Oral Presentation CD1-MR1 2024

NKT cell adjuvanted mRNA vaccines induce liver-resident memory T cells that protect against malaria (#86)

Gavin F Painter 1 , Ian F Hermans 2 , William R Heath 3 , Lauren E Holz 3 , Sarah L Draper 1 , Jordan J Minnell 4 , Olivia K Burn 4 , Regan J Anderson 1 , Susanna T.S. Chan 1 , Benjamin J Compton 1 , Andrew J Marshall 1 , Kathryn J Farrand 4 , John C Mamum 4 , Stephanie Gras 5 , Jerome Le Nours 6 , Jamie Rossjohn 6 , David F Ackerley 7
  1. The Ferrier Research Institute, Victoria University of Wellington, PO Box 33436, Lower Hutt 5046, New Zealand
  2. Malaghan Institute of Medical Research, PO Box 7060, Wellington 6242, New Zealand
  3. Department of Microbiology and Immunology, at the Doherty Institute for Infection and Immunity, The University of Melbourne, 792 Elizabeth St, Melbourne, Vic, Australia
  4. Malaghan Institute of Medical Research, Wellington, New Zealand
  5. Department of Biochemistry and Chemistry, La Trobe University, Melbourne, Victoria , Australia
  6. Department of Microbiology, Biomedical Discovery Institute, Monash University, Clayton, Australia
  7. Victoria University of Wellington, Lower Hutt, New Zealand

Development of a highly effective malaria vaccine that that can be applied in malaria-endemic regions is still a major goal. With the recent identification of liver tissue-resident memory T (Trm) cells as crucial effectors for the control of liver stage Plasmodium infections we embarked on a strategy to develop an mRNA-based vaccine to prevent malaria. Here we show that while a standard mRNA vaccine could effectively induce circulating T cells, this approach was unable to generate liver Trm cells and failed to protect against challenge with Plasmodium sporozoites in mice. However, addition of glycolipid agonist compounds for type I Natural Killer T (NKT) cells, modified to effectively recruit NKT cell help under mRNA-vaccination conditions, showed efficient induction of liver Trm cells that were highly protective against parasite challenge in mice. Protection could be mediated by vaccination with both model and authentic parasite antigens and was dependent on liver Trm cells. Moreover, while prior exposure to blood-stage infection (as occurs in malaria-endemic regions) impaired traditional liver-stage vaccines, mRNA vaccination was unaffected. We describe a rational mRNA vaccine approach that exploits ‘NKT cell help’ for induction of liver Trm cells and the prevention of malaria.

 

  1. [1] Ganley, M.; et al against malaria tailored for liver-resident memory T cells. Nat. Immunol. 2023. DOI: 10.1038/s41590-023-01562-6