RSV - the bumpy road towards a vaccine

ESWI Secretariat: 0:00

Welcome to ESWI Airborne and our special series on intervention strategies for diseases caused by acute respiratory viruses. This episode on intervention strategies for respiratory syncytial virus and RSV disease is made possible thanks to the kind support of Moderna.

Clare Taylor: 0:32

Welcome to ESWI Airborne. In this podcast series we talk with the scientists and clinicians who know the most about acute respiratory viruses, the risks and how to prevent infections. Today we're talking all about RSV respiratory syncytial virus the vaccines, immunisation programs and protection against RSV for those most at risk. I'm your host, Clare Taylor, here today to share their expertise. I'm very pleased to welcome Stefania Maggi, distinguished Geriatrician, research Director at CNR, that's the Italian National Research Council in Padova. Regular ESWI airborne listeners may remember Stefania from our episode on RSV and reducing the burden of disease in older adults and indeed other episodes. Great to see you again, Stefania,

Stefania Maggi: 1:25

Thank you

Clare Taylor: 1:26

Next up we have Peter Openshaw from our "Meet the ESWI Members series and the unforgettable episode "A Mucosal Perspective on Pandemics. Peter is a respiratory physician and mucosal immunologist professor of experimental medicine at Imperial College in London. You wouldn't think it to look at him, I have to say, but he has worked on RSV and influenza since the mid-1980s. Welcome, peter,

Peter Openshaw: 1:52

Clare Taylor: 1:55

And finally, Federico Martinon- Torres, you're especially welcome as this is your first time on ESWI Airborne. You are Head of Paediatrics and director of translational pediatrics and infectious diseases at the Santiago Clinic Hospital in Spain, a lovely spot. You're also professor in pediatrics at the University of Santiago, member of the Royal Academy of Medicine and Surgery of Galicia, Spain, and I note that RSV is among your main research interests. Welcome, Federico.

Federico Martinon-Torres: 2:27

Thank you very much, Clare. My pleasure to be here.

Clare Taylor: 2:30

Awesome, Federico. I'm going to start with you as the newbie. How and why did you get interested in researching RSV?

Well, actually, during my training as pediatrician, I saw so many patients and I felt so limited about what I could actually offer to them. That always intrigued me and I was interested. As a matter of fact, I did my PhD on bronchiolitis and RSV infections Actually, it was about the use of Heliox in the treatment of these patients, and since then I never left the topic and I had the opportunity to further go in the subject from different angles. So here I am and I'm trying to provide my 50 cents to this podcast.

Clare Taylor: 3:11

Well, thank you so much. We're certainly glad that you're here and that's very interesting to hear you say it's from really your frontline, direct experience that you became a researcher in this topic experience that you became a researcher in this topic and regular listeners will, of course, be familiar with the dangers of RSV infections and about the serious risks, especially for very young children and older adults among other vulnerable populations. So vaccines really matter here to prevent the loss of life. However, RSV vaccines are only recently available. How long, Peter, have they been in development?

Well, so RSV was first discovered more than 60 years ago and there were immediate attempts to make vaccines, which were actually disastrous. They not only failed to protect, but they also caused enhanced disease. And I think they not only failed to protect, but they also caused enhanced disease. And I think there's that long history which has really, really overshadowed the whole field. The breakthrough came just a few years ago, when it was realised that by stabilising the main protein on the surface, the fusion protein, in a particular configuration, it was now possible to induce very strong neutralising antibody. And since that time there's been a rush of vaccines in development, several of which have now actually reached the market, so tremendously exciting time for those of us who've been in the RSV field for a few decades.

Clare Taylor: 4:40

And how important was this RSV vaccine development work for the rapid development of the COVID vaccine.

That's an interesting question. I mean I've talked to Barney Graham, a very distinguished vaccinologist who recently retired from NIH, and we both worked in the field of RSV and we kept reflecting during COVID just how much there was a parallel between all that we've understood about RSV and how it causes disease and how we might make vaccines, and COVID. So much that we've learned over the years from the RSV field actually has a sort of reflection in our understanding of COVID and how that causes disease as well.

Clare Taylor: 5:22

I feel that we should do an episode on this topic at some point and bring Barney in. But back to the topic at hand, RSV vaccines have become available recently. What vaccines and where, Stefania?

Well, there are mainly three vaccines that have been approved recently and that are available for use in the population older than 60 years of age. Two are recombinant vaccines and one is a messenger RNA-based vaccine. The data from the clinical trials are encouraging and their efficacy has been proved in large pivotal clinical trials. The first one, the recombinant bivalent profusion for RSV-A and B subtypes is a non-adjuvanted vaccine, as it is indicated, in the population over 60. And in the pivotal Renoir study, where about 36,000-37,000 people were randomly allocated in the vaccine and in the placebo group, the efficacy was indeed very high, about 89% efficacy in the prevention of three symptoms of the lower respiratory tract disease associated to RSV. Then the other, recombinant Prefusion F for the RSV-A subtype, is an adjuvanted vaccine and also the pivotal trial, the ARES-D trial that was carried out in about 25,000 people over 60, has shown efficacy of over 82% and with the similar results for RSV-A and B subtype. So this is also considered very effective. And the last approved is the messenger RNAi vaccine that encodes for a stabilised perfusion F protein for RSV-A subtype. And the pivotal trial, the Conquer RSV, that was carried out in more than 35,000, also has shown more than 82% efficacy in preventing the two or three signs of symptoms of lower tract infections associated to RSV. So I think that the three of them have comparable effectiveness and efficacy in these clinical trials, and we are waiting, of course, to see the effectiveness data in the population.

Clare Taylor: 8:48

We'll come back to that point again, Stefania. Thanks so much for setting that out for us. Federico, do you want to come in there? Have you got anything to add to that?

Yes, indeed, because in fact one of the vaccines that Stefania has mentioned, the bivalent inactivated vaccines, has been also approved for the use in pregnant women to prevent RSV infection and the consequences of RSV infection in the infant. So actually it's like it's an immunoprophylaxis, but it's the same vaccine that has been proven and assessed in the pregnant women population. I I think this is a major milestone in the development or in our fight against RSV and it's important to align that. Also, at the same time, not a vaccine strictly speaking, because it's monoclonal antibodies, but the same sort of strategy immunoprophylaxis of the infants. A new generation of monoclonal antibodies is under development and the first one, Nirsevimab, has been already approved in several countries by different regulatory agencies. So in the field of RSV prevention in the infant age, we have now at least two tools that can be used for universal prophylaxis of RSV in infants. One, the maternal vaccine, the same as we use in older adults but approved also for the use in pregnant women, and the other would be the direct administration of monoclonal antibodies, last-generation monoclonal antibodies, which has they have a long-lasting half-life which allows, with a single dose, to protect for the whole duration of the season. So we need also important milestones in the prevention of RSV in the infant age.

It sounds like everything has been completely smooth and we're home and dry. I think I'd just like to add a word of caution. I mean there have been quite a few sort of road humps that we've had to go over in order to get to where we've got. You know, there are major manufacturers who have taken vaccines right through to almost the final stage and have then terminated their program and pulled out. There's also, as Frederico was mentioning, the maternal vaccination, which is going forward with some manufacturers, but not with all. I mean, there have been some apparent adverse effects and I think we need to keep a very close eye on that. I think there's also a gap in that we don't yet have anything that we can use for protecting toddlers and for protecting the mucosal infection, for protecting toddlers and for protecting the mucosal infection. So I think there is still further to go in terms of protection against RSV disease.

Clare Taylor: 11:32

Okay, so it's a new dawn, is what I'm hearing from you. And, in terms of a kind of rollout, what are we seeing from national governments? What are the various approaches to preparing immunisation programs at national level?

I think what impresses me is the diversity of approaches, even just in Europe. I can really only speak for the UK, but we've had a very cautious adoption in the UK where we've gone for maternal vaccination to protect infants not the nocevimab long-acting antibody that was mentioned by Federico and we're also using that same vaccine to protect older adults and we've been very cautious in restricting that vaccination to those who are aged 75 to 79, but not to the younger adults in whom the trials that Stefania was mentioning were largely conducted. And I think we're watching and waiting for further real world data before widening our prevention program, which I expect to see at some stage but is very much limited in the UK by the financial arguments about the benefits of vaccinating particular populations.

Clare Taylor: 12:55

And that exchange will continue to run. I suppose, Federico, what are you seeing in Spain?

Well, I mean, I think that we can find as many approaches as countries exist. I agree with Peter that each country has specificities. The financial constraints are usually one of the most important and limiting factors in any of these decisions. And, of course, I think in some manner all decisions are right. It depends on the country's specificities, the affordability, the resources and the actual burden of the disease for the specific target groups in those specific populations. In the case of Spain, by the time the decision was made because we were very early adopters of immunoprophylaxis or universal immunoprophylaxis by that time the only option available was the monoclonal antibody, the nircevimab. So it was a simple solution, a simple decision I mean it's that option or keep without any sort of prophylaxis. So NIRSEVIMAP was adopted and now we stick with that decision based on the very positive results of the first year administration, at least in the short term. But again, as I mentioned, it's subject to so many factors that it's difficult to make a single rule that applies to all.

Clare Taylor: 14:19

And Federico, when was that adopted?

Yeah, it was in early March last year, 2024. Galicia in Spain announced the introduction. Then there was some sort of a snowball reaction all over Spain and Spain included in the national immunisation program for free for all infants born during the season and those below six months at the time of the start of the season, plus the rescue of those up to two years of age with specific risk factors. And the campaign went very well with evolved 90% uptake and with impressive positive results with the reductions in hospitalisations due to RSV in the target population around 90%. So I mean it doesn't mean that other strategies cannot reach the same point, but indeed the positive results reassure the official authorities to stick with that strategy and this year we will do the same. It's different with the other adults where there is no specific official recommendation reimbursed in the older adult population. It's only local in specific regions and there are medical associations recommendations and they use on the private market but not we are, let's say, one step behind as compared to the UK, because Peter mentioned, but other countries also in older adults RSV prophylaxis.

Clare Taylor: 16:15

And on that Stefania, perhaps you'd like to come in and comment on what

Well you know for sure there are the standard precautions such as the non-pharmacological approaches. Hand hygiene and the use of masks to prevent the droplet transmissions that are always very, very valuable interventions to be implemented, and also the ventilation in rooms, particularly in crowded environments such as nursing homes, for example. So this is a general, non-pharmacological approach. In terms of vaccination, as it has been said, different countries are selecting different strategies and there is one aspect related to the timing of the vaccination, because we have data from the available vaccine now that it seems that they keep efficacy also in the second season. So for now we are offering one time in the life course the RSV vaccination for older adults, but we do need more data and follow-up to assess the real effectiveness in the general population. In terms of target population, for example, in Italy, as well as in Sweden, the vaccine is offered on an age-based over 75 to everyone, because it is assumed that people at that age are more at risk of severe disease and also to those 60 and over with concomitant diseases that increase the risk of severe outcomes and therefore we include here people with cardiorespiratory diseases, hepatic, hematological, renal diseases, immunocompromised people, and this should be extended, of course, also to the younger cohort. Again, as it was said before, financial aspects are considered by each of our countries and will be definitely a factor affecting the availability for the vaccines. But the other aspect is that we must work all together to increase the awareness and the education among the general population, but also among the healthcare practitioners, because it is low and in Italy we have data showing that less than 50% of healthcare practitioners really are aware of the impact of RSV in older individuals and in high-risk groups. And even if we have, you know, a good vaccine available, it's not enough to see them used and intervention implemented in the population.

Clare Taylor: 19:29

And Peter, do you think this is something that's getting enough attention? I mean, we've been talking about specific populations older people, infants under six months of age but in terms of other populations who are vulnerable to RSV, do you think more needs to be done?

Well, I think in the adult pulmonology arena, many of us are maybe a bit disappointed that the RSV vaccines are not being recommended for our patients who have chronic bronchitis, asthma and other chronic respiratory diseases, where we do see quite serious adverse effects. But I think we need more data to support the extension of the vaccination immunisation program to those other vulnerable people. I think it's perfectly understandable that we do need to be cautious and we do need to be very sensitive to the economics of introducing new vaccines, because there are many other vaccines with which we're competing now and many other demands on healthcare.

Clare Taylor: 20:31

There's some very interesting points there, among which the kind of need for more data and, Federico, just to come back to you, know what you were describing as the very encouraging results from, let's say, the first wave of the immunisation program. How soon, how quickly will we see the effects in hospitals and who is presenting ill?

Well, I think it's very compared to other diseases or other prophylaxis campaigns, the short-term impact is immediate because the burden is very high. Let's keep in mind that RSV hospitalisation is the most frequent cause of hospitalisation in infants. So if you get any positive results, you will see immediately a pretty obvious and this was what has been seen in the very early results of the use of nilcebimab in Spain has been published and the same results have been replicated in other countries like the States, France, Italy and the numbers are impressive and pretty consistent, with effectiveness against hospitalisation around 90%. Effectiveness against intensive care admission around again 80 plus percent. All costs LRTI around 50 to 60%. So those numbers lead to a very important impact, at least in the short term, not meaning that we still need to, you know, see which will be the midterm effect, the eventual impact in the short-term, morbidity, etc. I think that's the advantage of nircevimab over the monoclonal antibody oh sorry, over the maternal immunisation, is the availability of data, the fact that it was licensed before it has allowed to already gain real world experience, not meaning that the vaccine cannot produce similar results. So we will be watching the data coming from the UK and also Argentina that has adopted the maternal immunisation to see how is the behaviour in that regard. But in any case, I mean better than what I have said. Anyone that want to go and see an update review on immunoprophylaxis in infants and the data and the strategies can have a look at the recent paper at Lancet that we published, whose first author is Clint Pecenka and everything in detail is up to date is there if you want to see more details about what has happened around the world in terms of RSV prophylaxis in infants.

Clare Taylor: 23:09

Okay, great Thanks for that reference. We'll include it in the description of this episode. Peter, what's your take on this?

I won't say I'm holding my breath because I think that I would suffocate before the data comes through, but I really, really do want to see what impact these enormously effective prevention measures will have. We've been arguing for years about how important RSV is, both in infancy, in respiratory health in later childhood and in older adulthood in particular, and I think we may be greatly underestimating the impact, particularly in older adults, because it's quite hard to diagnose and it may be that we've been missing a lot and with a very highly effective vaccine that will finally tell us just how much health improvement we get with RSV prevention. So there are many questions that we're still waiting to answer once we get real world data, but we do know with some other vaccines I mean, for example, the human papillomavirus vaccine, which is being rolled out very widely in adolescents that's had a huge impact in terms of cervical cancer rates, which have been plummeting almost to zero in areas where that vaccine has been widely used. And of course, you know recent experience with COVID vaccines. It looks like they do produce a significant reduction in so-called long COVID. So you know there are many benefits of vaccination beyond the immediate impact, which is what we're seeing so far.

Clare Taylor: 24:44

Federico, do you want to come in there?

Well, I mean, I think that again, I agree that we need more data. I think probably the benefits of immunisation are even greater than what we are actually seeing, because we are now looking and getting the low-hanging fruits, and I think it will be very important because that can also change the actual efficiency of these interventions and allow more countries to introduce these products into their immunisation programs. But I think, so far so good. The data is pretty impressive. I think we couldn't dream of so good tools with so good results, even in the clinical trials, but now the real-life data coming from all the models vaccination and pediatric immunisation are awesome. So we have very powerful tools now in our hands and I think the main challenge ahead of us is to make these tools available everywhere, and particularly in those countries where the burden is the highest. At this moment, vaccines or monoclonal antibodies are available in around 50 to 60 countries around the world, not meaning that these countries actually have included any of these vaccines into their NIPs, but just available. And most of the countries where it's not available are those specifically where the burden is the highest, and RSV infection in infants means mortality, for example. So I think we are still lagging behind and we need to do one especially to make this happen, because clearly there is a before and after. We have very good tools, but we need to reach also these countries where RSV means death.

Clare Taylor: 26:27

Federico thanks a lot for bringing in it. Really, it's a very important point. This is really a matter of life and death in many places. With the vaccines now available, it's early days. It's also exciting days. I know that there's many more RSV vaccines in development, so not that the scientists here, of course, would ever look into a crystal ball. But if you did look into a crystal ball, Stefania, for example, what is coming next in relation to RSV vaccines for older adults? You mentioned a combined vaccine. What do you see?

Yes, definitely. I think that one of the major areas of research is indeed the offer of combined vaccine, because if we are able to deliver more than one with one shot, that would definitely improve the coverage and the adherence to the vaccine calendars in all our countries. But while waiting for them, I think we should also focus on the possibility of co-administering, at the same time, two vaccine with two shots, but that would definitely help, particularly for older adults, to increase the adherence to the vaccinations. And again, even more than that, I would say that what was underlined as a major economical problem, seen by the countries, it should be supported by data from the cost and benefits, not only on the cost of the vaccine but, as we expect, if this vaccine is able to decrease the hospitalisation and the mortality, the cost benefit is going to be definitely positive, and the suggestion is that indeed, there is the chance to decrease hospitalisation. In older individuals hospitalisation means increased risk of frailty and disability and therefore that would definitely be an area where we do aim to collect data in order to support this vaccine in older adults and the population at risk for the presence of comorbidities, as it has been underlined before.

Clare Taylor: 29:14

So there's still a lot more work to do there. Federico, what do you see as the next steps for protecting children from RSV?

Well, the very first step is to make the widespread use of the available tools. I think I'm repeating myself, but I think it's so important. I mean we have now available tools safe, effective and we need to make them available. It's also true that we are working in different next generation vaccines, looking at the toddler specifically, which is second in importance during the pediatric age in terms of burden, and also the combination vaccines including other pathogens like metapneumovirus that can increase, let's say, the preventing potential on respiratory burden in our patients. But going back to my first comment, first, we have now very successful tools. We need to make them available worldwide.

Clare Taylor: 30:10

Indeed, it's a really important point and I am glad to hear you say it again, Peter. This is a lifetime's work you've spent around this field. What do you see as happening next?

Well, it is hugely exciting to see vaccines and long lasting antibodies being available to protect against RSV disease, but I think we have to remember that it was a long and bumpy road and some pretty big bumps along the way, and I think it's possible that there are going to be new things thrown up during the rollout of current and future vaccines. We just need to keep an eye and see where it's going next. I think, to my mind, one of the things which is lacking is some method of protecting transmission. These vaccines are very good at preventing severe lower respiratory tract disease, but in terms of mucosal protection and therefore protection against transmission, I think there's a bit of an open space there, you might say. I'd just really like to end by absolutely agreeing with Federico in particular that protecting children in developing countries in resource-poor settings is so vital. 99% percent of the worldwide deaths from RSV in childhood are estimated to be in resource-poor settings, and that's really where we need to get these protective measures rolled out. It's marvellous to have them in our relatively wealthy countries, but we need to have vaccines that are cheap enough to be rolled out worldwide. So there's a lot to do, but it's exciting times.

Clare Taylor: 31:55

Great. Thank you so much for that and for that, really, really such an important note to end on. Peter, thanks a lot, and to you, Stefania and Federico, for sharing your expertise with us today. Folks, if you enjoyed this episode on RSV, good news there's more to come. Don't miss it and keep tuning in to get the latest on intervention strategies from experts in the ESWI network. And until next time, dear listeners, stay safe.

ESWI Secretariat: 32:30

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.

RSV - the bumpy road towards a vaccine

ESWI Airborne: Intervention Strategies of Acute Respiratory Virus Infections

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