British Society for Immunology (BSI) – Written evidence (INQ0057)

As an organisation, the British Society for Immunology, the largest immunological society in Europe, represents over 3,700 immunologists working in academia, clinical medicine and industry. Our objective is to promote and support excellence in research, scholarship and clinical practice in immunology for the benefit of human and animal health.

Scientific Basis

1. The scientific understanding of the immune system as the body ages is not as complete as it could, or should, be. Whilst some areas are better understood than others, e.g. the adaptive immune system is better comprehended than the innate immune system, and we know there are stark differences between young and old immune systems, in general terms there is much more work to be done to understand the basic science and biological processes behind the effects of ageing on the immune system. It is vital that we pursue this course of scientific enquiry however, because the ageing immune system has a wide range of known effects, including decreasing the efficacy of vaccines, increasing risk of cancer due to less efficient immune system surveillance, increased susceptibility to infections and pathogens, increasing inflammation and age related inflammatory diseases, and an increasing the risk of autoimmune diseases[1]. Cellular senescence is a phenomenon by which somatic cells cease to divide and is accompanied by the production of inflammatory mediators. The accumulation of senescent cells in human tissues during the ageing process is a primary contributor to these age-related pathologies[2]. The mechanisms by which this occurs however, are not yet clear.

It should also be noted that scientific understanding of the way many drugs interact with immune system in older people is lacking, often because of a dearth of this age demographic in clinical trials. It is much more expedient to use younger people, who are more likely to have fewer confounding variables, e.g. comorbidities, in clinical trials. It is likely that there would need to be more funding for immunology research into this specific area, in order to address this imbalance and further investigate this vital field.

The current funding landscape is very much geared towards disease specific research, with a significant portion of funding being awarded through medical research charities that, unsurprisingly, have a specific disease focus. This leaves a gap for a broader focus on research into ageing and how bodily systems change during this process, e.g. the immune system, and for research into understanding the basic molecular interactions that underlie the ageing process. Researchers into ageing without a specific disease focus often find themselves to be only eligible for funding via research councils such as the Biotechnology and Biological Sciences Research Council (BBSRC) or the Medical Research Council (MRC); they must also compete for this funding with those eligible to apply to medical research charities too. This funding squeeze has seen researchers leave ageing research to pursue more disease specific work where they perceive to be better opportunities. It is crucial that this is corrected if we are to understand ageing properly. It should be noted that the funding landscape is different to that in the United States, where there are funding calls from charities focused on basic ageing research. This is an approach that is unfortunately not replicated in the UK.

In terms of technology, there are two key advances required to take ageing research forward. The first of these is getting the right technology in place to allow further research, e.g. in particular using the right experimental model that can replicate the human ageing process accurately; mouse models are currently not fit for purpose. Steps forward in this area are already being made with a suction blister protocol to study human T-cell recall responses in vivo[3]. The second is increasing bioinformatic skills in the UK to a level that allows the evaluation of large scale datasets and provide direction for where to target research areas next.

2. The scientific basis for public health advice underlying campaigns to increase coverage of the influenza vaccine amongst the elderly is robust. It is known that the elderly are at a greater risk from influenza, and indeed increased age is not the only factor that contributes to this but the older a person is the more likely they are to suffer from chronic diseases and to receive medication that makes them immunocompromised[4].

It is a matter of scientific accord that whilst the initial responses of the elderly to influenza vaccination are comparable to those observed in younger individuals, studies have shown that the older immune systems fail to maintain or expand on these initial responses, which can render the latter more susceptible to influenza infections despite being vaccinated. The NHS has is now offering those aged 65 and above a newly introduced enhanced adjuvant version of the traditional trivalent influenza vaccine[5]. This has the effect of boosting their immune response, which increases the vaccine’s effectiveness.

This is an excellent example of science underpinning public health policy with respect to our ageing population. Influenza remains a serious illness, in part due to its epidemic potential, but also because the challenges that it presents healthcare providers due to increased hospital admissions and the capacity of the patient to contract serious secondary complications. It is critical that we continue to invest in research into the ageing immune system so that we can further improve our response to this annual issue, and others too. This broader issue is of course relevant to the two other vaccines the NHS offers to the elderly, the shingles and pneumococcal vaccines.

3. It is anticipated that a breakthrough could be imminent within the next five to twelve years in the field of senolytics, a process which targets senescent cells for removal[6]. Due to senescence occurring widely across multiple complex organ systems, current efforts are focused at specific conditions associated with the ageing process including osteoarthritis, chronic obstructive pulmonary disorder (COPD), glaucoma, and age related macular degeneration. Efforts toward this are currently attract much venture capital investment in the United States. There are additionally efforts to use cancer immunotherapy to slow down the ageing process[7].

There are also a number of existing drugs that have been part of the physician’s armamentarium for decades, but now are being looked at differently: through the prism of reducing the effects of ageing. One of these is metformin, developed in 1922 and used to treat diabetes since at least the 1950s. Recent studies have found that by reducing the production of inflammatory markers, metformin is able to block processes that lead to cellular damage, and through other mechanisms is able to reduce superoxide production, which, in turn, lessens DNA damage and mutations[8].

Another drug being examined because of its effect on the ageing process is rapamycin. Discovered in 1972 on Easter Island from which its name is derived, it is currently used as an immunosuppressant to prevent organ transplant rejection. In a similar mechanism to metformin, it acts on the mammalian target of rapamycin (mTOR) to limit DNA damage and mutations, which works to suppress cancers[9]. Consequently, this has the effect of increasing lifespan, and research continues into whether it can also slow down the ageing process itself.

As mentioned previously, with increasing age comes a decrease in the efficacy of vaccines. The current shingles vaccine used in the UK is Zostavax, a live attenuated vaccine, and should not be given to those who are immunocompromised[10]. It is not offered to adults aged 80 or over as the vaccine’s effectiveness declines in older age groups; instead the NHS offers it exclusively to people in their 70s[11]. Zostavax reduces the number of cases of shingles in adults aged over 70 by 38%.

A new vaccine, Shingrix, offers the prospect of better protection both for the general older population and also for those who have previously been contraindicated. Shingrix has been shown to reduce the risk of shingles in people aged 70 or older by 89.8% compared with placebo. Being inactivated, it is less likely to cause problems in those without a healthy immune system (who are often at high risk of shingles); as such, in 2018 the Joint Committee on Vaccination and Immunisation (JCVI) recommended its use for those currently aged 70 to 79 and are unable to have Zostavax[12].

With Shingrix requiring two doses, compared with Zostavax’s one dose, and being more expensive, it will need to undergo rigorous assessment to determine its cost effectiveness before any potential recommendation for further use in the UK. It is evident however, that immunology research is providing an opportunity to reduce the incidence of shingles in the UK to unprecedented levels, and in doing some increase the quality of life and healthspan for many older people.

4. How complete is the understanding of behavioural determinants and social determinants of health in old age, and of demographic differences?

It is known that prolonged or chronic psychological stress can have a deleterious effect on the function of the human immune system. This is particularly relevant in the case of ageing as it is especially common in elderly individuals and, furthermore, prolonged stress has been found to cause premature and accelerated ageing of the immune system[13].

Caring responsibilities have been found to induce stress in the elderly, dampening their immune function[14]. Loneliness and social isolation have been shown to have similar effects on the immune systems of adults of all ages[15], but when one considers how loneliness can often go hand in hand with ageing, this is an especially prevalent problem in the elderly. Investigation into the ageing immune system and how this interacts with external stressors is an especially important path for immunology research to follow if the Government if serious about tackling the effects that loneliness can have on the elderly and supporting carers in their caregiving responsibilities. There needs to be therefore, more sources of funding for immunology research into the effects of ageing on the immune system and the way this interacts with external, psychological stressors that are more and more common social effects associated with getting older.

Industrial Strategy

9./10. The UK is the world leader in immunology, ranking first amongst G7 countries for the quality of its immunological research[16]. It is now recognised that the immune system is not a distinct entity unto itself, and instead that immunology is, for example, integral to the pathologies of metabolic, cardiovascular, and neurodegenerative diseases, that were all once studied separately. Demand for immunology expertise is increasing as drug development shifts, with novel immune-based therapies increasingly seen as the answer to conventional problems, as in the case of cancer immunotherapy, or creating new vaccines that will both prevent disease and simultaneously work to combat antimicrobial resistance (AMR). Any and all of these innovations have the potential to increase the healthspan of individuals, from more effective influenza and shingles vaccines that work more effectually in ageing immune systems, to cancer immunotherapy that will allow individuals to better fight a disease that becomes much more prevalent with age.

This increased demand for immunology expertise, however, is met with a widening skills gap. A recent report[17] by the Association of the British Pharmaceutical Industry (ABPI) laid bare the threat posed: immunology is listed as an area of significant apprehension, with over 50% of member pharmaceutical companies stating that a widening skills gap was a cause for concern, and every respondent echoing worries about the capacity of the whole immunology career pipeline from PhDs and postdocs to the most experienced staff.

We have a unique opportunity strategically: to prioritise capacity growth in disciplines in which the UK leads the world currently but where a skills gap threatens expansion, such as immunology. Doing this will enable us to train more UK researchers and attract more from overseas, all whilst encouraging inward investment from industry into the UK, resulting in more innovation, a stronger economy and even more patient benefit.

Based on figures reported by UKRI officials during March 2019[18] and applying a coefficient from a report commissioned by the former Department of Business, Innovation and Skills[19], we can extrapolate that currently for every £1 increase in public expenditure on R&D, there would be a £1.74 increase in private investment in R&D. Achieving the Government’s aim to reach the target of 2.4% GDP R&D funding will mean continuing to generate enormous rewards for the UK.

There is already booming commercialisation of immunological innovations in the UK economy, and enormous potential for growth as well. From established pharmaceuticals to spin offs funded by venture capital, immunology has emerged as the powerhouse of the life sciences sector economy. Earlier this year, the Department for International Trade announced that UK exports of vaccines in 2018 had grown to be £3.2 billion, more than any other G7 economy; exports to Mexico alone rose from £3,000 in 2008 to £46.2 million ten years later, and we have seen exponential growth in vaccine exports to the USA and Asia too[20]. Likewise, we see success in commercial spin offs from our universities. Autolus, spun off from University College London in 2014 and still headquartered in London, is at the forefront of a revolution in cancer treatment through its development of CAR-T therapy, and recently had a market capitalisation approaching £1 billion. We believe that it is only greater public funding of R&D targeted at successful areas where capacity building is needed to expand that will stimulate private investment that is needed to continue to see entrepreneurial spirit and pioneering scientific innovation come together to grow our strong economy.

It should be noted that within the context of the Industrial Strategy’s Ageing Society Grand Challenge, that the Government should be making sustained investment available to scientists trying to understand the basic biological concepts of ageing, as well as translational research efforts to develop therapeutics. It should be reinforced that it is by understanding the biological causes of ageing and using therapies to ameliorate the effects that that will have on the human body through which our population will be able to enjoy longer lives and longer healthspans.

Healthier Ageing

11.               To sum up abovementioned points, the Government’s aim to provide five more years of health and independence in old age by 2035 is feasible, and indeed laudable, but requires urgent action and investment immediately. Many of the mechanisms for achieving this objective are rooted in a much better understanding of the ageing immune system and utilising the existing tools and the potential of immunological research in the short and medium term.

This means (1) capacity growing investment in the immunology sector; (2) a larger range of funding opportunities for non-disease specific and basic research into the ageing immune system; (3) a focus on our ability to translate basic research into a clinical setting; and (4) action by the Government to tackle the known causes of psychological stress with deleterious effects on the immune system in the elderly including, but not limited to, caregiving responsibilities and loneliness and social isolation.

This will require bringing together a wide array of healthcare providers, commissioners and funders across the NHS, as well as policy makers and advisors from the Department of Health and Social Care and non-departmental public bodies such as Public Health England, and ensuring they work with funders of research including UKRI and the research councils, whilst taking into account the broader social aspects of loneliness, which currently falls under the remit of the Department for Digital, Culture, Media and Sport. It would be very likely that a cross government implementation taskforce or even an ad hoc Cabinet Committee would be needed to ensure cross working most effectively. Any such body should be willing and able to take advice from external experts.

20 September 2019