Team Trivia! Test Your Knowledge and Take Infant RSV Prevention to New Heights

[00:24:54]

Round 2: Elevate Developments in Infant RSV Prevention

Dr Pablo Sanchez (Nationwide Children’s Hospital): [00:29:48]

RSV: Virion Structure

So let's start the discussion here. And first of all, I really wanted to show you the - what we're talking about today this virus, this RSV virus that you can see here. And the whole point of this slide is really looking at this y-shaped on the surface of the RSV that is really the fusion protein, the F protein. This virus was first discovered back in 1955 by Morris. It was a chimpanzee coryza agent and then was discovered in children back in 1957 by Chanock.

But this F protein is a glycoprotein, and this primary function of this F protein is to mediate fusion of the viral and host cell membranes, therefore resulting in the syncytium. That is why respiratory syncytial virus, that's how it gets its name. So this is the F protein that we're going to be really dealing with today.

[00:30:58]

The Heros: Protection for All Infants

And so, as Joe said, the heroes is protection for all infants. And how can we do that? We're either going to vaccinate pregnant women with a maternal RSV Prefusion vaccine, or we're going to be giving long-acting monoclonals that have extended half-life for infants. And so the half-life for clesrovimab is about 43 days or so, whereas nirsevimab is about 73 days.

So the recombinant RSV Prefusion vaccine is given as a single dose. It was approved and recommended back in 2023. Nirsevimab, on the other hand, is the long-acting monoclonal antibody, again given as a single dose and approved back in 2023 as well.

Clesrovimab is the new product. It's the new kid in town. The New England Journal paper just came out a couple weeks ago. It was approved and recommended in this past summer, in June by CDC and the FDA as well. And you'll see some of the data today.

Palivizumab is what we have traditionally been giving to our high-risk babies. I will say that as of December 31st, you will not be able to get nirsevimab or palivizumab at all in the United States. So you can really forget about palivizumab completely.

We have better products and we have much easier to administer. Palivizumab, if you remember, was monthly dose times 5 doses, and now we can prevent severe RSV by means of giving a single intramuscular injection.

[00:32:45]

Maternal RSVPreF Vaccine

So let's go first with the maternal RSV Prefusion vaccine.

[00:32:50]

Maternal RSVpreF Vaccine: Effect Estimates

So this vaccine was given to pregnant women from 24-36 weeks gestational age, but it was approved and recommended for vaccine at 32-36 weeks of pregnancy. With respect to the vaccine efficacy when given at 32-36 weeks, medically attended RSV associated lower respiratory tract infection, the efficacy was 51.5%. Whereas RSV hospitalization was similar, 57%. And certainly there was some waning of efficacy from the first 3 months to the second 3 months. But still, it was still efficacious even through 6 months of age in these infants.

[00:33:40]

BERNI Study: Real-world Effectiveness of Maternal RSVpreF Vaccine in Argentina

And this vaccine now has been—we're starting to get some real-world data. And the RSV prefusion vaccine for pregnant women is now the mode of RSV prevention in Argentina in this study, the BERNI study. Berni, by the way, is an Argentinian artist and that's where it got its name. The study was named after this Argentinian artist.

The real-world effectiveness of maternal RSV Prefusion vaccine. So they're giving the vaccine to women from 32-36 weeks. They did a case control study from the 2024 season, and they looked at infants who were 6 months of age or less, who were born 14 or more days after maternal vaccination was administered.

And then how many were hospitalized with lower respiratory tract infections due to RSV. Vaccine effectiveness was against RSV lower respiratory tract infection was 78.6% from birth to 3 months of age, and it was 71.3% from birth to 6 months of age.

Reduced RSV hospitalization and medically—and lower respiratory tract infections due to RSV by 71% to 78%. That is amazing. And vaccine effectiveness against severe RSV lower respiratory tract infection was 76.9 from birth to 6 months. And really, Argentina has really led the way in implementation of the maternal RSV vaccine for all their population.

[00:35:24]

RSV Long-acting Monoclonal Antibodies

So the other strategy is the RSV monoclonal antibodies.

[00:35:31]

RSV Fusion (F) Protein

And the RSV fusion protein, that Y-shaped molecule that stuck out of the virion is exists in 2 forms. This F protein exists as a prefusion and then when it attaches to the host cell, there exists as a post-fusion. And what's fascinating is that to be effective, these monoclonal antibodies and the prefusion vaccine have to be neutralized the prefusion version of this F protein, because once it attaches and becomes the post-fusion the infection has already started. And so we cannot prevent that fully.

So it's really fascinating how it was discovered as a prefusion. And palivizumab is against the prefusion. Nirsevimab is against the prefusion. And clesrovimab is mostly prefusion, but also against some post-fusion as well.

[00:36:30]

Nirsevimab

So let's talk with the first long-acting monoclonal, nirsevimab.

[00:36:36]

ACIP/CDC: Nirsevimab Efficacy Estimates

So overall in terms—this was randomized controlled—placebo-controlled studies that were done internationally. And with respect to medically attended RSV lower respiratory tract infection, the efficacy was 79%. When you looked at RSV lower respiratory tract infection with hospitalization, the efficacy was 80.6%.

RSV lower respiratory tract infection with ICU admission, the efficacy was 80.6%. I mean, these are amazing numbers. During the study, there were no deaths recorded secondary to RSV, although we know, as Joe said, that some cases do occur principally in developing countries. But even in the United States, we do see some rare deaths.

All-cause medically attended lower respiratory tract infection, the efficacy was 34.8%. I mean this is a monoclonal that is directed against RSV only. And all-cause lower respiratory tract associated hospitalization, the efficacy was 44.9%. So actually it's really interesting because the interplay of RSV with other viral agents as well as bacterial agents like pneumococcus is really interesting.

And by preventing RSV, we may also prevent the bacterial co-infections and sequelae that can occur principally with pneumococcus.

[00:38:09]

Nirsevimab: Real-world Effectiveness

And this nirsevimab now we have real-world effectiveness data. It is being given around the world. Spain has led the way. It's been great. You can see overall the real-world effectiveness range is 65% to 90%. Chile has done an amazing job. You should read that article. Chile, the National Health Service pays for it. These infants are receiving it at birth as well as in the primary care centers, and it has reduced RSV hospitalization by 90%.

And actually, the previous year they had 13 infant deaths due to RSV. During the year that they gave nirsevimab, there were zero deaths due to RSV. They've done an amazing job. It is working and we just need to - and Sharon will discuss this. We just needed to get it into our patients.

[00:39:05]

Nirsevimab and Wheezing

And as Joe mentioned, this ongoing concern about RSV and wheezing. And actually in this population-based cohort study, and using the identified medical record database from 93 healthcare organizations, mainly in the United States, giving nirsevimab actually was associated with less wheezing over the 365-day observation post prophylaxis. So I think we have also other things that we could prevent, such as wheezing and possibly even asthma-like symptoms.

[00:39:41]

Nirsevimab Season 1 Safety: Healthy Term and Pre-term Infants

So how about the safety? And when comparing - in these studies comparing nirsevimab to placebo, you can see the overall adverse effects were very similar in the 2 groups. Importantly, when you looked at fever, they were similar. It was 1 case in nirsevimab and none in the placebo. And adverse events, there was more rash in the nirsevimab group that occurred in the 7 days after its administration. There were no anaphylaxis or hypersensitivity reactions. And really it is really quite well tolerated.

[00:40:16]

Nirsevimab Season 1 Safety: Infants With CLD and/or CHD

How about in infants with chronic lung disease and/or congenital heart disease? And this was a second study looking at comparing—so these are infants who qualified to receive palivizumab. And a placebo controlled trial in these patients was not felt was not going to be ethical because they needed RSV prophylaxis. So they compared these infants, high-risk infants with nirsevimab vs palivizumab.

And what you can see here is that the adverse effects were very similar as well. And so it was very well tolerated including injection-site reactions were minimal.

[00:40:56]

Clesrovimab

So how about clesrovimab?

[00:40:59]

CLEVER: Clesrovimab Efficacy and Safety in Healthy Infants

So clesrovimab, as I mentioned, this is a new kid in town. There was a double blind, randomized, placebo-controlled study that was done in healthy infants and some premature infants, moderate preterm and late preterm infants who did not qualify to receive palivizumab an international trial, including the United States.

So clesrovimab was compared to placebo, and there was surveillance done for respiratory infection during RSV season 1 and season 2. The primary endpoint was RSV associated medically attended lower respiratory tract infection due to RSV.

Secondary and tertiary endpoints, as you can see there, RSV hospitalization, RSV-associated lower respiratory tract infections, hospitalization, and severe medically attended lower respiratory tract infections due to RSV.

[00:41:50]

CLEVER: Clesrovimab Outcomes in Days 1-150

So with respect to the primary outcome, medically attended lower respiratory tract infection, the efficacy of clesrovimab—and it's not a vaccine—it was 60.4%. And secondary outcomes, RSV hospitalization, the efficacy was 84%. RSV lower respiratory tract hospitalization was 91%, and severe medically attended lower respiratory tract infection was 91.7%. And you can see there that safety outcomes also were similar in the 2 groups.

[00:42:28]

SMART: Clesrovimab in CLD, CHD, or Prematurity

So again, similar to nirsevimab, preterm high-risk infants as well as premature infants who were recommended to receive palivizumab, these infants were compared to clesrovimab. They looked at season 1 and then they're also studying season 2. Season 2 that has been—the study has been completed. We're awaiting that data. So until we see that data, clesrovimab is only recommended for season 1.

The primary outcome was safety and tolerability in RSV season 1 with the following endpoints—secondary endpoints similar to before.

[00:43:10]

SMART: Clesrovimab Season 1 Safety

And what you can see here that in terms of safety, the 2 were very similar in terms of overall adverse effects. The adverse events of special interest, such as rash, anaphylaxis were similar between the 2 groups. There were none with anaphylaxis or hypersensitivity. And there was some fever associated with this administration. However, both were similar. So really it was as safe as palivizumab. And so we feel very comfortable with this administration.

And as I mentioned, available data from season 2 suggests that 210 mg vs the double dose is safe and well tolerated in infants less than 24 months of age. But we are awaiting that data to be published and to be provided.

[00:44:00]

SMART: Clesrovimab Season 1 Efficacy

In terms of the efficacy comparing clesrovimab to palivizumab, the efficacy was very similar. Medically attended lower respiratory tract infection due to RSV, the efficacy was 3.6% in the clesrovimab group and 3% in the palivizumab. Hospitalization was 1.3 vs 1.5.

So really it's easier to give. It is well tolerated, it is safe and it works.

[00:44:32]

Recommendations: Dosing and Timing

So how about some recommendations for the dosing and timing?

[00:44:38]

CDC Recommendations: Preventing Severe RSV Disease in Infants Aged <8 Mo in Their First RSV Season

So we have 3 options, clesrovimab and nirsevimab. Either can be administered to infants in their first season or less than 8 months of age. Suggested timing depends on when you're seeing the low RSV in your community, the local epidemiology, which in general is October to March.

You can see that clesrovimab is 105 mg. It's a standard dose irrespective of the weight. Whereas with nirsevimab, if the infant weighs less than 5 kilos, the dose is 50 mg. If the infant weighs 5 or more kilos, then it is 100 mg.

And a second season nirsevimab is 200 mg. And maternal pre - RSV Prefusion vaccine is for pregnant women 32-36 weeks. It is currently, in the United States, a seasonal vaccine. It is being given from September to the end of January.

[00:45:36]

Maternal RSVpreF Vaccine Recommendations

So in terms of the vaccine recommendations, what about the maternal RSV Prefusion vaccine? As I mentioned, 32 to 36 weeks gestation. And as I mentioned, it's also seasonal and only administered once in a lifetime currently.

So even in adults with the RSV vaccine to the elderly, the immunogenicity lasts for at least 2-3 years. And we need studies to see about the safety and actually even the need for subsequent dosing and subsequent pregnancies. Those studies are ongoing, but at this point, we only give RSV Prefusion vaccine to pregnant women once.

In a subsequent pregnancy, we have other modalities nirsevimab or clesrovimab to administer to the baby for RSV protection.

So the timing is key. So once you give the vaccine to anyone, you need 14 days to develop antibodies and then to cross the placenta to the fetus. So 14 or more days are needed for development and transplacental transfer and protect the newborn. So this is critical. And in your practices, you really need to know when the mother received the vaccine in order to assess whether that infant should get nirsevimab or clesrovimab. If it is less than 14 days, that infant is considered not protected against RSV. And 1 of the monoclonal antibodies should be administered.

[00:47:18]

Long-Acting RSV mAb Recommendations: Infants During or Entering First RSV Season

So the long-acting monoclonal antibodies, clesrovimab or nirsevimab. Less than 8 months of age on the day of administration. That is important. It's not just less than 8 months at the start of the RSV season. On the day that you administered that baby needs to be less than 8 months. He's going through his first RSV season.

Why? Because the mother did not receive the RSV vaccine during pregnancy. If you don't know her status and you ask her to check my chart and it is not there and you can't find it, and she doesn't know. And if you don't know, you give the monoclonal to the baby if the infant was born less than 14 days of maternal RSV vaccination, as we discussed.

[00:48:07]

Long-Acting RSV mAb Recommendations: Infants Entering Second RSV Season

So how about a second season? There are some high-risk infants who - in children who should be protected during a second season. Currently, it is only nirsevimab. Clesrovimab, the study's been concluded. We're awaiting that data.

So these are children 8-19 months of age who are entering their second RSV season. So why and which infants? So these are babies—these are children who have chronic lung disease or BPD, who have required medical therapy for their BPD in the previous 6 months before the start of the RSV season. And children who are severely immunocompromised, we're giving them in a second season. And very high risk and more medically complicated cystic fibrosis patients are also receiving it in their second season.

The American Indian and Alaska Native children who live in those areas - who live, they have really high rates of RSV hospitalization in their first year as well as in the second year. And so these Alaska Native and American Indian children who live in those areas where it's endemic are receiving the monoclonal in a second season.

[00:49:29]

Long-Acting RSV mAb: Timing of Administration

So the timing of administration. For most infants, optimal timing is shortly before the RSV season, October 1st to through March in most of the United States. In Columbus, Ohio, I just sent out the memo today. October 1st is our due as we start, and can be given also any time during the RSV season.

For infants born shortly before and during the RSV season, administer the monoclonal, hopefully preferably within the first week of age. We would love to do it at the birth hospitalization. As you know, it's an ongoing issue. But if it can be done in the birth hospitalization that would be optimal.

Can adjust the timing based on local epidemiology and local RSV season. And it can be coadministered with routine childhood vaccines. Don't wait until the baby needs their 2 month, 4 months. They need the monoclonal if they are eligible today. They needed it yesterday. So don't wait for the next 2 month visit. Please, we need to protect them today.

Optimal time for infants with prolonged birth hospitalization generally is shortly before or—I prefer before discharge, or certainly promptly after as soon as possible, and may consider during hospitalization based on clinical judgment.

And per FDA, children who receive clesrovimab or nirsevimab should not receive palivizumab in the same RSV season. That's going to be out of the way anyway. Eligible infants may receive clesrovimab or nirsevimab after an RSV infection. So 1 episode does not protect them against severe RSV hospitalization or disease if they're less than 8 months of age and still eligible to receive it. So we recommend that that you can give it. And oftentimes I know in past years, if an infant less than 8 months of age was hospitalized with RSV, we would give it when they go home.

[00:51:26]

Eligibility for Long-Acting RSV mAb Based on Maternal RSVpreF Vaccination

So how about eligibility for long-acting monoclonals based on maternal PreF vaccination? So infants born 14 or more days after maternal vaccination. Some of them are eligible to receive the monoclonal antibody. If the mother was immunocompromised and received the vaccine, we're not sure if she actually developed adequate immune response to protect the baby.

Also, as I've learned, women who are HIV infected, there may be inconsistent transplacental transfer of antibodies. So the mother who is HIV-infected may have received the vaccine at the appropriate time, but actually that newborn and that infant should receive the RSV monoclonal. And then there are some infant factors. So ICU admission required oxygen at discharge. They can still get it. And hemodynamically significant congenital heart disease, also those infants should get the RSV monoclonal, even if the mother received the vaccine at the appropriate time.

Any infant who undergoes ECMO or cardiopulmonary bypass for repair of congenital heart disease, even if they received nirsevimab or clesrovimab before, they should get it after their ECMO or cardiopulmonary bypass.

[00:52:50]

(Not So) Unique Clinical Scenarios: Previous Maternal Vaccination

So not so unique clinical scenarios: previous maternal vaccination. Should a pregnant mother receive the maternal RSV vaccine during their current pregnancy if they already received the RSV vaccine during a prior pregnancy in a previous season?

[00:53:10]

(Not So) Unique Clinical Scenarios: Previous Maternal Vaccination

So, no. People who received the maternal RSV vaccine for a previous pregnancy should not receive additional doses. The infant should be immunized with RSV monoclonal per guideline recommendations.

[00:53:23]

(Not So) Unique Clinical Scenarios: RSV Infection

Should an infant who had a confirmed RSV infection this season still receive RSV immunization?

Yes. Eligible infants may receive clesrovimab vs nirsevimab after an RSV infection.

[00:53:35]

(Not So) Unique Clinical Scenarios: Infant Born at End of RSV Season, Not Immunized

And if an infant was born at the end of March and did not receive nirsevimab, can they receive clesrovimab vs nirsevimab in October?

Yes. If they are less than 8 months of age at the time, that they're going to receive their RSV monoclonal and it's the first season.

[00:53:59]

(Not So) Unique Clinical Scenarios: Infant Born at End of RSV Season, Immunized

A healthy infant was born in March and received nirsevimab because you were giving it, the RSV season was going on till the end of March. They will be less than 8 months of age this coming October. Should they receive another dose of nirsevimab or clesrovimab?

No. They received RSV immunization during their first RSV season. This coming October will be the infant's second RSV season, and they are not high risk.

You know we really - that's a good point. And yes, we need to develop vaccines for the older infants. That's the future.