MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines
Amini A., Garner LC., Shaw RH., Kelly NW., Adele S., Skelly DT., Dejnirattisai W., Greenland M., Liu X., Heslington A., Hackstein C-P., Murray SM., Vano CR., Stafford L., Johnson S., Sayaf K., Pudjohartono MF., Clutterbuck EA., Bibi S., Conlon CP., James T., Jeffery K., Kronsteiner B., Mentzer AJ., O’Shea D., Ramasamy MN., Screaton GR., Snape MD., Hogan AE., Barnes E., Lambe T., Dunachie SJ., Provine NM., Klenerman P., Ali M., Bridges-Webb A., Chalk J., Deeks AS., Dold C., Eyre D., Frater J., Frending L., Goulder P., Jamsen A., Malone T., Matthews PC., Phillips E., Rongkard P., Simmons B., Turtle L., Stuart ASV., Aley PK., Andrews NJ., Cameron JC., Charlton S., Collins A., Dinesh T., England A., Faust SN., Ferreira D., Finn A., Green CA., Hallis B., Heath P., Hill H., Lazarus R., Libri V., Mujadidi Y., Plesteda E., Ramsay M., Read RC., Robinson H., Singh N., Turner DPJ., Turner PJ., White R., Nguyen-Van-Tam JS.
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.