Steph’s Note: Welcome back! I know what you’re thinking… Didn’t these fools JUST publish an article about pediatric vaccines?? Why, yes. Yes we did. But that article wasn’t geared towards premature infants like this one, so you’re not getting repeat content. Scout’s honor.

*Insert three-finger salute here*

Resident tl;dr pediatric expert Courtney Howell is back this week to add on to her ridiculously informative NICU Series by dipping into the world of infectious diseases. (If you haven’t already, you really should check out parts one, two, three, and four! Also, you need THIS PEDIATRIC POCKET GUIDE. That’s all I’m gonna say because the all caps say more than I ever could about its awesomeness.) Teach us again, Courtney!

This was supposed to be a short little two(ish) page section kicking off our discussion on infectious diseases, but it got away from me real quick. Ten pages later (oopsies!), I decided to split the content into two separate articles.

Prevention of infectious diseases is just as important as management, so I’d be remiss if I didn’t talk about vaccines. We’ll also cover some non-vaccine prophylaxis options for a common respiratory virus.

Maternal Vaccination as a Protective Measure

Before we get too far into the NICUsphere, let’s talk about someone else whose vaccination status can affect a baby’s immunity to vaccine-preventable diseases: Mom.

As if growing a human wasn’t enough of a superpower, now you’re telling me women pass forcefields of antibodies to their growing baby too?? So freakin’ cool. (Image)

When we give a vaccine to a pregnant patient, their immune system is activated, and antibodies are formed. These antibodies can be passed to baby through the placenta in utero or through consumption of breast milk after they are born. Because the antibodies are already formed, this is called passive immunity.

The CDC currently recommends routine vaccination of pregnant patients for Tdap and influenza (if pregnant during the flu season). COVID-19 vaccination is also recommended, although it doesn’t yet fall into that “routine use” category.

Live vaccines like MMR and varicella are NOT recommended in pregnant patients, although it IS recommended for pregnant patients to receive the MMR vaccine BEFORE pregnancy if they didn’t receive it as a child to prevent Congenital Rubella Syndrome (CRS).

Remember, it’s not cool to shoot a live virus into someone with a blunted immune system, especially when they happen to be carrying a whole other human - whose immune system is also garbage.

Respiratory Syncytial Virus (RSV) is a common respiratory virus that is usually harmless but can cause severe complications in infants and premature neonates. As of now, there are no vaccines approved for use in infants to prevent complications from RSV. BUT, as of August (this literally JUST got approved, y’all!), there is a vaccine approved for use in pregnant individuals. It’s called ABRYSVO, and it’s administered to the mother between 32 and 36 weeks gestation to protect infants from lower respiratory tract disease (LRTD) caused by RSV from birth through six months of age.

Alright, let’s hop back on the baby train.

NICU-Specific Vaccine Considerations

If you take a peek at the CDC’s Birth to 15 Months Immunization Schedule, you’ll notice one vaccine (Hepatitis B (HepB)) is given right at birth, and then a bunch are given at two months of age.

These vaccines are administered directly to the infant. They provide active immunity because, unlike the protection conferred by maternal immunization, the antibodies are not already formed. The patient’s immune system needs to mount a response to the vaccine to create antibodies.

In general, preterm infants should be vaccinated according to the same schedule and with the same doses as their full-term counterparts. Birth weight and size do not play into the decision as to whether or not to vaccinate a clinically stable preterm infant.

Of course, there are always exceptions. In this case, those exceptions are HepB and rotavirus.

The first dose of the HepB vaccine is typically given within 24 hours of birth in medically stable infants. However, decreased seroconversion rates have been observed in some preterm infants with a low birth weight (LBW, < 2000 g). FYI, “seroconversion” is just a fancy term for the time it takes for antibodies to show up after exposure to a virus. By one month PNA, birthweight is no longer a factor, and all preterm infants are likely to respond adequately to the HepB vaccine.

Because of this, the CDC recommends that infants born to HBsAg-negative mothers weighing < 2000 g at birth should receive the first dose of the HepB vaccine series at one month PNA or at hospital discharge, whichever comes first. This holds true even if they still weigh < 2000 g. Only the monovalent vaccines should be administered before six weeks of age.

The minimum required interval between HepB doses is four weeks, and since the second dose is administered at two months, we really need to get that first dose in by one month of age.

But what if Mom is HBsAg-positive? Or if we just plain don’t know their HBsAg status?

Infants born to mothers with unknown or positive HBsAg status should receive the HepB vaccine within 12 hours of birth, regardless of birth weight. In both cases, three additional doses of the vaccine should be administered starting at one month of age if birth weight is < 2000 g. If you’re keeping score, that’s four doses total.

Hepatitis B Immunoglobulin (HBIG) should also be given within 12 hours of birth to all infants whose mother is HBsAg-positive, and to those born to mothers with an unknown HBsAg status and weighing < 2000 g at birth. If the mother’s HBsAg status is unknown and the infant weighs ≥ 2000 g at birth, we have seven days to figure out that status and administer HBIG if the mother is positive.

Here’s a lil’ flow diagram for all you visual learners out there:

Quick side note: in addition to the HepB vaccine, it is also recommended to administer a vitamin K injection to prevent vitamin K deficiency bleeding (VKDB) and a topical eye medication (usually erythromycin ophthalmic ointment) to prevent gonococcal ophthalmia neonatorum, a condition that can cause blindness. You may see this regimen affectionately referred to as “eyes and thighs.” Sure, it doesn’t have anything to do with vaccines, but it’s the only place in the series I could think to put it where it made a lick of sense. Sue me.

Actually tho… why are kids so expensive?? (Image)

Actually, wait… Please don’t. I have a family (and student loan debt).

Now let’s talk about the other exception: rotavirus. I hope you like a good celebrity gossip, ’cause this gal’s more controversial than Kim K.

The Advisory Committee on Immunization Practices (ACIP) currently recommends deferral of the rotavirus vaccine until the time of discharge if an infant has been hospitalized since birth. This recommendation is based on a theoretical risk of horizontal transmission to other infants in the same unit who have not yet been vaccinated.

The rotavirus vaccine contains the live attenuated virus and is administered orally. Because it passes through the GI tract, traces of the virus (albeit a weakened version) can be shed through the stool. Nurses are generally responsible for the care of multiple infants during any given shift, and part of this care includes diaper changes. So, in theory, the virus could be spread from one infant to another if they were being cared for by the same nurse (especially if their hand hygiene was subpar).

Exposure to the shedded attenuated virus doesn’t usually affect healthy individuals, but we’re not talking about healthy individuals here. And you know what rotavirus does? It causes vomiting. And diarrhea. Lots and lots of diarrhea.

That sounds… bad. So waiting to vaccinate until discharge sounds like a good idea, right?

Well, this would be fine if not for one small problem: this vaccine has an age limit. Some studies have found a small increased risk of developing a type of bowel blockage called intussusception following the first or second dose. Due to a lack of safety data, it’s not recommended to initiate the series after 15 weeks of age.

But tons of babies are in the NICU longer than 15 weeks, and they’ll age out and never have the chance to get vaccinated. Is the theoretical risk of horizontal transmission in the unit greater than the risk of being unvaccinated at discharge? That’s where the controversy lies.

Multiple organizations -- including the AAP -- have called for reevaluation of this recommendation in light of recent safety data. But, as of today, it still stands.

Monoclonal Antibodies (mAbs) for RSV

Keeping in line with our discussion about vaccine-preventable diseases, we’re going to talk about a couple more tools we have in our arsenal to protect our patients from complications of RSV: palivizumab (Synagis) and nirsevimab-alip (Beyfortus).

But these aren’t vaccines, they’re mAbs (like everything else these days, amirite?). They both target the F protein, which helps RSV fuse with human cells, but they work in slightly different ways. The specific pharmacology is beyond the scope of this article, but if you need to know because you’re a nerd like me, you can find the mechanisms of action here and here.

Like when antibodies pass from mom to baby in utero or through breast milk, these mAbs also provide the infant with passive immunity. The difference here is that we are simply injecting the infant with lab-made antibodies rather than relying on Mom’s immune system to form them.

Yeah, yeah, I know. Billy Mays never actually said this. Mandela Effect and all that. But I like the meme template, ok? (Image)

Even though these mAbs work similarly, there are some key differences between the two:

Approval Date

Palivizumab was approved by the FDA way back in June of 1998 (if you’re too lazy to do the math, this means we’ve been using the drug for 25 years!). On the other hand, nirsevimab was approved in July… of 2023. That’s right, another huge advancement in RSV prevention THIS YEAR!

Side note: An RSV vaccine (yes, really a vaccine this time) called Arexvy was also approved in May for the prevention of LRTD caused by RSV in adults 60 years and up. What a year for RSV!

Indications

Before we dive into the specifics, I want to point something out: I’m going to use the phrase “RSV season” multiple times, but know that this definition can vary (even within the United States)! This is particularly true for Alaska and areas with a tropical climate, so be sure to check with your local regulatory bodies if you are practicing in any of these locations.

Another thing to consider: the COVID-19 pandemic really threw a wrench in the seasonality of RSV. Historically the “RSV season” has fallen between mid-October and late March, but these days RSV cases are really sporadic.

I mean seriously, parents in the audience, are your kids ever NOT sick?!

It hasn’t been updated since November of 2022, but the AAP put out some interim guidance for the use of palivizumab for RSV prophylaxis to account for this shift in seasonality. They’ve also stated that providers may adjust administration schedules for nirsevimab based on local RSV activity.

Alright, back to the indications for these bad boys. We’ll start with palivizumab. Prior to the approval of nirsevimab, palivizumab was the sole option for prevention of RSV. But it’s not for everyone. In fact, the eligibility criteria are pretty specific. It’s important to note that these criteria are based on the literature and do not necessarily reflect the approved indications outlined in the package insert.

In 2014, the AAP -- in conjunction with the Committee on Infectious Diseases (COID) and the Bronchiolitis Guidelines Committee -- released a policy statement containing updated guidance on who should receive palivizumab for RSV prophylaxis. Their recommendations are as follows:

Infants born before 29 weeks gestation who are less than 12 months old at the start of RSV season. Palivizumab prophylaxis is not universally recommended for patients born after 29 weeks gestation and is not recommended in the second year of life solely based on a history of premature birth.
Consider administration during the RSV season for preterm infants in their first year of life who develop chronic lung disease (CLD) (defined as GA <32 weeks and a requirement for > 21% oxygen for at least the first 28 days after birth). Prophylaxis for a second RSV season is not recommended for infants with CLD who do not continue to require medical support in the second year of life.
Certain infants who are ≤ 12 months of age with hemodynamically significant congenital heart disease (CHD) may benefit from palivizumab prophylaxis. The key words here are “hemodynamically significant”. Not all infants with CHD qualify, and they only qualify if they are under 12 months of age (UNLESS they are less than 24 months and underwent extracorporeal membrane oxygenation (ECMO), cardiac transplant, or another surgical procedure requiring cardiac bypass during the RSV season). A 15 mg/kg postoperative dose should be considered for qualifying patients due to an observed 58% decrease in serum palivizumab concentration following cardiopulmonary bypass.

These are the considerations you’d come across most often in the NICU, but other populations (patients with anatomic pulmonary or neuromuscular disorders, a compromised immune system, Down syndrome, and cystic fibrosis) are also addressed in the policy statement.

A technical report published by the AAP in June states that there is insufficient evidence to warrant a change in policy. Thus, the above recommendations still hold true.

The eligibility criteria for nirsevimab are much more straightforward. The AAP and ACIP are recommending nirsevimab for all infants younger than eight months born during or entering their first RSV season AND for those eight through 19 months who are at increased risk of severe disease and entering their second RSV season.

As you can see, these mAbs can be indicated for children as old as 24 months, so it wouldn’t be at all uncommon to see these prescribed outside the NICU setting.

Dosing

Palivizumab is given as an IM injection at 15 mg/kg per dose. Protection from each dose only lasts about a month, so (unfortunately) monthly injections are required throughout the RSV season. The typical maximum is five doses, but more or less may be warranted depending on the clinical situation. The likelihood of multiple RSV hospitalizations in the same season is very low, so monthly prophylaxis should be discontinued if a patient experiences a breakthrough RSV hospitalization.

Nirsevimab is also given as an IM injection. Just one dose provides around 5 months of protection, so there is no need for that pesky monthly dosing. The following is recommended in the package insert:

Neonates and infants born during or entering their first RSV season
- < 5 kg: 50 mg IM once
- ≥ 5 kg: 100 mg IM once
Children up to 24 months of age who remain at increased risk for severe RSV disease in their second RSV season

200 mg IM once

A postoperative dose is recommended for children undergoing cardiac surgery involving cardiopulmonary bypass to ensure adequate serum levels (sounds familiar, no?). The dose will depend on body weight, whether the child is in their first or second RSV season, and how much time has passed since the initial dose of nirsevimab.

Cost

On paper, the dosing for nirsevimab seems more complicated, but (spoiler alert!) it’s not. It comes neatly packaged in prefilled 50 mg and 100 mg syringes. So, even if your patient requires a 200 mg dose, you just use two 100 mg syringes. Easy peasy.

Palivizumab, on the other hand, comes in a 50 mg or 100 mg single-dose vial. The package insert states that each vial should only be used for one dose and the remainder should be discarded. Okay, fine. Whatever. BUT, according to the RED BOOK in Micromedex, the wholesale acquisition cost (WAC) for a 50 mg vial is $1,820 and the average wholesale price (AWP) is $2,185. Yowza! Due to high cost, it’s important to minimize waste as much as possible. The AAP recommends a vial-sharing scheme (i.e., setting a standard administration time so doses for multiple patients can be prepared at once) to accomplish this.

Nirsevimab is much cheaper (WAC $495, AWP $595 for a 50 mg dose) and will be covered by the Vaccines for Children (VFC) program. This means it will be available for children whose families may not be able to afford it.

ABRYSVO, Beyfortus, and Synagis -- Oh My!

So, now we have a bunch of options to prevent RSV-associated LRTD. Which ones do we actually use? Just one? All three?

Because of its lower cost, easier dosing, and wider range of eligibility, nirsevimab is the preferred mAb. Here is the current guidance from the AAP:

If nirsevimab is administered, palivizumab should not be administered later that season.

If palivizumab was administered initially for the season and less than five doses were administered, palivizumab should be discontinued, and the infant should receive one dose of nirsevimab.
If palivizumab was administered in season one and the child is eligible for RSV prophylaxis in season two, the child should receive nirsevimab in season two, if available. If nirsevimab is not available, palivizumab should be administered as previously recommended.

Nirsevimab won’t be available in all clinical settings right away. It’s a brand new product, and high demand is already causing supply issues. If nirsevimab is unavailable or not feasible to administer, the AAP recommends administration of palivizumab for eligible patients. Both palivizumab and nirsevimab can be administered with routine childhood vaccinations.

Alright, so nirsevimab is preferred. Got it. But what if Mom got ABRYSVO during pregnancy? Do we still give a mAb?

While an official recommendation has yet to be made, you can view the slide deck of the proposed recommendations presented at the most recent ACIP meeting on their website. I’ll give you the tl;dr version.

Nirsevimab is not needed for most infants born 14 days or more after maternal vaccination. It is recommended for those born less than 14 days after maternal vaccination or whose mother did not receive (or it is unknown whether the mother received) the maternal RSV vaccine. Other clinical situations may warrant consideration of nirsevimab for infants born 14 days or more after maternal vaccination.

The tl;dr of Vaccines in the NICU

There are a couple ways we can confer vaccine-mediated immunity to an infant. Through 1. maternal immunization during pregnancy and 2. direct immunization. The first (maternal immunization) confers passive immunity as antibodies are already formed and are simply being transferred to the infant. Vaccines recommended for pregnant individuals include Tdap, influenza, and COVID-19 (note that MMR is recommended before pregnancy if the individual wasn’t vaccinated as a child). A new maternal vaccine for prevention of RSV-associated LRTD just dropped and is recommended for pregnant patients between 32 and 36 weeks gestation.

Direct immunization confers active immunity because the infant must make their own antibodies after being vaccinated. In general, preterm infants should be vaccinated according to the same schedule and with the same doses as their full-term counterparts. The exceptions to the rule are HepB (based on birth weight and mother’s HBsAg status) and rotavirus if the patient has been hospitalized since birth (although this is up for debate). There are also non-vaccine options for preventing RSV-associated LRTD in infants: palivizumab (old) and nirsevimab (new). These are mAbs, so they don’t require an immune response and provide the infant with passive immunity.

Well, there you have it! Be sure to join us next time for a discussion on infectious diseases!

NICU Series Part 5: Vaccination Considerations in the NICU