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Clinical trial in healthy malaria-naive adults to evaluate the safety, tolerability, immunogenicity and efficacy of MuStDO5, a five-gene, sporozoite/hepatic stage Plasmodium falciparum DNA vaccine combined with escalating dose human GM-CSF DNA.


ABSTRACT: 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 ?g of each plasmid plus escalating doses (0, 20, 100 or 500 ?g) 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-? 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.

SUBMITTER: Richie TL 

PROVIDER: S-EPMC3601132 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Clinical trial in healthy malaria-naïve adults to evaluate the safety, tolerability, immunogenicity and efficacy of MuStDO5, a five-gene, sporozoite/hepatic stage Plasmodium falciparum DNA vaccine combined with escalating dose human GM-CSF DNA.

Richie Thomas L TL   Charoenvit Yupin Y   Wang Ruobing R   Epstein Judith E JE   Hedstrom Richard C RC   Kumar Sanjai S   Luke Thomas C TC   Freilich Daniel A DA   Aguiar Joao C JC   Sacci John B JB   Sedegah Martha M   Nosek Ronald A RA   De La Vega Patricia P   Berzins Mara P MP   Majam Victoria F VF   Abot Esteban N EN   Ganeshan Harini H   Richie Nancy O NO   Banania Jo Glenna JG   Baraceros Maria Fe B MF   Geter Tanya G TG   Mere Robin R   Bebris Lolita L   Limbach Keith K   Hickey Bradley W BW   Lanar David E DE   Ng Jennifer J   Shi Meng M   Hobart Peter M PM   Norman Jon A JA   Soisson Lorraine A LA   Hollingdale Michael R MR   Rogers William O WO   Doolan Denise L DL   Hoffman Stephen L SL  

Human vaccines & immunotherapeutics 20121101 11


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  ...[more]

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