Abstract
Protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill Plasmodium-infected cells. A new malaria vaccine strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver tissue-resident memory (TRM) CD8+ T cells have been shown to be necessary and sufficient for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunotherapeutic responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary, however this is not feasible at large scales in human trials. Here, as part of a phase I/II P. falciparum challenge study of prime-target vaccination, we performed deep immune phenotyping, single-cell RNA-sequencing and kinetics of hepatic fine needle aspirates and peripheral blood samples to study liver CD8+ TRM cells and circulating counterparts. We found that while these peripheral ‘TRM-like’ cells differed to TRM cells in terms of previously described characteristics, they are similar phenotypically and indistinguishable in terms of key T cell residency transcriptional signatures. By exploring the heterogeneity among liver CD8+ TRM cells at single cell resolution we found two main subpopulations that each share expression profiles with blood T cells. Lastly, our work points towards the potential for using TRM−like cells as a correlate of protection by liver-stage malaria vaccines and, in particular, those adopting a prime-target approach. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. We provide a blueprint for understanding and monitoring liver TRM cells induced by a prime-target malaria vaccine approach.
Highlights
Malaria is the most problematic parasitic disease in human history
Given the important role CD8+ T cells and tissue-resident memory (TRM) cells have been shown to play in protection from rodent malaria [9–11], an assay to measure TRM-associated cells in human peripheral blood could be a means of measuring liver TRM cells and, potentially, viral vector liver-stage malaria vaccine performance
In our study we identified a population of TRM-like cells in the circulation that correlated quantitatively and qualitatively to TRM cells isolated from the liver by fine needle aspirate (FNA)
Summary
A highly efficacious vaccine could curb the hundreds of millions of cases and hundreds of thousands of deaths occurring each year. It has been over 30 years since Ruth and Victor Nussenzweig identified that protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill Plasmodium-infected cells [1]. To this end, substantial effort has been invested in optimising viral vector strategies able to generate high frequencies of antigen-specific CD8+ T cells [2–7]. CD8+ T cell numbers following vaccination correlate with efficacy, suggesting that increased numbers of circulating CD8+ T cells are associated with improved protection
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