The Future of Immunological Medicine: Why Immune Responses Differ

Welcome to the ESWI Airborne series Shaping the Future of Respiratory Virus Research
 A central question explored in this informative episode on immunological medicine is why individuals respond so differently to the same virus, or even the same vaccine. Early career scientists Alina Tscherne, postdoctoral researcher at the Ignaz Semmelweis Institute, Medical University of Vienna, Austria and Valentino D’Onofrio, postdoctoral researcher at the Center for Vaccinology, Ghent University, Belgium expertly explain the key factors that shape diverse immune responses and why maintaining a balanced immune response is so crucial for clinical outcome.
Together they share insights into the future of vaccine design arguing that biological diversity and variability should not be seen as confounding factors but instead be embraced as opportunities. The episode also explores some of the major gaps between immunology research and real-world application and reveals what “going to the gym” has in common with getting a flu shot?

Transcript

Welcome And Why Averages Fail

ESWI Secretariat 0:00

Welcome to ESWI Airborne. In this series featuring our early career scientist community, we explore how the next generation is shaping the future of respiratory virus research. This series is made possible thanks to the kind support of CSL Seqirus and Sanofi Pasteur.

Jane Barratt 0:39

I'm Dr. Jane Barratt. Today we are talking about the future of immunological medicine and one question that sits right at the heart of respiratory virus research. Why do people respond so differently to the same virus or the same vaccine? For a long time, immunology has been translated through averages. Average immune responses, average protection, average risk. But people are not averages. Immune responses are shaped by age, sex, immune history, underlying health, prior infection, vaccination history, genetics, and the wider biological context around immune system. Today I'm delighted to be joined by two early career scientists whose work helps us explore these from different but connected angles. First of all, it's my pleasure to introduce Dr. Alina Tscherne, is a postdoctoral researcher at the Infection Research Medical University of Vienna. Her work focuses on vaccine platforms and immune protection against emerging and respiratory viruses, including MVA-based vaccine candidates, mucosal COVID-19 vaccines, and correlates or protection for next generation influenza vaccines. So welcome, Alina. And our other expert researcher is Dr. Valentino D'Onofrio. He is a researcher at the Center for Vaccinology, Ghent University, and Ghent University Hospital. His work focuses on vaccine immunology, immunomonitoring, adjuvanted influenza vaccines, and the clinical interpretation of immune responses in infectious diseases. So I welcome both of you to this very important podcast. So hello to Valentino and hello to Alina.

Valentino D'Onofrio 2:42

Hello.

Alina Tscherne 2:42

Hello.

Jane Barratt 2:46

Good to have you with us. So today during this podcast, we're going to move from vaccine-induced immune response to clinical outcomes to what this means for respiratory virus research.

The Many Drivers Of Variability

Jane Barratt 2:58

And Alina, I'm just going to turn to you initially because your work sits very closely to the moment where a vaccine first meets the immune system. So when you think about immune variability, what are the main factors that shape how someone really responds to a vaccine?

Alina Tscherne 3:19

There are actually a lot of factors, and there are still factors which are not known, especially with these new vaccine platforms we have. But factors that are known, for example, are intrinsic factors such as our age. Also, there is a bias between females and males that vaccines are that the immune response induced by the vaccines is different. Also, the genetic background plays a role. And also comorbidities are known to play a role in inducing different immune responses. And it's also actually something we are focusing at the moment. But there are also other factors such as our behavior. So, for example, smokers, or if you drink alcohol, also our sleeping behaviors, or also stress, for example, plays a role in shaping the immune response. But also the vaccine vaccines itself play a role. So we have these different platforms, mRNA vaccines, verbal vectors, and those are also inducing different immune responses. So to give you examples.

Jane Barratt 4:24

So I really want to talk to Valentino and come in with your perspectives. You know, from your perspective, what separates a protective immune response from one that is insufficient or misdirected or clinically harmful? And do you have any thoughts about these different gender perspectives in this?

Valentino D'Onofrio 4:45

Yes, so from my perspective, I'm very much interested in the innate immune response. So of course I'm going to going to say and answer this question with the innate immune response, and especially inflammation is an important factor in driving a coordinated immune response or a harmful, clinically harmful immune response. So it's all about quality and the balance of the immune response. Of course, inflammation is needed when you encounter an antigen and it starts the whole immune response and it leads to antigen presentation, germinal center reactions, and eventually the adaptive response and your antibodies. But of course, if the pathogen is that powerful that your inflammation is going in overdrive, your inflammatory response starts to attack the tissues, the organs, and it creates this damage that then develops as disease and severe disease. So basically the quality is important, and we see differences in gender between the genders as well. So we know that women in general have a more coordinated, innate, and antiviral response. They are better at antigen presentation, which means that the response to infectious diseases less likely develops into a severe into severe disease compared to men.

Jane Barratt 6:09

How do you measure quality, Valentina? You've measured quality a couple of times. How do you measure the quality response?

Valentino D'Onofrio 6:16

So that's indeed very difficult to measure, but basically the introduction of novel omics techniques has given us a lot of tools to study a lot of different aspects of the immune response. So we don't only measure concentrations of cytokines, we can also measure gene expression, we can measure epigenetic changes, and then when we combine this, we can basically look at the whole system and we can see if the immune system is rewired towards a coordinated response, or is it or if it's going in overdrive.

Jane Barratt 6:52

I'll come back to you about the the gender perspective because we don't really look at that when we we you know we talk to nights and and they're deliberating. There's there's uh you know, I think this is the first time I've really sort of talked with someone that has that perspective, so I'm going to come back to you.

Inflammation, Quality And Sex Differences

Jane Barratt 7:10

But Alina, you mentioned various vaccine platforms that you've worked on, including MVA-based candidates and mucosal vaccines. What have these platforms really taught us about the kind of response we should be trying to generate?

Alina Tscherne 7:28

I mean, the overall goal for vaccine development is of course that we want to have a long-term immunity. We want a protective immunity, and the immunity should be very balanced. So not only focusing on humor immunity, but also on cellular immunity, so that we really get a good adaptive immune response by vaccinating. And of course, we also want to have a broad reactive immunity, meaning that when we design the vaccines, we um in how should I say, ideally not only focus on one part of the vaccine, um, but also focusing on different parts of the vaccines. So, for example, if we seen for SARS-CoV-2, where we had this immune evasion or this um escape mutants, um by by focusing on different parts of the virus, we can um how should I say that, we can um avoid uh that the immune response to the vaccine is decreased.

Jane Barratt 8:22

So you're really you know looking at a number of different platforms to determine you know the degree of the immune response. Is that correct?

Alina Tscherne 8:33

Well, I was mainly focusing on MVA vaccines, which is a good T cell in TSA besides humor immunity. Um, but we did not really do a comparison between those platforms.

Jane Barratt 8:43

Okay. Well, that's that's an interesting perspective. As we turn to Valentino now and talk with you about severe respiratory infections, you know, we often focus on the virus itself, obviously.

Valentino D'Onofrio 8:57

But how much of the severe disease is actually driven by the host response from my perspective, I would say a lot of the uh the disease is driven by the host response. Of course, it depends on the pathogen. But if we take, for example, COVID-19, um, we know that um timing is very important. And we know that viral load or viral burden does not always correlate with the severe disease. Um, we know that from um studies with antiviral treatments. Um, so antiviral treatments are um basically only effective in the early stages of infection, so the first couple of days, but after that, they're not helping that much anymore, indicating that the inflammation, the immune response is going probably going in overdrive and is doing the damage. So it's the host that is overreacting rather than that the um the virus is doing damage. But of course, timing is is important, it's the pathogen um that sets everything in motion and um baseline factors such as comorbidities or age also influence this um this inflammatory response.

Jane Barratt 10:06

Yeah, we we look at vaccination in such a simple way, don't we, as general public? But when you talked about timing, I immediately go to when vaccines are scheduled, you know, and COVID is a good example. You know, in some countries now we have you know two doses per year, and in other countries there aren't doses for certain populations. Would you like to just comment on that?

Valentino D'Onofrio 10:33

Well, I think it's um it's um a timing, uh it's it's dependent on the population. Um so if we if we know that older adults are more susceptible to severe disease, it makes sense to give them more uh vaccine doses because a vaccine in Tiere gives you a coordinated immune response, a high quality response that is less likely to go in overdrive compared to an effect a response to an infection. Um so we can give that more often to older people to protect them from severe disease. But if you're not as susceptible to severe disease, it is less um important to vaccinate. So vaccinating the general population um might not be needed for COVID-19 all the time.

Jane Barratt 11:19

It it really becomes very complicated when you've got complex comorbidities and age, etc., and gender, now we know.

Measuring Protection Beyond Antibodies

Jane Barratt 11:28

Um but Alina, we often talk about antibodies as the end point of a vaccine response, but your field seems to be asking deeper questions about correlates of protection. What should we be really measuring if we want to understand protection more fully?

Alina Tscherne 11:46

Yeah, you're right. Uh just focusing on antibodies alone might not be enough. And the the problem is also that in preclinical studies, so when using animal models, there's more possibilities to test different aspects. So not only human immunity, but also T cells, um, because you can actually euthanize the animals and get more, let's say, sample material to test, which is for clinical trials with human a bit more difficult. Um, and also the sampling for humans itself is difficult. So when talking about respiratory viruses and talking about mucosal antibody, uh mucosal um responses, it's it's easy to sample the nose with swaps. But if you want to go deeper to look for lower and uh lower resp, uh how's it called lower airway samples, it becomes difficult because it's also quite painful if you do a lavage, for example. So it's also a problem that you can sometimes not really test all the measure or the parameters you you measure, for example, preclinical trials. And to really fully understand the protection of the vaccine, it's it's important to focus on you also on the different aspects. So also when measuring um antibodies, there's different types of antibodies you can measure: IgG, IgA, also systemic IgG, mucosal IgG, so there are mucosal IgA. So there are different um parameters which can actually be tested and would should really be recommended to test it to really get an idea what is the protective efficacy of the different vaccines, especially if it's a new vaccine.

Jane Barratt 13:14

So there's certainly different ways of measuring that we should be paying attention to. So thank you.

Boosting Responses In Older Adults

Jane Barratt 13:20

Um, Valentino, I'm going to continue the theme of at-risk populations and talk with you about older adults and your work on influenza vaccine adjuvants. So, what does that work tell us about improving vaccine responses in populations whose immune systems may respond differently? So the natural response of immunosinescence, but then the layering effect of chronic comorbidity. So, what do what does your work tell us about that?

Valentino D'Onofrio 13:51

Um, so basically, um what it says is that we that we we need different platforms or different delivery systems for different at-risk populations. So, for older adults, um, we know that several aspects of the immune response are weakened. There's less antigen presentation, there's less toll-like receptor activation, T cells are becoming exhausted. And in the case for influenza, for example, we um we um it is recommended for very old older adults, so um 70 or 75 or older, and especially those in nursing homes that are very, very vulnerable to vaccinate them with an adjuvented vaccine or with a high dose antigen, uh high dose level of the antigen. Um, because we know that adjuvants are uh acting on those specific pathways that are weakened in those older adults. So adjuvants boost toll-like receptor activation, boost antigen presentation, can boost uh T cell immunity and does overcome or mitigate the effects of the immunosinescence that we see. So it's very effective in vaccinating older adults. But of course, adjuvants are also come along with higher reactogenicity, so there are more adverse events. So it might not be as useful in children, for example. Um so really the different platforms and the different delivery strategies need to be adapted for for every uh population.

Jane Barratt 15:22

And and that's so true in older people or people with disabilities, you know, living in long-term care facilities. I think what we're trying to do there is really, you know, decrease the health system burden on the frontline professionals as well as maintain their functioners for as long as possible. So I think what you've said there is particularly important not only for researchers, but you know, people that are making policies. So what we've done in the first part of the podcast is really linked questions around how vaccines generate protection and how immune responses translate into protection.

Vaccine Design For Diverse Populations

Jane Barratt 16:02

I want to now bring both of you together and look forward. So really the discussion is about what connects both of your work is the idea that immune responses are not fixed or uniformed and they're easily reduced to one measurement. So both Alina and Valentino, perhaps if you can respond to me around the question if immune responses vary this much between people, what does that mean for the future of vaccine design? And Alina, perhaps you can take that question from the perspective of a vaccine platform and Valentino from the immune monitoring and clinical perspective. So Alina, perhaps if you go first.

Alina Tscherne 16:49

Yeah, it's uh it's quite a difficult question to answer, and it might depend also a bit on which virus we are looking at. I mean, it has been seen in the past, for example, for smallpox, where everyone was vaccinated with the same vaccine that it worked. We could eradicate smallpox with that. Um, but um in speaking about future pandemics or future viruses for vaccine development, um, there's a trend towards a more maybe personalized um vaccine development. Um, but therefore we would need a more detailed knowledge into individual immune profile, which is sometimes not known, which needs to be investigated, which might be cost effective. So um, and that that's why it might not be suitable for now, but there is research going on on that. Um yeah.

Jane Barratt 17:35

You know, certainly what you're saying is that greater investment is required, you know, to actually answer this question about the future of vaccine design. From your perspective, Valentino, um, what what are your thoughts about immunomonitoring and clinical?

Valentino D'Onofrio 17:53

Yeah, so I think for the for the future of vaccine design, again, we corresponding to my previous answer, we should embrace the diversity of platforms and delivery strategies that we already have and optimize those to the clinical, to the risk population and to the clinical outcome. Um, so uh again, adjuvants might be useful for older adults, but not so much for children. But also, what do we want to prevent? Um, do we want to prevent the infection or do we want to prevent severe disease? Um, for very old adults or at-risk adults, um, it might be enough to prevent infection uh the sorry the disease, because then it it reduces the burden of healthcare and hospitals. And if they don't get hospitalized, that's already well enough. But for children, you might want to go for strategies that um reduce or protect against infection, just so it doesn't get spread that easily and so that it doesn't dribble into other layers, layers of the population as well.

Jane Barratt 18:51

You know, we've all experienced the pandemic, um, and we're still experiencing the consequences of this pandemic um throughout healthcare systems.

Next Pandemic Signals And Real-World Gaps

Jane Barratt 19:02

And uh so I want you to put your future hat on and answer the question if a new respiratory virus emerged tomorrow, what early signal would most concern you? So, Alina, your thoughts about that? Because we hear in the in the background, in the noise, that there'll be another pandemic. Um, and I'm just curious as to what early signal would concern you most?

Alina Tscherne 19:33

Yeah, so I also think there would be a new pandemic. We don't know which one which virus will cause it, but there will most likely be one. And I mean, in a compared to past pandemics, there were also already signs. So if if we see an unexpected or unexplained pneumonia, respiratory illness in a population which is was previously not affected, like health, young population. And also if we see an infection that it's really um human to human spreading, then I might be worried to see.

Jane Barratt 20:03

Okay, well, I would certainly be worried. So thank you for that. Valentina, your thoughts about this?

Valentino D'Onofrio 20:08

I think I would look at uh symptoms and how fast people get uh get ill and get severely ill. Um, because that means um, as we've seen with COVID, um uh this inflammation is getting disproportionate, people are getting a sepsis-like syndrome, they are getting hospitalized. Um so um that that completely to me changes the strategy in in vaccine design as well, because then the the initial priority might be reducing the healthcare burden, reducing hospitalizations, and reducing severe disease. Um, so then we need to study what is happening. Um, how is the pathology, what is the disease trajectory, who is going uh for who is staying with with asymptomatic disease and who is who is uh developing into severe disease.

Jane Barratt 20:54

It's interesting, both of you, you know, as researchers, you've taught policy, and and I just want to commend you on that because you know, quite often, you know, researchers kind of stay in their research kind of territory, but both of you are really talked about you know the evidence that you're creating and how that can inform policy. But I want to come to one of the last questions, and that is what is the biggest gap today between immunology research and real-world application? And I'll I'll come back to you, Valentino, first. So, how do you see the gaps today?

Valentino D'Onofrio 21:34

Um, to me, I think um the diversity and the variability is still a big gap. Um, so often, and we we've talked about this briefly, often, age and comorbidities or gender are confounding factors that we we measure and we we record, but we try to factor them out in our models and in our in our data so that they're not that confounding. But I I'm not sure this is the right strategies. The variability that we see in humans. It's huge, it's enormous. So we should just try to embrace this, embrace this and try to understand this better rather than factor this out. I think in the long run it will leave us with more information.

Jane Barratt 22:15

Look, I think that you're absolutely quite right. By factoring it out, we're actually compounding the problem of not understanding. So thank you. Alina, your thought?

Alina Tscherne 22:26

Yeah, what I see as a problem is that often in preclinical models we see positive results. They look promising and then they fail in in real life or in clinical trials. And there is really an improvement needed. And also it's in, as I said, in real life patients, and also especially people with comorbidities are sometimes not that recognized or tested in clinical trials. They're healthy individuals tested. But when the vaccines are tested, then in elderly people or people that have other illnesses, they are not working. So there is definitely improvement needed. And also, um, as Valentino also mentioned, there is the variability of these platforms where we really need to further invest, develop, also focus maybe more on mucosal vaccines. There is no research going on, but there's definitely room for improvement. And also regulatory hurdles, hurdles of um vaccine um approval is still a problem, which takes too long, too many um issues. So there's things that need to be improved on that.

Jane Barratt 23:28

You know, you're really both talking about policy. So you might think about a career in policy after this. You know, you really are challenging, you know, the decision makers, you know, to look at vaccine development and various platforms, you know, through the lens of different populations, you know, and that's really cutting edge for today. Um, one rapid question before we we close to our final messages. What is one assumption in immunology that you believe we need to challenge? Valentino.

Valentino D'Onofrio 24:02

I think that um that the assumption that we just should take vaccines when uh we are affected by it. I think if you have the opportunity, go get that influenza vaccine, go get all the vaccines that you can get, because in essence it's a training for your immune system. It's like going to the gym. You do it because you you try to stay healthy. And even uh recent evidence shows that there are more health benefits than only preventing infection or disease uh by vaccination.

Jane Barratt 24:30

You know, I think that's a tag, training for your immune system. I think that we're going to use that going forward. So, Alina, one assumption in immunology we need to challenge.

Alina Tscherne 24:41

Yeah, Valentina already took uh the thing I wanted to say, so I can completely agree what Valentina has said.

Jane Barratt 24:48

Good. Well, I think that's a that's a um we we've agreed there's consensus. So as we come to uh the close of this podcast, which I've really enjoyed talking with both of you, what is your final message to the audience today? So, Alina, we'll start with you and uh finish off with Valentino.

Alina Tscherne 25:09

Okay. Um just to make it short, so vaccines are important. And uh, if you're interested in vaccines, uh there are a lot of research groups who are working on that topic. So join, um, work on that. There will be a new pandemic, and maybe you can contribute uh to a vaccine for the next pandemic virus.

Jane Barratt 25:29

And that's really a call out to all of the ESWI audience and their networks as well. So thank you. Valentino.

Valentino D'Onofrio 25:38

Yes, so as for all aspects of society, I think also in vaccinology and immunology, we need to embrace diversity. So we don't need to leave or go away from diversity, equity, inclusion is initiatives. We need to embrace it. We need to embrace and understand variability. Um and yeah, just work with it. Everyone is unique and that is beautiful.

Jane Barratt 26:01

So make that central to the work that we do and who we are. So today's discussion makes one thing very clear to me. The future of immunological medicine will not be built on averages, it will be built on understanding variation across biology, across age, across sex, immune history, across clinical risk, and across populations. And we've touched on all of those in our discussions today. That is not a narrow scientific point. It's really central to whether vaccines work well in people who need the most. And it's central to how we interpret severe disease. And lastly, it is central to how we prepare for the respiratory virus threats still ahead. My sincere thanks to Dr. Alina Tscherne and Dr. Valentino D'Onofrio for joining us today, and thank you to our audience for listening to this Eswee Airborne.

ESWI Secretariat 27:11

ESWI Airborne is brought to you by ESWI, the European Scientific Working Group on Influenza and other acute respiratory viruses. These episodes would not be possible without the team's efforts, and I would like to extend special thanks to our ESWI Secretariat, our technical and IT teams, our arts team, and our host. The podcasts are recorded virtually, and we thank our guests for their participation in this inspiring and educational series. Talks are adapted to a global audience and are intended as recommendations and guiding principles. For any specific medical questions you may have, these should be addressed to your local general practitioner. Many thanks to our sponsoring partners, and thank you for listening.