New study identifies innate immune pathway that predicts mRNA vaccine responses

Led by the Centre for Immunology & Infection with Professor Malik Peiris, Professor Roberto Bruzzone, and in collaboration with the Institut Pasteur, researchers from Milieu Intérieur (Institut Pasteur), the Department of Paediatrics and Adolescent Medicine and the School of Public Health at HKU, this study has identified a key innate immune pathway that predicts individual responses to mRNA vaccines.

In a study published in Science Advances, the research team demonstrates that pre‑existing variation in type I interferon responses triggered through the TLR3 pathway is strongly associated with antigen‑specific T‑cell responses following mRNA COVID‑19 vaccination. The findings were validated across three independent cohorts, including large, well‑characterised populations in Hong Kong and Europe.

Predicting vaccine responses before vaccination

While vaccines are highly effective at the population level, individual responses vary considerably, particularly for immune pathways involved in long‑term protection. Identifying biological predictors of vaccine responsiveness has remained a major challenge in immunology and public health.

The study shows that stronger pre‑vaccine type I interferon responses induced via TLR3 were consistently associated with enhanced post‑vaccine T‑cell responses, but only in individuals who received the mRNA vaccine. This association was reproduced in an independent cohort of nearly 1,000 healthy adults from the Healthy Human Global Project – Hong Kong (HHGP‑HK) and further confirmed in the French Milieu Intérieur cohort.

A genetic link to vaccine responsiveness

Beyond functional immune responses, the team also identified a common genetic variant in the TLR3 gene that influences interferon production and, in turn, mRNA vaccine‑induced T‑cell immunity. Individuals carrying specific TLR3 genetic variants showed stronger interferon responses and more robust T‑cell activation following mRNA vaccination, explaining part of the variability observed in vaccine responses.

These findings provide direct human evidence that variability in innate immune pathways—not just age or sex—can shape vaccine responsiveness, and that different vaccine platforms rely on distinct innate immune mechanisms.

Implications for future vaccine strategies

By pinpointing a specific innate pathway essential for optimal mRNA vaccine responses, the study opens new possibilities for tailoring vaccine design, adjuvants, and vaccination strategies to different populations or individuals. It also highlights the importance of validating vaccine‑related immune mechanisms across diverse ancestral backgrounds.

“This study showed that the use of functional immune assays could identify the specific innate immune pathway that recognizes mRNA vaccines in humans, and using established population based cohorts identify genetic contributors to variable vaccine responses.” said Dr Darragh Duffy, Principal Investigator, InnoHK C2i, Director of the Translational Immunology Unit and Co-coordinator of the LabEx Milieu Interieur project at the Institut Pasteur.

Building on global immune diversity

The study leverages unique, deeply phenotyped cohorts established in Hong Kong and Europe, including HHGP‑HK, which was created to address long‑standing gaps in immune reference data for Asian populations. Together, these resources allow researchers to disentangle genetic, environmental, and biological drivers of immune variability at an unprecedented scale.

The findings underscore the importance of systems immunology approaches in humans and reinforce the need for population‑specific data as vaccines and other immune‑based interventions continue to evolve.

• More information:

https://www.c2i.hk/post/study-led-by-innohk-centre-for-immunology-infection-identifies-innate-immune-pathway-that-predicts

• Link to the publication:

https://www.science.org/doi/10.1126/sciadv.aed8930