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ABSTRACT

A prime and target vaccine for liver-stage malaria results in sterile protection in mouse disease models and appears safe for human use. A malaria vaccine to harness hepatic immunity Plasmodium, the parasitic agent of malaria, has a fairly complicated life cycle in different organs of the host. Malaria vaccines can be designed to disrupt a particular parasitic stage. Gola et al. are interested in developing a malaria vaccine that protects against liver-stage malaria. To do so, they used nanoparticles or viral vectors. The vaccines induced tissue-resident memory CD8+ T cells in mice, which conferred sterilizing protection against sporozoite challenge. One of the viral vector vaccine candidates was tested in healthy human volunteers and was found to be safe. The investigators are hopeful that this vaccine can induce protective liver-resident T cells in humans. 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 Plasmodium-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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