLSA1 and PfLSA3. Thirty-two, malaria-naïve, adult volunteers were enrolled sequentially into four cohorts receiving a mixture of 500 µg of each plasmid plus escalating doses (0, 20, 100 or 500 µg) of a sixth plasmid encoding human granulocyte macrophage-colony stimulating factor (hGM-CSF). Three doses of each formulation were administered intramuscularly by needle-less jet injection at 0, 4 and 8 weeks, and each cohort had controlled human malaria infection administered by five mosquito bites 18 d later. The vaccine was safe and well-tolerated, inducing moderate antigen-specific, MHC-restricted T cell interferon-γ responses but no antibodies. Although no volunteers were protected, T cell responses were boosted post malaria challenge. This trial demonstrated the MuStDO5 DNA and hGM-CSF plasmids to be safe and modestly immunogenic for T cell responses. It also laid the foundation for priming with DNA plasmids and boosting with recombinant viruses, an approach known for nearly 15 y to enhance the immunogenicity and protective efficacy of DNA vaccines.


Assuntos
Antígenos de Protozoários/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Vacinas Antimaláricas/imunologia , Vacinas Antimaláricas/uso terapêutico , Plasmodium falciparum/imunologia , Plasmodium falciparum/patogenicidade , Esporozoítos/imunologia , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico , Adulto , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Vacinas Antimaláricas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Plasmídeos/genética , Vacinas de DNA/efeitos adversos , Adulto Jovem
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