title: 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.
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.
authors.affiliation: Naval Medical Research Center; Silver Spring, MD, USA. Thomas.Richie@med.navy.mil
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Richie
authors.forename: Yupin
authors.initials: Y
authors.lastname: Charoenvit
authors.forename: Ruobing
authors.initials: R
authors.lastname: Wang
authors.forename: Judith E
authors.initials: JE
authors.lastname: Epstein
authors.forename: Richard C
authors.initials: RC
authors.lastname: Hedstrom
authors.forename: Sanjai
authors.initials: S
authors.lastname: Kumar
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Luke
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Freilich
authors.forename: Joao C
authors.initials: JC
authors.lastname: Aguiar
authors.forename: John B
authors.initials: JB
authors.lastname: Sacci
authors.forename: Martha
authors.initials: M
authors.lastname: Sedegah
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Nosek
authors.forename: Patricia
authors.initials: P
authors.lastname: De La Vega
authors.forename: Mara P
authors.initials: MP
authors.lastname: Berzins
authors.forename: Victoria F
authors.initials: VF
authors.lastname: Majam
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Abot
authors.forename: Harini
authors.initials: H
authors.lastname: Ganeshan
authors.forename: Nancy O
authors.initials: NO
authors.lastname: Richie
authors.forename: Jo Glenna
authors.initials: JG
authors.lastname: Banania
authors.forename: Maria Fe B
authors.initials: MF
authors.lastname: Baraceros
authors.forename: Tanya G
authors.initials: TG
authors.lastname: Geter
authors.forename: Robin
authors.initials: R
authors.lastname: Mere
authors.forename: Lolita
authors.initials: L
authors.lastname: Bebris
authors.forename: Keith
authors.initials: K
authors.lastname: Limbach
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Hickey
authors.forename: David E
authors.initials: DE
authors.lastname: Lanar
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ng
authors.forename: Meng
authors.initials: M
authors.lastname: Shi
authors.forename: Peter M
authors.initials: PM
authors.lastname: Hobart
authors.forename: Jon A
authors.initials: JA
authors.lastname: Norman
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: Soisson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hollingdale
authors.forename: William O
authors.initials: WO
authors.lastname: Rogers
authors.forename: Denise L
authors.initials: DL
authors.lastname: Doolan
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hoffman
mesh_terms: D000328:Adult; D000953:Antigens, Protozoan / Q000276:immunology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010957:Plasmids / Q000235:genetics; D010963:Plasmodium falciparum / Q000276:immunology* / Q000472:pathogenicity*; D034101:Sporozoites / Q000276:immunology*; D019444:Vaccines, DNA / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D019444:Vaccines, DNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor