Study led by InnoHK Centre for Immunology & Infection identifies innate immune pathway that predicts mRNA vaccine responses

Variability in the TLR3–type I interferon pathway before vaccination is associated with the strength of T‑cell responses following mRNA COVID‑19 vaccination.

The InnoHK Centre for Immunology & Infection (InnoHK C2i), established through a strategic partnership between The University of Hong Kong (HKU) and the Institut Pasteur,  together with collaborators from Milieu Interieur (Institut Pasteur), the Department of Paediatrics and Adolescent Medicine (HKU), the School of Public Health (HKU) and international partners, has identified a key innate immune pathway that predicts how effectively individuals respond 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.

o   Link to the publication:

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

Funding and Acknowledgements

This research was funded by a grant from InnoHK, an initiative of the Innovation and Technology Commission of the Government of the Hong Kong Special Administrative Region. The clinical study was funded by the research grants HMRF COVID19 F02/F10/F12.

We sincerely thank all the children and their parents for their invaluable participation and contribution to the COVAC study.

About the research team

The research is led by Dr Darragh Duffy, Principal Investigator, InnoHK C2i, Director of the Translational Immunology Unit and Co-coordinator of the LabEx Milieu Interieur project and Prof Yu Lung Lau, Doris Zimmern Professor in Community Child Health and Chair Professor of Paediatrics, Department of Paediatrics and Adolescent Medicine (HKU), who led the COVID‑19 Vaccination in Adolescents and Children (COVAC) clinical study.

About the InnoHK Centre for Immunology & Infection (InnoHK C2i)

The InnoHK Centre for Immunology & Infection is the fruit of a long-standing partnership of more than 20 years between the LKS Faculty of Medicine of the University of Hong Kong and the Institut Pasteur, two major institutions combining their expertise to establish this centre of excellence. Within the InnoHK initiative, InnoHK C2i adopts innovative strategies to identify and contain emerging infectious diseases and transform Hong Kong and the Greater Bay Area into a global hub of knowledge and research.

InnoHK C2i’s work is centered around four major research programs to face public health challenges and make Hong Kong a global center of excellence for precision medicine population strategies and innovative interventions targeting emerging infectious diseases. They aim to characterise immune responses to infectious agents and their components in a healthy Asian population and develop new vaccine platforms for influenza, new strategies for mosquito-borne viruses and new treatments for lethal respiratory virus infections.

Website: https://www.c2i.hk

About the Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, HKUMed (HKU)

Professor Lau’s research work is in the field of immunology and infection. His team has studied the immunogenicity and safety of COVID-19 vaccines in children and adolescents with their parents during the COVID-19 pandemic in Hong Kong.  The knowledge generated from his COVAC study has shaped the Hong Kong Government’s policy on how to use the 2 COVID-19 vaccines in children and adolescents.

Website: https://paed.hku.hk/en1/

About the School of Public Health (HKU)

The School of Public Health, HKU has a long and distinguished history in public health education and high-impact research. With world-leading research on infectious diseases, as well as on non-communicable diseases of both local and global importance, the School has made a significant contribution through its research and advocacy to improve the health of populations and individuals, both locally and globally. The School is a leading research and teaching hub in public health on influenza and other emerging viruses, control of non-communicable and infectious diseases, tobacco control, air pollution, psycho-oncology, behavioural sciences, exercise science, life-course epidemiology, population mental health, health economics, and health services planning and management. This work has informed international, national and local public health policies.

Website: https://sph.hku.hk

About the Healthy Human Global Project – Hong Kong (HHGP-HK)

InnoHK C2i and HKU have established the Healthy Human Global Project – Hong Kong (HHGP‑HK), together with collaborators from Milieu Interieur (Institut Pasteur), between July 2022 and September 2023, a rigorously characterized cohort of 1,025 healthy adults aged 20–79, balanced by sex and designed to serve as a long‑term resource for understanding immune variability in East Asian populations.  A significant number of HHGP-HK participants were drawn from the FAMILY Cohort (HKU, School of Public Health), a longitudinal population-based study of physical, mental, and social wellbeing at the individual, household, and neighbourhood levels in Hong Kong. The establishment of the original cohort was funded by the Hong Kong Jockey Club Charities Trust from 2007 to 2014.

Website: https://www.hhgp.hku.hk/

About The Institut Pasteur

A non-profit foundation established in 1887 by Louis Pasteur, the Institut Pasteur is a world-class biomedical research center dedicated to studying and combating disease, particularly infectious diseases. From the invention of the rabies vaccine to the identification of HIV and the discovery of messenger RNA, some of the most significant breakthroughs in modern biomedical science were achieved here. The excellence of Pasteur’s research has been recognized with 10 Nobel Prizes in physiology or medicine.

The Institut Pasteur employs more than 3,100 stab members representing nearly 100 nationalities, including 1,700 scientists and engineers. Its Paris campus hosts hundreds

of researchers from other organizations, notably Inserm and the CNRS, and it collaborates with numerous leading international research institutions, including EMBL, the University of Oxford, the Francis Crick Institute, Rockefeller University and UCSF.

A member of a network of more than 30 institutes across five continents- the Pasteur Network- and host to nearly ten WHO Collaborating Centres, the Institut Pasteur works on the ground alongside communities to advance public health worldwide.

Website: https://www.pasteur.fr/en

About Milieu Intérieur (the Institut Pasteur)

The Milieu Intérieur (MI) project, coordinated by Dr Darragh Duffy and Prof Lluis Quintana-Murci at the Institut Pasteur, Paris was established in 2011 with the aim to define the parameters that characterise a healthy immune response and its natural variation across individuals, and in doing so, inform clinical strategies for managing disease. For this, 1000 healthy volunteers (1:1 sex ratio; stratified across 5 decades of life from 20 to 69 years of age) were recruited. For each individual, a detailed eCRF of lifestyle and demographic variables, whole blood for immune phenotyping, immune stimulation and genomic analysis, as well as faecal samples and nasal swabs for metagenomic studies of microbiota, were collected. Punch skin biopsies were also taken to generate primary fibroblast lines and iPSc (from selected donors) to enable mechanistic studies. The MI project has provided a definition of protein and transcriptional immune signatures for healthy immune responses. The project also revealed new insights into the genetic and non-genetic factors driving immune response variation. In addition to key fundamental insights, the MI project has established a rich sample repository and data-warehouse, supporting ongoing integrative research in systems immunology.

Website: https://www.milieuinterieur.fr/en/

Media enquiries:

InnoHK Centre for Immunology & Infection (InnoHK C2i)

Simon Muller (Tel: 6194 7531 | Email: simon.muller@c2i.hk)