Extreme CD8 T cell requirements for anti-malarial liver-stage immunity following immunization with radiation attenuated sporozoites

• Published in: PLoS pathogens Vol. 6; no. 7; p. e1000998
• Main Authors: Schmidt, Nathan W, Butler, Noah S, Badovinac, Vladimir P, Harty, John T
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2010; Public Library of Science (PLoS)
• Subjects: Animals; Antimalarials - immunology; Care and treatment; CD8 lymphocytes; CD8-Positive T-Lymphocytes - immunology; Cellular immunity; Genetic aspects; Immunity; Immunization; Immunologic Memory; Immunology; Infectious Diseases/Protozoal Infections; Liver - immunology; Liver - parasitology; Malaria; Malaria Vaccines - administration & dosage; Malaria Vaccines - immunology; Mice; Parasites; Plasmodium berghei; Rodents; Sporozoites - immunology; Sporozoites - radiation effects; T cell receptors; Vaccination; Vaccines; Vaccines, Attenuated - immunology; United States; CD8-Positive T-Lymphocytes; Immunization; Animals; Malaria Vaccines; Liver; Sporozoites; Vaccines, Attenuated; Antimalarials; Immunologic Memory; Mice; Immunity
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1000998

Radiation-attenuated Plasmodium sporozoites (RAS) are the only vaccine shown to induce sterilizing protection against malaria in both humans and rodents. Importantly, these "whole-parasite" vaccines are currently under evaluation in human clinical trials. Studies with inbred mice reveal that RAS-induced CD8 T cells targeting liver-stage parasites are critical for protection. However, the paucity of defined T cell epitopes for these parasites has precluded precise understanding of the specific characteristics of RAS-induced protective CD8 T cell responses. Thus, it is not known whether quantitative or qualitative differences in RAS-induced CD8 T cell responses underlie the relative resistance or susceptibility of immune inbred mice to sporozoite challenge. Moreover, whether extraordinarily large CD8 T cell responses are generated and required for protection following RAS immunization, as has been described for CD8 T cell responses following single-antigen subunit vaccination, remains unknown. Here, we used surrogate T cell activation markers to identify and track whole-parasite, RAS-vaccine-induced effector and memory CD8 T cell responses. Our data show that the differential susceptibility of RAS-immune inbred mouse strains to Plasmodium berghei or P. yoelii sporozoite challenge does not result from host- or parasite-specific decreases in the CD8 T cell response. Moreover, the surrogate activation marker approach allowed us for the first time to evaluate CD8 T cell responses and protective immunity following RAS-immunization in outbred hosts. Importantly, we show that compared to a protective subunit vaccine that elicits a CD8 T cell response to a single epitope, diversifying the targeted antigens through whole-parasite RAS immunization only minimally, if at all, reduced the numerical requirements for memory CD8 T cell-mediated protection. Thus, our studies reveal that extremely high frequencies of RAS-induced memory CD8 T cells are required, but may not suffice, for sterilizing anti-Plasmodial immunity. These data provide new insights into protective CD8 T cell responses elicited by RAS-immunization in genetically diverse hosts, information with relevance to developing attenuated whole-parasite vaccines.