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

• Published in: Human vaccines & immunotherapeutics 2012-11, Vol.8 (11), p.1564-1584
• Main Authors: 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 G., 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., Hoffman, Stephen L.
• Format: Article
• Language: English
• Subjects: Adult; Antigens, Protozoan - immunology; clinical trials; controlled human malaria infection; DNA vaccine; Female; GM-CSF; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Humans; malaria; malaria challenge; malaria vaccine; Malaria Vaccines - administration & dosage; Malaria Vaccines - immunology; Malaria Vaccines - therapeutic use; Male; Middle Aged; Plasmids - genetics; Plasmodium falciparum; Plasmodium falciparum - immunology; Plasmodium falciparum - pathogenicity; Research Paper; Sporozoites - immunology; vaccine safety; Vaccines, DNA - adverse effects; Vaccines, DNA - immunology; Vaccines, DNA - therapeutic use; Young Adult
• ISSN: 2164-5515; 2164-554X
• DOI: 10.4161/hv.22129

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.