Federico Martinon-Torres (00:08): Hello. We are going to get started. Hello and welcome everybody. Those of you brave still
standing after this intense and long ESPID. Also, welcome to those that are following us from home online and my name is Federico
Martinon. I'm a pediatrician and clinical researcher based in Santiago Hospital in Spain. Also, I want to say hello to the
online chairman, which is Kenneth Alexander that will be on the other side addressing the questions from the online audience.
And also he will direct the discussion after this meeting for those following the backstage pass. (00:54): I'm very glad to
be here in this Medscape educational activity. Probably at this stage of the ESPID you may think you know everything about
RSV, but I will try to prove that you are wrong. And for that I have in this table two good friends and experts on the field
of RSV that probably will provide you some angles and some details that may complement all the things you have learned so
far and even the knowledge you already have on this rapidly moving target like RSV. (01:31): So for this meeting I have on
my left Asuncion Mejias, she's a pediatrician. She works now at the St. Jude's Children's Hospital in Tennessee in the United
States. And she's a world reference expert in the field of RSV and you all have read several publications of her and her group
for sure. And here on my right we have Paolo Manzoni, professor in pediatrics and neonatology. He's now the director of the
division of pediatrics and neonatology in the Nuovo Ospedale degli Infermi Ponderano Infermi in Italy. (02:08): So with their
help we will try to address all possible questions regarding RSV. You also will have the chance to make your own questions.
Please for that, use the online app to send any question you might have during our presentation. So as said, this is us and
I should probably have shown you that before and then I would not have not missed time presenting them. And as I mentioned,
Kenneth Alexander will be the online chair. (02:42): So today what we'll try to discuss is, well, discuss and try to give
another twist to the burden and the trends of RSV in children, which are the current prevention strategies for RSV. And there
are important novelties and rapidly new novelties coming also as we have seen in this same meeting. And also we will have
the chance to have some conversation among us and with you on potential gaps and challenges in the knowledge of RSV. (03:13):
Before we move forward, I would like you to interact with us. It's not a difficult question and I know you have a very high
level, but I will ask you to scan in this QR from home following the app to answer to this question. How knowledgeable are
you about the burden of RSV among pediatric patients? So the answer choices are one, not knowledgeable, two, slightly knowledgeable,
three, moderately knowledgeable, four, mostly knowledgeable, or five, very knowledgeable. So please if you don't mind, pose
your vote and after I think you have already voted, then we will move forward and we will see later the results. (03:58):
So we are now doing the math, but I don't think we are going to see the results right now, but later on just for the sake
of time. It's taking time. I could do it with my hands. Okay, so let's get started. So Asuncion, whenever you want is going
to talk us about RSV in children and specifically addressing important insights on the burden and the recent change in the
epidemiology. Asuncion, whenever you're ready. Asuncion Mejias (04:38): Thank you, Federico, and thank you all for being here.
As Federico said, you are champions for being at the last part of the meeting. I'm going to review the burden of RSV. We've
seen several talks at ESPID and I was pleased. I've been studying RSV for 22 years and nobody was paying that much attention,
but now it's a very hot topic so I'm very happy with it. We'll see the changes in the epidemiology, the role of coinfections
with RSV. This is a topic that is very common and yet we haven't gone deeper. And then the role of immune response, not only
to understand disease pathogenesis but to assess this disease severity. (05:20): This is RSV. I think by now you all have
met the virus at least once. This is, it looks simple, it's a single strand of RNA. It's different than flu. Flu has eight
segments that recombine and RSV is very stable. It has only one strand, it's an orthopneumovirus with 10 genes that encode
for 11 proteins. We all know about the F, it's the major antigen determinant, and the G. But I wanted to focus your attention
in these two proteins, the NS, non-structural proteins. These are proteins that counteract the interferon activity and this
a mechanism of action the virus. COVID has 16, RSV has two, and they've definitely given us a lot of headaches. (06:05): What
is the burden of RSV? So we're going to review not only the acute but the long-term sequela. And in terms of the acute burden,
RSV is the number one cause of hospitalization in infants here in Portugal, in Spain, in Europe, in the US, all over the world.
We did this study where we compared children less than two years of age hospitalized with RSV or non RSV. And all these children
underwent viral testing and as you can see, 70% of them were less than six months of age, but 50 were less than three months
of age. So age is definitely a risk factor for severe disease. And not all viruses are the same. You can see that this is
not the case for the non RSV cases. (06:51): What is very, very important is that the majority of these children that are
hospitalized in the first year of life are healthy. More than 70% of these children are previously healthy and do not have
any risk factors for severe disease. That's the importance of preventing the burden of the disease in the whole newborn population.
We analyzed also the risk factors in children one to five years of age. And as you can see in the slide, the proportion between
healthy and risk factors really flips. And in older children the majority has some risk factor, most of it was reactive airway
disease. (07:28): The burden of the disease, however, is much, much larger in the outpatient setting. This is a very nice
study conducted by the CDC where children were followed four or five years in the outpatient setting. And if you see in the
upper plot, they graphed the number of visits to the emergency department and underneath the pediatric offices visits. And
the peak of ED visits was around four months of age and in the PCP around six. So it's a little bit later compared to the
hospitalization peak. But what is very impressive to me isn't the bottom part. See, there is a peak, but it really doesn't
decrease. So the burden is continuous. So I think our pediatricians are going to be very happy when we have the interventions
up and running. (08:15): And lastly, and this is one of the most important points also, RSV is a major, major cause of mortality.
This landmark study that was published more than 10 years ago showed that is only second to malaria as the cause of mortality
in children less than one year of age. So this is a major priority to prevent mortality in low and middle income countries.
But the burden of the disease is not only limited to the acute infection, but many, many studies, including studies that were
done ourselves many years ago, have shown that there is a clear association between early RSV infection in the first year
of life and the development of recurring wheezing or asthma. (08:59): In this study that we published a couple of years ago,
we analyzed more than 250,000 children to determine whether having RSV in the first year of life was associated with the development
of recurring wheezing or asthma until year five. So these children, the study took over 16 years and it was based on insurance
claim data. So what we found was that indeed having had RSV compared to the group that was not hospitalized and didn't have
an RSV infection, those children that had RSV in year one, in the first year of life had an increased incidence and cumulative
incidence of recurring wheezing or asthma on year two, on year three, on year four, and on year five. And this incidence was
even greater in children under Medicaid, which is the public insurance in the United States. (09:53): Very important study
that was published a week ago and showed that not only severe disease. In those studies that I was mentioning, the RSV infection
was defined mostly by RSV bronchiolitis or RSV lower respiratory tract infection. This study that was published last week
showed that having had an RSV infection and most of these children were evaluated in the outpatient setting or not evaluated
at all but were diagnosed by an intense protocol by serology or PCR. Those children that had RSV in year one had an increased
risk of recurring wheezing the first couple of years and then it faded away. And this is actually, when I was reading the
study, this is what we see clinically. After RSV, most children will have a lot of recurring wheezing that is much more intense
the first couple of years. And they found that. In this study, this is a birth cohort, they enrolled more than 2000 children.
(10:47): But importantly, on year five, children that had an RSV infection, and as I said this was a very mild or some of
them asymptomatic, had an increased risk of asthma, 21% of them had asthma, especially non-atopic asthma compared to 16%.
So I think right now we are in the perfect situation with the interventions that Paolo is going to tell us to assess whether
preventing an RSV infection is going to also prevent or decrease the incidence of recurring wheezing and asthma. We saw those
results many, many years ago. I was a mousologist, I did a lot of mouse studies and showed that by using monoclonals as a
prevention, we were able also to prevent the long-term sequela. So I think this is what is going to happen in the near future.
(11:36): We've seen also during ESPID a lot of talks and a lot of data regarding the changes in epidemiology. So I'll go through
the data a little bit. This is our local epidemiology data at Nationwide Children's. It's in Columbus in Ohio, and this is
the second largest hospital in the country. And you can see that before the pandemic, the RSV seasons were predictable. We
have a peak every December, January and then it faded away. We waited until next season. And again, but these are hundreds
and hundreds of children. (12:07): In 2019, just before the pandemic, our season was really, really bad. We had more than
2000 children diagnosed with RSV infection. And we all know what happened. RSV disappeared because COVID came. But I wanted
you to pay attention to this summer season just before the pandemic because in that summer we had a lot of activity, a higher
level of activity for RSV, much higher than what was expected, more than 10%, 9%, 8%. And at the same time, in Minnesota,
a neighboring state, a new [inaudible 00:12:41] of RSV was identified that had some mutations in one of the other surface
proteins, in the SH protein. Of course now we don't know what could have had happened afterwards because we have all the implementation
of the non-pharmaceutical interventions because of COVID. But sometimes I wonder whether we were somehow already prone to
have an somehow off season circulation of RSV. (13:08): As I was saying, COVID came. So in 2020, no RSV anywhere. And in 2021,
this is again US data from our center. In May, 2021, the restrictions were totally lifted in the US and we started to see
RSV activity in June 27. That's when we declared the onset of the RSV epidemic. And the peak was in the summer, totally unexpected
and coincided with the delta wave. You can see we saw more than 6,000 children with delta and 2000 with RSV. Just notice that
the axes are different. These are in the hundreds and these are in the thousands. (13:46): This season, the 2021 season lasted
around six months. It was much longer than expected, but it went down. And then we had the second season in 2022 later. It
was shifted three months later. It started in September and it finished in January. A recent study from the CDC that was published
also two or three weeks ago just showed and suggest that based on the past two RSV seasons, the circulation of RSV is going
to go back on track. So hopefully by next season it'll be more similar to the previous ones. (14:23): But we were wondering
because we were seeing older children like everyone else. So what we decided to do is to compare the proportion of children
hospitalized according to age. In the pre-pandemic period, these are the compilation, the addition of six respiratory seasons,
more than 5,000 children. As you can see here, the proportion of children greater than six months to five years of age is
pretty similar. And the median age of that pre-pandemic season for hospitalized children was around five months. (14:59):
In the 2021 off season season of RSV, you can see that the proportion of children older than two years of age significantly
increased, it was 19% and the median age six months. So we saw an increase. And this increase, these trends continued to rise.
In the 2022 season the proportion of older their children was also higher, 23% with a median age overall of eight months.
And the main question was, are they sicker? Are they not sick? What we found was actually the children older than six months
when we are finishing analyzing this data because this is thousands and thousands of patients that we've reviewed manually.
But we found that children over six months of age were longer in the hospital, required mechanical ventilation, and had greater
rates of ICU care. (15:49): So it appears that especially one segment of the population, the older infant had a more severe
disease phenotype. You may wonder why, was this due to a different RSV strain that was circulating? There is recent data that
was released last week in the New England Journal and a group of Massachusetts in Boston sequenced a number of RSV strains
in the 2022 season and found that the predominant strain was RSV-A GA2. And that strain really was circulating before. So
it doesn't seem that this increase in severity is driven by a more virulent variant, but it's just probably a bigger pool
of naive children. (16:32): So my take also on this is that we've seen that age is a risk factor for severe disease, but definitely
a primary RSV infection also plays a very, very big role. This is a summary slide. I don't want you to read this, but it's
just to show you that this phenomenon has happened all around the world, in Australia, in Canada, in Brazil, in Portugal,
in Denmark. They've seen a shift in RSV seasons and an increased age in the onset of RSV for older children. (17:05): What
do we know about biological infections? Do they play a role? So we detect them, but we don't know what to do with them. And
I think we can do a better job. For many, many years we know that rhinovirus and adenovirus, they like to go with RSV. They're
the most common viral coinfection in children with RSV, and actually the endemic coronaviruses, there are four, they're the
third cause. They're responsible for around 10% of viral coinfections. But we never pay attention to them because we didn't
know what to do. And now they're becoming very, very relevant. And you will see why. On the other hand, coinfections with
RSV and [inaudible 00:17:42] flu are pretty uncommon. (17:45): So what happened with COVID? So what we did, and this is a
study in which the denominator is different, these are children with COVID that we analyzed in terms of the clinical phenotype
and the viral coinfections. And here the different variants were PCR sequenced. So it's not just based on the circulation.
And what we found in this study was that in children with COVID, it was frequent to detect rhino or adeno. They are always
there. However, the detection of other viruses such as RSV or influenza was lower and it coincided with the circulation of
these viruses in the community. (18:20): But going back to the RSV endemic coronaviruses paradigm, you see that here in the
2021 season, we have a lot of cases of COVID, more than 6,000 children infected with the delta variant. And more than 2000
children infected with RSV. So based on our previous knowledge with endemic coronaviruses, we were expecting a high rate of
RSV/COVID coinfections, but we didn't. We only found 2.6% of children that were coinfected. However, those children were sicker
somehow. And you will see in a minute some of the data. (18:59): Omicron came and as you know, Omicron replicates better in
the respiratory tract, behaves more in children like a regular respiratory virus. And during the coincidence between Omicron
and the second wave and the 2022 season of RSV, what we found was an increase in the proportion of children that were coinfected
but yet not as high as what we would've expected based on endemic coronaviruses, which is around 10%. So it went from 2% to
4%, still very low and yet very sick. (19:32): So what we did to characterize this clinical phenotype, we divided patients
in three major groups to assess who was playing a role. When we find these coinfections, chances are that children are not
infected at the same time with the two viruses, but probably they're infected with one virus and then the other virus comes
along. And it really depends how the first disrupts the immune response what is going to tip them over. So what we did here
divided the cohort in children based on viral loads in acute for both, for RSV and COVID, which was not the most common. The
most common were children with acute RSV. So they have high viral loads for RSV, but convalescent COVID. So the viral loads
for COVID were low compared to the other groups, the convalescent convalescent. But this group of children had acute RSV and
had COVID probably two or three weeks ago were by far the sickest ones, and these were previously healthy children. The rates
of ICU were high, 62%, mechanical ventilation 25% and length of stay pretty high too, more than six days. (20:36): So I always
question where this is a form of, I call it MISB as bronchiolitis suggesting that a prior COVID infection somehow disrupts
or alters immune response. So makes these children more prone to experience a more severe disease. How can we understand this
better? We've been using several biomarkers in the blood and lately also in the mucosa. This is a study that we need to finish
in which we looked at the global transcriptomic response in children with RSV that were hospitalized. So these are all sick
children. And here each column is a patient and each row is a transcript. (21:14): What you see in blue means that the genes
are suppressed and red that they are overexpressed. We divided the cohort into validation and derivation cohorts as we always
do, and what you can see, and as suspected, children with RSV have much higher expression of interferon and antiviral response
genes and suppression of B-cells. But we've been able to apply biomarkers, cytokines that are much more useful and with a
faster turnaround time. And we did these studies only with an NP swab. So with an NP swab you can measure the type of virus,
the viral loads, and also mucosal responses. (21:49): What did we find? So what we found was that children with mild disease,
and these are outpatients, children evaluated in the outpatient setting that did not require hospitalization, has significantly
higher concentrations of these two cytokines. This is IP10, which is an interferon inducible cytokine, and mucosal interferons,
interferon lambda. You can see that compared to the inpatients, the sicker patients, the patients have a much more robust
response. They were fighting the infection better. Does this apply to all viruses? It doesn't. Because in COVID sicker patients
is the opposite. They have higher concentration of the cytokines of IP10 and interferon lambda compared to screening patients,
meaning asymptomatic and to controls. (22:33): So in summary, we've seen that RSV is associated with significant morbidity,
mortality, and also long-term respiratory sequela. That the changes in seasonality resulting from COVID are significant with
a lot of variation, but it looks like next year it will be back on track. We've seen also the importance of viral testing
for surveillance, for diagnosis, and really to help us classify patients according to severity and the value of mucosal responses
to understand disease pathogenesis and also disease severity. And with that, I will give the podium to Paolo because he's
going to tell us the cure of RSV. He has them all in his talk. So thank you very much. Federico Martinon-Torres (23:18): Thank
you very much, Asuncion. So now we move on in this Medscape educational program on RSV with our nest speaker. He's Paolo Manzoni,
I already presented you him. He has been involved in several aspects of clinical research in RSV and recently also in the
clinical development of nirsevimab. So, Paolo, the floor is yours. Paolo Manzoni (23:39): Thank you, Federico, thank you,
Asuncion, soon for preceding me and it's a pleasure to be here and to move forward in this session with a few hints on the
current and future prevention strategies for RSV. We now have palivizumab as you know, but we can see now a brighter future
and probably a brighter immediate future with other monoclonals, vaccines and so on. And we'll take all these points starting
from very, I would say trivial considerations, very basic medicine consideration. We do need antibodies in order to prevent
upper respiratory tract infection by RSV becoming lower respiratory tract infections because once bronchiolitis is there,
antibodies are no more needed, are no more affected, but we need a cellular response. (24:38): So the point is to provide
antibodies in any way in the critical moment where a baby affected by a common rhinitis can progress to bronchiolitis. And
in this view we have data showing that there's already a transfer of antibodies from the pregnant mother to the child. A transfer
that somewhat prevents early inception of RSV whenever this transfer has been accomplished and available. And the evidence
shows that the more antibodies we have inherited from the mother, the more the baby can get defended in the first weeks of
life. (25:21): So this is a model to understand and to make us think that by providing antibodies early in life, we can prevent
the progression of the disease from rhinitis to bronchiolitis in the first months of life where the risk of severity is higher.
But unfortunately, as you see in this current overview of strategies available, we add only palivizumab, we've been adding
only palivizumab and only reserved for niche categories of high risk infants. Very recently nirsevimab came up providing an
additional opportunity and some others we'll add likely to these list of possible strategies in the next few years. (26:14):
But since we need to make a starting point in the area of prevention, let's take a look at the figures provided by the evidence
regarding the effectiveness of the monoclonal antibody in preventing RSV disease. We so far had only palivizumab and palivizumab
proved largely effective in preventing hospitalization by RSV based on this Cochrane systematic review and based also on the
most recent perspective, randomized clinical trial assessing the effectiveness of palivizumab in preventing not only hospitalization
but also episodes of bronchiolitis leading to medical attention but not necessary leading to hospitalization. (27:05): This
was the MEDLEY trial and the point of this trial has been confirmed by all historical cohort studies that are available and
most of all by all those studies reporting experiences of babies undergoing or not undergoing palivizumab prophylaxis due
to changes in the policies of administration. Whenever these studies have been performed, the ultimate message is always consistent.
If we administer a monoclonal, we do prevent effectively hospitalization. If we do not administer hospitalization, rise up
again. (27:48): So now we are in a situation where new perspectives can be available and in this cartoon you are shown all
the possible strategies and they are critical landmarks in order to understand what are we targeting and which mechanisms
of prevention or treatment are we using. I would focus our attention on the higher frame in this cartoon concerning the modalities
of action of the new monoclonals. But first of all, I want to sum up which are the weaknesses of the currently available monoclonals
before switching to the modern ones. (28:41): We all know that palivizumab is very expensive, but most of all has been always
reserved and authorized only to a very limited risk group of preterm infants or infants with comorbidities. As a whole, no
more than 5% of all babies born yearly can be eligible for palivizumab. So it's clearly a surrogate of prevention that cannot
be the only solution that we can have if we want to tackle prevention in a wider way. (29:23): And so coming back again to
the modalities of actions of the monoclonals, you see here that all of them target specific epitopes in the preF confirmation
of the profusion protein of the RSV. These sites are numbered from zero to six. Palivizumab targets site two, clesrovimab
site four, nirsevimab site zero. All of them look effective because all of them target sites that are generally conserved
and do not change very much over the years and over the confirmation. (30:14): Clesrovimab is the first one that I will draw
your attention to because it's late in development compared with nirsevimab but shares the same main characteristics, namely
a mutation in the FC region, a mutation called YTE that is able to extend half-life up to 80 days. This means an incredible
progression in the ability to cover RSV prevention for more than one month, but probably for all the epidemic season. (30:57):
The pipeline of research of this monoclonal includes a study comparing effectiveness of this product versus placebo in preterm
infants otherwise eligible for palivizumab and full term infants, but also a study assessing in a non-inferiority design the
ability of this monoclonal to be at least as effective as palivizumab in babies eligible for this drug. At the end of this
pipeline of research, likely in two years from now, we'll probably have a new product being able to tackle prevention in a
widespread way. But luckily we are two years ahead with nirsevimab having been completed very recently all the pipeline of
research and related publication covering safety and effectiveness based on the evidence in both preterm infants otherwise
eligible for palivizumab and in term infants not eligible for palivizumab and in categories of infants with high risk due
to underlying morbidity like CLD patients of critical congenital cardiac disease patients. (32:27): The whole of the data
from these three studies that I will show you in detail later on confirm not only efficacy but also safety and make nirsevimab
ready to be used in a widespread way differently from palivizumab once more that were reserved only for a category of high
risk group infants. (32:54): The first main trial that paved the way to nirsevimab pipeline of research was this one published
almost three years ago where in a design of a study that was mimicking the first palivizumab authorization trial, some 1500
preterm infants otherwise ineligible for a synergist due to the current, at that time, guidelines were enrolled and randomized
in a two-to-one fashion to nirsevimab or placebo targeting as a key endpoint the incidence of hospitalization and the incidence
of medically attended lower respiratory tract infections during the first 150 days after dosing. (33:48): In order to comply
with this design, it was needed to convene and to agree on a predefined definition of lower respiratory tract infection. And
this definition that was used for this study has become a model that will be a standard reference for all studies that will
be further performed in this area. Efficacy was very high and was spent equally towards the two RSV strains, A and B, without
development of anti-drug antibodies and with no safety signals. Medically attended lower respiratory infections were decreased
by 70%, whereas hospitalizations were decreased by 78%. (34:49): Importantly, there was no evidence of replacement by other
respiratory pathogens. In other words, the place left vacant by RSV was not taken by other respiratory viruses. And this was
very important because if we think to use widespread these kind of products, we need to know that no dangerous epidemiological
shift might occur in the future. Safety was absolutely reassuring, and if we compare the two authorization trials for palivizumab
in 1998 and 20 years later for nirsevimab, we can see a greater strength of this nirsevimab data because this data come now
from 23 different countries equally distributed in the two hemispheres. Whereas the palivizumab study was conducted only in
UK, Canada, and US, only in the Northern hemisphere and in preterm infants belonging only to settings where a specific approach
to prematurity is taken. (36:13): So reliability of this recent data, in my opinion as a neonatologist, is far greater than
what it used to be for palivizumab. In addition, the second big study on nirsevimab addressed efficacy in healthy late preterm,
beyond 35 weeks of gestational age, and term infants. Again versus placebo and again recruiting some 1500 infants. Once more
the two main outcomes were the same as the previous one. This study was hampered by the occurrence of the COVID pandemic and
so recruitment slowed down during the lockdown and the pandemic period, but nonetheless provided very significant data that
were published in the New England one year ago showing an important decrease in all outcomes that were targeted. (37:12):
Completion of the study after the COVID period was able to provide the ultimate results vouching for a 75% rough decrease
in medically attended lower respiratory tract infections, in hospitalization, and also in NICU or ICU admissions. Once more
safety profile was absolutely reassuring. And as such, this data provides clear evidence that one single shot of this product
is able to cover the whole epidemic season. Clearly we can have better compliance, we'll likely have reduced cost because
it's likely that this product will cost much less than palivizumab, at least I wish so. (38:07): There's a potential that
is revolutionary to be addressed for all in season infants and for possibly most infants born outside season. At the very
least, those with the highest risk even in the second semester of life. Efficacy is equal in preventing not only hospitalization
but also medically attended bronchiolitis. And this makes things much more meaningful because we are covering and targeting
settings that may have different approaches and attitudes towards hospitalization and management of bronchiolitis. (38:49):
Future scenario for this product is to be the first new actor on the scene. And my wish is that others will let clesrovimab
as the potential to add in the next future years in order to go beyond a regime of monopoly that has been the one in which
neonatologists like myself have been struggling over the last 20 years with one single product being available only for few
infants that we were challenged to choose and to pick up somewhat arbitrarily among all our patients. (39:37): But there's
not only monoclonal antibodies, there's also vaccines in development and production. The point of vaccines, I will be quick
in this brief summary, is not easy to perform because historically there have been failures, there have been disasters. Several
issues are related to providing and developing a vaccine for RSV in infants, in children, in pregnant mothers, in elderly.
Professor Martinon-Torres is a world renowned expert in this. So I will not invade very much his era of expertise. I will
only show you this cartoon detailing how many differences and nuances need to be foreseen, addressed, and responded when designing
a vaccine for different categories of patients. (40:47): But as for concerns for me as an neonatologist and for many of you
dealing with neonates and young infants, we now have these very recent results published by [inaudible 00:41:04] Beta Keman
one month ago in the New England Journal of Medicine showing efficacy and safety of this product, this vaccine provided to
pregnant mothers in the third trimester of pregnancy. This was a phase three double-blind trial conducted in 18 countries
with almost 4,000 pregnant women receiving this RSV preF vaccine versus placebo. Efficacy was beyond 80% preventing. As for
concerns, prevention of RSV medically attended episodes in the infants in the first 90 days after birth. (41:53): Efficacy
lowered a little bit down to 79% when considering this outcome at six months of life. But as a whole, these studies showed
for the first time full and significant efficacy of a maternal vaccine in preventing severe cases of bronchiolitis in the
infants in the first three to six months of life. So this strategy will become available soon, will add to the possible portfolio
of opportunities that we as physicians have to prevent RSV and additional options will add to this evolving list in the next
future years. (42:51): In conclusion, as for vaccines, maternal vaccination is already there, is already a possibility. There
will be the opportunity of very comprehensive discussions about the strategy, about the identification of groups of mothers
of infants being eligible or being more indicated to receive a vaccination or monoclonals or both. Let's not forget that active
vaccination in infants is a under development and this will be an opportunity for children older than six months and this
will likely add as an additional strategy to decrease the burden of circulation along with active vaccination in the elderly.
Elderly very often mix and mess with infants. So reduction of circulation provided by early vaccines will be an additional
tool to improve the cocooning effect and improve our ability to prevent. Thank you very much for your attention and I leave
the floor to my chairman here to go on with the session. Federico Martinon-Torres (44:10): Thank you, Paolo. We are going
to start the discussion, but before I would like to ask you again the same question just to see something change and to see
finally the results. And while you please answer the question and while we wait for your answers, just to remind you, although
we have received already plenty of questions, but if you have questions either from home or here, just use the Medscape question
and answer system to send us any questions you might have. (44:45): So the question is the same and we will see now the results
and the comparison with the starting point. As we wait for these results, I think we can open the discussion because there
are several interesting questions. I don't know if this is the first. I suppose. So most people is knowledgeable, which is
good. And I don't know if this is the first time they answered. Okay, here you can see the difference. Well, more or less
the same. Some people moved from slightly to moderate, which is an achievement. (45:22): Okay, thank you for the participation
in this poll. So there's several interesting questions. I will start with one simple one for both of you. Monoclonal antibodies
or maternal immunization? It's a repeated question in the chat and you have 30 seconds. We cannot have all the day discussing
that. Your views on that? Asuncion Mejias (45:43): Go first, Paolo. Paolo Manzoni (45:46): Ladies first please. Asuncion Mejias
(45:48): Well, I think that they're complementary and have we seen during this meeting the rates of maternal vaccination really
varies between countries. So there is a chance that moms will get vaccinated, but a significant proportion of them will not.
So we need to have another strategy to prevent these babies. You cannot compare head-to-head studies because they were different
and they both have advantages and disadvantages. The monoclonals have a very prolonged half-life vaccines induced polyclonal
responses. So I think we are in an extremely amazing situation right now and we're finally going to be able to prevent RSV,
which is unheard of. So it's going to change the way we manage these patients. So I think they're complementary. Federico
Martinon-Torres (46:32): Paolo? Paolo Manzoni (46:36): My first target and my first vision is to have as many antibodies as
we can to be delivered to the baby, to the young infant. So whether this infant receives antibodies from the mother or externally
with the monoclonal, it's not important for me. It's important to deliver to him. And in this view, if we have uncertainties
about the amount of antibodies needed to achieve full protection, let's give both. Or at the very least, let's not exclude
that a baby born from a vaccinated mother is not eligible to receive also monoclonals. There's a lot of strategies that we
can think about. We are just at the beginning of a process where the best possible strategies need to be still identified.
Asuncion Mejias (47:33): Well- Federico Martinon-Torres (47:34): I love to disagree. Asuncion Mejias (47:35): Sorry. Federico
Martinon-Torres (47:36): No, no, I love to disagree in the sense that what you say is not feasible. No country can afford
two simultaneous programs and doing maternal immunization AND monoclonals. The cost, it's unaffordable. Theoretically it might
work, but I don't see that might happen. How do you see that could happen? Paolo Manzoni (48:00): I like the discussion because
it's like the discussion I have with my general manager. That is you think to money and I think to science and to prevention
in my patients. I would like as a clinician as a vision to focus only on the ability to prevent and then to leave to the payers
the burning question about which strategies can I afford? This is a different point, I agree with you obviously in that this
probably will not be affordable, but I think that as a scientist and physician, we would need to provide payers a clear picture
of what is helpful for our patients and then possibly provide advice if they ask us choose A or B. But in principle it'll
be not me choosing A or B based on budget reasons. Asuncion Mejias (49:02): But still, I think at the end of the day, a major
driver to decide if we're going to use vaccines, monoclonals, or both is going to be the cost. Because it's unsustainable
to use, in my opinion, to use both. So it'll be driven by cost because both products have shown a really good profile, but
having both in the same situation I think is going to be challenging. Paolo Manzoni (49:28): But may I go on, Federico? Federico
Martinon-Torres (49:32): No, because we have several questions we want to bring some of them in. Another question we have
is regarding palivizumab. You mentioned the role in palivizumab, now that we already have next-generation more potent monoclonal
antibodies and upcoming maternal vaccines. Do you see any use of palivizumab anymore or do you think that with the new possibilities
available this will be, well, an option in those countries that won't have any of these new alternatives? So who is first?
Paolo Manzoni (50:11): I'll take it. I think that as for the moment, the bulk of evidence in favor of palivizumab below 29
weekers and in bronchopulmonary dysplasia babies and critical congenital heart disease is still greater than the evidence
shown for nirsevimab. So at this stage, I would say today I still see palivizumab as preferable, or at the very least as indicated,
because besides having the evidence, we need to have society recommendations. And society recommendations still do not include
nirsevimab for below 29 weekers or for these categories. Probably they will include shortly after. But waiting for that, I
see still a room for palivizumab. Federico Martinon-Torres (51:09): You're provoking me, Paolo, all the time. I will leave
because I don't think the same, but I will first listen to ... Asuncion Mejias (51:18): I also agree to disagree. I think
once we have the phase 2B, the head-to-head comparison with nirsevimab and palivizumab, the profile is very good. And in my
mind, once we have the compound, we have the efficacy data, it's going to, in my mind, substitute palivizumab. It's going
to be less costly to bring these children once a month to give a shot with another drug that has an amazing profile and a
very long half-life. We've been using palivizumab all this time at the same dose that other children were using. So in my
opinion, once we have up and running nirsevimab, palivizumab is going to be an obsolete, it's not going to be used that much.
Paolo Manzoni (52:03): But I tell you- Federico Martinon-Torres (52:03): I'm on her side. Just to give you a concrete example,
me and Alicia, we were going to start nirsevimab, we are only going to use nirsevimab in both the healthy infants and all
the high risk groups. It makes no sense even for a same eventual impact. That is not according to the numbers we have, but
let's assume they could do the same. It's much costly to do it with palivizumab than with nirsevimab. So I don't see the point
once you have that approved to still use it because the cost is unaffordable plus five injections to the preterm as compared
to one. So even from an acceptance perspective, I think it'll be easier. But today you and me are fighting all the time. Paolo
Manzoni (52:49): The point that I'm raising is that in neonatology, especially with premature infants, we are very sticking
and compliant with the societal recommendations. So an accessory step is that these new products are included in the society
recommendations because [inaudible 00:53:09] paves the way also to reimbursement, at least in Italy or in several other countries.
So I absolutely agree that we'll arrive to a moment where nirsevimab will be administered widespread, but I don't see it occurring
tomorrow. I see it occurring in some time that probably are those needed for these steps to be accomplished. Federico Martinon-Torres
(53:33): More questions we have. One is related to ... You both can say, but you were already mentioning that we will have
a normalized decision this year. It's very easy. Asuncion Mejias (53:44): Yeah, super. I have my crystal ball. No, I think
based on what we've seen in the past two seasons, we are getting back toward normal seasonality and the CDC data shows that,
our previous season in the US shows that. So we may be a little bit off, but I think we are getting there. And this happened
also with the influenza pandemic in 2009. For two years in a row we were off season and somehow the viruses got back to the
normal behavior, if you will. So I think this year we'll be much closer if not normal. And the following one for sure. So
we are getting there. Federico Martinon-Torres (54:23): You already have Asuncion's forecast for next year. So you cannot
deny, it's recorded. We all know what she said. Not to put pressure on you. So there are more questions about the role of
either monoclonal antibodies or maternal immunization on the mid and long-term impact morbidity, let's say within infant asthma.
What are your expectations in that regard? Because we don't have data of course. Asuncion Mejias (54:46): Well, I think as
[inaudible 00:54:49] said, the best pneumococcal vaccine is an RSV intervention. It's going to prevent the most common coinfections
or infections in children with RSV or otitis media and pneumonia. 60% of these children currently develop an ear infection
and the most common cause is pneumococcus. So when we prevent RSV, I think it's going to change the way we manage these children
from the acute perspective and the subsequent development of bacterial complications to the long-term sequela and wheezing.
The study that was just published in the Lancet, it showed that clear association, and this was really, really mild RSV infection,
between RSV and long-term wheezing. In the animal models we showed many, many years ago that by preventing RSV infection you
could prevent the long-term sequela. And Bubont also showed that effect in the first year of life in premature infants. I
think with these new generation monoclonals and vaccines, by preventing RSV infections, severe RSV infection, we're going
to prevent a lot of the long-term sequela. Paolo Manzoni (55:52): I agree. The point will be to understand whether these monoclonals
besides changing the whole epidemiologic scenario, will be able to modify the natural history of health and the natural history
of respiratory health of those infants who will be receiving these antibodies. This is the ultimate goal and the ultimate
challenge. And I'm very confident that something very good will happen with this. Asuncion Mejias (56:25): Yeah, and to me
also- Federico Martinon-Torres (56:26): No, no, no. You have 10 seconds. Asuncion Mejias (56:29): Thank you. Thank you. The
beauty is that the monoclonals and the vaccines have shown to prevent lower respiratory tract infection, not only hospitalization.
And more than 30% of outpatient visits are because of LRTI. So we're going to be able to see a reduction in those visits to
the pediatrician. So I think we're going to be in a totally different paradigm. Federico Martinon-Torres (56:51): There are
more questions than we can actually handle for the time being. But I want to remind the people that is online, the discussion
will follow on with the chairing of Alexander, Kenneth. So they will try to address those questions and others. Before finishing,
there are several other questions, but I would like to also make a wish because it's a question that has no answer and it's
not been the first time it has been said during these days. (57:23): Today Sabin Mario already raised that aloud and said
it clearly that we have now a unique opportunity to really deal with RSV, but we should not forget where are the children
dying from RSV. So we have to work altogether to make these solutions available in those countries where the true priority
is mortality. Not meaning that our burden in the, let's say better or more privileged countries in terms of development is
not important. But indeed we have to make a huge effort. Now we have solid solutions to make available for those countries
indeed. (58:05): So my concluding remarks are simple, RSV is indeed an important burden of disease. Again, not only death
but also short and long-term morbidity. And I think that this before and after, with the possibility of the monoclonal antibodies
we have seen today, the new results of the nirsevimab just presented on the HARMONY study, real life conditions reassuring
again the same point estimates in the clinical development. We have seen the recent phase three trials of maternal immunization.
So we are really in a new era in terms of RSV prevention and I think we are all privileged to see and to witness and hopefully
to see soon the results of their implementation and to see how this actually saves lives and prevents this burden of disease.
(59:00): So I only want to thank you all once more for attending this session. I would like to thank also Medscape team, Medscape
also on site and online for making this possible and allowing us to enjoy this space and to remind all the people at home
that they can still be connected. And well looking forward to seeing you in other Medscape educational activities. Thank you
very much for your attention and for those still here, if you want any additional comment we'll be available for you. Thank
you very much. Asuncion Mejias (59:33): Thank you. Thanks so much.
