Universal flu vaccines – soon a reality?

Clare Taylor: 0:16

Welcome all of our listeners to ESWI Airborne. This is the podcast of the European Scientific Working Group on Influenza, otherwise known as ESWI. I'm your host, Clare Taylor speaking, and you're in the right place for all the latest expertise on all things viral, and we'll hear it directly from ESWI members. These are the people who know the most about viruses, pandemics, vaccines and more. Now, today, I'm excited that we are discussing a very hot and current topic, that of universal vaccines, and I'm really looking forward to learning more about this from Florian Krammer, professor of Vaccinology at the Department of Microbiology at the ICAN School of Medicine at Mount Sinai in New York, and he is, of course, an ESWI member. Florian, welcome to ESWI Airborne.

Florian Krammer: 1:09

Hi Clare. Thank you very much. How's it going?

Pretty good, pretty cold today, but yeah, it's warming up here already. Florian, 12 years ago, in 2010, you graduated from the University of Natural Resources and Life Sciences in Vienna and I have to say that your list of professional accomplishments since then is truly awesome. We have some high flyers on this podcast, but I hope I'm not making them jealous by saying really, this is such a dazzling career and I'm really curious to know the origins of this. Can you tell us where did it start and how did you first become interested in virology?

Well, that all started back in Austria and Vienna, right, I was always interested in viruses. I grew up in an area where people get Pumala virus infection, so that's a hunter virus. That made me interested in viruses. And then when I was studying in Vienna, there were a few groups that worked on viruses and viral vaccines and I was very interested in that. I joined one of those groups to do my bachelor thesis. So I had to do a bachelor thesis, then a master thesis, and in addition to that my university required that we would do internships, and so I did an internship at Baxter Bioscience, which was a company it doesn't exist anymore that produced a lot of viral vaccines, including in biosafety level three spaces, and I did internships there and I found that super interesting and that's when I decided I want to work on vaccines and on viruses.

So how important was Professor Weingart Grabherr for your professional development.

Very important. First of all, I was always lucky with my mentors. I always had a lot of support and I'm usually working relatively independently and always had mentors who basically allowed me to do that. And so she had a lot of knowledge about virology and vaccinology and biotechnology and, of course, helped me with that. But she also let me do what I wanted to do. She was relatively hands off when I worked there and so I was able to explore different things and I really enjoyed that. And, of course, I got a lot of support from her and I'm still working with her. I have collaborations with her and once in a while we have students that come from her lab to my lab to, you know, do parts of projects here that cannot be done in her lab. So I think she was very, very important for my career and very supportive.

And still is, it sounds like a very fruitful collaboration. Now, Florian, you're so prolific and one of these aspects is in terms of, well, scientific publishing, but also, I suppose, in the support to your peers. You're a member of the editorial board for three different journals and you're a peer reviewer for, let's say, very many at least over 100 journals by your own account. You've lost count of how many. Is that right?

Yes, that's correct.

So I'm guessing you must enjoy this work. What do you like about it?

Yes, I do enjoy working in general and enjoy this work. I'm a very curious person and I'm very curious about all aspects of virology and immunology, right. And so I kind of I don't make a distinction between what I do for work and what I do as a hobby. In a way, what I do for work is my hobby and that, in a way, allows me to to put in a lot of work, a lot of hours, and I really enjoy that. I enjoy, you know, working on projects in in our laboratory. I enjoy collaborations and that's one of the reasons why I have many co-authorships, because we really collaborate a lot and I think that's super important for science at this time and age. Without collaborations you cannot do good science. But I also like to review papers, for example, because you give valuable input to the authors and you learn about things before they get published, right. So I think it's just curiosity that drives me and, yeah, I'm actually not very talented, it's just I have good work ethics and, as I said, I had good mentors and good support, always.

And tell me, how does this good work ethic apply to your Twitter following? Because before we've had this episode, we labeled dear Dr Ted Van Essen as a viral influencer, but you have more than 300,000 followers on Twitter and you write op-eds for the New York Times, so how does this fit into your curiosity?

Yeah, that's an interesting story. So before the pandemic I didn't have a lot of followers and there's this thing that's called science Twitter, where scientists follow other scientists and there is information exchange, right, and that was very helpful. I was mostly in a network of influenza virologists on Twitter before the pandemic. When this all started we didn't have enough information out there in the population about SARS-CoV-2, specifically in the US, because we had issues with the CDC and political involvement there and not a good communication from the government. And so people who were able to provide good information, initially about the virus but later on about vaccines, on Twitter, on Facebook and so on and so forth. You know those people got a lot of followers very quickly and so I did that from the get go and at some point I wrote a very long tweetorial, so a number of tweets more than 100 about SARS-CoV-2 vaccines and that was very popular. People needed that information and I think this was more or less a question of service right. I wanted to provide that information, basically from a reliable source. I'm actually much less active on Twitter now, just because I think people have the information that they need. The public is very educated right now, and so are journalists, right. So all of a sudden everybody is a specialist and a lot of people really know a lot, and so my service on Twitter is not needed that much anymore.

Well, it was certainly a great public service to do at that time and in the time of that administration also. And would you say that you're at home in New York now, after 12 years since you moved to Mount Sinai?

Well, it's always a question if you ever become a New Yorker, if you were not born in New York. Right, I feel at home here. I feel very much at home here. I like to live in New York. There's a lot of energy here and that's what I really enjoy. I'm really an outdoor person, so if I have free time, I go upstate and I go hiking, but I enjoy the energy that the city has. But, I have this feeling that I'm also European, right. I like to be in Austria, I like to be in other parts of Europe, so I like both, but in a way, New York is kind of very international anyways, right, and so I think it fits well into my European background.

And I guess it's been a very successful time professionally or it's been very fertile ground for your practice. I suppose I have two questions here. First, this great title of principal investigator that you acquired in 2019. Can you tell us a little bit about that?

Well, I became principal investigator, which just means you're running a lab in 2014. But in 2019, I got an endowed professorship. I got an endowed professorship, which is a Mount Sinai professor in vaccinology, and that's, of course, nice. That's a supporting part of my salary and that's really pointing out that I'm the person at Mount Sinai working mostly on vaccines, so it's a recognition from the university. It's also support financial support for my laboratory, and so that's very helpful, and it was in time for the pandemic, I think.

And your laboratory is called the Krammer Laboratory right? It's yours and that's not from a great benefactor, another Krammer, it's all for you

Yeah, but I mean that's normal that labs are named, at least in the US, after the principal investigator, right? So my neighbor here is Peter Polizzi and his lab is the Polizzi Laboratory.

So what was it like being in New York during the onset of the pandemic? You were spending some time on Twitter, evidently, but that was really ground zero at the beginning. What was the experience like for you?

It wasn't a nice experience. We started to prepare very early for this right. The sequence of the virus came out on January 10th and that's when we started to make creations to build assays to measure immune responses. I sat down with a colleague of mine, Viviana Simon, and we decided to bank samples from people who tested negative for flu and for RSV but had obvious respiratory symptoms. And so we started all of this work in January already, and then it took some time until we really had the first official cases here. Unofficially, the virus was probably here in January, but the first real cases came up end of February and were then confirmed on March 1st. And then it moved very quickly right. There were more and more cases. There was a lockdown. I continued to go to work. I found it unfair to ask my lab staff to be at work, me doing home office, so I joined them every day and it was really depressing to walk to work at these times. Nobody was on the streets except for ambulances. After a few days they started to convert the open space that we have downstairs in the hospital to bed space, and then you had to kind of walk in through a side entrance and through the tunnels and then they started to build a field hospital in Central Park right outside. It was very depressing and we had a lot of deaths in the hospitals. At peak times we had up to 80 deaths on the main campus per day.

So you know, everybody was very stressed, very emotional. It was not a good time at all. Of course, people learned a lot and New York in the following waves never had big issues anymore. There were, of course, waves of infections, there was also increases in deaths, but it never got as bad as in the beginning anymore and I feel also people, the population of New York, saw this and decided this is something serious, we have to be careful. And so we didn't have a lot of opposition to countermeasures, to masks, to restaurants closing and only having service outside, stuff like that. There wasn't really a movement against that in New York, as you have seen it in other places.

You described there how you really got to work January 2020, but had you anticipated a pandemic before this? Had it been something on your mind and you know? When did you first become aware of the spread of COVID-19?

Well, I mean in general, if you talk to people who work on flu or coronaviruses, they will tell you that their pandemics will happen. The question is, just when right? So we always anticipate a pandemic coming. For me, I think I was a little bit in panic mode after I learned it's a coronavirus and it looks very closely related to SARS-Coronavirus-1. Sars-coronavirus-1 was always that example that I gave in lectures when I was teaching. I have courses on emerging viruses.

This was always the example of where a pandemic almost happened and this was kind of my horror scenario. And then a virus comes that looks very similar and you could follow it right In January. First the idea was, yeah, there's no human to human spread. But that wasn't true and that turned out to be not true very quickly. Then the idea was, okay, nobody's dying. But then people started to die and so everything spun out of control very quickly and, to be honest, I started to write a newsletter for my friends and for my family every week in January and basically told them that there's a risk that this is going to become a pandemic and I had panic about that. Honestly, I asked my team to really make sure that we have everything ready. At some point I really panicked. I went to the hardware store and bought N95 masks, which at this point were still available, and two weeks later you couldn't get them anymore. So I think I was aware of this very early and basically putting in the work to get prepared for it calmed me down a little bit. But I think it was pretty obvious from a very early point in time that this would have a bad impact.

And has it changed you? Has it changed your attitude or your practice in any way? What's the experience?

I mean, of course, the last three years have changed everybody working in virology and public health and so on and so forth. There was a huge amount of work that had to be done right. There was a lot of stress. That changes you. I learned a lot of things on the virus side, of course, but also how to work with media, how to communicate better with the public. I do a lot of outreach. I give lectures for I don't know teachers, for people who work in the subway all of this to make sure that they have information that they need. So I had to learn how to communicate these things in a way that everybody understands it. I also had to really learn how to interact with media in a way that doesn't get the wrong message across.

So that certainly changed me and, yeah, I think there's a lot of things that change for people like me. But the truth is, when the pandemic started in the first year, my assumption was now people will get it that we need better pandemic preparedness. Now governments will act right, we'll have large-scale programs like the Manhattan Project in World War II, that really put effort into preparing for the next pandemic. And the truth is I'm now very disappointed that this is not happening and I actually think that for the next pandemic, with all these anti-vaxxers and all this basically pushback on doing something against virus infections, that we might be in a worse shape than we were in 2020.

That is quite a frightening prospect.

You could say I'm a little bit more negative than I was before.

And, I suppose, coming to talk about vaccine development, as we kind of talk first about mucosal immunology. Some of our listeners may remember another episode on this series and we talked with Peter Openshaw about his perspective, his mucosal perspective on pandemics, where he referred to the battalions, meaning the mucosal membranes' frontline status within the immune system. So, Florian, what is it about this kind of frontline status that makes mucosal immunology so interesting for vaccine development?

Well, I mean, first of all, it's a stepchild for immunology and vaccine development. We know less about mucosal surfaces and what happens there than we do for example, what happens in the blood after you get vaccinated, and the development of mucosal vaccines has always been a stepchild of vaccinology. But from a concept for a respiratory virus the virus has to get in via the upper respiratory tract, it has to land on our respiratory surfaces and it has to find cells and infect cells there. That's how an infection gets started. And, of course, if you have strong immunity there, you prevent infections. Now the question is how to get to strong immunity in these places. That's a different question, right. But I think from a concept perspective, this is certainly something we learned and that might be important when the next pandemic with a respiratory virus comes. Maybe the first thing to do is to develop a mucosal vaccine or a vaccine that gives you good mucosal protection, because then you might not run into the issues later on that we have now with breakthrough infections, transmission in vaccinated individuals and so on and so forth. The current vaccines are good. They protect us very well from severe disease very, very well, and initially they did protect us from infections too. But once the antibody status go down a little bit and you don't have IgG on mucosal surfaces anymore, then that protection from infection is gone, and that's the problem that I see right now.

So the strategy is to reinforce the battalions, reinforce the frontline with this.

Exactly.

And are there major differences in developing universal vaccines, say between the flu and a universal vaccine for SARS-CoV-2, are there big differences?

Yes and no, I mean for flu we know good targets. The question is how to induce immune responses against those targets very effectively. These targets might include the stock domain of hemagglutinin, certain epitopes on the neuraminidase internal proteins that are very conserved for T-cell immunity, the ectodomain of the M2 ion channel. So there's a lot of targets, right. The question is can you develop a vaccine that triggers an immune response against these targets effectively? That's the big question.

For SARS-CoV-2, it's a little bit different. We don't have the targets yet. There is more and more knowledge about what is needed, in terms of broad neutralisation, for example. But some of these things change over time, right. There is, for example, antibodies that neutralise SARS-CoV-2 and SARS-CoV-1, right, and we thought, okay, if that antibody neutralis es both of these viruses, that's probably a good epitope, the antibody epitope as a basis for a universal vaccine, or at least the Benz or Beco vaccine. But then a lot of these epitopes actually changed when the virus changed. The variants changed that, right. And so not just because something is conserved between two viruses doesn't mean it can't change when the virus evolves in the population. And so we're still figuring out what doesn't evolve where the virus doesn't tolerate pressure, right, where the virus doesn't tolerate pressure, right. There might be a few good targets, but it's not clear if they in the end will still be good targets once we have observed significant antigenic drift in the population. From that perspective it's a little bit different. And then it's also for flu e have a lot of ideas what a universal vaccine should be, what a broadly protective vaccine should be, and so on and so forth. We have definitions, at least partially, for that. For SARS-CoV-2, we're still struggling with that. You know, people when they talk about universal SARS vaccines or coronavirus vaccines, that can mean anything from a variant proof vaccine to a ban-Sarbeco vaccine, to a ban-Beta coronavirus vaccine, to a ban-coronavirus vaccine. And while maybe making a variant proof vaccine or a vaccine that protects more broadly against Sarbeco viruses is something that could be developed in the near future maybe not next year, but in the next few years, making a vaccine that protects against all beta coronaviruses is much more challenging. And the question if a universal vaccine against all coronaviruses could be developed, that's open, right. That might not be possible. And the question also is, is it needed? Because a lot of these viruses will probably never infect humans, right?

So are these part of the aspects that make the universal vaccine like a holy grail? Is it possible, is it viable? How is it regarded within your field? Like? Is a holy grail an accurate kind of way to describe the search for the universal vaccine?

Of course there are believers and non-believers, right. There are people who say, okay, a really truly universal vaccine for influenza will never be developed. There are people who say, yeah, you can make something like that, but it's probably more restricted, it's probably within a subtype. And then there are people who think that the current system is a good solution and we won't find anything that's better. Right? I'm one of the believers, otherwise I wouldn't do what I do. I think that it should be possible to develop vaccines that protect against any influenza A or influenza B virus out there. We can get to that point in animal models with appropriate vaccination strategies, and I think that's also possible in humans. Of course, it's complicated to do the clinical development for that. It will take time. It's unclear at this point how a regulatory strategy would look like. What type of efficacy trials would need to be run in order to enable that. It's very likely that you would need multi-year trials to benchmark against regular seasonal vaccines, including years when the seasonal vaccine is not working well. Then you would need to do better, but then from a regulatory perspective that doesn't prove that you, for example, get protection in humans against H10 or H7. You would need to wait for a pandemic to happen in order to see that. So I think from a scientific concept and from testing in animal models, I think we're on the way to showing that this could work. But then how to implement it really in humans, that's a very different story.

And the other question is the question of longevity of immunity, and that's a separate question. It's very important we know that for regular flu vaccines you can get waning of immunity even within a year, and we haven't solved that issue. And if you have a universal flu vaccine that gives you a really nice broad protection, but only for six months, that's not going to help you a lot. Right, it might help in the case of a pandemic, but that's still also a problem. And I think what we don't have right now is a good immunological understanding of how to induce really high, long-lasting immune responses. Right, we know that with some of the vaccines that we are using we get that. With others we don't, but we still don't understand the differences very well and I think we need more work in that area to understand what correlates with long-lived, high immune responses.

And how far away are we from a universal vaccine, say for flu? You're saying that you think it's possible, but there are, you know, years of trials and so on ahead. Would you care to make a guess at timelines on this stuff?

I mean my guess there was a big setback with the pandemic because, A a a lot of people who work on flu had to work on SARS-CoV-2. And B), because for you know, vaccines that were in early clinical development a lot of times materials for making the vaccine in the right quality and GMP quality were not available because there were shortages and everything was prioritised towards SARS-CoV-2, rightfully so. But I think from this point in time, maybe if the funding is available and if there is really enough enthusiasm about it, I think five to seven years would be a realistic time frame. If the candidates work out well in the clinic, you can have nice things that work out in animal models and then they might fail in the phase three trial. And the truth is we had D cell based vaccines in phase three trials that were universal flu vaccines and they failed. That's also something that we have to keep in mind. Just because it looks good doesn't mean it works out in the end. But I think for coronaviruses, depending on the definition, it might take significantly longer.

What are the biggest priorities for you in the coming years? I mean, you're a self-confessed believer, but what would you most like to achieve?

Well, I think the most important thing is to start up clinical trials again with our candidates that we have. We're exploring a few different strategies right now, but again we have also struggled with GMP manufacturing because there was issues with availability of materials. I think the priority is to get this phase one and maybe phase two trials going again. That's, I think, what is for me, the most important point right now. On the clinical development side, on the preclinical side, I think we're investing right now a lot of time into understanding how to get good mucosal immune responses. So that's not just something that's important for SARS, coronavirus too, that's also very important for influenza and I think it's important for every respiratory virus. So we're trying to do a lot of work on that in order to understand what needs to be done to get really robust mucosal immune responses.

Well, that's a worthwhile ambition for sure, and I've no doubt at all that you're the right man for the job, Florian, you've been a really wonderful guest. Thank you so much for coming to the studio today.

Thanks for the invitation. It was a really nice discussion.

Well, that's all we've got time for today folks. Do keep on tuning in to ESWI Airborne, the viral podcast series, for all the latest on pandemics, vaccination, influenza, battalions of mucosal immunology and more, and get your news directly from the members of ESWI, the European Scientific Working Group on Influenza. Until next time, dear listeners, stay safe.

Aida Bakri: 30:04

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.

Universal flu vaccines – soon a reality?

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