George Kassianos (00:00:08):

Ladies and gentlemen, colleagues, friends, good evening and a very warm welcome to our session on reaching for New Heights, breaking down influenza trends and prevention efforts. I would like to really welcome you to this and look forward to our discussion.

(00:00:28):

I'm Dr. George Kassianos. I'm a family physician and the National Immunization lead for the Rare College of General practitioners in London and also president of the British Global and Tribal Health Association. I have participated in advisory boards, meetings, chaired spoken research with every single vaccine manufacturer in the UK. That's my declarations.

(<00:00:55):

With me I have co-pro professor Terho Heikkinen who is professor of pediatrics at the University of Turku in Finland, and also Professor Tina Tan, professor of pediatrics Northwestern University, Feinberg School of Medicine, pediatric infectious diseases, attending on Robert H. Lurie Children's Hospital of Chicago in the United States.

(00:01:49):

So this is our agenda. After a short introduction I will do, Professor Terho Heikkinen will speak on burden of influenza revisited and then Professor Tina Tan will talk on new and emerging influenza vaccines. After that, we'll have a conversation with some questions I have prepared and then we'll open it to you with all the questions you have and also questions we will receive online.

(00:02:21):

So this slide shows in England, the incidents of influenza like illness presenting to general practitioners and is from the Royal College of General Practitioners. We have a Research and Surveillance Center based at Oxford University and every Thursday we extract information from the computers of general practitioners in England. As you probably know, all GPs in the UK are computerized with one system and we prepare really slides for the UK Health Security agency and so on. And what you see here is the incidence of influenza-like illness with the dark line being really the five-year average, but the blue one is actually children under the age of 15 years. The green is the 65 and over, and in orange is actually 15 to 64. And that's basically how it was this year. This was one of the latest slides we have.

(00:03:24):

Also, general practitioners who participate in this and it's about the third of the population of England, all sent respiratory swabs to Colindale, that's the UK Health Security Agency for analysis. And you can see here that they're analyzed according to the virus we actually find there. And SARS-CoV to the red one has always been there, but we have had RSV and when we had the peak on November December, you can see that the peak was really A H3N2. So all the time we know week by week we get this information, we know what is happening in our primary care and the hospitals.

(00:04:10):

Now, this is showing the leading causes of death in children one to nine years is 2016, we haven't got really latest figures, but this is actually a representative of what is happening. As you can see in male children, influenza and pneumonia is the fourth most common cause of death. And in female children, influenza pneumonia is the second most common cause of death. And of course, every year we get a number of deaths around eight, 9,000 a year. And you can see here the last five years, but look at the last year, just under 8,000 deaths. Mainly they involve the older adult, 6,900 deaths, but younger adults and children also die of influenza. So it is an infection that we could largely prevent and this is what we're going to discuss today. So I would like now to ask Professor Terho Heikkinen to come to the podium and present on the burden of influenza revisited. Terho.

Terho Heikkinen (00:05:35):

Dear colleagues, dear friends, when we say the words influenza in children, many times the response is, "Hey, isn't that something that's a problem for the elderly population only?" And the simple answer is wrong. No, it's not a disease only of the elderly population, but very much a pediatric illness. These are data from just a couple of years ago from a global analysis of influenza in children younger than five years of age. And the data show that every year when you discuss this age group, there are more than 100 million episodes of influenza in the world, 10 million or lower respiratory infections caused by influenza, almost a million hospitalizations, and about 35,000 deaths. Certainly most of these deaths occur in low income countries and only a minority in high income countries. But what people usually have in mind is a graph like this.

(00:06:51):

This is data from the US showing the population based mortality due to influenza. And certainly we all know mortality due to influenza is highest in the older population. It depends on where you draw the line, but the older you get, the higher the rate of deaths in that age group. There is very small mortality in children, as George already alluded to, but it's not zero. These are data from the United States during an eight-year period just showing that every year there are a number of children who die of influenza, perhaps too few to motivate a vaccination program. But what is most important here in this slide is that almost half of the children who died of influenza were previously healthy. They didn't have any underlying conditions that would've served as a warning sign.

(00:08:05):

But instead of mortality, when we start discussing morbidity and the attack rates of influenza, everything turns upside down. You can take any outbreak, any year, whether it's influenza A or influenza B, the incidence of virologically confirmed influenza is by far higher in children than in adults. It's manyfold higher, and this is true for all seasons as I said.

(00:08:42):

Clinical presentation of influenza varies a lot. We know that there are practically asymptomatic cases as well as in adults. And then there's a full range of illnesses. And the other end of the spectrum is a deadly infection, which fortunately is infrequent. Most children have a typical respiratory infection with high fever, which is a hallmark symptom of influenza, and many children get complications due to the original viral illness. These are data from our two-year prospective study in the outpatient setting in Finland where we wanted to determine the natural course and the complications related to influenza. And as you can see here, especially when you look at the age group younger than three years of age, ear infections, acute hepatitis media is by far the most frequent complication. About 40% of children younger than three years of age get hepatitis media as a complication of influenza, so almost every second child. Naturally when you go up in the age, this complication gets rarer and that's true with hepatitis media in general. In most countries, hepatitis media leads to antibiotic treatment and that's something that we would want to reduce for reasons that everyone understands.

(00:10:32):

Influenza also sends children to the hospital very frequently. These are again, data from Finland from a 16-year analysis, population-based analysis of the incidence of influenza hospitalizations, virologically confirmed influenza hospitalizations. And as you can see here, the curve looks very clear. The younger the child is, the higher the risk of hospitalization. And what is really important is the leftmost bar here, which shows the incidents in children who are younger than six months of age. This is the age group that we don't have a licensed vaccine for. So basically there is no vaccine based prevention for this age group who we might think would most urgently need some prevention. Although many children are hospitalized. It's also important to remember that the bulk of the burden of influenza is not in the hospitalized children, it's in the outpatient setting. These are nice data from the US showing that the red bars indicate the hospitalized children.

(00:11:58):

Yes, some children, especially the young children are hospitalized. But even in that age group, the vast majority of children with influenza are treated in the outpatient setting. So basically when you think about the burden of influenza, it looks like this. In the bottom, there are children who don't even go to see a medical practitioner, they just stay home. They have a mild illness, mild respiratory symptoms, no need to go anywhere. But then there is a huge number of children who seek medical care, but still remain in the outpatient setting. And some children, the tip of the iceberg, they are hospitalized. The problem is that we usually do virologic diagnosis only in the hospital settings. It's infrequently performed in the outpatient setting. This may be one of the problems why people underestimate the importance of influenza outside the hospital settings, because the virological diagnosis is not made.

(00:13:16):

Children also have another important role besides getting sick themselves, and it's in the transmission of influenza in communities. I already showed you that the attack rates are highest in children, but we know that children also shed viruses much longer than adults and the titers of viruses in their secretions are higher than in adults and this all makes children the main transmitters, the main disseminators of influenza in the community. Both in the household and the entire community.

(00:13:57):

Therefore, when we discuss influenza vaccination of children, there are two distinct sides of the coin. The first one and absolutely the most important side is the prevention of influenza in the vaccinees themselves, because it's being shown that if you can prevent influenza in the children, you can effectively also prevent the complications that develop later in the course of influenza infection. So there is clearly the greatest benefit of vaccination of children is to the children themselves. But there's another side of the coin, which is related to the fact that children are the main transmitters of influenza viruses. If the incidence of influenza is lower in children, it automatically turns into reduced transmission of influenza in other people in the community, and especially the elderly population among whom mortality due to influenza is highest.

(00:15:10):

We all know what happened during the past two three years, we had the COVID pandemic and as it turned out, we missed one complete influenza season. Most probably because of the social restrictions. We can't be sure whether there was any viral interference, but most probably the lack of seeing any influenza cases was because of the extraordinary restrictions. And so there was one full season without influenza at all on a global scale. Then when these restrictions were lifted, influenza started to circulate again. And certainly we have, at least most of us, have experienced a huge outbreak of influenza during the past winter. What happened in relation to the COVID pandemic was that we saw an unfortunate decline in the vaccination coverage against influenza in many, many countries. This is just one example from the United States where they have been very effective in advancing with the pediatric vaccinations.

(00:16:42):

If you look at the uppermost curve there, which shows the age group six months to four years of age, they had reached already 75% vaccine coverage before the COVID pandemic. But then when the pandemic came and there was no influenza, there was a clear declining trend that was seen during the next two years. And now that influenza is turning back into the normal epidemiology, it at least it looks like that now, I think now is the right time to start emphasizing influenza vaccination of children again and to get back to the curve that we were before the pandemic. So basically this is a brief overview of the burden of illness, and at this point I would like to leave the podium to Dr. Tina Tan and continue from here. Thank you very much.

Tina Tan (00:18:07):

Okay, well good evening, everyone. And as you all just heard, influenza causes a huge burden of disease in the pediatric population that is associated with morbidity and mortality. So what I'm going to do during this part of the program is talk to you a little bit about the influenza vaccines that we currently have, because as Dr. Heikkinen just said, we know that vaccinating individuals against influenza is the most effective way of protecting them against the disease and protecting them for hospitalization and dying from the disease. We're also going to look at some of the limitations that are associated with the vaccines that we currently have and then we're going to talk about some of the vaccines that are in development. Some of these are very, very exciting. So this basically shows you the license influenza vaccines that are available here in Europe as well as in the United States.

(00:19:06):

What you notice is that there are three different vaccine production platforms that we use influenza vaccines from. They're either egg-based, they're cell culture-based or the recombinant. And there are certain age groups for whom these different vaccines can be used, especially in the older age population or those individuals that have anaphylaxis to the egg-based or cell culture-based vaccine, you want to use a recombinant vaccine. But you can see that there is an influenza vaccine that is available for persons in every single age group.

(00:19:44):

So this basically shows you some of the differences with regards to the inactivated injectable influenza vaccines, the live attenuated vaccines and the recombinant influenza vaccines. So the vaccine that is probably used the most commonly are the quadrivalent, injectable, inactivated influenza vaccines. These are made from killed influenza viruses and they cannot cause infection. And all of us have always had patients that say, "I don't want the influenza vaccine, because I got the injection and then I got influenza from it." And we all know that this is a killed virus. It cannot give you influenza.

(00:20:24):

These vaccines contain two different influenza A strain. There's one H3N2 strain and one H1N1 strain, and then two different influenza B strains and it's administered by injection. The quadrivalent live attenuated influenza vaccines are made from attenuated or weakened influenza viruses and they really should not cause infection. There have been multiple studies that have shown that the risk of an individual transmitting this virus to other individuals is extraordinarily small. This vaccine contains two different influenza A viruses and two influenza B viruses and is administered via nasals spray.

(00:21:03):

Then the recombinant quadrivalent influenza vaccines are made by only cloning the virus's Hemagglutinin gene, which is then combined with a baculovirus resulting in a recombinant baculovirus and it's administered via injection. This is a unique vaccine compared with the other vaccines, because it never involves the virus itself. It only involves genetic material from the virus. It contains three times the antigen content contained in standard dose influenza vaccine and small studies have actually demonstrated that these recombinant vaccines have improved relative vaccine effectiveness versus standard injectable influenza vaccine. And this is good, because in the elderly population, because of immune senescence, they don't respond very well to standard dose influenza vaccine. So this is one of the options that you can get these individuals so that they get good protection against influenza.

(00:22:07):

Now if we look at egg-based versus cell culture-based influenza vaccine and the way that they're produced, there are some limitations with regards to these vaccines. So the traditional manufacturing process for making influenza vaccines is using fertilized chicken eggs for vaccine production. The vaccines are produced in very large volumes, because each dose of the vaccine requires four fertilized eggs to make that dose of the vaccine. And one of the limitations of this process is that it takes a fairly long time. On average it takes about six months to make a vaccine. And as we saw with the COVID-19 pandemic, we need to be more agile and nimble and be able to respond to producing a vaccine much quicker than six months.

(00:22:58):

Influenza virus adapts to binding to avian receptors that are found within the eggs to allow for its growth and this is known as egg adaptation. But one of the risks associated with egg adaptation is that you can get changes in key viral antigens that may result in antigen mismatch between what is in the vaccine and what's circulating in the community and this results in reduced vaccine effectiveness. If you look at cell culture-based influenza vaccine, the cell derived C viruses do not require fertilized eggs and therefore this eliminates the potential for these types of vaccines to create egg adaptive changes. This particular technology improves the match between the vaccine associated viral strain and the viruses that are circulating in the community and has been associated with increased vaccine effectiveness during a predominantly influenza A H3N2 season.

(00:24:04):

Now, if you look at the real world data, does it make a difference if you use egg-based influenza vaccine versus cell culture-based vaccine and what is that difference? So we know that influenza vaccine effectiveness really depends upon the year that the vaccine is being produced and the fitness of the strain match between those contained in the vaccine and those that are circulating in the community. And it's been estimated that in a good year the vaccine effectiveness of these vaccines are somewhere between 50% to 70% against influenza caused by any influenza A or B strain.

(00:24:45):

If you look at the relative vaccine effectiveness of cell culture-based quadrivalent vaccine compared to egg-based quadrivalent vaccine, we know that the cell culture-based vaccine gives you a little bit more effectiveness somewhere between 5% and 10% over those vaccines that are produced through egg-based culture. These cell culture-based vaccines also in studies have been shown to have greater reduction in influenza related hospitalizations and ED visits all cause hospitalizations and serious respiratory hospitalizations and ED visits versus individuals who receive an egg-based influenza vaccine. If you look at these injectable vaccines, they have a very, very excellent safety profile with the most common adverse reactions that you see in infants and children being fever, irritability, pain, and mild swelling and redness at an injection site. So all the same types of side effects that you might see with any injection that a child would receive.

(00:25:54):

If you look at the safety and effectiveness of the live attenuated influenza vaccines, remember that these vaccines are administered via a nasal spray and these types of vaccines as well as the injectable vaccines may be administered with all other routinely recommended childhood vaccines and COVID vaccine with no immune interference with any of the vaccines. The LAIVs have also been shown to be very safe with the most common adverse reactions being congestion, cough, malaise, and fever, which all resolve very, very quickly.

(00:26:31):

We know that LAIV effectiveness differs depending upon the vaccine strains that are contained in it. At least in the United States, there have been multiple years of poor effectiveness against the A H1N1 pandemic strain contained in LAIV vaccines. For several years we've seen poor effectiveness against the A H3N2 strains. The factors underlying this decreased effectiveness include reduced thermal stability of the vaccine virus and reduced replication fitness of the pandemic H1N1 virus that was contained in the vaccine. So by changing the viral strain to one that is more thermal stable and has increased replication, fitness seems to really have resolved this problem. And the LAIV vaccines that are currently used in the US now are quite effective. If you look at vaccine effectiveness, it is wide-ranging. Again, depending upon the year, it ranges anywhere from 16% to 80% against influenza that's caused by either influenza A or influenza B.

(00:27:45):

Now, because of the limitations of the influenza viruses that we currently have, and because as you heard Terho talk about, the fact that we've had decreases in vaccination rates and we really need to get patients to understand the importance of vaccination, there has been a lot of effort put forth in creation of new influenza vaccines that are much more immunogenic and that will last for a longer period of time. So the concept of a universal influenza vaccine is not a new one, it's been out there for multiple years. We know that vaccination against influenza is an efficient and a cost-effective way to contain influenza epidemics and also to maintain public health. As I mentioned, the current influenza vaccines have limitations, primarily because of the frequent antigenic drifts and the occasional antigenic shift that occurs among the influenza viral strains. And this leads to vaccine and circulating viral mismatch and decreased vaccine effectiveness.

If we could create a universal influenza vaccine that that would provide protection against all subtypes of influenza viruses and the way that it does this is providing homo subtype immunity and hetero subtype immunity so that you get cross protective immunity and protection against any of these influenza viruses that may be emerging. There's several novel platforms that are in clinical development that are being used to study the development of a universal influenza vaccine.

So there are a number of different factors that drive the need for the development of new influenza vaccine. As I just mentioned, and as you just saw, there's an enormous global burden of influenza disease that occurs in pediatrics. And actually influenza is considered a global public health priority, because of the amount of disease that it causes. And we also have this constant threat of the emergence of a novel influenza A virus that would lead to a devastating influenza pandemic, much like what we saw with the emergence of the 2009 H1N1 pandemic virus. We also know that our current vaccines have variable effectiveness in different age groups so that for older individuals remember that there's a higher dose influenza vaccine or recombinant vaccine that is recommended. There's also variable vaccine effectiveness from year to year and one of the major limitations of our current vaccines that it takes a very long production time.

(00:30:41):

There's also limited duration of protection, because the influenza strains included in the vaccines differ from year to year so that the vaccines that we use today really only last for less than a year, and that tends to be a problem. So when you look at the development of universal influenza vaccines, you're looking for a vaccine that's going to be effective in all age groups and that would have a duration of protection ranging anywhere from three to five years. There are also economic and programmatic difficulties in conducting influenza vaccination campaigns globally in low to middle income countries. The conduction of an influenza vaccination campaign is very, very costly and because of the costs, there are many low to middle income countries that cannot afford to do influenza vaccination campaigns. So this really leaves their pediatric population at risk for influenza and the complications associated with it. One of the other limitations is that there is limited access to antiviral agents for the treatment of influenza infections in many areas of the world. And because of that, many individuals who have complications will die from their complications, because we cannot treat them for their infection.

(00:32:06):

Now one way of making a universal influenza vaccine is looking at the influenza A virus and the conserved antigens of that virus. And when you look at the conserved antigens of an influenza A virus, the conserved antigens are your hemagglutinin stem, your matrix protein one, your matrix protein two ectodomain, and your nuclear protein. And these are the conserved antigens that are being developed into what will become a universal influenza vaccine. This basically shows you a number of different vaccine development platforms that are being tested to develop this universal influenza vaccine. So you can have, if you look at A, it's viral like particles platform. B is a synthetic virus platform. C is a DNA vaccine platform. D is what we use today for COVID vaccines, which is an RNA vaccine platform that use self-amplifying mRNA technology. And then E is a viral vector platform which we also have used for the production of COVID-19 vaccines.

(00:33:25):

This basically shows you where we are with regards to the clinical development of these different types of vaccines. So if you look at your nucleic acid vaccine technology platform, and these are primarily your DNA vaccine types, your mRNA types, and then you have several viral hemagglutinin vaccines in development, you can see that the vast majority of these vaccines are in phase one to two clinical trials. Actually there is an mRNA influenza vaccine that has now entered phase three clinical trials. If you look at vector vaccine technology platform. So here you're looking at chimpanzee adenovirus, modified vaccinia virus, and actually some nanoparticle technology, these are mostly in early phases of clinical development. So most of these are in phase one clinical development. You look at recombinant protein and virus-like particle technology, these are in phase two to three clinical trials. So these are the furthest along.

(00:34:34):

Then if you look at live virus technology, these are in phase two trials. So you can see that we are moving along actually very well with regards to the development of new influenza vaccines that are going to be more effective, that can be used in all age groups, and that basically will have a much longer duration of protection.

(00:34:58):

Now one of the major platforms that is being investigated is the mRNA platform. And as you saw with the COVID-19 vaccine, we were very, very rapidly able to create an effective vaccine against this virus, which is something that needs to be done for influenza so that we can get more individuals vaccinated. And if you look at the mechanism of action of the mRNA-based vaccines, basically you have nRNA of the virus that is encapsulated in a delivery vehicle that is taking up by an antigen presenting cell.

(00:35:36):

The delivery vehicle itself is digested and the mRNA is released and then the mRNA is translated by the host ribosome and your antigen is formed. And one thing that you heard throughout the COVID pandemic is that people did not want the vaccine, because it interfered with the nucleus of the cell and the nuclear DNA. And you can see here that all of this happens outside of the nucleus and has no impact at all on the nuclear DNA. Then after the antigen is formed, it can be processed through different pathways so that you're actually able to develop effective antibodies against the virus.

(00:36:20):

So there are also combination vaccines that are in development. As you know, this past year has been really, really stressful with regards to the emergence not only of COVID-19 but also of influenza and RSV and other respiratory viruses that were circulating at the same time, so really just overwhelmed many hospital systems. There are now combination vaccines in development for the prevention of COVID-19 and influenza. There are three mRNA combination vaccine candidates in phase one and phase two clinical trials. And these are three mRNA candidate vaccines that are combination for COVID-19 and for influenza. Actually, one of those influenza virus vaccines contained in the combination has actually gone through phase three clinical trials.

(00:37:15):

There are multivalent vaccines protecting against multiple strains of SARS-CoV-2, and of influenza A and B that are in development. These are using the bivalent COVID-19 vaccine that we currently have combined with a vaccine that is effective against influenza A and B. And there's actually one triple combination vaccine candidate that would be effective against influenza, RSV and SARS-CoV-2 that has just started phase one clinical trials for older adults. So this is very, very exciting, because if we can get these vaccines out there, they really overcome some of the limitations that we have with the current vaccines that we have available. With that, I'm going to turn this back over to George who's going to talk about controversies and conversations and start the round table panel discussion.

George Kassianos (00:38:17):

Lovely, thank you very much, Tina. Thank you. Yes, we'd like to first look at the impact of vaccinating children against influenza. For that I would like to show you what we did in the UK when in 2013 we introduced vaccination of children from the age of two to 17 with the live attenuated influenza vaccine, but we couldn't start vaccinating all those 9 million children at the beginning of the academic year within six weeks. So we started vaccinating in primary care GPs and nurses two to four year olds. And for the other ages we actually did the pilots to understand, what is the best way to vaccinate children, whether in schools, whether GPs and pharmacists should do it, and so on. So this is the pilot of 2014, '15. In a year, the A H3N2 is dominating an drift of B strain. Now, please take into consideration that children in clinical groups have always been vaccinated from the age of six months.

(00:39:28):

Here is when we vaccinated all children. So the pilot areas were distinct geographic areas where the children are being vaccinated and I'll show you the ages in a second, and we could compare them with other distinct, very similar geographic areas where the children were not vaccinated. So in both pilots and non-pilots, children aged two to four years were being vaccinated by GPs and we were achieving about 35% vaccination rate. In the pilot areas, primary school children aged five to 10 years, but also two cohorts of the secondary school age 11 to 13 were also vaccinated and they achieved 55% vaccination rate. Does that actually make a difference if you vaccinate those children and you compare them with the non-piloted areas where you don't vaccinate children? Now where I shaded the area, the P value as you can see is statistically significant.

(00:40:28):

In everything we looked, there was a distinct difference favoring the areas where we're vaccinating children against the non-pilots we are not vaccinating children represented by the upper dot. And the lower dot is actually the pilot areas. And primary school children age five to 10 years were offered the vaccine, 55% accepted it and statistically significantly that group of children age five to 10, saw their general practitioners with influenza-like illness less than in the non-pilot areas.

(00:41:03):

Age under five, again, there was a difference. But what also surprised us was the fact that everybody age 18 years and older, older adult, younger adults, the teachers, everybody, were visiting their GPs statistically significantly less with influenza-like illness in the areas where we are vaccinating children, 55% vaccination rate as compared to the non-pilot areas, where we're vaccinating children. Also, in the pilot areas, children statistically significantly visited the emergency department with respiratory symptoms and were also admitted to hospital with confirmed influenza infection statistically significantly less. So this is what Professor Heikkinen was saying earlier on, that children actually benefit from being vaccinated.

(00:42:02):

So here is the relative risk reduction of 94% visits to GPs with influenza-like illness in the areas where we're vaccinating children. And emergency department, 74% reduction, 93% relative risk reduction in admissions to hospital, because of proven influenza and 59% of adults visiting their GP less with influenza like illness. So the question now is, what is the vaccine uptick in pediatric population? I can only show you the UK. I'm going to ask my colleagues there to comment on their achievements. In the year 2021, '22, you can see the two and three year olds, GPs vaccinated 48.7% with two and 51.4% with three year olds. In my practice, the Ringmead, you can actually see what we achieved there. And in the schools you see that the average was 52% vaccination rate. For this year we have got what the GPs have achieved, you can see they're 42% and 45%. We don't yet have the figures for the rest. So can I ask you, Terho, perhaps, how are you doing in Finland with this problem?

Terho Heikkinen (00:43:21):

We've had a influenza vaccination in our childhood immunization program in Finland since 2007, which means that currently all children younger than seven years of age get a free influenza vaccination if they so wish. And the current vaccine coverage in Finland is, if I say 43%, something in that range. It's not higher than that unfortunately. And there are several reasons that we should consider behind relatively low figures like that. But yes, that's what it's currently.

George Kassianos (00:44:05):

In the United States?

Tina Tan (00:44:07):

So in the US I mean, as Dr. Heikkinen showed, in the really good years we had vaccination rates that were over 70% in the youngest population. With the pandemic we had a significant drop in the uptake of influenza vaccines and now we're probably hovering somewhere between 50% and 60%. We don't have all the data for the 2022, 2023 year, but we still are well below where we were prior to that.

George Kassianos (00:44:44):

As you can see there, as the child gets older, the vaccination rate drops in a similar statistic actually Terho showed earlier on for the United States. Tina, why is that?

Tina Tan (00:44:54):

Because when you look at younger children, they go to the doctor much more frequently for well-child checks. As a child gets older, usually, well-child check is once a year and a lot of times those older children do not keep that well-child check. So you don't have as many opportunities to immunize somebody as you would when they're younger and we don't have very many school-based programs.

George Kassianos (00:45:21):

Right, Terho.

Terho Heikkinen (00:45:22):

Yes. I would like to remind all of us that when we are looking at the vaccine coverages in the UK and the US and Finland, let's not forget about the main fact that these are three countries officially recommend vaccination of all children and it's been in the program for a long time. When we look at many European countries, the vaccine coverage among children is lower than 20%. In some countries it's a single digit number practically close to zero. So these are kind of exceptions. This is not the norm in European countries.

George Kassianos (00:46:03):

Yeah. When the JCBI back in 2012 was contemplating vaccination of children, they had some mathematics and modeling. What they showed there, that if you achieve 10% to 30% vaccination rate of children, is cost saving, it saves, but doesn't really pay for the campaign. Once you achieve 50% vaccination rate, is cost-effective. Yeah, that's the difference. So what are the barriers to vaccine uptake in children? So I'll pass it over to you, Tina.

Tina Tan (00:46:36):

Thank you. So this was actually data from a qualitative study of parental barriers to influenza vaccination that was done in Scotland. Just remember that when you look at vaccine barriers, there are barriers on the provider side and then there are barriers on the parent side. And every single one of these five themes that were identified in the study is applicable everywhere in the world. So one of the themes was uncertainty about indication for vaccination. We know that healthy children that are younger as well as children that have underlying diseases are at higher risk for complications if they were to get influenza. However, what the parent hears when the healthcare provider is talking to them is that, "You want me to get the vaccine, because my child has this condition, but my child's condition is very well controlled, why should I get the vaccine?" Well, I think we need to explain to the parents that just because the child's condition is well controlled doesn't mean that they're not at increased risk for getting complications should they get influenza disease. We need to really emphasize the importance of protecting these individuals from potential complications.

(00:47:50):

Another theme that came out was the issue of choice. Parents really want to feel like they want to make the decision. That I want to vaccinate my child or I do not want to vaccinate my child. People don't like someone to tell them what to do. And in this particular study, basically the person had chosen not to immunize their child, because they felt that the current vaccines don't cover every single influenza virus that's circulating and why should I get the vaccine if it's not 100% coverage? We know that the four influenza viruses that are contained in the quadrivalent vaccines make up the vast majority of all the influenza disease that is seen in the community. So these vaccines are very protective with regards to coverage against the most common circulating viruses.

(00:48:46):

The other thing is that there are challenges with access. Many people feel like they don't have access to the vaccine or easy access to the vaccine. So as a world, we need to make the access to influenza vaccine much more accessible to larger groups of individuals. And we saw that with COVID-19 vaccine and testing where people that live in rural areas, people that live in lower economic areas really found it a challenge to get vaccine. There's lack of parental priority. People say that I have 10 things on my list to do, but getting an influenza vaccine for my child is not one of them. We really need to make sure that these individuals understand that the vaccine is very important to get for your child so they themselves don't get complications and they don't transmit the disease to other individuals in the household, especially to a grandparent or an aunt and uncle who might have underlying conditions and who they themselves don't respond well to vaccination.

(00:49:55):

Then there were a lot of issues related to health beliefs. Many parents feel like what they read on the internet and what they read in the information that you give them, they understand that as what's true about a vaccine or about a virus. They don't want to hear what you have to say, because their understanding is what comes from social media or from their interpretation of the information. I think we have to be much better at providing clear, concise communication to parents in order for them to understand the importance of protecting their child with an influenza vaccine.

George Kassianos (00:50:36):

Of course, the most important advice to parents is actually the health professional that they trust. They have to trust that health professional. And we actually did the survey in the UK back in 2018 called Moving the Needle by the, it was the Royal College of Public Health. And it showed that the number one reason was the appointment was not at the right time. Number two is that, I'm not going to get influenza. And number three, influenza is not effective. We have got a question here. You mentioned quite a number of technologies for producing a vaccine. Why do we need so many technologies?

Tina Tan (00:51:20):

We need different viral platforms, because we have to find the platform that's going to be most effective at producing an influenza vaccine that can be used in all different age groups. So one vaccine, because now we have multiple vaccines that are used in different age groups, that has a longer duration of protection and that has high vaccine effectiveness in all age groups. The only way that we're going to be able to find what the most appropriate platform is going to be, is if we study all these different types of platforms to see what's going to work the best for everyone in the community.

George Kassianos (00:52:08):

Okay. Well, the JCBI back in 2018 pointed out to us that they looked at the [inaudible 00:52:16] study. Everybody probably knows, 11 seasons, no vaccine effectiveness, particularly for age three and two and particularly for the older adults who was about 26%. And the [inaudible 00:52:31] studies as the [inaudible 00:52:31] and so on. They pointed out there are three reasons why we have low effectiveness, is the antigenic drift, is immunosenescence, and egg adaptation. Of course, antigenic drift we need to send more and more respiratory swabs to our laboratories so that the WHO gets better information. For immunosenescence, well, we add an adjuvant or we increase the amount of antigen. And for egg adaptation we produce the vaccine as you pointed out, not using the egg cell base and the recombinant. Yeah. Thank you. So what are the practical considerations with selecting which vaccine for children?

Tina Tan (00:53:11):

So when you think about the practical considerations, this really applies to practitioners in any area of medicine. In the US, the CDC recommends influenza vaccination for all persons six months of age and older on an annual basis. And it doesn't matter which influenza vaccine you give these individuals, the major goal is to get the vaccine into the person. And factors that practitioners think about that may determine which vaccine they use, includes the age of the person, the presence of comorbid conditions and fear of needles, because we know that the live attenuated influenza vaccine, which is a nasal spray, is not being utilized probably as much as it could be. And people are just foregoing getting influenza vaccine, because they don't want a needle. So we know that LAIV, at least in the US, is recommended for those two to 49 years of age.

(00:54:08):

In Europe, it's recommended for those between two and less than 18 years of age who have no underlying conditions, and one of those underlying conditions includes asthma. So these individuals have to be completely healthy. For everyone else, the most common vaccine that is used, especially those with underlying conditions, is the injectable vaccine. Now for healthy patients that refuse to get a vaccine, because it involves a needle, you can seriously consider using live attenuated influenza vaccine to be an appropriate vaccine to use in these individuals so that they get the vaccine, because again, the major goal is to get the vaccine into the person. Practices generally try to choose a vaccine or vaccines that would be applicable to most of the patients that they see. So George being a general practitioner, will probably have to carry a number of different vaccines, because he sees patients at all different age groups.

George Kassianos (00:55:07):

Yes. And one of the considerations we must point out is that in the United States you have got a longer license for the LAIV. We don't. It's from two to 17 years of age.

Well, we have come to the end of our time there. I would like, on behalf of everybody, thank our two speakers here. Thank you very, very much and I would like to thank the organizers for really getting us together to discuss this with you. I would like to thank you for attending and wish you a very, very good evening. Thank you.