title: Artesunate versus chloroquine infection-treatment-vaccination defines stage-specific immune responses associated with prolonged sterile protection against both pre-erythrocytic and erythrocytic Plasmodium yoelii infection.
abstract: Sterile protection against malaria infection can be achieved through vaccination of mice and humans with whole Plasmodium spp. parasites. One such method, known as infection-treatment-vaccination (ITV), involves immunization with wild type sporozoites (spz) under drug coverage. In this work, we used the different effects of antimalarial drugs chloroquine (CQ) and artesunate (AS) on blood stage (BS) parasites to dissect the stage-specific immune responses in mice immunized with Plasmodium yoelii spz under either drug, as well as their ability to protect mice against challenge with spz or infected RBCs (iRBCs). Whereas CQ-ITV induced sterile protection against challenge with both spz and iRBCs, AS-ITV only induced sterile protection against spz challenge. Importantly, AS-ITV delayed the onset of BS infection, indicating that both regimens induced cross-stage immunity. Moreover, both CQ- and AS-ITV induced CD8(+) T cells in the liver that eliminated malaria-infected hepatocytes in vitro, as well as Abs that recognized pre-erythrocytic parasites. Sera from both groups of mice inhibited spz invasion of hepatocytes in vitro, but only CQ-ITV induced high levels of anti-BS Abs. Finally, passive transfer of sera from CQ-ITV-treated mice delayed the onset of erythrocytic infection in the majority of mice challenged with P. yoelii iRBCs. Besides constituting the first characterization, to our knowledge, of AS-ITV as a vaccination strategy, our data show that ITV strategies that lead to subtle differences in the persistence of parasites in the blood enable the characterization of the resulting immune responses, which will contribute to future research in vaccine design and malaria interventions.
authors: Department of Pathogenic Biology, Third Military Medical University, Chongqing 400038, China; Seattle Biomedical Research Institute, Seattle, WA 98109; and.
authors: Xiaohong
authors: X
authors: Peng
authors: Seattle Biomedical Research Institute, Seattle, WA 98109; and.
authors: Gladys J
authors: GJ
authors: Keitany
authors: Seattle Biomedical Research Institute, Seattle, WA 98109; and.
authors: Marissa
authors: M
authors: Vignali
authors: Department of Pathogenic Biology, Third Military Medical University, Chongqing 400038, China; Seattle Biomedical Research Institute, Seattle, WA 98109; and.
authors: Lin
authors: L
authors: Chen
authors: Seattle Biomedical Research Institute, Seattle, WA 98109; and.
authors: Claire
authors: C
authors: Gibson
authors: Seattle Biomedical Research Institute, Seattle, WA 98109; and.
authors: Kimberly
authors: K
authors: Choi
authors: Department of Pathogenic Biology, Third Military Medical University, Chongqing 400038, China;
authors: Fusheng
authors: F
authors: Huang
authors: Seattle Biomedical Research Institute, Seattle, WA 98109; and Department of Global Health, University of Washington, Seattle, WA 98125 ruobing.wang@seattlebiomed.org.
authors: Ruobing
authors: R
authors: Wang
mesh_terms: D000818:Animals; D000852:Anopheles / Q000276:immunology; D000913:Antibodies, Protozoan / Q000096:biosynthesis / Q000097:blood; D000962:Antimalarials / Q000008:administration & dosage / Q000627:therapeutic use; D019306:Artemisia / Q000276:immunology; D037621:Artemisinins / Q000008:administration & dosage* / Q000627:therapeutic use; D000077332:Artesunate; D002738:Chloroquine / Q000008:administration & dosage* / Q000627:therapeutic use; D004912:Erythrocytes / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology*; D005260:Female; D008288:Malaria / Q000097:blood / Q000276:immunology* / Q000517:prevention & control; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000097:blood / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008517:Phytotherapy / Q000379:methods; D010967:Plasmodium yoelii / Q000187:drug effects / Q000276:immunology*; D034101:Sporozoites / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D013997:Time Factors; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000913:Antibodies, Protozoan; D000962:Antimalarials; D037621:Artemisinins; D017780:Malaria Vaccines; D014613:Vaccines, Attenuated; D000077332:Artesunate; D002738:Chloroquine