Immunisation & Treatment - New approaches to influenza prevention and treatment - lessons learnt from COVID- 19

Aida Bakri: 0:00

Welcome to ESWI Airborne. This series on immunization and treatment is made possible thanks to the kind support of AstraZeneca, GSK, Novavax and Roche.

Clare Taylor: 0:33

Welcome listeners to this episode of ESWI Airborne. Today we'll be talking about some of the lessons learned from the recent pandemic and what it could mean for how we deal with the flu. Here in the studio to enlighten us, we have ESWI board member, pandemic veteran and respiratory physician Peter Openshaw. Good to see you again, Peter.

Peter Openshaw: 0:48

Great to be here.

Thanks. I'd also like to welcome Susanne Herold, Professor of Medicine, Infectious Diseases and Pulmonary Research, University Hospital Gießen und Marburg in Germany. How are you, Susanne?

Susanne Herold: 1:00

I'm fine, thank you. Happy to be with you today.

And last but not least, we have Professor Anthony Gordon, Chair in Anesthesia and Critical Care, National Institute for Health Research Professor and Senior Investigator at London's Imperial College. Professor Gordon, may I call you Tony?

Anthony Gordon: 1:19

Yes, please do. It's a pleasure to be here.

Great thanks a million. Well, what a crew. I'm going to start with a big question, like the mother of all questions: what did we learn during the COVID pandemic that can help us to improve how we deal with influenza?

For me, it was how we embedded clinical research, clinical trials, into everyday clinical practice so that we learned how best to treat patients. If we think back at the beginning of March 2020, we had no known treatments to treat the disease, but within a few years, we had multiple treatments that had been proven to save lives, speed up recovery. And I think we should learn those lessons now for influenza and arguably for all diseases, so that we rapidly learn while we do. We learn what works while we're still treating our patients.

Is this something you could call action research, this learning while you're doing?

I think so. I think it's just about embedding research into clinical practice not thinking of them as two separate but parallel universes, but bring them together. The two go hand in hand. We can treat patients and through rigorous clinical trials, we can still learn and continue to improve our care. And I think we've seen the benefit from that. And that's what patients want. They want to know what works best for them so they get the best outcomes.

That is for sure. Susanne, how about you?

For me, I think there are two main things that I learned and that we can implement in future research with respect to influenza. First of all, it was really interesting to see the evolution of viral adaptation to the new host, to the human, and vice versa. That occurred at a large scale in a global infection scenario, in an immune-naive population. And we have learned quite a lot about antiviral immune responses and how to make use of this in generating new vaccines. And on the other side, we also learned about how respiratory viruses adapt to new hosts and develop immune escape strategies. And then a second thing was that I was really surprised to see so many long-term sequelae of SARS-CoV-2 infections, and these are symptoms that might also occur after severe influenza infection, but we are just maybe at the beginning to understand and to learn about the underlying pathomechanisms in these long-term sequelae that we have called long COVID, but maybe there's also something that we can call long influenza.

Wow, long influenza also. Peter, how about you? What were among your many surprises?

Yeah, I think we were surprised by so many things during COVID, weren't we? And I think one of the things which really surprised me was just how much fantastic research could be done so fast by people like Susanne and Tony. You know, given the resources and the backing, so much research happened so quickly, which revealed so much about, you know, what treatments to use and when to use them, most importantly. So, I think, you know, as an immunologist, vaccinologist, you know, I think the vaccines were absolutely amazing. But I must admit that I thought that they were not only going to prevent disease but they were also going to prevent infection and transmission. You know, that was the sort of inbuilt assumption that I had. And the antiviral treatments, you know, we'd all think that those would be absolutely fundamental, but they and the passive antibody treatments really only worked if they were given very early and not during the sort of inflammatory later stage. And it's in that inflammatory later stage that the immune modulation treatments became so important. So we've never had studies that have been that detailed and well designed in influenza. Maybe we can learn from COVID what studies need to be done in other infections, including influenza most importantly.

Okay, really a lot to unpack there. I guess I asked for it. Let's do our best. But first, can you remind us why it's important that we get better at preventing and treating influenza?

So, you know, influenza has always been with us for as long as we've been able to study it, since its first discovery, and it's in a way become a forgotten killer. You know, every year it comes around in the winter, and also we have these recurrent threats of influenza evolving in other species and then jumping into humans, possibly causing really serious disease.

And I would add that in planning for pandemic trials, we had always thought of influenza as being the next pandemic that was coming and of course it may still be coming and then worrying about highly pathogenic variants which we can't rule out, and so we need to be prepared for those as well.

Right and maybe I can add, as already mentioned by Peter, it really comes with a substantial burden of disease and patients at risk, particularly the elderly, and something that we always forget about is that it also increases the risk of cardiovascular diseases after the acute infection. So there is some kind of add-on morbidity to that and this is really substantial. And preventing influenza infection in the elderly, or at least severe disease course, would really lower this morbidity and mortality during the winter season.

Thanks Susanne, and of course regular listeners to ESWI Airborne will remember our three parts special on the burden of disease and that preventing influenza really matters. So what does this mean for us? I mean, does prevention mean that masks and social distancing during flu season is going to be something that is advised, just like for the pandemic?

I don't know what the advice will be, but certainly we know masks and other similar interventions do work with COVID. They work against flu, they do drive down rates and when we're treating patients in hospital we wear masks for sure.

I mean, I think another thing we learned with COVID was that SARS-CoV-2 really doesn't transmit so well in outdoor settings and that poorly ventilated indoor settings are really optimal for transmission of SARS-CoV-2. The same sort of message probably applies to many other respiratory airborne pathogens, including influenza, maybe TB. You know Victorians built these schools with very high ceilings and excellent ventilation, really quite unpleasantly cold in winter. But I think, you know, they got it right in terms of the way in which they built for excellent ventilation and getting rid of indoor transmission.

And certain settings right. So in certain settings we really should be looking to mask up again. Is that right, Susanne?

Exactly so I think definitely in hospital settings. When we see that there is a rising number of flu infections in a certain area, we should really consider to wear masks to prevent influenza transmissions, because we know that these transmissions happen in hospital settings and there are patients that are at risk to have severe infections. Maybe also in other settings. This would be something to envision in nursing homes, etc.

I think there's more social acceptance of it now. I mean, I see people out and about, you know, with masks on occasionally. I think it's something that's more acceptable since then. But that's for the non-pharmaceutical interventions. But what about the vaccine? I mean I'm particularly interested in, you know, the point that Peter brought in about prevention versus like a less serious dose as a consequence of the vaccine. I mean, do we see any changes in what is recommended? Peter, maybe you can take us through it first. What did we learn about vaccination during the pandemic that can be applied to influenza?

Well, I think we need to absolutely redouble our efforts to make better flu vaccines now. One of the things we learned from our studies on COVID was that there is a real separation of the immune response into the mucosal response, on one hand, within the moist linings of the nose and lung, and then the systemic response which is very powerfully induced by intramuscular vaccines. When we inject vaccines into the muscle, the immune system hasn't got any clue that where it needs to focus is into the mucosa, and I think that is a general learning. We need to find ways of directing the immune response into the mucosal site. I think just the other thing which we all know is vital is that we need to maintain really good surveillance. I mean, with COVID, I think it was a surprising discovery that by monitoring wastewater you can find out how much virus there is out there in the community. That may be partly because coronaviruses aren't just respiratory viruses, they're also replicating the intestinal tract and maybe they could be amplified within, say, sewer rats. We don't know that for sure, but you know, say, sewer rats, we don't know that for sure, but wastewater is really good. The same may not apply to flu and RSV, but I think we need to redouble our efforts to monitor community infection levels. That's another thing which I think we've learned.

That's for sure. So marshalling those mucosal battalions and also surveillance but I think we need to find a better term for that. Susanne, how about you? What are the big learnings, you think, in regard to the flu vaccines?

Yeah, I guess we have learned a lot about immune responses in the aged people and that these responses are less with respect to the responses that you can elicit in younger people. Right, and this is really important because the elderly are the persons and the patients at risk. So we have already adapted to this regarding the flu vaccine, by just simply increasing the antigen dose in vaccines for the elderly. However, we have to further increase our knowledge on how immune responses and how the immune system in this age population actually works and is different from those in the young, and how we can improve our vaccination strategies, not only for flu, maybe, or against flu, but also with respect to RSV vaccines and others.

And Tony, what did you see on the front lines, so to speak?

For me working in intensive care, the benefit of vaccines as they came online during the pandemic was just abundantly clear. Once the majority of the population had been vaccinated, the only patients we saw that came into the intensive care unit critically ill, fighting for their lives, were those who hadn't been vaccinated, and that includes the young patients and also those who were immunocompromised for other reasons, whether it be the underlying illness or either treatments they were getting. And so I hope that there would be widespread use of better flu vaccines has been talked about that hopefully prevents that severe disease, so that people don't get so seriously ill and aren't in the intensive care unit needing to be on ventilators etc. So, vaccines are crucial, I think, for that.

And staying with you for that, I mean it's fascinating to hear that perspective of what you saw coming in. And I'm just staying with people who are more seriously affected, like for most of us, the advice is okay, a couple of days in bed, plenty of fluids and so on. But what actually happens in the case of people who are more seriously affected by influenza and hospitalized?

The majority of patients do get a mild illness, but for some it is more serious. So as they become more seriously ill, their breathing will usually be more of a problem. They may be breathing very fast, they may find it harder work breathing and ultimately that can lead to the oxygen levels dropping. So they need to be treated with oxygen, maybe a simple oxygen mask, but they also may need respiratory support via one of the different types of machines that we have. We have a whole range of those. But also, as people become sicker you said, they may need to take plenty of fluids. It may be hard to keep up with all those fluids and they can actually become dehydrated and then they may need an intravenous drip. And of course, for some of those patients who become seriously ill and end up in intensive care units, their vital organs other organs, heart, kidneys may be involved as well and of course need support as well. So there's a whole spectrum of illnesses and people do get critically ill with influenza.

So this is, some of what you're describing is really a lot of intervention, indeed, right, but along with this range, there must be different approaches depending on what stage of the illness you're at.

Right, yeah, there are lots of treatments and not everybody needs everything. But we could probably break it down into categories. There's the drug treatments and there's the organ support, the breathing support type of treatments. So if we take the drug treatments, probably the first thing to think about is the drugs that will fight the virus, the antivirals. But also then, as people get sicker, we also need to be treating the effect the virus has on the body. So the patients response to that, whether that be anti-inflammatory drugs or immune modulating drugs. There are the simple oxygen masks that everybody knows about and has had when they're unwell. But we have for those just get a little bit sicker different types of oxygen devices that either give very high flow or very high pressure rates. That again can just help get that extra oxygen in for those patients who need that little bit extra. But those who are really struggling with their breathing, obviously they might need to come to the intensive care unit and need support from a machine, a ventilator. And for the really, really sick patients, sometimes when the lung injury is so severe, even with the ventilator we struggle with their oxygenation they may need to be referred for what we would call extracorporeal support, ECMO, where it's essentially a heart and lung machine that they use in cardiac surgery, where the oxygenation of the blood is done outside of the body, outside of the lungs, while we wait for the lungs to recover. So we have a whole spectrum of different supports available.

It sure is a spectrum and some of it are so mind-blowingly sophisticated, but of all this kind of treatment that is available, do you think this kind of huge amount of experience that was gained during the COVID pandemic, did it change the way that treatment is being offered to people severely ill with influenza?

I think it's made us start to think about it slightly different and approach it. I think, early on the focus is on giving the antivirals. So treating the virus, trying to reduce its impact within the body. And then it's at the later stages where we've seen that actually it may not be the virus itself or tackling the virus may not be the best way to improve outcomes for patients. It's actually tackling the immune response. So, whether that be with anti-inflammatories such as steroids or more specific immune-modulating drugs, we saw those benefits tocilizumab, baricitinib that were shown to be beneficial in COVID, where there's a brisk inflammatory response. We still see that inflammation in the sevelial influenza patients, and so I think we're exploring now whether those similar treatments may be a benefit in severe cases of influenza as well.

And how about trials, trials for influenza like there were for COVID-19?

Yeah, I think that's the bit where we've seen the real benefit and there's support for that. So that's what we're looking to do within the international REMAP-CAP trial platform. That was designed to study community-acquired pneumonia in inter-pandemic periods but adapt to tackle any new viruses, which we did in COVID and now we're doing for influenza, and so we're taking the same approach. We're testing different antivirals. This time we have multiple antivirals that we know are active against influenza. So we're testing which of those is best. Are they better given in combination? Or maybe by the time they come into hospital where the trial is running, it may be too late to actually have that effect, which is useful to know. If the benefit is all in the community, we should focus our efforts on treating people in the community and it may not be a benefit by the time people come into hospital. So we're testing those antivirals, but then in the same platform we're also testing whether it's beneficial to give steroids. Just the dexamethasone benefit we saw in COVID. We'd seen pre-COVID observational data that had suggested that maybe giving steroids might be harmful for flu, rationale being that if you give an immune suppressant you make the virus worse. But, as we saw, if you actually give the treatment to the most seriously ill, the virus itself may not be such a problem. It's affecting the body. So we don't know that for flu yet and so we're testing that, randomizing patients to get steroids and not now with flu, and then similarly for the most severely ill, where we've seen the benefit of the immune modulating drugs IL-6 blockers, JAK- inhibitors, tocilizumab, baricitinib. Maybe they have a role in the sickest patients with flu. So we're testing those as well. So we're testing them in the platform, multiple countries and hopefully we get answers that tackle this virus that we've known about for a lot longer than SARS-CoV-2. So I hope that we get the same level of high quality evidence to tackle flu going forward.

There certainly is a lot going on still in this inter-pandemic time. Susanne, what did you see on how the treatment, how influenza treatment, changed?

Yeah, I think the experience that we made with COVID, as already outlined, really helped. And I think one important aspect to mention is that there have been a lot of different efforts to very deeply phenotype patients with less or more severe COVID-19 courses by large sets of clinical parameters and by biomarkers. Maybe biomarkers that we had applied before or some of them were newly identified and they can be taken or analysed in the blood or in the serum of patients or in other body fluids to really deeply phenotype such patients together with the clinical data that we have. And this really gives us the opportunity to personalise the treatments according to the disease course much better and in much more detail. For example, that we can define whether this patient is in a more early disease course or in a later pro-inflammatory or high inflammatory disease course, as just pointed out and we could earlier apply antivirals or antibodies against influenza or other respiratory viruses. I think we need to think beyond flu only. And in later stages apply anti-inflammatory drugs we have heard about steroids or anti-cytokine strategies, but also other agents that are targeting the host response are on the agenda and according to patient disease phenotypes and then determine the underlying pathomechanisms that are related to all these findings will also help in future and we can translate a lot of things to influenza as well that we learned in COVID. So not all of these parameters can be directly transferred from COVID to influenza, but I think there is substantial overlap that will allow us to also phenotype flu patients much better and to decide which treatment combination or which treatment strategies might be the best for which patient.

Okay, so that is really a major development let's say. And Peter, I remember I think the last time we were talking on ESWI Airborne we were kind of marveling at the speed with which the COVID-19 vaccines were developed and kind of enjoying how unprecedented this was. Do you think there's a kind of a wider effect on the pace at which new approaches to influenza are developed? I mean some of what Susanne and Tony have just been talking about there. What's your take?

Maybe the first thing to say is that we really need to admit that flu vaccines that we have are not really good enough. You know, we've become acclimatised to thinking, well, that's the time to get my flu vaccine and accepting that efficacy of something between zero and 60% is really good enough. But I don't think it is. I think we've learned from COVID that that sort of level of effectiveness or efficacy is not really good enough. I think you know new vistas in vaccinology are opening up because of what we've learned in COVID. The speed with which vaccines were developed was just amazing, not only the RNA vaccines, but also the vector vaccines and adenovirus vector vaccines and the nanoparticulate vaccines and the new adjuvants. You know, all of that I think needs to be applied to new developments in influenza vaccinology. And also directing the immune response to the mucosa. And also developing combination vaccines so that we can vaccinate people not only against, you know, COVID and flu but also RSV, maybe in a single shot ultimately. Because being jabbed three times in the preparation for winter is quite a lot. But I'm hugely optimistic that we are entering this new era in vaccinology, but it's too early to say for sure just how fast that will impact on flu vaccines.

So what kind of possibilities do we see in this new era?

Another thing which I think we mustn't forget was quite amazing was how quickly the public learned to sample themselves using these nasal and throat swabs, those self-administered diagnostics. We didn't think that was going to be possible, particularly not at a cost that was realistic. But if we're going to have a range of new antivirals and early treatments for flu, I think those need to be ramped up and become more available.

Tony, what do you see coming in the new era?

I think well, again, learning the lessons, we saw that actually it is possible to modulate the host response to infection and improve outcomes. And I think there was - amongst critically ill patients we've tried that in the past and it's usually been unsuccessful. But we actually saw there was real progress made in that field and so I'm hopeful that we will continue to develop more specific host response therapies immunomodulation for influenza, for other infections, going forward in these sick patients who desperately need new therapies. I hope we also, again in that whole umbrella of critical care, just continue to improve our support of failing organs, whether it be what type of ventilator, when to start ECMO and so on, and we again have learned that we can make a difference to the sickest patients and we will continue to evaluate those treatments and improve them.

And while we're on this, well, not exactly blue skies, thinking it's the wrong term, but, Susanne, what do you see on the horizon?

Yes, I think one important thing that we learned is that when we want to go with antiviral treatments, we need to be fast. The fact that we now have rapid diagnostics that can be self-administered is a really big chance and a big advance now, also for influenza. Because we can provide therapies that people can take at home immediately before they have the first contact with their physician, or at least this will be much more faster than before. And successful antiviral therapies have to be administered in the first 48 hours post first symptoms. Otherwise they are not helping anymore, because viral replication is then already at its peak and the inflammation already kicks in. So I think this is something that we learned and something that we can easily implement now in our treatment strategies.

You say that this is something we can already implement. But I'm curious about, kind of, how quickly we anticipate change happening. Are we talking about like this can happen next year or this can happen 10 years time?

It's actually both. So we have antivirals against influenza in place, but they need to be applied right. So this is something that we need to better communicate on the one side, and on the other side, we need to join forces to develop new and better working antivirals that we might combine with those that are already on the market.

I would agree that we can improve things now and we could get answers quickly If we include patients in clinical trials now this winter, particularly if we work internationally, like we did during the pandemic. We can recruit patients into the trials, learn what works now. But it's a continuous process. We will learn of those treatments we have now: which one is best, are they better in combination now? But then as new treatments come along, if we're continuously learning, we will then compare the new ones to the old treatments. Are they better? Should we substitute them? Should we add them? And so I really want to emphasise I think we should make clinical trials part of our everyday clinical practice, not just in COVID but now and going forward. If we can always learn while we do, we will improve our treatments and improve our outcomes, and surely that's the right thing to do for our patients.

Right and maybe I can add to this important comment. I mean, we have conducted clinical trials within hospital settings. We have heard about RemapCab and other platforms and a lot of clinical trials have been performed. But we need to go more into the communities, into those that are not hospitalised. This is not an easy task because study infrastructure is not well established, at least not in each and every country, right. But we need to also include those that are not yet hospitalised, to go more for preventing severe disease, in those that are in their early disease courses, and integrate those patients in the outpatient setting into clinical trials as well.

Yeah, maybe I could just add how important it is that we have this collaborative approach to developing trials. Trying to do a small scale trial in your own institution and be in total control is not the way forward. We need to have really good platform trials which are international, which are inclusive and which are collaborative. And that works so well in COVID and we have to continue to work this way and to expand that type of team working. So, particularly when there are relatively few cases. I think the trials work particularly well in COVID because we had a vast number of cases to enroll, isn't that right, Tony, Susanne? I mean, the cases just kept coming and that meant you could run your trial and get results relatively fast, but if you've got rarer events, it takes so much longer and we have to be internationalist, we have to be collaborative and we have to build team science.

Absolutely yeah. When I look back now, I can see in one week in 2020, we recruited more patients into the trial than it's often taken me two or three years to recruit to normal trials. There were so many cases. But importantly, it is that international collaboration. I think our funders have seen now the benefit of that. Speaking personally, the National Institute for Health and Care Research is really pushing to embed it in clinical practice and work internationally. There are many funders working within Europe and around the world coming together and say let's coordinate our work, bring the collaboration together and we can still get the answers quickly. If we look at the whole world, there are plenty of influenza cases each year around the world. We should be learning from all of them and, of course, it's seasonal, so we can be learning the Northern Hemisphere and the Southern Hemisphere throughout the whole year.

So I sense a whole lot more is coming now for new developments in the influenza field and new vistas in vaccinology. And that's the last word, I think, for now anyway, although clearly there is a whole lot more to be said and done on this topic. So I'd like to thank each of you Peter, Tony, Susanne for sharing your expertise with us today on ESWI Airborne.

Thank you very much.

Thank you.

And thanks to you listeners for tuning into this episode of ESWI Airborne. A reminder that this is one of a three-part special on immunisation and treatment. Other episodes feature a trip through the wonderful world of travel medicine and a discussion on the societal benefits of immunising children. So don't miss it. And I hope that you got some good takeaways from this episode on influenza prevention and treatment. And until next time, dear listeners, stay safe.

Aida Bakri: 34:51

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 we would like to extend special thanks to our ESWI secretariat, our technical and IT teams, our arts team and our host, Clare Taylor. The podcasts are recorded virtually and we thank our guests for their participation in this inspiring series. Talks are adapted to a global audience and are intended to be educational. 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.

Immunisation & Treatment - New approaches to influenza prevention and treatment - lessons learnt from COVID- 19

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