In this Q&A, Ian Kimber, Emeritus Professor of Toxicology in the Faculty of Biology, Medicine and Health at the University of Manchester, provides an immunological perspective on current issues impacting upon the life sciences sector, ranging from recently approved cancer drugs to COVID-19 vaccines.
Professor Kimber has broad research interests at the interface between toxicology and immunology, with a particular focus on immunotoxicity, allergy and inflammation. He has published over 575 peer-reviewed research papers and review articles, over 100 book chapters and six books as well as receiving numerous awards and grants. He has previously worked in senior positions at a number of pharmaceutical companies and currently holds a variety of positions on national and international expert and scientific advisory committees, including the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Can you tell us more about your role as Emeritus Professor of Toxicology at the University of Manchester and what drew you to specialising in the fields of toxicology and immunology?
My first love was immunology, but I was recruited from academia to industry to specialise in toxicology. I spent nearly 25 years in senior scientific, management and research positions at a variety of companies (chemical, pharmaceutical, agrochemical and biotechnology). I then moved back to academia in 2007 to take the Chair of Toxicology at the University of Manchester. My main interests are at the interface between immunology and toxicology, with particular interests in allergy (skin allergy, respiratory allergy and food allergy) and mechanisms through which chemicals and drugs can compromise immune function.
From an immunological perspective, what patient factors make someone more susceptible to a virus and further, more at risk of that viral disease progressing?
This is a big question. The lack of a fully functional immune system can be described as immunodeficiency – the individual is immunocompromised and unable to defend themselves adequately against infectious microorganisms, including viruses.
There are two main types of immunodeficiency disorders – known as primary and secondary immunodeficiency:
- Primary immunodeficiency describes the condition where a child is congenitally (from birth) deficient or functionally compromised in one or more components of their immune apparatus. Some primary immunodeficiency disorders are very severe and the child is susceptible to overwhelming infection. Others are less severe.
- Secondary immunodeficiency – also known as acquired immunodeficiency – is when an individual acquires compromised immune function at some point during their life. So, the question is who has a compromised immune system and might be more susceptible to viral infection. One important factor is age. With increasing age the functional activity of the immune system declines, and that is why the elderly (those over 70 years) are at greater risk of serious illness or death from COVID-19. There are other factors that can impact to a greater or lesser extent on the functional activity of the immune system. These include: general poor health, adoption of an unhealthy lifestyle, lack of vitamin D, treatment with drugs that suppress immune function etc. We also know that (in the UK at least) some groups (in addition to the elderly) show increased susceptibility to COVID-19 (those with cardiovascular disease, or type 2 diabetes, certain ethnic groups, males, those who are obese, and those who are blood group A). In most of these cases, the mechanistic basis for the increased susceptibility is not entirely clear.
It must also be borne in mind, that in the same way that humans differ in many ways according to genetic make-up (height, hair colour, eye colour, inheritable susceptibility to a range of diseases etc.), we all differ in the activity of our immune systems.
Does a vaccine offer more protection than naturally being infected with a virus, and if so, why?
This is an interesting and important question, and one that is very topical at the moment. There is no reason to believe that a vaccine cannot be at least as effective, and often even more effective, than natural infection. For instance, there is evidence that human papillomavirus (HPV) induces a more protective immune response than is seen with natural infection.
So why might vaccines be more effective than natural infection? Perhaps the most important reason is that vaccines can be engineered so that they elicit immune responses that target important viral proteins. Moreover, many vaccine products contain materials that act as adjuvants (substances that non-specifically boosts immune responses). In addition, it is of course possible to ensure that the vaccine is delivered to an anatomical site where an immune response can flourish.
It is perhaps too early to be able to draw robust conclusions about the effectiveness of COVID-19 vaccines compared with natural infection. However, the data emerging from the UK and elsewhere suggest that both the Pfizer and Oxford/AstraZeneca vaccines are very effective, and I would not be surprised if it turns about that they give more effective, and possibly longer-lasting, protection than natural infection.
Did the knowledge of previous human coronaviruses assist the medical community in their response to COVID-19 from an immunological perspective?
There are perhaps six coronaviruses (in addition to the SARS-CoV-2 that causes COVID-19) that can infect humans. Knowledge of these other coronaviruses has undoubtedly played an important role in guiding the thinking of the medical research community. However, in my opinion, the most important factors are these: (a) the existence of national centres of excellence for vaccinology and vaccine research. In the UK this expertise is provided by the Edward Jenner Institute for Vaccine Research at the University of Oxford, and (b) the expertise, resources and technical sophistication of companies such as AstraZeneca, Pfizer, BioNTech and Moderna (and others) that have played, and will continue to play, a pivotal role in the design, testing, manufacture and distribution of vaccines.
It is also worth mentioning that collectively, the medical research community has been very active in rapidly gaining an understanding of COVID-19 and how best to manage and treat the disease. A case in point is the finding that an existing drug, dexamethasone (an anti-inflammatory corticosteroid), can be used to reduce mortality.
What impact will the emerging COVID-19 variants have on the effectiveness of the available vaccines and the development of vaccines going forward?
COVID-19 variants can potentially cause problems. They will inevitably arise as selective pressure is brought to bear on the virus creating an environment where variants that are resistant (or at least less susceptible) to immune responses induced by the vaccine, evolve through mutation and thrive. To date, most variants seem to be controlled to a greater or lesser extent by the currently available vaccines, but it is possible that others will emerge in the future that will require modified vaccines to be developed. It is my view that much of the hard work has already been done, and with the experience and expertise that is now available then the development and approval of new vaccines can be accomplished at pace.
What are biomarkers and what can they tell us about a disease?
A working definition of a biomarker is a measurable indicator of physiological function, or of disease. Their value is that they can provide useful information about a physiological or disease process without the need for an invasive investigation. Typically, biomarkers are proteins that can be measured in body fluids or excretions (blood, saliva, urine, faeces) using a variety of analytical methods. In practice, the diagnostic or prognostic value of biomarkers depends upon the accuracy with which they can be measured and how well they correlate with a particular disease process.
Palforzia, the first food allergy drug intended to treat people with existing peanut allergies, was approved by the FDA in 2020. What is your reaction to oral immunotherapy drugs? Does this mean those allergic to peanuts are able to eat peanuts whilst using this drug?
Palforzia has been introduced for the treatment of peanut allergy. It does not treat symptoms of allergy. Instead, the intention is to induce immunological tolerance in children with peanut allergy.
It is assumed that in subjects with food allergy, there has been a breakdown of immunological tolerance such that they mount allergic responses to a particular food. It is known that immunological tolerance can be restored, in at least some subjects, by oral administration of the food to which they are allergic. Palforzia is in fact peanut powder, and the treatment plan is that peanut allergic children are given increasing levels of the powder in their diet to try and reverse their allergy.
My view is that this is a legitimate therapeutic approach. The really important point is that treatment is initiated with very low doses of the peanut powder (to avoid provoking an allergic reaction), and to then gradually progress to increased levels of exposure until tolerance has been achieved.
The only caveat is that I am not sure whether there is any certainty yet that the restoration of immunological tolerance (and the loss of responsiveness to peanut) will be permanent in all children.
Equally interesting is the possibility that allergy to certain foods can be prevented from developing in the first place by ensuring dietary exposure to the food during weaning. The argument is that if a food is experienced in the diet during a certain developmental window then tolerance will be induced. It has been found that introducing foods such as eggs and peanuts into the weaning diet at periods from four to six months can reduce the likelihood of the child developing allergies to those foods. In this case, allergy is prevented from developing in the first place, rather than having to reverse it at a latter stage.
What treatments are immunologists currently focusing on and what do you think could be the next innovation in the field of immunology?
There are many interesting developments, but let me pick just one. This is the development of CAR T cell therapy for malignant disease. Chimeric Antigen Receptor (CAR) T cells are engineered in the laboratory to provide a membrane receptor that recognises determinants (antigens) on tumour cells. These T cells are then expanded in number and infused into the patient. Following binding to the tumour antigen, the CAR T cells are activated and primed to kill the malignant cell. There are many CAR T cells in development, and there have been some remarkable successes with treatment of some lymphomas and leukaemia. The next challenge is treatment of solid tumours.