From Pages to Practice

By Julie Barzilay, MD, MPhil

Published March 28, 2024


Each fall and winter, pediatric emergency rooms fill with infants in distress due to respiratory syncytial virus (RSV). Estimates of global disease burden suggest that one in every 28 deaths in children aged 28 days to 6 months is attributable to RSV. Typically, the effects of RSV are milder after infancy, though the risk of severe illness increases again in older age as patients become more vulnerable. Recent research on RSV prevention has led to the development of an RSV vaccine for older adults, and one for pregnant patients that is designed to confer immunity to infants. In addition, a new RSV-neutralizing monoclonal antibody given as a single injection, nirsevimab, was recently approved for the prevention of RSV in infants.

Previous trials have shown that nirsevimab was safe and effective against RSV-associated lower respiratory tract infection (LRTI) in healthy preterm and term infants. Now, a new study published in NEJM in December 2023 demonstrated that nirsevimab prevented hospitalization for RSV-associated LRTI and protected against very severe RSV-associated LRTI in healthy preterm and term infants under conditions approximating real-world settings.

In the open-label, phase 3b HARMONIE trial, 8058 infants younger than 12 months in France, Germany, and the United Kingdom were randomized to receive nirsevimab or standard-care (no intervention). The infants had been born at ≥29 weeks’ gestation, were not eligible for palivizumab (a monoclonal antibody given to high-risk infants) and were entering their first RSV season. The primary endpoint was hospitalization for RSV-associated LRTI (hospital admission with an RSV-positive test).

Eleven infants (0.3%) in the nirsevimab group and 60 (1.5%) in the standard-care group were hospitalized for RSV-associated LRTI, representing nirsevimab efficacy of 83.2% (95% confidence interval [CI], 67.8 to 92.0; P<0.001). Very severe RSV-associated LRTI occurred in 5 infants (0.1%) in the nirsevimab group and 19 (0.5%) in the standard-care group, representing nirsevimab efficacy of 75.7% (95% CI, 32.8-92.9; P=0.004). No major safety concerns were reported.

This trial provides further evidence that in a real-world setting across multiple clinical practices, nirsevimab protected infants from RSV-associated hospitalization. Although cost and supply issues may present challenges, these results lend weight to the recommendation that infants receive a dose during the next RSV season.

Read the following NEJM Journal Watch summary for more details of this study.

Efficacy of Nirsevimab at Preventing RSV-Related Hospitalization in Young Infants

Deborah Lehman, MD, reviewing Drysdale SB et al. N Engl J Med 2023 Dec 28

Recently, the monoclonal antibody nirsevimab (Beyfortus; administered as a single intramuscular dose) was approved in the U.S. for prevention of RSV disease in young infants (NEJM JW Infect Dis Aug 2 2023 and U.S. Food and Drug Administration 2023 Jul 17. opens in new tab). Now, investigators in France, Germany, and the U.K. (all countries where nirsevimab had been approved 1 year prior) have conducted the phase 3b, open-label, manufacturer-supported HARMONIE trial, in which 8058 infants aged <12 months and born at ≥29 weeks' gestation were randomized 1:1 to receive a single dose of nirsevimab (before or during RSV season) or standard care (i.e., no prophylaxis). Incidence of hospitalization and severe RSV disease were assessed in both groups. Key findings are as follows:

  • Hospitalization for RSV-associated lower respiratory tract infection occurred in 0.3% of nirsevimab recipients versus 1.5% of standard care patients (83.2% efficacy).

  • Very severe RSV disease occurred in 0.1% of nirsevimab recipients versus 0.5% of standard care recipients (75.7% efficacy).

  • Nirsevimab also appeared to be moderately protective against hospitalization for lower respiratory tract infection from any cause during RSV season (58.0% efficacy).

  • No significant adverse events or safety concerns were noted in the nirsevimab group.

In a retrospective analysis from Massachusetts General Hospital, 1146 patients who underwent thymectomy were matched to control patients who underwent cardiothoracic procedures with thymus sparing. In the thymectomy group, 511 had cancerous thymomas, and 370 had “suspected thymic masses;” additionally, 265 underwent thymectomy during cardiac surgery, thyroid/parathyroid surgery, or for indeterminate reasons. At 5 years, thymectomy patients were significantly more likely than controls to have died (8.1% vs. 2.8%) or to have developed cancer (7.4% vs. 3.7%); types of cancer varied, and they were more aggressive and recurrent in thymectomy patients. Even when all prior malignancies were excluded, mortality and postoperative cancer were significantly more common in thymectomy patients at 20 years. New T cell production decreased, and levels of inflammatory cytokines increased in thymectomy patients.

Comment: This trial confirms previous studies demonstrating nirsevimab's efficacy and safety in preventing serious RSV disease in young infants, while attempting to simulate real-world administration. Given its excellent safety profile and efficacy against severe disease and hospitalization, the main barrier to widespread use of nirsevimab will likely be cost of annual administration (although limited supply could represent another challenge). In general, cost savings from preventing RSV-associated hospitalizations and —more importantly — morbidity and mortality should buoy enhanced production and uptake of this preventive therapy.

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Julie Barzilay, MD, MPhil, is a 2023–2024 NEJM Editorial Fellow. She is currently a pediatrician in the Division of General Pediatrics at Boston Children's Hospital. She completed her pediatrics residency in the Boston Combined Residency Program at Boston Children's Hospital and Boston Medical Center.