First-in-human evaluation of genetically attenuated Plasmodium falciparum sporozoites administered by bite of Anopheles mosquitoes to adult volunteers
Spring, M; Murphy, J; Nielse, R; Dowler, M; Bennett, JW; Zarling, S; Williams, J; De La Vega, P; Ware, L; Komisar, J; Polhemus, M; Richie, TL; Epstein, J; Tamminga, C; Chuang, I; Richie, N; O'Neil, M; Heppner, DG; Healer, J; O'Neill, M; Smithers, H; Finney, OC; Mikolajczak, SA; Wang, RB; Cowman, A; Ockenhouse, C; Krzych, U; Kappe, SHI
Background: Immunization with genetically engineered, attenuated malaria parasites (GAP) that arrest during liver infection confers sterile protection in mouse malaria models. A first generation Plasmodium falciparum GAP (Pf p52(-)/p36(-) GAP) was previously generated by deletion of two pre-erythrocytic stage-expressed genes (P52 and P36) in the NF54 strain. Methods: A first-in-human, proof-of-concept, safety and immunogenicity clinical trial in six human volunteers was conducted. Exposure consisted of delivery of Pf p52-/p36- GAP sporozoites via infected Anopheles mosquito bite with a five-bite/volunteer exposure followed by an approximately 200-bite exposure/volunteer one month later. Results: The exposures were well tolerated with mild to moderate local and systemic reactions. All volunteers remained blood stage negative after low dose exposure. Five volunteers remained blood stage negative after high dose exposure. One volunteer developed peripheral parasitemia twelve days after high dose exposure. Together the findings indicate that Pf p52-/p36- GAP was severely but not completely attenuated. All six volunteers developed antibodies to CSP. Furthermore, IFN-gamma responses to whole sporozoites and multiple antigens were elicited in 5 of 6 volunteers, with both CD4 and CD8 cell cytokine production detected. Conclusion: Severe attenuation and favorable immune responses following administration of a first generation Pf p52-/p36- GAP suggests that further development of live-attenuated strains using genetic engineering should be pursued. (C) 2013 Elsevier Ltd. All rights reserved.