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

Q3 · MEDICINE

Article

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

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.

01 Jul 2001·Gene TherapyQ3 · MEDICINE

Safety of a GM-CSF adjuvant-plasmid DNA malaria vaccine

Q3 · MEDICINE

Article

Author: P Hernandez ; S Kumar ; WO Rogers ; JA Norman ; SE Parker ; P Hobart ; H Horton ; A Vilalta ; D Monteith ; R Hedstrom ; CE Bentley ; J Hartikka ; A Chang ; SL Hoffman ; R Hof

MuStDO 5 is a multivalent plasmid DNA vaccine for malaria comprised of five plasmid DNAs encoding five proteins from Plasmodium falciparum and one plasmid DNA encoding human GM-CSF. To evaluate the safety of MuStDO 5, a series of pre-clinical studies were conducted in mice and rabbits. In pharmacology studies in mice, GM-CSF could not be detected in the serum following either intramuscular or a combined intramuscular/intradermal administration of the vaccine, but was readily detected in the muscle following intramuscular administration. In a tissue distribution study in mice, MuStDO 5 plasmid DNA was detected by PCR initially in highly vascularized tissues, while at later time-points the plasmid DNA was detected primarily at the site(s) of injection. In GLP safety studies in mice and rabbits, repeated intramuscular/intradermal administration of the MuStDO 5 vaccine was found to be safe and well tolerated without any evidence of autoimmune pathology.

20 Mar 1999·Human Gene TherapyQ2 · MEDICINE

Plasmid DNA Malaria Vaccine: Tissue Distribution and Safety Studies in Mice and Rabbits

Q2 · MEDICINE

Article

Author: Hobart, Peter ; Wenk, Martin L. ; Hoffman, Stephen L. ; Norman, Jon A. ; Borellini, Flavia ; Parker, Suezanne E. ; Hedstrom, Richard ; Le, Thong

To evaluate the safety of a plasmid DNA vaccine, tissue distribution studies in mice and safety studies in mice and rabbits were conducted with VCL-2510, a plasmid DNA encoding the gene for the malaria circumsporozoite protein from Plasmodium falciparum (PfCSP). After intramuscular administration, VCL-2510 plasmid DNA was detected initially in all of the highly vascularized tissues, but at later time points was found primarily in the muscle at the site of injection, where it persisted for up to 8 weeks. After intravenous administration, plasmid DNA initially distributed at a relatively low frequency to all the tissues examined except the gonads and brain. However, plasmid DNA rapidly cleared, and by 4 weeks postadministration could be detected only in the lung of one of six animals evaluated. In a safety study in mice, eight repeated intramuscular injections of VCL-2510 at plasmid DNA doses of 1, 10, and 100 microg had no adverse effects on clinical chemistry or hematology, and did not result in any organ pathology or systemic toxicity. In a safety study in rabbits, six repeated intramuscular injections of VCL-2510 at plasmid DNA doses of 0.15 and 0.45 mg had no discernible effects on clinical chemistry, hematology, or histopathology. No evidence of autoimmune-mediated pathology, anti-nuclear antibodies (ANA), or antibodies to dsDNA were observed in the mouse or rabbit studies.

100 Deals associated with Malaria DNA vaccine(Naval Medical Research Center)

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Indication	Highest Phase	Country/Location	Organization	Date
Malaria	Phase 2	-	Naval Medical Research Center	-

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