Abstract
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.
Highlights
Plasmodium infections are a global health crisis resulting in,300 million cases of malaria each year and,1 million deaths [1,2,3,4,5]
Relative resistance after Radiation-attenuated Plasmodium sporozoites (RAS)-vaccination of both rodents and humans is commonly studied by sporozoite challenge 1–2 weeks following the last immunization [8,11,19,20] and evaluates immunity mediated by recently stimulated T cell populations
To examine the protective CD8 T cell response elicited by RAS-vaccination, we applied our recently described surrogate activation marker approach, based on downregulation of CD8a and upregulation of CD11a (CD8aloCD11ahi) [18], to identify RAS-induced CD8 T cells
Summary
Plasmodium infections are a global health crisis resulting in ,300 million cases of malaria each year and ,1 million deaths [1,2,3,4,5]. Most vaccines under clinical evaluation are only partially protective and, for unknown reasons, immunity rapidly wanes [6]. Development of an effective malaria vaccine that provides long-term protection remains an important goal to improve global health. Immunization with radiation-attenuated sporozoites (RAS) is the only documented means to induce sterilizing protection in both humans [7,8] and rodents [9] and, importantly this approach is under evaluation in clinical trials [10]. The precise characteristics of protective memory CD8 T responses following RAS-vaccination remain poorly understood. One reason for this relates to the limited number of defined CD8 T cell epitopes derived from rodent species of Plasmodia
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