title: Superior antimalarial immunity after vaccination with late liver stage-arresting genetically attenuated parasites.
abstract: While subunit vaccines have shown partial efficacy in clinical trials, radiation-attenuated sporozoites (RAS) remain the "gold standard" for sterilizing protection against Plasmodium infection in human vaccinees. The variability in immunogenicity and replication introduced by the extensive, random DNA damage necessary to generate RAS could be overcome by genetically attenuated parasites (GAP) designed via gene deletion to arrest at defined points during liver-stage development. Here, we demonstrate the principle that late liver stage-arresting GAP induce larger and broader CD8 T cell responses that provide superior protection in inbred and outbred mice compared to RAS or early-arresting GAP immunizations. Late liver stage-arresting GAP also engender high levels of cross-stage and cross-species protection and complete protection when administered by translationally relevant intradermal or subcutaneous routes. Collectively, our results underscore the potential utility of late liver stage-arresting GAP as broadly protective next-generation live-attenuated malaria vaccines and support their potential as a powerful model for identifying antigens to generate cross-stage protection.
authors.affiliation: Department of Microbiology, University of Iowa, 3-512 Bowen Science Building, Iowa City, IA 52242, USA.
authors.forename: Noah S
authors.initials: NS
authors.lastname: Butler
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Schmidt
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Vaughan
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Aly
authors.forename: Stefan H I
authors.initials: SH
authors.lastname: Kappe
authors.forename: John T
authors.initials: JT
authors.lastname: Harty
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000469:parasitology; D017353:Gene Deletion; D006801:Humans; D008099:Liver / Q000276:immunology / Q000469:parasitology*; D008288:Malaria / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000235:genetics* / Q000254:growth & development / Q000276:immunology*; D010967:Plasmodium yoelii / Q000235:genetics* / Q000254:growth & development / Q000276:immunology*; D034101:Sporozoites / Q000254:growth & development / Q000276:immunology; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D017780:Malaria Vaccines; D014613:Vaccines, Attenuated