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Gola, Anita; Silman, Daniel; Walters, Adam A; Sridhar, Saranya; Uderhardt, Stefan; Salman, Ahmed M; Halbroth, Benedict R; Bellamy, Duncan; Bowyer, Georgina; Powlson, Jonathan; Baker, Megan; Venkatraman, Navin; Poulton, Ian; Berrie, Eleanor; Roberts, Rachel; Lawrie, Alison M; Angus, Brian; Khan, Shahid M; Janse, Chris J; Ewer, Katie J; Germain, Ronald N; Spencer, Alexandra J; Hill, Adrian V S
Science translational medicine, 09/2018, Volume: 10, Issue: 460Journal Article
Despite recent advances in treatment and vector control, malaria is still a leading cause of death, emphasizing the need for an effective vaccine. The malaria life cycle can be subdivided into three stages: the invasion and growth within liver hepatocytes (pre-erythrocytic stage), the blood stage (erythrocytic stage), and, finally, the sexual stage (occurring within the mosquito vector). Antigen (Ag)-specific CD8 T cells are effectively induced by heterologous prime-boost viral vector immunization and known to correlate with liver-stage protection. However, liver-stage malaria vaccines have struggled to generate and maintain the high numbers of -specific circulating T cells necessary to confer sterile protection. We describe an alternative "prime and target" vaccination strategy aimed specifically at inducing high numbers of tissue-resident memory T cells present in the liver at the time of hepatic infection. This approach bypasses the need for very high numbers of circulating T cells and markedly increases the efficacy of subunit immunization against liver-stage malaria with clinically relevant Ags and clinically tested viral vectors in murine challenge models. Translation to clinical use has begun, with encouraging results from a pilot safety and feasibility trial of intravenous chimpanzee adenovirus vaccination in humans. This work highlights the value of a prime-target approach for immunization against malaria and suggests that this strategy may represent a more general approach for prophylaxis or immunotherapy of other liver infections and diseases.
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