Understanding the Transmission of Respiratory Viruses

Welcome And The Big Questions
ESWI Secretariat 0:00

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

Jane Barratt (Host) 0:44

I'm Dr. Jane Barrett. Today we're exploring the transmission of respiratory viruses through two questions. How do we detect infections that might otherwise go unnoticed? And what can we learn about immunity where these viruses enter the body? During the pandemic, daily case numbers became very familiar to us all, but those numbers really depended on who was tested and whose results were reported. Understanding immunity also depends on where we look, including where we examine antibodies in the nose and mouth alongside those in blood. Today I'm joined by two fine researchers bringing together different perspectives to these questions. Dr. Nicole Tsang is a postdoc fellow at the University of Hong Kong School of Public Health. Her research explores respiratory infections in the community, including testing, surveillance and vaccine effectiveness. And Dr. Kevin Selva is a research fellow at the Peter Doherty Institute for Infection and Immunity at the University of Melbourne. He studies antibodies in blood and in samples such as nasal fluid, saliva, and tears. Nicole and Kevin, welcome to the podcast.

Kevin Selva 2:07

Thanks for having us.

Nicole Tsang 2:08

Hello.

What We Miss Without Testing

Good to have you with us. First of all, look, we'll kick off with Nicole. Nicole, I'm really interested in the infections that go unnoticed. If we mainly test people who feel unwell or seek medical care, what are we really missing about the infections in the community? And why does that really matter?

Nicole Tsang 2:30

Yeah, this are really a great question. Because what seems like the most logical way to track a virus can actually leave us with a massive bundle. So on a purely intrinsic level, if you want to know who have the disease, then you test the sick people. You test the people showing up at hospital and kidneys. But those people showing up at hospital represent the more severe cases. The people who are feeling really unwell, but um the problem is the clinical spectrum of infection is huge. It ranges from those very severe cases all the way down to very mild cases, or even people with no symptoms, but they feel perfectly fine. So if we only look at the hospital, then we're only looking at one end of the clinical spectrum.

That's really interesting. But I'll turn to you, Kevin. You know, and I want to talk to you about, you know, immunity and where viruses really enter. Nicole's explained a little bit about why some infections go unnoticed and the span, but let's turn to what really happens when a virus encounters the body's defenses. So, what is mucosal immunity? And why do you study antibodies in the nose and mouth alongside those in blood when we're trying to understand protection against respiratory infection?

Kevin Selva 3:59

Yeah, that's a fair question. Most of the time, most people will study it in blood because it's a lot easier to collect it in blood. We are getting more tools these days to actually collect it in saliva, nasal, and maybe even tears as well. But in terms of why they are different, because most of us, when we're getting a vaccination, we get it in the arm. But what we've noticed, particularly in brought to the forefront in COVID vaccines as well, is that even if you get a shot in the arm, it doesn't actually make good antibodies to protect you at the mucosal surface, which is the actual site where the infection is happening. And what we know from the past is that uh having either infections or sometimes certain mucosal vaccines as well, are a really good way to actually promote better immune responses to protect you a lot better at those sites. So, yeah, getting the right thing at the right place does matter.

Rapid Community Testing In Hong Kong

Yeah, look, Kevin, you make it sound so simple, something so complicated. Um, but Nicole, let's go back and talk about how do we get a more reliable picture of the spread? Because, you know, in COVID, you know, we weren't getting that reliable spread. So during Hong Kong's Omicron wave, lab testing came under enormous pressure. Now, your team established a regular rapid testing in the community. How did that system work and how did it help you understand what was really happening?

Nicole Tsang 5:21

Yeah, it was a really intense time during the pandemic. So during the Omicron wave in Hong Kong, um, I think maybe in um other countries as well, the official lab testing system was stretched to its uh limit. So we have people queuing for hours just for getting a PCR swap. But actually, those um testing that uh people queuing for uh lab tests actually is a huge problem for us because uh what we call a fluctuating testing practice, that the number of people getting tested every day was fluctuating. So it really depends on whether people feel sick and whether people willing to go to have a test and wait for it, and really whether people are forced to have uh this kind of testing. So in that case, if you only look at case number, so even though the case number is like going down, but we cannot really sure that whether the virus is really going away because uh we don't have the denominator, we don't have a very reliable, uh stable testing practice as a baseline. So in that sense, our team realized that uh we need to um find a top uh find an alternative way to do it. So instead of waiting people to go to the testing center, uh we have a group of people in the communities and we provide them with rapid antigen tests so they can have the tests at home very easily. And it makes sure that we have a very stable testing practice and give up a very reliable denominator so that we can estimate the positive rate of um having a disease in the communities.

Yeah, that's really interesting. I've been to Hong Kong many times, and it's such a densely located population, isn't it? So the rapid response teams in the local community make perfect sense. Would that be right?

Nicole Tsang 7:28

Yes. Um, because of uh this um regular testing practice also helped us to identify some Mao or asymptometic cases, which also helped us to like uh find out some hidden cases in the communities and to let us have a more comprehensive understanding of what's the disease burden and what's the clinical spectrum of uh COVID-19 in Hong Kong.

Mucosal Immunity Beyond Blood Antibodies
Nicole Tsang 7:58

It's really fascinating. Kevin, you know, Nicole's really explained to us something about the patterns of infection, but your research also asks about previous encounters with viruses that might shape our immune responses. I think that's really an important area to dig a little bit deeper. Um, in the H5 bird flu study that you're you worked on, people born in different periods have different patterns of antibodies. I'm just really curious. What does that suggest about our earlier encounters with influenza and how it shapes our body's responses?

Kevin Selva 8:38

In terms of, I agree, like in terms of the previous exposures, that that really shapes how we actually uh our body reacts in future uh cases where it emits the antigen. And the reason the body does that is to actually prime itself to meet a better, a quicker demand of uh antibodies or innate and adaptive immune responses as a whole towards the foreign target that we're seeing. So with influenza, what we have is a very longitudinal cohorts. We have ability to go back into the past because influenza has been with us for about 100 years at this point. We can look at people who were born in the 60s, 50s, go back all the way there and see when they were actually exposed to only one influenza like H1, H2, or H3 and H1 in the most uh recent strains. Was there a difference in the population's uh immunity as a whole and how would you react to something newer as well? And what we're seeing is that when we actually look at people in the past, as compared to H5, which most of them wouldn't have seen at this point, people in the past that were exposed to H1 or H2, the first two influenza waves, they actually made more antibodies that were cross-reactive or could recognize the unseen H5 at this point. And what we think is possible is that uh it's because there is some similarities in influenza, like it's mutating, but there are some parts they're still keeping the same. And the past is keeping the same, it's actually being recognized or kept remembered by the body across the different uh years, even though it's been so long.

So this may be a tangential question, but how could your findings help research investigate susceptibility to a future influenza threat? That you know we often hear it in the media, isn't it? We're we're just waiting for the next pandemic. So, does your work help us understand what we need to be looking for?

Kevin Selva 10:28

Yes, and I think for our group, what we we looked at was building upon some of the research that Scott Hansley's group really done in the US as well. In the other group, what they did was uh looking at it in blood. For us, we looked at it at the mucosal surface, and what we're seeing was similar trends, although the method of imprinting was slightly different. Like what we find in the mucosal didn't really line up with what we're finding in blood. So it depends on which is the route of vaccination that we're going with. In Scott's uh paper, what his group actually showed was if you look at people who were born uh in the first few pandemics, like uh H1 and H2, and then you gave them a H5 vaccine, what they saw was that people who already had much more antibodies in the past and kept on having more antibodies cross-reactive to H5, they actually made less H5 responses than as compared to people who were totally naive to H5 at this point.

Kevin Selva 11:19

So by screening people's immunity before giving them the vaccine, this could be a way that we could tailor and make the most optimal response for people to be better protected against uh future vaccines, uh future viruses.

Seems like we need more investment, isn't it, in prevention?

Kevin Selva 11:35

Yeah, that's true.

Yeah, it's it's very true. Nicole, I just want to go back and just ask you a little bit more about the spread of infection. Um, and it's a question that's raised a lot now. Um, you know, if the reported cases fall, how do we tell whether infections are falling or fewer people are being tested? Because I think that's one of the big questions now that remain unanswered. So, from your work, what are your thoughts about that?

Nicole Tsang 12:06

Yeah, um, I think it's really why the denominator we talk about is so important, because um, let's say imagine if we only have 100 uh tests being conducted, but we find 50 positive results on Monday, and then on Tuesday we conduct um a few tests, like 10 tests, but we only find five positive results. So if you only look at the case number, then it went down from 50 to 5. It looked like that uh the case are disappearing, but actually we are conducting fewer tests. So that's why it's very important that um we have a very stable testing practice that um make sure that even if the general public get tired of testing, uh it won't affect our testing um practice and the measurement of the test result. So it's important to make sure that uh for people that we are looking at, they are having stable testing practice, doing it very in a very steady manner. For example, have a regular testing so that we make sure that we have the very similar pattern of denominator and testing practice over the time so that we can monitor the trend and so that the changes can be attributed to the really the vibrant activity in the community, but not the testing practice or human behaviors over time.

Easier Sampling For Wider Surveillance
Nicole Tsang 13:43

Look, I just want to stay with you for a minute because collecting samples is is central to your work. But how do we do this across a community? And I'm particularly interested in those people who are disadvantaged, and how do we reach those people in in um socioeconomic areas that have a um a low poverty? So your earlier research examined alternatives to swabs taken deep in the nose for PCR testing. What did you learn about making sample collection easier while keeping it reliable?

Nicole Tsang 14:21

Yes, um, I think it's very important to have a um simply uh sample collection method because if we want to do it in a population level, then uh we need to find a very easy way for people to collect the sample. So, and also if we want to peep, if we want the people to test regularly, then uh we need to have a simple process for them to do this. So that's why our team explored alternatives that make the sample collection much easier and much more comfortable. So traditionally, people may, in the very early days, people may need to go to the hospital and have a very deep nasopharyngeal swap. But um we find that it may not be possible if we ask everyone to do that. So that's why I think many different research groups also propose that we can have some easier methods, such as we just look at swapping in front of the just uh swapping just the front of the nose or saliva or uh gaggle or just a full swap. So these are much easier way to do the sample collection. And so our team um conducts a meta-analysis and we try to reveal some evidence from different research groups and to see whether these alternative simple methods are also accurate or not. So the result is quite encouraging because uh we find that these simple methods are actually quite good at um doing the uh I think this um simple method actually are having some good performance compared to the deep nasal pharyngeal swap. So I think the uh the poor nasal and flow swap has the uh best performance among all these kinds of um methods, but I think other sample collection methods such as um flow swap, um such as saliva or uh nasal swap actually also have a very good performance. So I think it showed us it's they are all very reliable and it helped us to decentralize everything, not only to the hospital, but also to the community level, so that uh people can have can use this easy alternative to do the testing.

So, Nicole, were there any particular populations that were able to participate more readily than others? Did you look at it by you know age or gender, or did you have a look at that breakdown? Did you notice anything?

Nicole Tsang 17:07

Yeah, so um I think um these alternative methods also um enable um not only the adult but also children to the older elderly, they can also use this kind of a very easy method to do the um sampling and they can do the testing. Um even in nowadays when we have the rapid test, so basically we are also asking um our participants, such as um children to the older adults, to uh collect the sample themselves and do the rapid test themselves so that it's also as a way that helps us to do the committee testing.

Measuring Protection Beyond Hospital Data
Nicole Tsang 17:49

Okay, that's helpful. Kevin, I just want to go back and touch on mucosal immunity for a moment. And one of the big questions that we need to answer to then build a case to government is how does protection against becoming infected differ from protection becoming seriously ill? Because what we're doing is we take metrics about hospitalization. But I'd like your perspective about that.

Kevin Selva 18:16

Yeah, I think largely we look at it from a very workforce kind of a perspective, normally as the government. And we look at it like how many people are in the hospital, our hospitals overwhelmed, but we don't actually see the other burden that is happening. Like if I say a kid falls ill, technically both of the parents are out of the workforce as well. So that's where in the pandemic, particularly with COVID, I think that was something that um in Australia we actually focused on quite a bit. When we looked at families as a unit and we tried to look, okay, who was the first person that got infected? And if the adult or the child was infected, how many more people in the family actually got infected as well? And we were looking at that, what we saw was that in some cases, individual in partly was driven by viral load, so how much virus the initial person actually had, but at the same time, it was also so like who was actually falling sick. So, like in COVID, it was because uh children could actually contain the virus a lot better. So when the child was the first person to fall sick, we don't actually see most of the time the adults in the family falling sick. So then that gives more peace of mind to the parents as well. We could have the kids sleeping in our bed. Those are things that bring comfort to people in such difficult times as well. And in terms of like essays or like readouts that we can have, I think as a scientific community, we are moving towards more, including more kinds of correlates of protection. So that's other measures of what's actually protective or a number that we're giving to something that above this you're actually protected from infection. We are moving away from just blood tests, but actually moving towards uh more mucosal tests as well. And so there are groups in Sweden and the uh Imperial College London that are looking at different metrics that we could have that will actually help uh inform future outbreaks as well, and hopefully give us more ways to actually uh help the public understand where protection is and how protected it to be.

Yeah, look, thank you for saying that, Kevin. The public do need to understand, and I think if we had that kind of information, well then you know we would actually act in a different way. So it's been really interesting sort of hearing both sides of um you know your contribution. We've heard about detecting infections across a community and studying immune responses. What could we learn if we bring them together?

Longitudinal Family Studies Reveal Hidden Infection

So, Nicole, what would what would following infections over time allow you to see? And Kevin, what could immune samples from those same people add? So we'll start off with Nicole.

Nicole Tsang 20:46

Yeah, um, it's a good question. So um, if testing the committee on a single day, then it would be like a cross-sessional study that just gives us a snapshot of uh the virus or the um infection in the community. But following the individuals over time would let us have a more detailed pictures of the actual progression of the disease over time. So I think following people over time allows us to have more information to understand the disease and the virus. So uh normally if um people just go to the kidney, then it will just be like one at a time. So we can only see like the more severe uh picture of the disease. But if we track them over time, then we can see how exactly the illness is um going on. So we can see when the symptom is uh so we can try the duration of their symptoms, so how they feel bad, and how the symptoms progress, and what's the peak. Of the phyrochetting, and once the testing becomes negative again, so we can see the whole life cycle of the infection.

Okay. So turn to you, Kevin. What could immune samples from those people, from those same people add? And and I'm sure I I can hear what you're nodding. So what are your thoughts?

Kevin Selva 22:24

I think largely the more samples that we have, it helps build a better picture of what actually is happening in terms of the immune response. And I think what Nicole did capture at the start of the podcast as well is that we actually don't know how many people are actually asymptomatically infected most of the time. Most of us are walking around looking fine, but when we did our family studies and tracked people over time, it's taking samples, even if they were not infected as well. We started to notice that there were people who are actually showing up with viral loads in maybe their nasal samples or their stool samples, but they were not actually showing up as sick or actually serial converting in the blood as well. So we've only taken one sample, we will not have gotten the whole picture. And I think it's just shows how the in uh the body is actually fighting infections all day long. Like even if you don't know about it, the mucosal surface is like a war zone. It's so much is happening at that. And there's so much that we would we would understand a lot better, like all the different uh risk factors or things that actually help protect people as well. Because if it's if it's we're only thinking of the respiratory virus as in only in the upper respiratory tract, we might lose uh uh samples that might actually be the infection might actually be happening in the gut as well, and we might actually lose that that aspect as well.

What fascinates me about your work is you know the the notion of family studies. Um so I think that's a tremendous contribution to this field.

Early Priorities For The Next Virus

But I really want to ask both of you, you know, preparing for the next threat. If a new respiratory virus emerged next week, what is the one thing you would want in place early to help us all understand, you know, how it spread more quickly? So, Kevin, what's the one thing that you would you would fight to have on the agenda?

Kevin Selva 24:13

I think something that we did really well in the COVID pandemic in Australia, where a lot of the institutes just came together and worked together. So, like we had the children's hospital, we had the nursing homes, we had the families that were infected as well. I think just a community sense that we wanted to get to the answers and try to help as many people as possible. And that really spurred a lot of the response as well, because when we have like a lot of support from different institutes, we actually build on our strengths. And I think that's something that we can we can do a lot more. We can screen the amount of antibodies that are there, we can look at immune cells as well, we can look at different sample types, and that helps us answer a lot of questions. Like it's is one of the it's like in terms of a respiratory virus, we always think it's the children or the elderly. But like for COVID, it actually went against our expectations where the elderly was susceptible, but children were actually mostly fine. So then that frees up a lot of the policies that you could send children to the playground, you could send them to schools, it frees up the adults at that point as well. So there's a bigger uh kind of impact on the society as a whole if we know all this at the start of the pandemic.

You know, it gives me great comfort to say that you all came together. I think that's one of the key ways of working, coming together to really understand what each body, each each institute is doing, and then contribute to to the policy agenda. And also, you know, the fact that you know, COVID did impact, you know, people in the latter half, and also those were compromised, and then the children were less so. So I feel comforted in one way that um there is a model that could take us forward. But from your perspective, Nicole, what's the one thing that you would want in place early?

Nicole Tsang 26:02

Yeah, I think it would be um having a reliable rapid test ready to go because um the importance of testing early um is uh cannot be overstayed. So I think having some accurate information is very important so that um we can use them to guide uh prevention and control measures um during the pandemic. So um just like um what we mentioned before, if we don't have a reliable test, if we don't really be able to identify the people who are sick in the community early, so we end up would be like uh waiting for people to show up in the hospital, and then the virus would have already been like spreading everywhere already. So I think it's very important to have uh reliable tests so that we can identify those hidden cases in the community from the very beginning so that we can identify them and use um the public health resources and policy to um trigger the downstream control and prevention measures.

And it's interesting, you know, Australia and and Hong Kong are in the APAC region, and uh so I'm sure that there's some you know discussions, you know, across countries and within the regions, which is also you know a really positive outcome.

Assumptions Challenged By Real-World Immunity

So finally, what is one assumption about respiratory infections or immunity that your research has made you reconsider? So we'll go with Nicole first. Um is there something that you've thought, oh goodness, that's not what I thought? And it's made you sit back and and reconsider.

Nicole Tsang 27:50

Yeah, um, I think uh from the very beginning, um we always um also focus on some severe cases and we are very alert about like how many cases have died or how many people are in the hospital. So I think these are the ones that um draw our attention in the very beginning. But I think after the pandemic, um we try to realize that actually uh we also need to focus on some male cases in the community because um they are the cases that potentially that would lead to another um outbreak in the community setting. So I realize that uh mother cases actually also have the very important, some significant publication in implication, significant implications for public health, for infection control, and for prevention. So I think um it would be nice if uh we could also capture these kind of cases in the community very early.

Good. I I look forward to them being captured really early. Um, Kevin, what are your thoughts?

Kevin Selva 29:04

Yeah, for me it's I think largely with COVID and like influenza, what we see is that the virus is circulating around us and it's endemic around us. But I think what we don't usually think about is how we are interacting with it and how the environment affects our body as well. So, like in terms of immunity, we always think of it like okay, we have T cells, we have B cells, antibodies, but we don't think about the other factors as well, like the mucus layer, like how dry is the air. All these small little things actually add up as well because like anecdotal, we always think, okay, I'm gonna fall sick when I fly on a plane. But actually, we don't think about why we are falling sick when we're falling on a plane. Is it because the air is recirculated? Is it because the air is dry and we don't actually have nasal sprays to do that? We don't actually see visually, like we have dry eyes, we put eye drops, we have chaffed lips, we put uh lip balm, but we don't actually have like go about putting nasal sprays in winter most of the time until we have like nosebleeds and other things. But that's probably the extreme of that. Like if all these small other factors are actually affecting how easily we are just getting infected, then maybe more emphasis on how causal immunity or how the public could adapt small little ways into their lifestyle, like just to improve how they can actually protect themselves during winter or like when they're flying on a plane, that could help so much, uh, go so much and uh protect them as well.

Kevin, I spend a lot of time on a plane, so I'll be contacting you. I never ever thought about the climactic conditions. So you've really raised my interest in this particular area.

Key Takeaways And Thanks

Thank you, both of you. Understanding how respiratory viruses spread requires a really clear picture of infectious diseases across the community, including those that never even reach a clinic. And we've heard both from Nicole and Kevin in that sense. It does require careful investigation of immunity, what we measure, where we measure it, and whether those findings help explain who becomes infected. Connecting those perspectives, I think, in this podcast can help us better answer the questions and prepare more effectively for future respiratory virus threats. I particularly enjoyed hearing the different perspectives. You know, gone to Hong Kong many times, Nicole, and thinking about the density of the population, but also as an Australian, Kevin, and understanding the vast distances, but also the differences in climatic conditions. I really want to thank both of you, Dr. Nicole Tsang and Dr. Kevin Selva, for joining us and sharing their work. I really appreciate talking to early career scientists. You're at the forefront of this field, and the way that you've approached these questions is a way in which people can, you know, all people can understand what they need to do to contribute to their health and well-being. To all of the listeners, the audience today, thank you for listening to ESWI Airborne and our ECaS series, Shaping the Future of Respiratory Virus Research.

Credits And Medical Disclaimer
ESWI Secretariat 32:14

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

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