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Abstract
Protection against a malaria infection can be achieved by immunization with live-attenuated Plasmodium sporozoites and while the precise mechanisms of protection remain unknown, T cell responses are thought to be critical in the elimination of infected liver cells. In cancer immunotherapies, agonistic antibodies that target T cell surface proteins, such as CD27, OX40 (CD134), and 4-1BB (CD137), have been used to enhance T cell function by increasing co-stimulation. In this study, we have analyzed the effect of agonistic OX40 monoclonal antibody treatment on protective immunity induced in mice immunized with genetically attenuated parasites (GAPs). OX40 stimulation enhanced protective immunity after vaccination as shown by an increase in the number of protected mice and delay to blood-stage infection after challenge with wild-type sporozoites. Consistent with the enhanced protective immunity enforced OX40 stimulation resulted in an increased expansion of antigen-experienced effector (CD11ahiCD44hi) CD8+ and CD4+ T cells in the liver and spleen and also increased IFN-γ and TNF producing CD4+ T cells in the liver and spleen. In addition, GAP immunization plus α-OX40 treatment significantly increased sporozoite-specific IgG responses. Thus, we demonstrate that targeting T cell costimulatory receptors can improve sporozoite-based vaccine efficacy.
Highlights
Malaria remains a major threat to the lives of more than 3 billion people world-wide and there remains a pressing but unmet need for an effective vaccine, which can provide sustained protection against either infection or disease
We show in this study that treatment of mice with an agonistic antibody against the T cell costimulatory molecule OX40, a member of the tumor necrosis factor receptor (TNFR) superfamily (AlShamkhani et al, 1996), enhances protective immunity after immunization with genetically attenuated parasites (GAPs) sporozoites
OX40 is transiently expressed on T cells following cognate interactions between T cell receptors (TCRs) and antigen-major histocompatibility (MHC) complexes on antigen presenting cells (APCs) (Croft, 2010)
Summary
Malaria remains a major threat to the lives of more than 3 billion people world-wide and there remains a pressing but unmet need for an effective vaccine, which can provide sustained protection against either infection or disease. Despite three decades of clinical testing different (recombinant) sub-unit vaccines, only modest protection has been reported so far (Hoffman et al, 2015; Tinto et al, 2015; White et al, 2015; Mahmoudi and Keshavarz, 2017) and this has renewed an interest in whole parasite-based vaccine approaches (Pinzon-Charry and Good, 2008; Hollingdale and Sedegah, 2017) It was first shown in rodent models of malaria that complete protection against infection can be obtained by vaccination using live attenuated sporozoites (Nussenzweig et al, 1967, 1969). Rodent GAP studies have been critical in the creation of two P. falciparum GAP-based vaccines that are currently undergoing clinical evaluation (Khan et al, 2012; Mikolajczak et al, 2014; van Schaijk et al, 2014)
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