Journal Article

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

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

2014

Overview

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.

• Publisher: Elsevier Ltd,Elsevier,Elsevier Limited
• Subject: adjuvants / Adolescent / Adult / adults / Allergy and Immunology / antibodies / Antibodies, Protozoan - blood / antigens / Antigens, Protozoan - immunology / Applied microbiology / AS02 / Biological and medical sciences / Cell Proliferation / Challenge / Drug Combinations / Drug-Related Side Effects and Adverse Reactions - epidemiology / Drug-Related Side Effects and Adverse Reactions - pathology / Enzyme-Linked Immunospot Assay / Female / Fundamental and applied biological sciences. Psychology / Hepatitis / Human protozoal diseases / Humans / Immune interference / immune response / Immunogenicity / Infectious diseases / interferon-gamma / Interferon-gamma - secretion / Leukocytes, Mononuclear - immunology / Lipid A - administration & dosage / Lipid A - adverse effects / Lipid A - analogs & derivatives / Malaria / Malaria vaccine / malaria vaccines / Malaria Vaccines - administration & dosage / Malaria Vaccines - adverse effects / Malaria Vaccines - immunology / Malaria, Falciparum - prevention & control / Male / Medical sciences / Microbiology / Middle Aged / parasitemia / Parasitemia - prevention & control / Parasitic diseases / pathogenicity / Plasmodium falciparum / Plasmodium falciparum - immunology / Proteins / Protozoal diseases / Protozoan Proteins - immunology / RTS,S / Safety / Saponins - administration & dosage / Saponins - adverse effects / TRAP / Treatment Outcome / Vaccination - adverse effects / Vaccination - methods / Vaccines / Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects) / value added / Vector-borne diseases / volunteers / Young Adult