Episode 244: #57-1 RSV

The Virtual Curbside is a production of the Utah Chapter of the American Academy of Pediatrics, the Utah AAP, working together to improve children's lives through education, advocacy, and networking. Hi, this is Paul Workus from the Utah AAP. Welcome to this week's edition of the Virtual Curbside, where we bring pediatric providers together with subspecialists to get smarter about all things pediatric and better acquainted as a community of caregivers.

The virtual curbside is brought to you in part by a generous grant from Primary Children's Hospital. Primary Children's Hospital, the child first and always. Welcome back to the Virtual Curbside. We're very fortunate this month to be able to talk about infectious diseases. And for today's episode, to have back with us Dr. Andy Pavia. Welcome back, Andy. Oh, thanks for having me back. It's great to be here. Last time we talked was right in the middle of COVID.

And it's interesting because I was reading a novel a couple of weeks ago that was set during COVID, and it was really disorienting in a way to be reminded of what a different world that was. It was a very strange time. You know, during COVID, I actually read books like The Plague and Love in the Time of Cholera just to historically how people have dealt with this before us. Absolutely. And, you know, I'm not sure.

I'm not sure I can give us an A plus for how we dealt with it as a society, but we definitely dealt with it. We did. And, you know, we did a lot of things wrong. We did a lot of things right. I do worry that we're not spending enough time trying to make sure we've learned our lessons and that we're going to do better next time. But that's probably a subject for different hours discussion.

Right. And a spoiler, next week, we're going to talk a little bit about the state of the art with COVID right now. This week, we want to talk about RSV. Before we start, are there any conflicts you should disclose? Yeah, I did do a consultation for Sanofi, which is the co-marketer of Nurse Evumat that we're going to talk about today. I've also done some work on influenza with GlaxoSmithKline, and I'm an editor of the Sanford Guide, so I get royalties from that.

Excellent. Well, let's dive right into it. It's interesting because when I was a medical student, I remember that I learned a lot about a lot of viruses and bacteria, and when I arrived for my pediatric clerkship, the senior resident said, what do you know about RSV? And I had nothing but a blank look, because I think in context, it doesn't often, or at least in the time when I...

trained. It didn't often come up as something that was hugely historically important, but it's very important in both the lives of providers and of the children they take care of. Why is that?

Well, it's a really prevalent virus that in certain groups causes a lot of serious disease. Nowadays, when you mention RSV and you get a blank book, it's coming from an internist. because we're beginning to appreciate how much disease occurs in older adults. But if we think about kids, most pediatricians are pretty familiar with it.

But it causes a huge number of hospitalizations, 60,000 to 80,000 a year translates to about 1,000 in Utah. Most of the hospitalizations occur in the first year of life, the majority. in the first six months of life. On top of that, you've got another 150,000 kids who end up in emergency departments and probably about a million and a half end up in the doctor's office.

You know, it generates business. These are miserable kids. This overwhelms emergency departments. It overwhelms doctors' offices. And for parents, you know, it's a disease where your kids aren't able to breathe. They are not eating. We've all seen this. And it's kind of terrifying as an experienced doctor and extremely terrifying as a parent. Right. What is it about RSV that makes it more invasive? Well, it's not invasive in the traditional sense. It doesn't.

get into the bloodstream. It doesn't cause damage deep in the lungs in most people. But in young children, it causes this, you know, tremendous inflammation in the airways with lots of secretions that we've all suctioned out of kids' nose. Given the small airways of infants, that leads to obstruction of the airways and the classic bronchiolitis symptoms. And it equally importantly makes it really difficult for them to eat.

Kids with RSV typically can't breastfeed or bottle feed for a while, and that's often what ends them up in the hospital. Yeah, it's interesting when you talk to parents that one of the main things that comes up is hydration status. And, you know, it's just from intake, not from increased output. Do people get reinfected with RSV?

Well, that's the interesting thing about RSV. We get infected throughout our lives. Nobody knows how many times you like to have an RSV infection. You and I as pediatricians, it's probably in the half dozen to dozens. But once you develop partial immunity with your...

first infection, second and third, it becomes a milder and milder illness. So we probably get infected if we're not careful during the winter taking care of sick kids and barely know it. You know, you get a little bit of runny your nose in the morning. But then as your immunity wanes later in adulthood, in your 60s, 70s, and 80s, it becomes a very serious disease again. Now, the good news is that we've understood a lot more about how to tweak immunity.

Because the virus itself kind of hides the portion of the virus that induces the most effective antibodies, which is the prefusion confirmation of the F protein, the protein that it uses to attach.

and enter cells so when we're looking at changing the course of history with rsv are we trying to prevent disease are we trying to ameliorate the severity of the disease or both Both, I think, right? I mean, the end result is we want kids to be healthier. You know, if they have a, we can go from being hospitalized to having a mild disease that can be handled with a little bit of suction and some attention to hydration.

That's great if we can prevent the doctor's visit and the multiple visits to the suction shack to keep your airway clear. That's great. But, you know, when we get to talking about how. the monoclonal antibodies work on infants and how the vaccines work on adults, we really look at lower respiratory tract disease. That is disease that manifests itself as cough, shortness of breath, low oxygen level.

And that's where we've seen really nice benefits. So we've gotten fairly good at, I think, at least trying to understand how to help with the symptoms of RSV and try to keep the kids safe while they... work through it themselves. We're talking at the end of August right now. This launches in September of 2023. And there's a lot in the news right now about RSV.

both for infants and for adults. So let's talk about some of those things. And I wanted to start by talking about the product we've been using for RSV the past few years, and that's palivizumab. What is palivizumab? And what has it done? And then why are we ready to move on from Pelavizumab? The palavizumab is a first-generation monoclonal antibody. It was raised against RSV, but without a great understanding of exactly which antibodies were optimal to develop.

It is, as a first-generation immunoclonal antibody, has a pretty short half-life. It has to be given monthly to have any impact. And in a very high risk population of kids where it was studied, that is kids mostly with prematurity leading to severe lung disease or congenital heart disease. it reduced the incidence of hospitalization by about 55%. So not a bad benefit, but it required monthly infusions. It costs between $1,000 and $2,000 per infusion.

So very expensive for the benefit that we're getting out of it. And because of the cost to the benefit, we really tried to restrict it to the kids in whom it would do the most good. We couldn't conceive of bringing in. otherwise healthy children to spend $2,000 a month on giving them a drug that would reduce their chance of hospitalization that was starting out quite a bit lower, you know, about 2% of healthy kids.

will be hospitalized in their first year of life or have an ED visit, RSV. That's a lot. But to reduce that by 55% at a cost of $6,000 or... $8,000 an infant, you know, was a non-starter. Well, the other difficulty there, obviously, too, is that you sort of had to have your ear to the ground about when the RSV season is starting.

so that you can decide when to start and then when to stop. And then you're negotiating for whoever the payer is to make sure that it gets reimbursed through that whole time. Yeah, and I'm sure many of our listeners have spent too many hours on the phone with payers trying to get coverage.

percentages for their high-risk kids because the criteria are fairly strict and the payers didn't see it as a huge benefit and a big cost. So they were fairly cautious about approval. And hopefully that's a thing of the past.

As we go further into the newer drugs, we'll see that there still may be some issues. I think we all have a little bit of memory of the intricacy of the applications that you have to fill out. Not easy and a lot of work. Well, so now nircevimab has been approved, correct? Correct. It's been approved and has gotten its ACIP recommendation for all infants in their first year of life.

Maybe before we talk about that, could you explain to us the role of the FDA, the ACIP, and payers in this all coming together? Yeah, this is... It reveals some of the complexity of our American healthcare system, such as it is. So the FDA reviews drugs for safety and efficacy, and it does not really... think about optimal usage from a public health point of view, it reviews the data that are brought before it. So the studies include a certain population, the manufacturer requests approval.

for that population. The FDA decides whether there's reasonable proof of efficacy and whether the safety means that the benefits significantly outweigh the harms. So that's step one. ACIP, the Advisory Committee on Immunization Practice, is a committee that is hosted by the CDC that develops recommendations on how to use a drug or a vaccine, mostly vaccines.

These are pretty detailed recommendations that try and give us as clinicians real guideposts about who would benefit, when not to use it, when to use it. what the contraindications are, what the side effects to look out for are. And the ACIP is a pretty broad panel. Not everyone is an expert in every subject.

Their recommendations are not binding. They go to the director of CDC, who usually then approves those recommendations. Now, then the fun really starts. Because when a vaccine is recommended by the ACIP, since the passage of the ACA, it has to be covered by all payers. And so if you have insurance, a vaccine recommended by the ACIP for you will be covered. But that doesn't apply to drugs.

And a monoclonal antibody is mostly treated as a drug. And it doesn't apply if the recommendation is a softer recommendation, like may consider or joint decision making. Then it becomes up to the payer. to pay for it. Now, we should also always keep in mind that, you know, still some 20% of American children don't have insurance. And so luckily, Congress passed one of its really

Signal Achievement is the Vaccine for Children's Act that provides a program that provides vaccine to children regardless of insurance. It used to help out when the insurance was there but didn't pay for it. Now mostly it pays for kids who have no insurance. That's a huge step, right? Yeah, that was really a landmark. Now, the pediatricians listening to this will know that VFC is a little bit of a double-edged sword because there are some bureaucratic requirements that make it...

you know, a little bit more difficult than just purchasing the vaccine, putting in your fridge and giving it. But I think virtually everyone says the net benefit of having the VFC program is well worth it. And I suppose I ought to put my hand on my heart and reiterate, you just mentioned two great things that got done at the federal level. One is, as you mentioned, VFC. The other thing is, is that before the passage of ACA...

Something being recommended didn't necessarily mean it was going to be paid for, and the gap was often very significant. It was, and it was really preventive measures that got short shrift. If you think about it from an insurer's point of view, they're in the...

business of making money if they're going to spend money on prevention they want to see the benefit at the other end and because people change jobs and change insurance many insurance companies decided i'm not going to pay for a prevention benefit that your insurance company is going to reap, not mine. So the ACA got rid of that particular wrinkle of our system. And a good thing that is. Now, you touched on something because even the CDC refers to nursevimab.

as an immunization. I guess in the strictest sense it is because it's providing immunity, though it's passive rather than active. Is that partly so that it's easier for people to wrap their heads around the importance of this? It is. I think that when we're talking to parents, it's sort of hard to talk about active immunity and passive immunity. That's taking them back to first year of med school. And it's not that difficult to explain pre-made antibodies versus giving you something that...

stimulates your body to make antibodies. But, you know, it's a step. The other reason that ACIP recommended that to the extent that legally possible, we treat nercevumab as a vaccine is that provides... a number of things it meant that vfc could help pay for it for kids who don't have insurance it also means that the vaccine injury compensation act will kick in so if it does turn out that there are very rare severe injuries

there can be no fault insurance for that through the VICP. So what are the advantages of nircevimab? I think you touched on them, but what are the advantages of nircevimab over pelivizumab? Yeah. So let me start by being just a little bit nerdy because, you know, I love viruses. So in what will someday be Nobel Prize winning work, Barney Graham and his team at the NIH were really discovered what.

the target is on RSV that allows for effective immunity. And that is this F protein or fusion protein in one particular conformation, the pre-fusion conformation. That prefusion confirmation is not extremely visible to the immune system because there isn't circulating virus in the bloodstream. What they did was they were able to stabilize this prefusion confirmation.

then start to raise antibodies to it and make vaccines with it. Once the virus touches a cell, the fusion protein changes shape and goes into its post-fusion conformation, and antibodies against that really don't work terribly well. So nursevimab has several advantages. The biggest one is that advances in the production monoclonal antibodies have allowed it to have a very long half-life.

So the half-life is in the range of two and a half months. And so a single injection provides therapeutic levels for five to six months, maybe longer in some people. So that's great. One shot does it for the entire RSV season. The second advantage is because it was specifically raised against the pre-F confirmation, it is more effective. So if you had about a 55% reduction against hospitalization.

in a very high risk group that was likely to get hospitalized. With nercepimab, you have a 78% reduction in the risk of hospitalization in otherwise healthy infants who have a lower risk of hospitalizations. Although it's not a head-to-head comparison, this clearly appears to be substantially more effective. And that's huge. And if that was nerdy, it was still very nicely explained. I followed that very well.

Now, this is a brief aside. Is there a risk with RSV as with COVID, as with influenza, of significant mutation over time changing any of this? RSV is a relatively stable virus. There are two types, RSV A and B. And we've begun in the last couple of years to do a lot more sequencing and study it in more detail. And in any given year, there are very small immunologic changes in it.

It's really shifting back from A to B that allows us to have high years and low years. That said, it's, you know, the only selective pressure on the virus has been from the human immune system. And that's not really driven a lot of changes. It's certainly possible that when we apply a really strong selective pressure, the virus will find a way around it. The general thought is that the targeted regions are not prone to as much variability as we see in COVID, where the spike protein...

can change a lot and still bind very, very well. And of course, flu not only mutates a lot and changes its neuraminidase and its hemagglutinin, but it can bring in new genes from elsewhere. It can bring in a pig gene and a duck gene and a whale and a dog flu gene. And it gives flu basically superpowers to evade our immune system. Yeah, that's not good.

A couple of more things about undersevimab then. Is the reason that it is less expensive, which is very significant in this conversation, is that technologic? Is that just purely a business thing? Do you know? I don't know the answer to that. I wish I did. I do know from a friend who works in the industry that the technology production has improved dramatically. But, you know, like all things about drug pricing, it is a mystery that has not been revealed to us.

And as with sausage making, there may be some things we don't want to know. So as of end of August, as the ACIP has recommended this, There are a lot of people mobilizing to try to make this happen, but things do look promising, right? With the recommendation and the adoption by the CDC that, explain to me who's supposed to get this. And when? So the recommendation is basically we want to protect all infants during their first RSV season. And, you know, RSV season in Utah is pretty predictable.

in the pre-COVID years, ran from December to March or April, and really was intense for about eight to 12 weeks and then faded away. So you really are only exposed to one bad RSV season in your first year of life when you are very... vulnerable to it. For practical purposes, that means for infants born between October and March, their first RSV season.

is already happening. So they should get the vaccine, and I just referred to it as vaccine, but they should get nercephalumab at birth or as close to birth. So the recommendation is in the birthing hospital or at the first visit to their provider. For infants who were born earlier, they're going to be exposed to their first RSV season in that year. So infants born April through September, in this case, that would be, say, in 2023.

will want to get the drug in September or October. And we expect it to become available in the next two to three weeks. Although, of course, as we sit here just before Labor Day weekend, there's some uncertainty. And what could possibly go wrong with the supply chain these days? Well, I think the supply chain is not likely to be the problem here. I think where we're going to have, you know, the biggest challenges is figuring out.

who's going to pay and where we're going to give it. And let me elaborate on that a little bit. So the ideal way to do this and the way to put the least burden on pediatrician's office would be to do it in the birth hospital, the way we give hepatitis B vaccine. and if necessary, HBIG. Those are pretty cheap. You know, it's 30 to 40 bucks for hepatitis B vaccine. A normal healthy birth is paid for as a set amount under DRG.

And so the hospitals are willing to throw in a $40 vaccine for free, and they still do okay on the DRG. Now, the list price that we've seen from one of the suppliers is about $480 for a dose of Nersevumab. And that's going to be a lot more difficult for hospitals to absorb as a cost unless the DRG can be increased to encounter that. So we're working on that problem for Utah right now. We've got some meetings tomorrow and we'll see what we can.

do here in Utah about that. It may vary by insurer. It may be that the bigger integrated insurers like Select Health and Kaiser will add the payment to the birth. visit and give it at birth, but the other commercial insurers may not. And in this instance, where private providers or providers outside the hospital are not usually working under the constraints of a DRG, you would expect that the payment is probably simpler to calculate there.

It should be very similar to other drugs or vaccines that you give in your office in the sense that you'll get reimbursed for the cost. And it may be some degree of cost plus, I'm not sure. And there'll be an administration fee that will be provided. And the actual administration is not much more difficult than a vaccine. It's a single intramuscular injection can be given by an MA, an RN, or God forbid, a doctor can do it himself.

Although you would rather have an experienced nurse give your baby a shot than have me do it. But then the question is going to be, will all insurers be ready to cover it in the next two weeks? patient shows up in your office with their baby who was born in May and wants to get a dose of nersevumab, do they know for sure that at Narglucross or whoever is going to reimburse?

them for it. And that's one of the unknowns right now. I do have some inside information from Select Health that they are planning to cover it right away. But I don't have inside information from the other big payers. I like to think they'll all do the right thing as quickly as can happen in a big corporation. Right.

It is challenging timing, I think, trying to pull this all together in a few weeks. So, Andy, one of the difficulties, especially with this evolving so close to the time that we need to start giving it, is it's a huge... economic concern, I think, for anyone who needs to provide the vaccine. And it's especially concerning for small practices who, at $500 a dose, that's a large...

financial investment, and potentially a large financial risk. Any advice as to how to approach that? Yeah. So I think that the company is going to de-risk it. That is... they'll provide some sort of buyback as they do for flu vaccine. But you still have to come up with money and float it for five months, which could be enormous and really beyond the means of some practices.

The state health department is working with the county health departments to come up with an alternative. And we know so far that the big health departments across the Wasatch Front are going to provide nircevimab. So small practices that aren't able to. keep it in stock this year, will have a place to send their kids. Inconvenient for the parents. Obviously, you'd like to give it to them in their medical home. But it's such an important drug, I think, that this is a good...

alternative that is going to be feasible given the finances. Yeah, that's great to know.

Part of what confuses this issue right now is that we're also, as you alluded to earlier, now concerned about RSV in adults of a certain age. And so along with the discussion of nursevimab, we're also hearing a lot about an RSV that... vaccine. Now that is licensed for whom? So there are actually two RSV vaccines. One, I don't remember the trade names. They're sort of cute. And so they slip out of my mind, but they're very similar.

One is made by Pfizer and one is made by GlaxoSmithKline. They're both a single dose. The GlaxoSmithKline has an adjuvant in it, so it gives slightly sore arms, but perhaps will work better in older people and last longer. We don't know yet. So anyway, we have these two very effective vaccines, more than 80% effective at preventing low respiratory tract disease in people 60 and up. The indication so far is for anyone who is 60 years and older.

Now, this gets to be a little fun. The expert working group at ACIP strongly recommended that everyone over 65, that they give a recommendation. which would mean that it's covered. It's expected for everyone, just like pneumococcal vaccine for people 60 and up. But there were a few people on the working group who were concerned that they didn't know the price, that they...

didn't have enough information on how well it worked in people 80 and up because they weren't included in the trials. And they voted to give it a sort of softer recommendation, which is maybe given. with joint decision-making with your provider. Now, I think that the data strongly support a universal recommendation for 65 and up. And the Brits, who are much more cost-conscious,

gave it a strong recommendation for everyone 75 and up. But we'll see what happens with ASAP. The bigger problem with that is it means that it will now not be automatically covered. And it will depend on your insurance coverage as an older person. The part that as pediatricians, we are really interested in is the other use of the vaccine. So it was studied.

by giving a dose to pregnant women in their third trimester. And it was found that it provided really good protection against RSV in the mid-75% range for the first three months, and still some protection at about 55%. out to six months if you gave it to a pregnant person and they delivered a term baby so the baby was able to get a lot of maternal antibody that has not yet been

approved and gotten an ACIP recommendation. So we will hear about that probably at their October meeting. But once that happens, we're going to have two possible ways to protect babies. Vaccinate the mom. or give the baby a dose in her 7-man. So it would be or rather than and? For term babies who get a full complement of maternal antibody, it would be or.

It's just not cost effective and there's probably no additional benefit to doing both. But, you know, of course, if a woman gets her vaccine at 22 or 23 weeks and delivers a 26 week premature infant. There won't be much transfer of maternal antibodies, so we'll still have to use nircevamab for certain subgroups of babies whose mother got vaccinated.

We'll be doing math. Is there a prospect at some point that caregivers would also be candidates for the vaccine? We can only hope. So, you know, one of the key questions is. If you're vaccinated, are you less likely, and you're otherwise not at risk of being hospitalized, are you less likely to spread the virus? We haven't studied that yet. Because a common question is,

You know, I'm 65. I'm pretty healthy. I'm not in a big hurry to get the vaccine for myself, but I've got a grandbaby coming. And should I get vaccinated so I'm not a source of RSV in the family? We don't have the answer for that yet. We don't know what the effect on secondary spread is going to be. I would go ahead and say, hey, you're 65. You still have a chance of being hospitalized or ending up very sick with RSV.

Get the vaccine and hope that it protects your grandkids as well. Absolutely. So what are the prospects of a vaccine, of an RSV vaccine for kids? Mixed. There's still development work going on, but... And there are a number of different kinds of candidate vaccines. But so far, the candidates have required multiple injections to induce much immunity. And so it looks like most of the candidates would require...

something like a two, four, and six-month dose before you're protected. And that means that we would miss the period of greatest vulnerability. The next question would be, okay, so nircevumab wears off after five months. Should we have an active vaccine to prevent infection later on? And that's a more difficult question because if you don't get RSV until your second year of life, your chance of being hospitalized goes way down.

And even your chance of requiring a physician visit goes way down. So is there still an important benefit to getting vaccinated? We don't know yet. And that's an area of active study. And the history of RSV vaccine development goes way back, right? There was a bad experience in the 1960s, if I remember my history correctly. Yeah, there was. So the original vaccine was a whole inactivated virion vaccine. So basically...

you know, did it akin to something like the poliovirus or vaccine. And it turned out that a subset of kids who got this vaccine got more severe disease. And we now know that after it took like 30 years to figure it out, it was that most of the antibodies it induced did not actually prevent fusion and cell entry. And so they were not neutralizing antibodies.

It didn't really protect kids against infection, and it seemed to actually mediate what we call antibody-mediated severe disease. And so there was a small proportion of kids who actually got sicker. The problem there was that there was no F protein really expressed and you didn't make the right kind of antibodies. So with nirsevumab and with these new vaccines, you're kind of making tailor-made.

optimized antibodies rather than a commish of useless antibodies that that first vaccine created. And we may have learned more about how immunity works in the last 60 years. We've learned an enormous amount. There's much still to learn. If memory serves, the difficulty with the RSV vaccine had some effect, didn't it, on the way that the COVID vaccine was developed, that mRNA vaccine technology was suggested partly by...

bad experience with RSV vaccines? Yeah, that's probably not the whole story. But, you know, the advantage of mRNA vaccines is that it's a way of expressing exactly the antigen you want. in using the muscle cells of the patient as your antibody factory. And the biggest advantage of RNA vaccines...

is that you can make them quickly and you can change them quickly. We're going to see that this fall when we get our third version of the COVID vaccine, this one tailored against the rapidly changing virus. And that's our segue to next week's topic. We thought that mRNA would come up next week in talking about COVID. I should mention that there is still a mRNA RSV vaccine in development.

And the top line readout from that looks like it's a pretty effective vaccine as well. So hope for the future. Well, all right. This has been fascinating. I think I understand a whole lot more about what's going on with RSV just in time to start the RSV season. Andy, thanks for spending time with us. For those of you who have questions, please send your questions.

to questions at vcurb.com. Please like and subscribe so that people can find us, tell your friends and neighbors, and we'll talk again next week. Thanks, Andy. Thanks so much, Paul. Thanks for joining us. We look forward to getting together again next time. The virtual curbside is available on iTunes or wherever you find your other favorite podcasts.

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