A Single Shot for Two RSV Seasons: What New Trial Results Mean for High-Risk Babies

A Plain-Language Guide to the SMART Trial's Safety Findings on Clesrovimab in Premature Babies and Children With Heart or Lung Conditions

For babies born very early, or living with ongoing heart or lung problems, a common winter virus called RSV can mean a trip to the hospital, and until recently, protecting them meant a shot every single month all season long. A major new study of nearly 1,000 babies found that a newer, single-shot medicine called clesrovimab was just as safe as the older monthly option — even when a second, larger dose was given to protect the highest-risk children through a second RSV winter.

The Problem This Research Set Out to Solve

The study described in this article, called SMART (formal protocol name MK-1654-007) [1], set out to answer a specific question for the highest-risk babies: could a single injection replace a whole season of monthly shots, and would it still be safe if that baby needed protecting for a second winter, too? Respiratory syncytial virus (RSV) is one of the most common causes of serious lung infection in babies worldwide, and it is a leading reason young infants end up hospitalized with breathing trouble [2]. Most healthy babies recover from RSV with nothing more than supportive care at home, but a small group of infants — those born very early, those with chronic lung disease from being born prematurely, and those with certain congenital heart defects — face a much higher chance of a severe RSV infection that lands them in the hospital or even the intensive care unit. For these families, RSV season is not just a cold-and-flu worry; it is a season of heightened vigilance.

How Families and Doctors Faced This Problem Before

For roughly two decades, the only tool available to protect these highest-risk babies was a medicine called palivizumab, given as a monthly injection throughout the RSV season — often five separate trips to the clinic or pediatrician's office for a shot, on top of every other appointment a fragile baby with heart or lung problems already needs. A large registry study of children with significant congenital heart disease, called CARESS, showed that continuing these monthly shots into a second RSV season could still help protect kids who remained vulnerable [3], but families going through that second season had no single-dose option — just more monthly visits. In the past few years, two newer tools changed the picture for most babies: nirsevimab, a longer-acting antibody shot proven to protect healthy late-preterm and full-term infants with just one dose [4], including babies born prematurely [5], and a vaccine called RSVpreF that a pregnant person can receive so that protective antibodies pass to the baby before birth [6]. Both were wonderful advances for the general infant population, and RSV itself has also become somewhat less predictable in its timing since the COVID-19 pandemic, making year-round vigilance more important in some places [7]. But neither nirsevimab nor the maternal vaccine had been tested for a second season in the small group of children whose ongoing heart or lung condition keeps them at risk beyond their first year — which meant families of these children and their doctors were left extending an older, more burdensome regimen without dedicated evidence to guide them.

The Study: What Researchers Did

Clesrovimab is a newer antibody shot already shown, in a separate trial called CLEVER, to protect healthy babies from RSV with a single injection [8]. SMART [1] was designed specifically to test clesrovimab in the babies who needed it most: those already recommended for palivizumab because they were born very prematurely, had chronic lung disease, or had a serious heart defect. Researchers described their plan for this study in a separate paper before it began [9], and shared early results partway through as an interim report [10] before this final, complete publication. SMART included 997 babies who received a study treatment, at 110 hospitals in 27 countries and territories around the world. Half of the babies received one shot of clesrovimab (with a placebo, or "dummy," injection at day 28 so families and doctors could not tell which medicine was given, at least for the first two months); the other half received the standard monthly palivizumab shots. The main goal was not to see which medicine worked better — that question about effectiveness against RSV disease had already been studied separately in healthy babies — but to see whether clesrovimab caused side effects at a similar rate to the medicine already in use. Then, 276 of these children who remained at high risk going into their second RSV season — almost all of them because of an ongoing heart or lung condition — received one larger dose of clesrovimab (210 mg, given as two injections) before that second winter, and researchers tracked their side effects and RSV infections too.

What the Study Found

The results were reassuring. In the first season, side effects were similarly common whether a baby received clesrovimab or palivizumab: about 75 in 100 clesrovimab babies and about 80 in 100 palivizumab babies had some kind of side effect, most of them mild things like soreness at the injection site, fussiness, or sleepiness. Serious health problems occurred in about 25 in 100 clesrovimab babies and about 28 in 100 palivizumab babies — a reflection of how medically fragile this population already is, not something caused by either medicine — and doctors did not link any of these serious events to clesrovimab itself. No baby in either group had a severe allergic reaction. A mild, short-lived rash occurred slightly more often with clesrovimab (about 1 in 165 babies) than with palivizumab (about 1 in 500), but it resolved without any baby needing to stop treatment. RSV infections requiring medical care were rare and similar between groups: about 3 in 100 babies in each group developed an RSV lung infection needing medical attention by five months into the season, and roughly 1 in 100 clesrovimab babies versus 2 in 100 palivizumab babies needed hospitalization for it. When the 276 children received their second, larger dose before season two, the same pattern held: about two-thirds of babies had some side effect (similar to season one), no severe allergic reactions occurred, and only a small number of mild rashes appeared. Blood tests showed that the medicine reached and maintained levels in these children's bodies similar to the levels seen in healthy babies from the earlier CLEVER study [8], which is how researchers reasoned that protection likely continued into the second season, using the same kind of careful measurement of how a medicine moves through the body that has been used to study clesrovimab in babies of different sizes and ages [11]. In a handful of children (6 out of more than 1,000 studied), the virus itself changed slightly at the exact spot where clesrovimab attaches to it [12] — a reminder that scientists will keep watching for this as more babies receive the medicine.

What This Means for Families

If your baby is eligible for RSV prevention because of prematurity, chronic lung disease, or a heart condition, these results suggest that clesrovimab offers similar protection and a similar safety record to the older monthly-shot approach, but with far fewer needles and clinic visits — often just one or two shots per season instead of up to five. It is worth understanding one important nuance: unlike season one, which directly compared clesrovimab to palivizumab, season two did not have a comparison group, so researchers could not directly prove how well the second dose worked against RSV disease — they instead relied on the reassuring blood-level evidence described above. This does not mean the second dose is unproven or unsafe; it means the evidence for season two is a little less direct than the evidence for season one, and your child's clinical team can talk through what that means for your particular situation. The study also did not look at whether babies who had RSV go on to develop longer-term breathing problems like wheezing or asthma, so that remains an open question. In[Neo]Sight has also covered nirsevimab, the RSV shot now recommended for nearly all babies, and the RSV vaccine given during pregnancy — different tools, for different situations, that all share the same goal of keeping babies safe from this common virus.

What Researchers Are Working on Next

Scientists are continuing to watch several things going forward. They want to confirm, with more direct evidence, exactly how well a second-season dose of clesrovimab protects children rather than relying on blood-level comparisons alone. They are also tracking whether babies who had severe RSV infections go on to develop breathing problems later in childhood, and they are keeping an eye on the rare cases where the virus changes at the spot the medicine targets, to make sure clesrovimab keeps working well as more children receive it. Finally, researchers are studying how this medicine might best be used alongside the other newer RSV-prevention tools, like the vaccine given during pregnancy and the nirsevimab shot given to most infants, so that families and doctors have clear guidance no matter which prevention path a particular baby's health history calls for. For now, the biggest reassurance from this study is simple: a medicine that already needs far fewer needles than the old standard appears to be just as safe, giving families of the most vulnerable babies one less thing to worry about during two long RSV seasons.

References

  1. Zar HJ, Bont LJ, Manzoni P, et al, for the SMART (MK-1654-007) study group. Clesrovimab in Infants at Increased Risk For Severe Disease During 2 RSV Seasons: A Randomized Clinical Trial. JAMA Pediatrics. 2026;180(9):951-960. doi:10.1001/jamapediatrics.2026.2760 ↩
  2. Li Y, Wang X, Blau DM, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis. Lancet. 2022;399(10340):2047-2064. doi:10.1016/S0140-6736(22)00478-000478-0) ↩
  3. Li A, Wang DY, Lanctôt KL, Mitchell I, Paes BA; CARESS Investigators. Comparing first- and second-year palivizumab prophylaxis in patients with hemodynamically significant congenital heart disease in the CARESS database (2005-2015). Pediatr Infect Dis J. 2017;36(5):445-450. doi:10.1097/INF.0000000000001357 ↩
  4. Hammitt LL, Dagan R, Yuan Y, et al; MELODY Study Group. Nirsevimab for prevention of RSV in healthy late-preterm and term infants. N Engl J Med. 2022;386(9):837-846. doi:10.1056/NEJMoa2110275 ↩
  5. Griffin MP, Yuan Y, Takas T, et al; Nirsevimab Study Group. Single-dose nirsevimab for prevention of RSV in preterm infants. N Engl J Med. 2020;383(5):415-425. doi:10.1056/NEJMoa1913556 ↩
  6. Kampmann B, Madhi SA, Munjal I, et al; MATISSE Study Group. Bivalent prefusion F vaccine in pregnancy to prevent RSV illness in infants. N Engl J Med. 2023;388(16):1451-1464. doi:10.1056/NEJMoa2216480 ↩
  7. Rios-Guzman E, Simons LM, Dean TJ, et al. Deviations in RSV epidemiological patterns and population structures in the United States following the COVID-19 pandemic. Nat Commun. 2024;15(1):3374. doi:10.1038/s41467-024-47757-9 ↩
  8. Zar HJ, Simões EAF, Madhi SA, et al; CLEVER (MK-1654-004) Study Group. Clesrovimab for prevention of RSV disease in healthy infants. N Engl J Med. 2025;393(13):1292-1303. doi:10.1056/NEJMoa2502984 ↩
  9. Sinha A, Railkar RA, Castagnini L, et al. Evaluation of a monoclonal antibody against respiratory syncytial virus, clesrovimab, in infants and children: comprehensive rationale and study design for the late-stage clinical trials. Contemp Clin Trials. 2025;157:107995. doi:10.1016/j.cct.2025.107995 ↩
  10. Zar HJ, Bont LJ, Manzoni P, et al; SMART (MK-1654-007) Study Group. Clesrovimab in infants and children at increased risk for severe RSV disease. N Engl J Med. 2025;393(13):1343-1345. doi:10.1056/NEJMc2506107 ↩
  11. Hu Z, Hellmann F, Zang X, et al. Population pharmacokinetics of clesrovimab in preterm and full-term infants. Clin Pharmacol Ther. 2026;119(4):1036-1046. doi:10.1002/cpt.70199 ↩
  12. Tang A, Chen Z, Cox KS, et al. A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein. Nat Commun. 2019;10(1):4153. doi:10.1038/s41467-019-12137-1 ↩