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., Charoenvit, Yupin, Wang, Ruobing, Epstein, Judith E., Hedstrom, Richard C., Kumar, Sanjai, Luke, Thomas C., Freilich, Daniel A., Aguiar, Joao C., Sacci, Jr., John B., Sedegah, Martha, Nosek, Jr., Ronald A., De La Vega, Patricia, Berzins, Mara P., Majam, Victoria F., Abot, Esteban N., Ganeshan, Harini, Richie, Nancy O., Banania, Jo Glenna, Baraceros, Maria Fe B., Geter, Tanya, Mere, Robin, Bebris, Lolita, Limbach, Keith, Hickey, Bradley W., Lanar, David E., Ng, Jennifer, Shi, Meng, Hobart, Peter M., Norman, Jon A., Soisson, Lorraine A., Hollingdale, Michael R., Rogers, William O., Doolan, Denise L., and Hoffman, Stephen L. (2012) 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. Human Vaccines & Immunotherapeutics, 8 (11). pp. 1564-1584.

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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 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.

Item ID: 41435
Item Type: Article (Research - C1)
ISSN: 2164-554X
Keywords: malaria, Plasmodium falciparum, DNA vaccine, vaccine safety, clinical trials, GM-CSF, malaria challenge, controlled human malaria infection, malaria vaccine
Additional Information:

Copyright © 2012 Landes Bioscience

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Funders: Naval Medical Research and Development Command (NMRDC), United States Agency for International Development (USAID), Office of Naval Research Advanced Technology Demonstration (ONRATD)
Projects and Grants: NMRDC 61102A. S13.F.A0009, NMRDC 62787A.870.F.A0010, NMRDC 63002A.810.F.A0011, NMRDC 603792N.01889.135.A0039 , NMRDC 60000.000.000.A0062
Date Deposited: 22 Mar 2016 00:31
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110799 Immunology not elsewhere classified @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 100%
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