MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines
Ali Amini, Lucy C. Garner, R. H. Shaw, N. Kelly, Sandra Adele, Donal Skelly, Wanwisa Dejnirattisai, Melanie Greenland, Xinxue Liu, Amelia Heslington, Carl-Philipp Hackstein, Sam M. Murray, Cristina Riquelme Vano, Lizzie Stafford, Síle A. Johnson, Katia Sayaf, Maria Fransiska Pudjohartono, Elizabeth Clutterbuck, Elizabeth A. Clutterbuck, Sagida Bibi, Christopher P. Conlon, Tim James, Katie Jeffery, Barbara Kronsteiner, Alexander J. Mentzer, Donal O’Shea, Maheshi Ramasamy, Gavin Screaton, Matthew D. Snape, Andrew E. Hogan, Eleanor Barnes, Teresa Lambe, Susanna Dunachie, Nicholas M. Provine, Paul Klenerman, Mohammad Ali, Alice Bridges-Webb, Jeremy Chalk, Alexandra Deeks, Christina Dold, David W. Eyre, John Frater, Lisa Frending, Philip Goulder, Anni Jämsén, Tom Malone, Philippa C. Matthews, Eloise Phillips, Patpong Rongkard, Beatrice Simmons, Lance Turtle, Arabella Stuart, Parvinder K. Aley, Nick Andrews, J. Claire Cameron, Sue Charlton, Andrea M. Collins, Tanya Dinesh, Anna England, Saul N. Faust, Daniela M. Ferreira, Adam Finn, Christopher Green, Bassam Hallis, Paul T. Heath, Helen Hill, Rajeka Lazarus, Vincenzo Libri, Yama F Mujadidi, Emma Plesteda, Mary Ramsay, Robert C. Read, Hannah Robinson, Nisha Singh, David P. J. Turner, Paul Turner, Rachel White, Jonathan S Nguyen-Van-Tam, Jonathan S Nguyen-Van-Tam
Abstract
Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes—mucosal-associated invariant T (MAIT) cells and Vδ2 + γδ T cells—which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)–mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell–derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ–licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.