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

Kent E Kester; D Gray Heppner Jr; Philippe Moris; Opokua Ofori-Anyinam; Urszula Krzych; Nadia Tornieporth; Denise McKinney; Martine Delchambre; Christian F Ockenhouse; Gerald Voss; Carolyn Holland; Jolie Palensky Beckey; W Ripley Ballou; Joe Cohen; RTS,S/TRAP Group

doi:10.1016/j.vaccine.2014.06.033

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

Vaccine. 2014 Nov 20;32(49):6683-91. doi: 10.1016/j.vaccine.2014.06.033. Epub 2014 Jun 18.

Authors

Affiliations

¹ Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: [email protected].
² Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: [email protected].
³ GlaxoSmithKline Biologicals, Rixensart, Belgium. Electronic address: [email protected].
⁴ GlaxoSmithKline Biologicals, Rixensart, Belgium. Electronic address: [email protected].
⁵ Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: [email protected].
⁶ GlaxoSmithKline Biologicals, Rixensart, Belgium. Electronic address: [email protected].
⁷ Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: [email protected].
⁸ GlaxoSmithKline Biologicals, Rixensart, Belgium. Electronic address: [email protected].
⁹ Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: [email protected].
¹⁰ GlaxoSmithKline Biologicals, Rixensart, Belgium. Electronic address: [email protected].
¹¹ Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: [email protected].
¹² Statistics Collaborative, Inc., Washington, DC, USA. Electronic address: [email protected].
¹³ Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: [email protected].
¹⁴ GlaxoSmithKline Biologicals, Rixensart, Belgium. Electronic address: [email protected].

PMID: 24950358
DOI: 10.1016/j.vaccine.2014.06.033

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.

Keywords: AS02; Challenge; Immune interference; Malaria vaccine; RTS,S; TRAP.

Publication types

Clinical Trial, Phase I
Clinical Trial, Phase II
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Antibodies, Protozoan / blood
Antigens, Protozoan / immunology
Cell Proliferation
Drug Combinations
Drug-Related Side Effects and Adverse Reactions / epidemiology
Drug-Related Side Effects and Adverse Reactions / pathology
Enzyme-Linked Immunospot Assay
Female
Humans
Interferon-gamma / metabolism
Leukocytes, Mononuclear / immunology
Lipid A / administration & dosage
Lipid A / adverse effects
Lipid A / analogs & derivatives*
Malaria Vaccines / administration & dosage
Malaria Vaccines / adverse effects*
Malaria Vaccines / immunology*
Malaria, Falciparum / prevention & control*
Male
Middle Aged
Parasitemia / prevention & control
Plasmodium falciparum / immunology*
Protozoan Proteins / immunology
Saponins / administration & dosage
Saponins / adverse effects*
Treatment Outcome
Vaccination / adverse effects
Vaccination / methods
Young Adult

Substances

ASO2A adjuvant
Antibodies, Protozoan
Antigens, Protozoan
Drug Combinations
Lipid A
Malaria Vaccines
Protozoan Proteins
Saponins
thrombospondin-related adhesive protein, protozoan
Interferon-gamma