title: Preclinical evaluation of the safety and immunogenicity of a vaccine consisting of Plasmodium falciparum liver-stage antigen 1 with adjuvant AS01B administered alone or concurrently with the RTS,S/AS01B vaccine in rhesus primates.
abstract: Several lines of evidence suggest that targeting pre-erythrocytic-stage parasites for malaria vaccine development can provide sterile immunity. The objectives of this study were (i) to evaluate preclinically the safety and immunogenicity of a new recombinant pre-erythrocytic-stage antigen, liver-stage antigen 1 (LSA1), in nonhuman primates; and (ii) to investigate the potential for immune interference between LSA1 and the leading malaria vaccine candidate, RTS,S, by comparing the immune responses after single-antigen vaccination to responses after simultaneous administration of both antigens at separate sites. Using a rhesus monkey model, we found that LSA1 formulated with the GlaxoSmithKline proprietary adjuvant system AS01B (LSA1/AS01B) was safe and immunogenic, inducing high titers of antigen-specific antibody and CD4+ T-cell responses, as monitored by the production of interleukin-2 and gamma interferon, using intracellular cytokine staining. RTS,S/AS01B vaccination was well tolerated and demonstrated robust antibody and moderate CD4+ T-cell responses to circumsporozoite protein (CSP) and HBsAg. Positive CD8+ T-cell responses to HBsAg were detected, whereas the responses to CSP and LSA1 were negligible. For both LSA1/AS01B and RTS,S/AS01B, no statistically significant differences were observed between individual and concurrent administration in the magnitude or duration of antibody and T-cell responses. Our results revealed that both pre-erythrocytic-stage antigens were safe and immunogenic, administered either separately or simultaneously to rhesus monkeys, and that no significant immune cross interference occurred with concurrent separate-site administration. The comparison of the profiles of immune responses induced by separate-site and single-site vaccinations with LSA1 and RTS,S warrants further investigation.
authors.affiliation: Department of Immunology and Medicine, USAMC-AFRIMS, 315/6 Rajvithi Rd., Bangkok 10400, Thailand. Sathitp@afrims.org
authors.forename: S
authors.initials: S
authors.lastname: Pichyangkul
authors.forename: U
authors.initials: U
authors.lastname: Kum-Arb
authors.forename: K
authors.initials: K
authors.lastname: Yongvanitchit
authors.forename: A
authors.initials: A
authors.lastname: Limsalakpetch
authors.forename: M
authors.initials: M
authors.lastname: Gettayacamin
authors.forename: D E
authors.initials: DE
authors.lastname: Lanar
authors.forename: L A
authors.initials: LA
authors.lastname: Ware
authors.forename: V A
authors.initials: VA
authors.lastname: Stewart
authors.forename: D G
authors.initials: DG
authors.lastname: Heppner
authors.forename: P
authors.initials: P
authors.lastname: Mettens
authors.forename: J D
authors.initials: JD
authors.lastname: Cohen
authors.forename: W R
authors.initials: WR
authors.lastname: Ballou
authors.forename: M M
authors.initials: MM
authors.lastname: Fukuda
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000953:Antigens, Protozoan / Q000008:administration & dosage / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008253:Macaca mulatta / Q000276:immunology*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D010963:Plasmodium falciparum / Q000276:immunology*; D012503:Saponins / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D016207:Cytokines; D008050:Lipid A; D017780:Malaria Vaccines; C526041:RTS,S-AS01B vaccine; D012503:Saponins; C067302:liver stage-specific antigen, Plasmodium; C078785:saponin QA-21V1