Preclinical Evaluation of the Safety and Immunogenicity of a Vaccine Consisting ofPlasmodium falciparumLiver-Stage Antigen 1 with Adjuvant AS01B Administered Alone or Concurrently with the RTS,S/AS01B Vaccine in Rhesus Primates

• DOI: 10.1128/iai.00977-07
• Publication Date: 2007-10-22T23:11:08Z
• Authors: S. Pichyangkul; U. Kum-Arb; K. Yongvanitchit; A. Limsalakpetch; M. Gettayacamin; D. E. Lanar; L. A. Ware; V. A. Stewart; D. G. Heppner; P. Mettens; J. D. Cohen; W. R. Ballou; M. M. Fukuda
• Keywords: CD4-Positive T-Lymphocytes; 0303 health sciences; Time Factors; Plasmodium falciparum; Antibodies, Protozoan; Antigens, Protozoan; CD8-Positive T-Lymphocytes; Saponins; Macaca mulatta; 3. Good health; 03 medical and health sciences; Lipid A; Adjuvants, Immunologic; Malaria Vaccines; Animals; Cytokines; Malaria, Falciparum

ABSTRACTSeveral 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.