Rethinking protection: systems immunology, correlates, and vaccine confidence

Your research has spanned diverse vaccine platforms and respiratory pathogens. How has your understanding of what constitutes a protective immune response evolved with the advent of systems immunology and high-dimensional analytical tools?

JT: The idea of correlates of protection has been central to vaccinology for decades. The classic example is influenza, where human challenge studies showed that an antibody titer above a defined threshold reduced the likelihood of infection. This led to the 1 in 40 hemagglutination inhibition (HAI) titer that continues to guide influenza vaccine development.

Correlates of protection allow for smaller, smarter clinical trials. In influenza, for instance, correlates make it possible to adjust vaccine formulations annually without repeating full-scale Phase 3 trials. The same principle applies to pneumococcal vaccines, where adding new serotypes, from seven to 13 and now to 20, was supported by antibody correlates of protection.

Correlates have also guided vaccine design in respiratory syncytial virus (RSV). The monoclonal antibody palivizumab demonstrated that neutralizing antibodies targeting the F protein could prevent severe RSV disease and contributed to antigen design. That success provided the blueprint for antigen-stabilized RSV vaccines.

At a conceptual level, our understanding of immune protection has become more integrated in recent years. The ‘Swiss-cheese model’, coined by Shane Crotty (La Jolla), illustrates this well: multiple overlapping immune layers, mucosal IgA, serum IgG, T cells, and cell-intrinsic mechanisms, collectively prevent infection. Vaccines likely strengthen many of these layers simultaneously, even though we often measure only a single component of a multifactorial response, i.e., antibodies.

Which emerging analytical or immunological tools do you see as most transformative for dissecting vaccine-induced immunity, and what practical barriers still limit their wider adoption?

JT: Advances such as single-cell sequencing, spatial transcriptomics, and systems serology have given us unprecedented detail, but there is a danger of ‘stamp collecting’, subdividing the immune response into ever smaller and potentially transient cell populations. Immune cells are often plastic, and a snapshot at a single time point may not represent their true behavior.

The key is integration. Systems vaccinology, championed by researchers such as Bali Pulendran (Stanford University), links complex datasets to clinical outcomes. For example, if an HAI titer of 1 in 40 defines protection against influenza, can early transcriptional signatures, measured six or 24 hours post-vaccination, predict which individuals will achieve that protective threshold? Such approaches are beginning to reveal gene networks associated with durable immunity.

The challenge lies in combining these data streams into a coherent mechanistic framework. Protection rarely depends on a single gene unless a person has an inborn error of immunity. It is more about how networks of genes and pathways coordinate. Systems approaches will be transformative, but they require sophisticated computational integration and clear hypotheses to translate discovery into understanding.

Immune responses vary widely between individuals and tissues. How should study design and data interpretation account for this biological heterogeneity rather than averaging it away?

JT: Vaccines are, by necessity, population medicines. They must be safe, affordable, and effective for the greatest number of people. That means striking a balance between immunogenicity and safety, particularly because vaccines are administered to healthy individuals.

Within any vaccinated population, responses range from non-responders to individuals who experience strong reactions. When billions of doses are given, as during the COVID-19 vaccination campaigns, rare adverse events inevitably appear simply because of the scale of the program. The challenge is to identify and mitigate those risks early without undermining confidence.

Capturing heterogeneity requires both smart trial design and continuous post-marketing surveillance. Early studies should screen for extreme responses, while large-scale rollout demands ongoing monitoring and transparent risk communication. Many apparent cases of ‘hesitancy’ are in fact access issues: logistical barriers, clinic availability, or scheduling difficulties. Addressing those practical challenges can improve uptake more effectively than debating ideology.

As vaccine platforms diversify, how can we meaningfully compare immune readouts across studies or technologies without over-interpreting differences?

JT: Standardization is essential. When assays are harmonized, cross-study comparison becomes feasible. The HAI assay for influenza is a good example, widely used, reproducible, and directly comparable across laboratories.

However, as assays become more complex, such as T cell ELISpot or flow cytometry-based analyses, variability increases. Each laboratory introduces subtle differences that complicate interpretation. To compare results meaningfully, either testing must occur in centralized laboratories or protocols must be stringently standardized across sites. The greater the assay complexity, the greater the need for consistency.

Public communication often focuses on infection prevention, yet many vaccines confer broader health benefits. How can the scientific community better communicate these additional advantages to strengthen public trust and uptake?

JT: A key issue is that most people who are unvaccinated face access barriers rather than ideological resistance. Improving vaccination coverage starts with improving delivery, reducing logistical hurdles, ensuring supply, and making scheduling more convenient for families.

Equally important is how we frame vaccine benefits. Beyond preventing infection, vaccines reduce the risk of serious complications such as myocardial infarction. Both influenza and RSV vaccines have been associated with reduced risk of cardiac events. Communicating those broader health impacts resonates more strongly with the public than focusing solely on avoiding mild respiratory illness.

Similarly, the shingles vaccine Shingrix has been linked to a delayed onset of dementia. When people understand that vaccination protects not only against acute infection but also against long-term conditions, the perceived value changes. Viral infections are rarely benign; highlighting their downstream risks helps contextualize why vaccination matters. Clear, evidence-based messaging, rather than endless social-media debate, is the most effective way to sustain trust.

What are the biggest gaps in our current toolkit for probing vaccine-elicited immunity, and where do you expect the next breakthroughs to emerge?

JT: Vaccine progress is consistently driven by technology. Every major advance, from cell-culture systems for viral vaccines to sugar–protein conjugation for bacterial vaccines, has come from a new enabling technology. Even the success of mRNA vaccines was seeded by innovations in gene therapy and oncology rather than vaccinology itself.

I suspect the next leap will again come from outside the traditional vaccine field, perhaps a technology developed in another biomedical area that can be adapted to immunization. Vaccinology is a magpie discipline; it borrows and repurposes tools that prove transformative.

After two decades in this field, I can say it has never been more dynamic. The integration of new technologies with our growing understanding of immune networks ensures that the coming years will be as exciting as any period in modern vaccine research.

Biography

John Tregoning is currently Professor of Vaccine Immunology at Imperial College London, where he has studied the immune responses to vaccination and respiratory infection for more than 25 years. His group is currently focusing on the immune response to RNA vaccination and RSV infection (exploring how the virus evolves under antibody pressure). John has written more than 90 peer-reviewed scientific articles and over 50 articles on scientific careers for Nature, Science and Times Higher Education. He is also the author of two books Live Forever? and Infectious.

Affiliation

John Tregoning PhD, Professor of Vaccine immunology, Imperial College London, London, UK

Authorship & Conflict of Interest

Contributions: The named author takes responsibility for the integrity of the work as a whole, and has given their approval for this version to be published.

Acknowledgements: None.

Disclosure and potential conflicts of interest: John Tregoning received grants or contracts from MRC, EU, and Innovate UK. John Tregoning exchanged consulting fees with Sanofi and Moderna. John Tregoning possess a patent on A. baumannii antigens. John Tregoning is on the DSMB advisory board for human challenge and vaccination study.

Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.

Article & copyright information

Copyright: Published by Vaccine Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2025 John Tregoning. Published by Vaccine Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited.

Interview conducted: Oct 8, 2025

Revised manuscript received: Oct 22, 2025.

Publication date: Nov 3, 2025.