Oral Presentation Lancefield International Symposium for Streptococci and Streptococcal Diseases 2025

The Combo#5 mRNA-LNP Group A Streptococcus vaccine generates robust memory CD4+ and CD8+ effector T cells in mice. (118586)

Rhiannon A Bolton 1 , Ismail Sebina 1 , Isabel G Courtney 1 , Nichaela Harbison-Price 2 , Meredith Finn 3 , Amanda J Cork 2 , Samantha Falcone 3 , Fabio Silva 3 , Johanna Richter 2 , Laura Davis 2 , Brody Pullinger 2 , Nia Bickham 2 , Miguel Aguirre 2 , Obadiah Plante 3 , Christina Dold 3 , Mark J Walker 2 , Gabrielle T Belz 1
  1. Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia
  2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  3. Moderna Inc., Cambridge, Massachusetts, United States of America

Infections by Group A Streptococcus (GAS) present a significant global healthcare problem, necessitating an effective vaccine. The application of messenger RNA (mRNA) lipid-nanoparticle (LNP) vaccines against bacterial pathogens is limited. We have developed a non-M-protein-based mRNA-LNP vaccine to target five highly conserved GAS antigens (Combo#5) with low sequence variation amongst different serotypes. We employed a preclinical model by immunising mice intramuscularly with either Combo#5 mRNA-LNP vaccine or GAS M1 protein adjuvanted with alum (M1/alum) on days 0, 21 and 28, and subsequently infecting mice on day 42. Immunisation with Combo#5 mRNA-LNP vaccine or M1/alum both conferred early protection against invasive GAS infection. Next, we used high dimensional flow cytometry to measure T cell responses associated with vaccine-induced protection generated by Combo#5 mRNA-LNP compared to M1/alum. Combo#5 mRNA-LNP immunisation enhanced effector T cell responses in the spleen and lymph nodes compared with M1/alum. The effector CD4+ T cells from Combo#5 mRNA-LNP-immunised mice were skewed towards Th1 differentiation, rather than Th2 or Th17 responses. The Combo#5 vaccine also resulted in enhanced effector CD8+ T cell responses evidenced by elevated expression of chemokine receptors (CXCR3 and CX3CR1), the inducible T cell costimulatory molecule (ICOS) and effector cytokines (IFN-γ). Encouragingly, the Combo#5 vaccine induced CD8+ T cell differentiation into long-lived CD44hiKLRG1loCD127hi memory precursor cells in the spleen 140 days after prime immunisation. Overall, Combo#5 mRNA-LNP vaccine elicited a sustained T cell response compared to M1/alum indicating that mRNA-LNP-based vaccines could be a promising candidate for protection against GAS infections in humans.