Prime and target immunization protects against liver-stage malaria in mice

Abstract

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.

Resident memory CD8 T cells persist for years in human small intestine

“…In addition to their cytotoxic activity, CD8 Trm cells are efficient producers of proinflammatory cytokines that rapidly trigger both innate and adaptive protective immune responses (Schenkel et al, 2014). Thus, CD8 Trm cells are attractive targets for vaccine development against intracellular pathogens (Gola et al, 2018) and cancer immunotherapy (Park et al, 2018).…”

Clustering of activated CD8 T cells around malaria-infected hepatocytes is rapid and is driven by antigen-specific T cells

“…injected Plasmodium sporozoites does depend on the number of vaccine-induced CD8 T cells in the liver [22, 23, 58]. However, these previous studies are numerically inconsistent suggesting that either 3 × 10 4 [22] or 10 6 [23] memory CD8 T cells in the liver are needed for sterilizing protection. Further work is required to accurately quantify the number of T cells needed for protection.…”

“…Because liver stage is asymptomatic, removal of all liver stages prevents clinical symptoms of malaria and thus is highly desirable feature of an effective vaccine. Indeed, previous studies have shown that memory CD8 T cells are required for protection against a challenge with a relatively large number of sporozoites [14, 15] and that vaccination that induces exclusively memory CD8 T cells of a single specificity can mediate sterilizing protection against a sporozoite challenge [16–23]. Antibodies and CD4 T cells may also contribute to protection in some circumstances, for example, following inoculation of sporozoites by mosquitoes in the skin [24, 25].…”

“…Recent studies utilizing fluorescently labeled sporozoites and activated Plasmodium-specific CD8 T cells and intravital microscopy revealed clustering of CD8 T cells near the parasite in the mouse livers whereby multiple T cells were located in close proximity (≤ 40 μ m) of some liver stages [23, 29–31]. Interestingly, we observed that clustering of T cells near the parasite results in a higher chances of parasite’s death suggesting that clusters may increase the efficiency at which T cells eliminate the infection.…”

Vaccine innovations for emerging infectious diseases—a symposium report

“…He described a prime and target approach in which the boosting dose is administered intravenously, as opposed to intramuscularly, to increase efficacy by targeting CD8 + T cells to the liver. 23 In a field trial that used an intramuscular boosting dose, 67% efficacy, evaluated by polymerase chain reaction (PCR) positivity, was observed. 24 Hill is now look-ing at the feasibility of intravenous dosing in Africa to increase this efficacy.…”