December 11, 2014

expert reaction to new study on human gene that modifies the immune response to the flu vaccine

A study published in the journal PLOS Pathogens has examined how using small portions of a specific protein can improve the efficacy of the seasonal flu vaccine.

Dr Michael Skinner, Reader in Virology and Head of the Vaccine Vector Group, Imperial College London, said:

“The study by Egli et al. holds promise for enhancing the response of the seasonal influenza vaccine by blocking the receptor used for the innate immunity signalling molecule IL28B. They observed the effect in a cohort of transplant patients undergoing long-term immunosuppression, who were therefore susceptible to severe influenza. They found that those with a rarer genetic variant that reduced production of IL28B were better protected following influenza vaccination. They then identified synthetic peptides, based on the known structure of a molecule similar to IL28B, that could block the receptor – the hunt will now be on for small molecule antagonists.

“Successful antagonists, following clinical trials for safety and efficacy, could be incorporated into the seasonal vaccine as a way of enhancing responses. They could potentially play a role in the event of a pandemic, in this case by “antigen sparing”, allowing efficacy with lower doses of the influenza antigen – thereby allowing faster production of more doses of the vaccine as early as possible in the pandemic.

“Will this approach be universally applicable to all vaccines? Almost certainly not. The study relates to a particular type of vaccine (killed) against a particular virus, influenza, though the findings might hold true for other killed vaccines and for those vaccines consisting only of proteins produced by GM in bacteria, yeast or insect cells, against diseases such as hepatitis B (HBV) and human papilloma virus (HPV, the causative agent of cervical cancer). All of these have in common the fact that the active agent in the vaccine is a virus (or a part of the virus) that is incapable of replicating in cells, and the response we’re trying to induce is the production of protective antibodies.

“For other vaccines, we probably want to induce cell-mediated immunity to eliminate cells infected by any virus that gets past the antibodies. Blocking the IL28B receptor is likely to reduce the production of those protective cellular responses. This is illustrated by the observation that the rare genetic variant that is beneficial for influenza vaccination is detrimental for clearance of hepatitis C virus following standard interferon treatment. Applying this approach to live, attenuated vaccines would therefore demand considerable caution because blocking responses induced by IL28B might increase the likelihood of side effects.

“The really good point about this study is that it shows how genetics, informed by genome sequence analysis of large cohorts, can help us understand not only cancer and rare genetic diseases but also how to get the most out of existing vaccines or develop new ones against recalcitrant foes such as HIV (and even against non-viral agents such as malaria). This could bode well for advances that might arise from Genomic England’s 100,000 Genomes Project – but we must try to ensure that vaccination responses can be captured within the scope of that project.

“Paradoxically, the study does offer some good news for those working on live vaccines or live vaccine vectors because these are not just vaccine antigens but organisms in their own right that necessarily manipulate host responses (such as those involving IL28B) for their own survival. Altering the way they do might help us run them into better live, attenuated vaccines or vaccine vectors.”

Prof. Jonathan Ball, Professor of Molecular Virology, University of Nottingham, said:

“The IL-28B first came to the attention of virologists when it was shown that polymorphisms, small genetic changes, in this gene were associated with different hepatitis C virus treatment outcomes. In truth, we still don’t know for certain whether or not there is a direct effect of the gene.

“Here we see that the same IL-21B gene polymorphisms seem to influence the response to influenza virus vaccination, at least in a population of transplant patients who, because of their transplant status, have to receive immunosuppressing drugs. These individuals are particularly susceptible to the more serious effects of influenza infection, so improving vaccine efficacy in these people would be a real plus.

“The paper nicely shows that vaccination outcome is associated with the IL-28B mutations and suggests that this happens because they influence the type of chemicals – called cytokines – that are released to orchestrate the immune response. This identifies a new avenue for improving vaccine efficiency, but achieving this will not be a straightforward task.”

Dr Ben Neuman, Lecturer in Virology, University of Reading, said:

“Genetic differences affect more than hair and eye color – your genetic makeup will also determine how your body responds to infections. For example, there is growing evidence that subtle variations in the genes that help your immune system to recognise viruses can make the difference between survival and death in diseases like Ebola and the flu.

“These genetic differences between people are the biggest reason why it is difficult to make a vaccine that works for everyone – people respond differently, and not all the responses will protect against disease.

“Cells of the immune system communicate by passing small protein messages, and genetic studies have shown that different people will be predisposed to make different amounts of message, or even slightly different messages. This study looks at variation in one immunological message, and finds that people with the uncommon version of the gene will make more antibodies after being vaccinated. Antibodies help by sticking to specific viruses and preventing them from infecting our cells.

“This is an important paper because it shows how it might be possible to “tune” a person’s immune response to give better protection from disease. It would not be desirable in every case – antibodies are more important in fighting some infections than others – but it potentially gives vaccine makers a new tool that could be used to make vaccines more effective.”

‘IL-28B is a key regulator of B- and T-Cell vaccine responses against influenza’ by Adrian Egli et al. published in PLOS Pathogens on Thursday 11 December 2014. 

Declared interests

Dr Michael A. (Mike) Skinner is a Reader in Virology at Imperial College London and Head of the Vaccine Vector Group.

He receives research funding from the BBSRC to study host innate responses and recombinant vaccine vectors.

He is chair of the HSE’s Scientific Advisory Committee on Genetic Modification (Contained Use)

He is also member elect of the Council and governing trustee of the Society for General Microbiology

Commercial conflicts of interest – none