A Natural Peptide Antigen within the Plasmodium Ribosomal Protein RPL6 Confers Liver TRM Cell-Mediated Immunity against Malaria in Mice

Ana Maria Valencia-Hernandez,Anthony W Purcell,Nicole L La Gruta,Yu Cheng Chua,Lauren E Holz,Vanessa Mollard,Claerwen M Jones,Thiago M Steiner,Nazanin Ghazanfari,David G Bowen,Anton Cozijnsen,Winfried Barchet,Kirsteen M Tullett,Ian A Cockburn,Patrick Bertolino,Irina Caminschi,Sonia Ghilas,Tania De Koning-Ward,Mireille H Lahoud,Matthias H Enders,Cheng Huang,Alyssa E Barry,Wei Yi Ng,Myo Naung,William R Heath,Ralf B Schittenhelm,Geoffrey I Mcfadden,Lynette Beattie,Kieran English,Peter Tan ,José A Villadangos ,Stéphanie Gras ,Yiyong Cai ,Melody Menezes ,Daniel Fernandez‐Ruiz

doi:10.1016/j.chom.2020.04.010

Abstract

Liver-resident memory CD8+ T (TRM) cells remain in and constantly patrol the liver to elicit rapid immunity upon antigen encounter and can mediate efficient protection against liver-stage Plasmodium infection. This finding has prompted the development of immunization strategies where Tcells are activated in the spleen and then trapped in the liver to form TRM cells. Here, we identify PbRPL6120-127, a H2-Kb-restricted epitope from the putative 60S ribosomal protein L6 (RPL6) of Plasmodium berghei ANKA, as an optimal antigen for endogenous liver TRM cell generation and protection against malaria. A single dose vaccination targeting RPL6 provided effective and prolonged sterilizing immunity against high dose sporozoite challenges. Expressed throughout the parasite life cycle, across Plasmodium species, and highly conserved, RPL6 exhibits strong translation potential as a vaccine candidate. This is further advocated by the identification of a broadly conserved, immunogenic HLA-A∗02:01-restricted epitope in P.falciparum RPL6.

Highlights

Malaria remains a major global cause of morbidity and mortality
Characterization of Prime-and-Trap Vaccination Using PbT-I Cells Using adoptive transfer of MHC-I restricted, P. berghei-specific TCR transgenic PbT-I cells into berghei sporozoites in C57BL/6 (B6) mice to track T cell responses, we reported that prime-and-trap vaccination generates liver TRM cells that efficiently protect against infection by 200 P. berghei sporozoites at day 35 (Fernandez-Ruiz et al, 2016)
We found that concomitant administration of all vaccine components was as effective as delaying virus injection by 1 day (Figures S1A–S1C; 8(D0) versus 8), that 16 mg of targeting monoclonal antibody (mAb) was optimal for liver TRM cell generation (Figures S1A–S1C)

Summary

Introduction

Malaria remains a major global cause of morbidity and mortality. An efficient malaria vaccine could significantly aid malaria control. Elimination of liver-stage Plasmodium parasites, leading to the abrogation of blood-stage infection and clinical symptoms, is a highly desirable goal for vaccination. A recently defined subset of memory CD8+ T cells that patrol the liver, termed liver-resident memory T cells (liver TRM cells), offer efficient protection against liver-stage Plasmodium infection (Fernandez-Ruiz et al, 2016; Steinert et al, 2015; Tse et al, 2013). Unlike circulating memory T cells, TRM cells remain in the tissue where they are first formed (Mueller and Mackay, 2016), which they constantly patrol, eliciting rapid immunity upon antigen encounter (Fernandez-Ruiz et al, 2016; Gebhardt et al, 2011). % of mice Memory PbT-I cells % of mice A Non-protected Protected **** * ** n.s.****.

Results

Discussion

Conclusion