Intervention Strategies: hMPV - the (not so) new kid on the block

Claire Taylor: 0:16

Welcome to ESWI Airborne. You're listening to the podcast of the European Scientific Working Group on Influenza, otherwise known as ESWI. Today we're talking about a new one for me: hMPV or Human Metapneumovirus. It's the most important virus you've never heard of, a virus that can cause respiratory disease and is closely related to RSV. So it is my absolute pleasure to introduce our three guests today.

ESWI Luminary Professor Ab Osterhaus, member of the ESWI board since its inception and director of the Centre of Infection Medicine and Zoonosis Research at the University of Veterinary Medicine, Hanover, Germany. Welcome, Ab.

Ab Osterhaus: 0:59

Well, thank you.

Next up we have Bernadette van den Hoogen, associate Professor at Erasmus Medical Centre in Rotterdam. Very exciting, we have a scientist who identified the virus and knows a huge amount about it. Welcome, Bernadette.

Bernadette van den Hoogen: 1:16

Thank you.

And finally, Dr Anne Falsey, professor of Medicine, Infectious Diseases and co-director of the Vaccine Treatment and Evaluation Unit at the University of Rochester School of Medicine, and is widely recognized for her leadership on RSV research. It's an absolute honour to have you here with us today and welcome.

Ann Falsey: 1:37

And it's my pleasure to be with you as well.

So HMPV. This virus has been around for a long time, but only isolated for the first time in 2001 in the Netherlands. Ab, can you give us some background on what was happening at that time, more than 20 years ago, in the world of respiratory viruses?

So, basically, it's about 25 years ago that I took over the leadership of Erasmus Medical Center Virology Department and there, whilst we were starting up quite a number of new techniques, we were at the beginning even being blamed by the pediatricians that they saw so many cases of RSV infections in babies, in young babies, and they blamed us for not diagnosing them. And we had already a history of virus discovery. We had been working on on age five and one influenza virus that we all know today. But also my background is is veterinary background, so I we had identified quite a new animal viruses as well. So we were, we were quite challenged at that time, and so basically what we did is we set up a group of people who started to work with new technologies that we introduced in the lab to see what this virus was, if it was really RSV, a variant of it or it was something else. And, as a matter of fact, this particular group and Bernadette was there, as you have told that, and there were quite a few other people we worked on it for quite some time and then, surprise, surprise, we found the virus that we identified basically as a virus that looked much more like an avian virus coming from the animal world.

So we had about 30 children with this particular virus and we went to the parents and said have these children been in contact with birds, yes or no? Is something ongoing? And the answer was no. It was apparently not a bird virus, and we just wondered how the virus could have crossed over.

And, as a matter of fact, the next step we did then is we looked into all the children that we had serum samples of in Erasmus Medical Center and checked them for antibodies against this virus, and then we proved that over five years of age, virtually all the children were positive, had had this infection before, and we did that for the Netherlands, for Europe, and then we did it before, and we did that for the Netherlands, for Europe, and then we did it worldwide, and then we realized it could not be a bird virus, although it was a virus that had come from the avian world some couple of hundred years ago, and so we discovered it in young babies at the beginning, and then gradually, we realized the virus was like RSV, basically was infecting people throughout their lifetime and really gave problems, particularly in young babies and older adults and also in certain risk groups that we know from influenza, but we'll come back to that later.

So, basically, it was around the turn of the century that we were confronted with this diagnostic problem and actually picked up a new virus, and so that's how it happened.

Now, Bernadette. Along with Ab, you authored the first research paper on HMPV. Did this virus change your career?

Yes, definitely, because together with Ab and with Ron Pouchet and others, we indeed identify this virus and from there on you can just lay out different papers like what needs to be studied, and that was the ground basis for my thesis. So I did my PhD project on it and that changed my career and after that I never let it go. I still work on metapneumo ever since the discovery, and it's fun.

Okay, it's a fun virus as well. Well, depending on the context you encounter it in, I suppose Anne, how about you?

So I'm a clinical translational researcher and I had been very interested in adult populations and respiratory viruses and my primary interest was RSV. And from 1999 to 2003, ed Walsh and I here in Rochester were doing a very big, comprehensive study to try to figure out what the true burden of RSV was, because nobody was really testing for it. And so when my Dutch colleagues, you know, discovered this new virus, you know we got pretty excited about that and said you know, the study that we're doing is a perfect way to see what burden of disease metapneumovirus was causing, because we always know we test for all these different viruses and there's always a substantial portion of illnesses for which you don't get a pathogen and sometimes it's a test, but you always are concerned there's something else out there. So when they discovered metapneumovirus in 2001, it probably was about a couple of years later that we went back to our study and started to evaluate it, and it is a fun virus to be able to diagnose.

And how is it different from other respiratory viruses like RSV and influenza? It must be similar, but how does it differ in terms of symptoms and impact?

Doing the studies now, 25 years later, to really tease that out. But with all the respiratory tract infections at least in adults I'll speak to adults there's so much overlap in signs and symptoms and the target population. So just to say, the virus is affecting the similar populations as RSV and flu. We all are susceptible and can be reinfected, but the people that get into trouble and end up in the hospital generally have underlying conditions, typically heart and lung disease. And then as far as the illness itself, the presentation, there may be subtle differences in that, even though metapneumo is more closely related to RSV, in my mind and we're just doing some studies now it presents a little bit more like flu. There's more in the way of fevers, people have more in the way of sore throats and we're just doing a study now where the metapneuma patients seem to have more in the way of actual viral pneumonia where the RSV patients tend to get very bronchospastic and it's a wheezy disease.

And what do we know about the burden of disease? I mean, you're afraid to there's a similar populations are affected, um, as for rsv and for flu, or particularly acutely affected. But how much do we know about the burden of disease from hmpv itself, and is it something that's seasonal? Does it have the same season as RSV and flu?

Well, I can say that, just like the clinical impact, we also started to get more knowledge on that because we are testing now more so we can see more of the patterns and in general it is a seasonal virus, mostly in the winter. A lot of studies show that it's late winter, early spring. But just this morning I read a paper doing a study in school children where it was actually detected the whole year round, just like RSV, with a peak in January, just similar as RSV. So it is a typically seasonal virus with the most cases seen at late winter, early spring. We know that. But I think with the increased testing we will get more insight in the true seasonality of the virus.

Perhaps the only from the very early papers that we wrote. The only difference we saw in the in the very young children is that generally speaking RSV tends to be a little bit earlier than HMPV, although in later studies that has not been confirmed so clearly. But I think, generally speaking, when we look at the pediatric patients and that's completely different obviously from older adults and the high-risk groups then we see that a slightly later peak in their development shows the HMPV, which is an important thing because at that very early stage those respiratory infections like RSV and HMPV they're quite serious infections. Of course the younger you are, the more in danger you are.

If I could just add on a little bit. You know, one of the important things about defining the burden of disease is to again do what Bernadette suggested, is you really need to test year round, and we saw this problem with RSV in that many of the early studies were tag on to flu surveillance studies or flu vaccine studies, and so they're only looking for the other pathogen, rsv or metapneumavirus, in the period where they're testing for flu, and it overlaps. But it's not exactly the same, and so you may miss the true burden of disease because metapneumo, at least in the US, extends further into the spring. So that's an important part of when you really want to know the burden. You just have to test all year round and not restrict to convenience sampling.

And on that topic of testing, with all the unprecedented, I'd say large-scale testing that took place during the pandemic, did this give you a lot of new information on the prevalence of HMPV? Did it affect the knowledge at all?

Yeah. Well, what I thought is that there is way more let me say this again, way more. Let me say this again what we know now is that the impact is much higher than we thought it would be before the COVID period because we're testing more and we see it more and therefore the impact, the incidence, is higher than we thought before the COVID period.

I heard Anne say that it's more like flu. It's more flu-like and that relates probably to the severity, although in some of your papers I read that indeed, where you did this big surveillance studies, that, as a matter of fact, once diagnosed with RSV or HMPV, that your prognosis is worse than with influenza. Is that correct?

And so I think you know we, even though you guys discovered this so long ago that the research is really ongoing to define the clinical burden. We're still trying to assess. And you know what we, what we learned with COVID, is that you know, if you test for viruses, you will find them. Covid very much affected the epidemiology of the other seasonal viruses for a time, but they're all coming back and the burden of disease, you know, just by standard of care testing, may vary by the country. In the United States there's a new sort of hot thing where they call it stewardship testing, stewardship. And so in many hospitals you're not really allowed to do molecular diagnostics, which have a cost if there is no change in your management. So we test for flu, rsv and COVID, but human metapneumovirus is not part of standard of care testing, even though we're doing a lot of viral testing.

Well, this is a general problem also in the European laboratory diagnostic laboratories. So since there is no money for testing, it's very, very limited. But I think, as you said already during the COVID pivot, there has been much more attention and that continued after that for diagnostics for respiratory viruses and that's the reason that we have now also these lateral flow tests, which are multiple tests where we basically have the big three or now even the big four, or there might be big five, like flu, covid, rsv, now HMPV and human parainfluenza virus. So more and more data are emerging at the moment and that probably also explains why we have this hype in attention for HMPV.

Yeah, well, by testing we can see more variants, maybe by sequencing and testing and having the impact, so you can really define the target population for possible vaccinations. But at the same time, we need to do more fundamental research because, as I said, metapneumovirus is different from flu, it's different from RSV, but what exactly the differences are we still are uncertain about and we need more knowledge to have a more precise treatment option.

Well, I think, in terms of treatment, I think it's fair to say that to date there is no specific treatment for this particular virus. So for RSV, of course the vaccines are forthcoming, and that's very, very interesting. And so vaccines, they work preventive, and I think now that we have vaccines for pregnant women, but we also have a vaccine for older adults and hopefully we'll soon have vaccines available for young children as well. I think the same thing is probably going to happen for HMPV, because I think that most of the companies that are working now on developing and marketing RSV vaccines they're also involved in the next generation combined with HMPV. I think that's fair. And for RSV, you also have the human monoclonal antibodies. So these are antibodies that can be used preventively or very early during the infection. And since the principles of these two viruses, RSV and HMPV, they're quite similar for vaccine production and antibody production, it's my expectation that also soon there will be antibodies for the same purpose for human metapneumovirus.

Can I ask you ?. What do you think will happen after introduction of the RSV vaccines, with the incidence of metapneumovirus?

I'm a little bit pessimistic there because I think one of the big issues at the moment, at least in Europe, is reimbursement of the RSV vaccines and let alone when there's yet another one coming, making it even more expensive. So whilst the reimbursement is relatively low in Europe, most countries is not being reimbursed yet. Once we get the HMPV on board I think it will be even more difficult. So I think the impact on actually the incidence and prevalence of HMPV infection will not be too big. But that may be different than we could ask in the United States, because I think in the US it may be easier to get the vaccination for pregnant women and all the results implemented. I'm not sure with the current political situation obviously.

Yeah, well, we're fortunate in the US that the products are approved and they're recommended by the health authorities.

How acceptable they are to the general population seems to vary and I do worry we may be entering a more unfriendly time for vaccines in general.

But to get back to the original question, you know, I do think it comes back in part to testing.

You know, the companies, I think, are aware of the burden of disease and they are interested to develop products, both treatment and vaccines, but the populations have never heard of this virus.

That's how we started, and the more you test and the more people are aware of it, both the health authorities and the providers will be accepting of a cost of a vaccine, because, yes, it's significant, and I think we've got a good taste of this, of the big news coming out of China oh, my goodness, is this a pandemic? And I, you know, I think it's a lot of testing bias, but if you test for it, it is there, and so the more the general population sees it in their own countries and you can put a name, a specific virus, to the illness, that was quite devastating for someone, instead of saying, well, they had some sort of virus which just doesn't stick. So I'm not sure how to solve the testing problem. I think some of the diagnostic companies need to really lower their prices, but I think that's critical, along with the science, to move it along as far as accepting.

I think that the acceptance by the public at large is important and the name is not very lucky the name that was chosen, Claire. Even you are still struggling with it, that's for sure.

I don't know if there's any options to rebrand it at this stage, but I was just wondering if we can unpack for our listeners the reference Anne made to the big news coming out of China. Who wants to take that on?

Yeah, I think, as Anne already said, it is also a testing bias, of course, since now people are starting to test more and more, and especially from China there's a lot of these diagnostic tests coming these days. So then you get a surge of respiratory infections this time of the year and then basically they find flu, they find COVID, they find RSVs and then suddenly they also find HMPV, and from time to time it may even exceed RSV, depending on the history, and so basically it's just because the tests are there. I think that it has become such a hype. And coming back to the name, perhaps we could invent a new name for the virus you know more, an easier name, like we're not talking about influenza anymore, we're talking about flu.

So perhaps for methamphetamine we could, we could dream up something sometime this is really interesting what you said that, like the prevalence may exceed rsv and this really is the most important virus you've never heard of. In that context, right, what would it take to raise public awareness? Do you think on this?

Well, I think it's being erased as we speak at the moment. So there's a lot of publicity, media attention, et cetera. I think the most important thing will definitely be not only the diagnostics, which give you the burden of disease, but also once you have access to a vaccine or monoclonal antibodies and perhaps we didn't even talk about antiviral therapy, because there's a lot of work ongoing there as well and monoclonals are, in principle, antivirals, of course, the way they're being used. So, basically, with the diagnostics on the one hand and the public awareness that's forthcoming at the moment due to all the publicity, I think also when we have vaccines and antibodies, possibly antivirals, other talking about RSV, it was not in the people's mind either. I mean, you talk about older adults for young children, but even in the medical community, if you talk to GPs today and you give a talk about RSV, they are baffled when you tell them. Indeed, this is also a major problem in older adults.

So just to come back on that, to be clear, there's no specific treatment available today right for HMPV. And in terms of what is in development, like what do we know about what's in development in terms of vaccines and treatments?

Yeah, so, as I said, the monoclonal antibodies are being raised on the same principles as for RSV and the same is true for the vaccines, and there are vaccines in very late stages of development at the moment. Then it always takes quite some time before it's really being used large scale. But the big issue at the moment is also discussion for RSV and flu vaccination, flu COVID, rsv, how to combine these to give them at the same time, can you put them in one shot, all these kinds of questions, and that will take another five to 10 years before we have solved that.

You're saying, like Ab just said, five to 10 years. Is that the kind of timeline you'd anticipate, Bernadette as well? Yes, I think so too.

It might be a little bit quicker these days. If we could do it that quick for COVID, we can also do it that quick for methanol.

But you cannot make shortcuts there. So I think, especially when you start to talk about combination vaccines and we know there's companies working on that I still think you have to go the slow way that normally actually registering a vaccine all the way from phase one to including phase three, I think it will take you 10 years and it may be a little bit shorter. That's why I said five to 10 years, but within five years. Well, I'm always optimistic. So let's see what's going to happen. But a lot of work has to be done to increase the awareness, of course amongst the people at risk, but also the medical community for your kind of last word.

we've mentioned various what needs to be done raising awareness, more fundamental research but from each of you I would like to hear your top priority for what, in your view, needs to happen next.

Okay. So from my perspective, while my colleagues do the basic science, I would like there to be two approaches, which is, as we are working with the companies to design the proper trials for some of the products that are in later stage development, we continue to really press for more in the way of testing to not only increase awareness but really get a better sense of the seasonality and the burden of disease in all the age groups. We've been talking about adults, but this is a huge problem in young children, and so I would like those two things to be moving forward concomitantly.

Yeah, I can only agree with that. We need to get more insight in the targeted populations. What is really, who is most affected by the virus and who can be best treated with the vaccine. And yes, as a basic scientist, I think we need way more knowledge on the fundamental differences between RSV and metapneumovirus and how, if you bring this RSV vaccine on the market, how it will impact on the metapneumovirus epidemics.

I can only agree to everything that was said, all the way from basic science to the clinical science, the clinical testing, etc. It's all important and we have to work hand in hand. But my plea would really be for really funding there, because the funding landscape is really a difficult one, and so I think really investing in the prevention and the handling of HMPV infections is really cost effective in the end. And it's not only cost effective but it is also benefiting a population, the people at the extremes of age, as we said, also the young babies and the older adults, but also the people with underlying conditions, like we know for influenza. I think especially Anne's work has clearly shown that there is a big parallel there between flu, rsv and this particular virus, hmpv. So I think my, if I could say one word, it would be funding, and we realize that's limited, and in the US it may even be more limited, as I understand.

More funding. That's the takeaway message from today. I've really learned an awful lot from this conversation, so a massive thanks to our esteemed guests, professor Ab Osterhaus, dr Bernadette van den Hoogen and Dr Anne Falsey for sharing your expertise with us today.

Thank, you so

Thank you, Claire.

You did a good job.

Like I said, I've really learned a lot today. So that's all about HMPV metapneumovirus, the most important virus you've never heard of. You have heard of it now, and there is some very necessary work ahead, which also means funding all that research and raising awareness. So a reminder that today's episode is one in a four-part series on intervention strategies. We're diving deep into RSV, influenza and SARS-CoV-2, plus a special finale during which we'll discuss all of these viruses together. So keep tuning in, folks, to get the latest insights from the experts in the ESWI Network. And until next time, take good care of yourself, dear listeners, and stay safe.

Aida Bakri: 26:57

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 ESW I Secretariat, our technical and IT teams, our arts team and our host, Claire 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.

Intervention Strategies: hMPV - the (not so) new kid on the block

ESWI Airborne: Intervention Strategies of Acute Respiratory Virus Infections

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