CD8 T-cell-mediated protection against liver-stage malaria: lessons from a mouse model.

Natalija Van Braeckel-Budimir,John T Harty

doi:10.3389/fmicb.2014.00272

Abstract

Malaria is a major global health problem, with severe mortality in children living in sub-Saharan Africa, and there is currently no licensed, effective vaccine. However, vaccine-induced protection from Plasmodium infection, the causative agent of malaria, was established for humans in small clinical trials and for rodents in the 1960s. Soon after, a critical role for memory CD8 T cells in vaccine-induced protection against Plasmodium liver-stage infection was established in rodent models and is assumed to apply to humans. However, these seminal early studies have led to only modest advances over the ensuing years in our understanding the basic features of memory CD8 T cells required for protection against liver-stage Plasmodium infection, an issue which has likely impeded the development of effective vaccines for humans. Given the ethical and practical limitations in gaining mechanistic insight from human vaccine and challenge studies, animal models still have an important role in dissecting the basic parameters underlying memory CD8 T-cell immunity to Plasmodium. Here, we will highlight recent data from our own work in the mouse model of Plasmodium infection that identify quantitative and qualitative features of protective memory CD8 T-cell responses. Finally, these lessons will be discussed in the context of recent findings from clinical trials of vaccine-induced protection in controlled human challenge models.

Highlights

Malaria represents an enormous global health problem
We observed that more than 95% of animals with CD8+ T-cell frequencies exceeding a threshold of 1% of total peripheral blood leukocytes (PBLs) were protected against sporozoite challenge, while more than 95% of animals with CD8 T-cell frequencies below this threshold developed bloodstage infection and were not sterilely protected (Schmidt et al, 2008). These findings demonstrate that sterile protection against sporozoite infection requires a remarkably strong CD8 T-cell response, representing a substantial fraction of the total CD8 T-cell pool and highly exceeding frequencies of antigen-specific CD8 T cells required for plausible protection against various viral and bacterial infections (Schmidt et al, 2008)
INFLUENCE OF Plasmodium–HOST INTERACTIONS ON MEMORY CD8 T-CELL-MEDIATED PROTECTION AGAINST LIVER-STAGE Plasmodium INFECTION we demonstrated a clear threshold (>1% of PBL) for CD8 T-cell-mediated sterilizing immunity, our findings were limited to one mouse strain (BALB/c) and one Plasmodium species (P. bergei; Schmidt et al, 2008)

Summary

Introduction

Malaria represents an enormous global health problem. It is associated with around 200 million reported annual cases and more than 600,000 deaths, most of them recorded in sub-Saharan Africa (WHO, 2011). The earliest evidence of vaccineinduced, sterile, liver-stage immunity originates from mouse studies, in which it was demonstrated that vaccination with radiation attenuated sporozoites (RAS) prevented development of blood-stage Plasmodium berghei infection after sporozoite challenge (Nussenzweig et al, 1967, 1969).

Results

Conclusion