title: Sequential Phase 1 and Phase 2 randomized, controlled trials of the safety, immunogenicity and efficacy of combined pre-erythrocytic vaccine antigens RTS,S and TRAP formulated with AS02 Adjuvant System in healthy, malaria naïve adults.
abstract: In an attempt to improve the efficacy of the candidate malaria vaccine RTS,S/AS02, two studies were conducted in 1999 in healthy volunteers of RTS,S/AS02 in combination with recombinant Plasmodium falciparum thrombospondin-related anonymous protein (TRAP). In a Phase 1 safety and immunogenicity study, volunteers were randomized to receive TRAP/AS02 (N=10), RTS,S/AS02 (N=10), or RTS,S+TRAP/AS02 (N=20) at 0, 1 and 6-months. In a Phase 2 challenge study, subjects were randomized to receive either RTS,S+TRAP/AS02 (N=25) or TRAP/AS02 (N=10) at 0 and 1-month, or to a challenge control group (N=8). In both studies, the combination vaccine had an acceptable safety profile and was acceptably tolerated. Antigen-specific antibodies, lymphoproliferative responses, and IFN-γ production by ELISPOT assay elicited with the combination vaccine were qualitatively similar to those generated by the single component vaccines. However, post-dose 2 anti-CS antibodies in the RTS,S+TRAP/AS02 vaccine recipients were lower than in the RTS,S/AS02 vaccine recipients. After challenge, 10 of 11 RTS,S+TRAP/AS02 vaccinees, 5 of 5 TRAP/AS02 vaccinees, and 8 of 8 infectivity controls developed parasitemia, with median pre-patent periods of 13.0, 11.0, and 12.0 days, respectively. The absence of any prevention or delay of parasitemia by TRAP/AS02 suggests no apparent added value of TRAP/AS02 as a candidate vaccine. The absence of significant protection or delay of parasitemia in the 11 RTS,S+TRAP/AS02 vaccine recipients contrasts with previous 2 dose studies of RTS,S/AS02. The small sample size did not permit identifying statistically significant differences between the study arms. However, we speculate, within the constraints of the challenge study, that the presence of the TRAP antigen may have interfered with the vaccine efficacy previously observed with this regimen of RTS,S/AS02, and that any future TRAP-based vaccines should consider employing alternative vaccine platforms.
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: kent.kester@usuhs.edu.
authors.forename: Kent E
authors.initials: KE
authors.lastname: Kester
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: grayheppner@gmail.com.
authors.forename: D
authors.initials: D
authors.lastname: Gray Heppner
authors.affiliation: GlaxoSmithKline Biologicals, Rixensart, Belgium. Electronic address: philippe.moris@gsk.com.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moris
authors.affiliation: GlaxoSmithKline Biologicals, Rixensart, Belgium. Electronic address: opokua.ofori-anyinam@gsk.com.
authors.forename: Opokua
authors.initials: O
authors.lastname: Ofori-Anyinam
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: urszula.krzych1@us.army.mil.
authors.forename: Urszula
authors.initials: U
authors.lastname: Krzych
authors.affiliation: GlaxoSmithKline Biologicals, Rixensart, Belgium. Electronic address: nadia.tornieporth@sanofipasteur.com.
authors.forename: Nadia
authors.initials: N
authors.lastname: Tornieporth
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: deniseam52@gmail.com.
authors.forename: Denise
authors.initials: D
authors.lastname: McKinney
authors.affiliation: GlaxoSmithKline Biologicals, Rixensart, Belgium. Electronic address: martine.delchambre@gsk.com.
authors.forename: Martine
authors.initials: M
authors.lastname: Delchambre
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: cockenhouse@path.org.
authors.forename: Christian F
authors.initials: CF
authors.lastname: Ockenhouse
authors.affiliation: GlaxoSmithKline Biologicals, Rixensart, Belgium. Electronic address: gerald.voss@gsk.com.
authors.forename: Gerald
authors.initials: G
authors.lastname: Voss
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: carolyn.holland@us.army.mil.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Holland
authors.affiliation: Statistics Collaborative, Inc., Washington, DC, USA. Electronic address: alexandjolie@gmail.com.
authors.forename: Jolie Palensky
authors.initials: JP
authors.lastname: Beckey
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: ripley.w.ballou@gsk.com.
authors.forename: W Ripley
authors.initials: WR
authors.lastname: Ballou
authors.affiliation: GlaxoSmithKline Biologicals, Rixensart, Belgium. Electronic address: joe.cohen@gsk.com.
authors.forename: Joe
authors.initials: J
authors.lastname: Cohen
mesh_terms: D000293:Adolescent; D000328:Adult; D000913:Antibodies, Protozoan / Q000097:blood; D000953:Antigens, Protozoan / Q000276:immunology; D049109:Cell Proliferation; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008050:Lipid A / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D018512:Parasitemia / Q000517:prevention & control; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology; D012503:Saponins / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome; D014611:Vaccination / Q000009:adverse effects / Q000379:methods; D055815:Young Adult
chemical_list: C501939:ASO2A adjuvant; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D004338:Drug Combinations; D008050:Lipid A; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D012503:Saponins; C069428:thrombospondin-related adhesive protein, protozoan; D007371:Interferon-gamma
keywords: AS02; Challenge; Immune interference; Malaria vaccine; RTS,S; TRAP