Abstract
Whole sporozoite vaccines represent one of the most promising strategies to induce protection against malaria. However, the development of efficient vaccination protocols still remains a major challenge. To understand how the generation of immunity is affected by variations in vaccination dosage and frequency, we systematically analyzed intrasplenic and intrahepatic CD8+ T cell responses following varied immunizations of mice with radiation-attenuated sporozoites. By combining experimental data and mathematical modeling, our analysis indicates a reversing role of spleen and liver in the generation of protective liver-resident CD8+ T cells during priming and booster injections: While the spleen acts as a critical source compartment during priming, the increase in vaccine-induced hepatic T cell levels is likely due to local reactivation in the liver in response to subsequent booster injections. Higher dosing accelerates the efficient generation of liver-resident CD8+ T cells by especially affecting their local reactivation. In addition, we determine the differentiation and migration pathway from splenic precursors toward hepatic memory cells thereby presenting a mechanistic framework for the impact of various vaccination protocols on these dynamics. Thus, our work provides important insights into organ-specific CD8+ T cell dynamics and their role and interplay in the formation of protective immunity against malaria.
Highlights
Despite recent advances and the regulatory approval of the RTS,S vaccine [1,2,3,4], the development of an efficient vaccine still remains an urgent priority and one of the major challenges in malaria research
Analysis of the hepatic CD8+ T cell subsets further revealed that only a small fraction of around 10% of cells exhibited a TCM phenotype (CD44hi/CD62Lhi), which was seemingly unaffected from the choice of dose and number of injections (Figure S2 in Supplementary Material)
Comparing them to the responses in a corresponding mock-control group (MN), we found that hepatic TE/EM cells remained relatively stable at low levels throughout the vaccination schedule and constituted only about 20% of the TE/ EM numbers detected in the respective Plasmodium berghei RAS (PbRAS) immunized mice after three i.v. administrations (Figure 2C)
Summary
Despite recent advances and the regulatory approval of the RTS,S vaccine [1,2,3,4], the development of an efficient vaccine still remains an urgent priority and one of the major challenges in malaria research. Causing abrogation of parasite development during or shortly after the pre-pathological liver stage of malaria infection, either by radiation of sporozoites, their genetic modification or combined delivery with drug-treatment, has been proven to be the most successful approach to confer sterile protection against malaria infection [5,6,7,8,9,10,11,12,13]. These whole sporozoite vaccination (WSV) strategies, of which, to. The effective generation of such local immunity allowing for potent regional recall responses might, be of utmost importance for the rational design of protective vaccination strategies against malaria [21]
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