Respiratory Syncytial Virus Disease Burden and Nirsevimab Effectiveness in Young Children From 2023-2024

Heidi L Moline; Ariana P Toepfer; Ayzsa Tannis; Geoffrey A Weinberg; Mary A Staat; Natasha B Halasa; Julie A Boom; Eileen J Klein; John V Williams; Jennifer E Schuster; Leah Goldstein; Erin R McKeever; Casey Kalman; Clinton Paden; Lydia Atherton; Megha Aggarwal; Pavitra Roychoudhury; Pedro A Piedra; Leila C Sahni; Laura S Stewart; Rangaraj Selvarangan; Marian G Michaels; Elizabeth P Schlaudecker; Peter G Szilagyi; Janet A Englund; Benjamin R Clopper; Natalie J Thornburg; Gordana Derado; Meredith L McMorrow; Fatimah S Dawood

doi:10.1001/jamapediatrics.2024.5572

. 2024 Dec 9;179(2):179–187. doi: 10.1001/jamapediatrics.2024.5572

Respiratory Syncytial Virus Disease Burden and Nirsevimab Effectiveness in Young Children From 2023-2024

Heidi L Moline ^1,^2,^✉, Ariana P Toepfer ¹, Ayzsa Tannis ¹, Geoffrey A Weinberg ³, Mary A Staat ^4,⁵, Natasha B Halasa ⁶, Julie A Boom ^7,⁸, Eileen J Klein ⁹, John V Williams ^10,¹¹, Jennifer E Schuster ¹², Leah Goldstein ¹, Erin R McKeever ¹, Casey Kalman ¹, Clinton Paden ¹, Lydia Atherton ¹, Megha Aggarwal ¹, Pavitra Roychoudhury ¹³, Pedro A Piedra ^7,^8,¹⁴, Leila C Sahni ^7,⁸, Laura S Stewart ⁶, Rangaraj Selvarangan ¹⁵, Marian G Michaels ¹⁰, Elizabeth P Schlaudecker ^4,⁵, Peter G Szilagyi ^3,¹⁶, Janet A Englund ⁹, Benjamin R Clopper ¹, Natalie J Thornburg ¹, Gordana Derado ¹, Meredith L McMorrow ^1,², Fatimah S Dawood ^1,², for the New Vaccine Surveillance Network Collaborators

¹Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

²US Public Health Service, Rockville, Maryland

³Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York

⁴Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio

⁵Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

⁶Vanderbilt University Medical Center, Nashville, Tennessee

⁷Texas Children’s Hospital, Houston

⁸Department of Pediatrics, Baylor College of Medicine, Houston, Texas

⁹Seattle Children’s Research Institute, Department of Pediatrics, University of Washington, Seattle

¹⁰UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania

¹¹Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

¹²Department of Pediatrics Children’s Mercy Hospital, Kansas City, Missouri

¹³Department of Laboratory Medicine and Pathology, University of Washington, Seattle

¹⁴Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas

¹⁵Department of Pathology and Laboratory Medicine, Children’s Mercy Hospital, Kansas City, Missouri

¹⁶Department of Pediatrics, University of California, Los Angeles

Group Information: Members of the New Vaccine Surveillance Network Collaborators appear in Supplement 2.

Accepted for Publication: October 7, 2024.

Published Online: December 9, 2024. doi:10.1001/jamapediatrics.2024.5572

Correction: This article was corrected on December 23, 2024, to fix errors in a table, a figure title, the byline, and the author affiliations.

^✉

Corresponding Author: Heidi L. Moline, MD, MPH, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA 30333 (ick6@cdc.gov).

Author Contributions: Dr Moline had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Moline, Toepfer, Weinberg, Staat, Boom, Atherton, Piedra, Sahni, Schlaudecker, Thornburg, Derado, McMorrow, Dawood.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Moline, Toepfer, Tannis, McKeever, Paden, Aggarwal, Clopper, McMorrow, Dawood.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Moline, Toepfer, Tannis, Goldstein, McKeever, Aggarwal, Clopper, Derado.

Obtained funding: Moline, Weinberg, Staat, Halasa, Boom, Sahni, Selvarangan, Schlaudecker, Englund, McMorrow.

Administrative, technical, or material support: Moline, Toepfer, Weinberg, Staat, Boom, Williams, Kalman, Atherton, Aggarwal, Roychoudhury, Piedra, Sahni, Selvarangan, Schlaudecker, Englund, Clopper, McMorrow, Dawood.

Supervision: Weinberg, Staat, Boom, Williams, Schuster, Atherton, Roychoudhury, Sahni, Selvarangan, Schlaudecker, Englund, Thornburg, McMorrow, Dawood.

Conflict of Interest Disclosures: Dr Weinberg reported grants from the New York State Department of Health and consultant, scientific advisory or data and safety board, and/or textbook chapter honoraria from the New York State Department of Health, Inhalon Biopharma, Merck, Emory University, and ReViral outside the submitted work. Dr Staat reported grants from the National Institutes of Health (NIH), Pfizer, Cepheid, and Merck outside the submitted work. Dr Halasa reported grants from Sanofi, Quidel, and Merck outside the submitted work. Dr. Williams reported scientific advisory board fees from Quidel and independent data monitoring committee fees from GlaxoSmithKline outside the submitted work. Dr Schuster reported grants paid to their institution from the National Institutes of Health consultant fees from the Association of American Medical Colleges outside the submitted work. Dr Piedra reported grants from Novavax, Janssen, and Icosavax and data and safety monitoring board fees from Sanofi Pasteur outside the submitted work. Dr Sahni reported travel support from the Gates Foundation outside the submitted work. Dr Selvarangan reported grants from Biomerieux, Hologic, Abbott, Qiagen, Merck, and Cepheid and advisory board fees from GlaxoSmithKline outside the submitted work. Dr Michaels reported grants paid to their institution from the NIH and Merck and nonfinancial support from Viracor outside the submitted work. Dr Schlaudecker reported grants from Pfizer and advisory committee fees from Sanofi Pasteur outside the submitted work. Dr Szilagyi reported grants from the University of California, Los Angeles, during the conduct of the study. Dr Englund reported grants from AstraZeneca, GlaxoSmithKline, Pfizer, and Moderna and personal fees from AbbVie, AstraZeneca, Ark Biopharma, GlaxoSmithKline, Merck, Meissa, Moderna, Pfizer, Shinogi, and Sanofi Pasteur outside the submitted work. No other disclosures were reported.

Funding/Support: Each participating institution received grant support from the US Centers for Disease Control and Prevention for the conduct of this work.

Role of the Funder/Sponsor: The US Centers for Disease Control and Prevention was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The New Vaccine Surveillance Network Collaborators appear in Supplement 2.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the US Centers for Disease Control and Prevention.

Data Sharing Statement: See Supplement 3.

^✉

Corresponding author.

PMCID: PMC11667569 PMID: 39652359

This case-control study examines data from 7 academic pediatric medical centers to compare the epidemiology and disease burden of RSV-associated acute respiratory illness among children during the 2023-2024 season with 3 prepandemic seasons, estimate the effectiveness of nirsevimab, and compare nirsevimab binding site mutations among circulating RSV.

Key Points

Question

Did new respiratory syncytial virus (RSV) prevention products reduce RSV hospitalization rates during the 2023-2024 season?

Findings

In this case-control study, RSV hospitalization rates were similar to average 2017-2020 seasonal rates overall and among age groups eligible for prevention product protection. Nirsevimab and maternal RSV vaccine uptake was low, but nirsevimab was effective against RSV-associated hospitalization.

Meaning

RSV continues to cause high disease burden in young children, but there is potential for a substantial public health impact with increased RSV prevention product coverage.

Abstract

Importance

During the 2023-2024 respiratory syncytial virus (RSV) season in the United States, 2 new RSV prevention products were recommended to protect infants in their first RSV season: nirsevimab and Pfizer’s maternal RSV vaccine. Postlicensure studies are needed to assess prevention product impact and effectiveness.

Objective

To compare the epidemiology and disease burden of medically attended RSV-associated acute respiratory illness (ARI) among children younger than 5 years during the 2023-2024 RSV season with 3 prepandemic RSV seasons (2017-2020), estimate nirsevimab effectiveness against medically attended RSV-associated ARI, and compare nirsevimab binding site mutations among circulating RSV in infants with and without nirsevimab receipt.

Design, Setting, and Participants

This study included prospective population-based surveillance for medically attended ARI with systematic molecular testing for RSV and whole-genome sequencing of RSV positive samples, as well as a test-negative case-control design to estimate nirsevimab effectiveness. The study was conducted in 7 academic pediatric medical centers in the United States with data from RSV seasons (September 1 through April 30) in 2017 through 2020. Participants were children younger than 5 years with medically attended ARI.

Exposure

For the nirsevimab effectiveness analyses, nirsevimab receipt among infants younger than 8 months as of or born after October 1, 2023.

Main Outcome and Measure

Medically attended RSV-associated ARI.

Results

Overall, 28 689 children younger than 5 years with medically attended ARI were enrolled, including 9536 during September 1, 2023, through April 30, 2024, and 19 153 during the same calendar period of 2017-2020. Of these children, 16 196 (57%) were male, and 12 444 (43.4) were female; the median (IQR) age was 15 (6-29) months. During 2023-2024, the proportion of children with RSV was 23% (2199/9490) among all medically attended episodes, similar to 2017-2020. RSV-associated hospitalization rates in 2023-2024 were similar to average 2017-2020 seasonal rates with 5.0 (95% CI, 4.6-5.3) per 1000 among children younger than 5 years; the highest rates were among children aged 0 to 2 months (26.6; 95% CI, 23.0-30.2). Low maternal RSV vaccine uptake precluded assessment of effectiveness. Overall, 10 of 765 case patients (1%) who were RSV positive and 126 of 851 control patients (15%) who were RSV negative received nirsevimab. Nirsevimab effectiveness was 89% (95% CI, 79%-94%) against medically attended RSV-associated ARI and 93% (95% CI, 82%-97%) against RSV-associated hospitalization. Among 229 sequenced specimens, there were no differences in nirsevimab binding site mutations by infant nirsevimab receipt status.

Conclusions and Relevance

This analysis documented the continued high burden of medically attended RSV-associated ARI among young children in the US. There is a potential for substantial public health impact with increased and equitable prevention product coverage in future seasons.

Introduction

Respiratory syncytial virus (RSV) is the leading cause of hospitalization in US infants and accounts for 50 000 to 80 000 hospitalizations annually in children younger than 5 years.^1,2,3,4 The highest hospitalization rates occur during the first months of life, and most RSV-associated hospitalizations occur in healthy, term infants.^5,6 In the US, RSV circulation typically follows a seasonal pattern, lasts a median of 27 weeks, and peaks nationally during December through February each year.^7,8 RSV circulation was disrupted after the COVID-19 pandemic, which resulted in earlier season onset and higher hospitalization rates during the atypical 2021 and 2022 seasons.^6,9,10 Before 2023, only palivizumab, a monoclonal antibody, was recommended to prevent severe RSV disease in a small number of high-risk infants.^11,12

In 2023, 2 RSV prevention products were approved by the US Food and Drug Administration and recommended by the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices to protect infants from RSV lower respiratory tract illness. Nirsevimab, a long-acting monoclonal antibody that prevents infection by binding to site Ø of the RSV F protein in its prefusion state, was recommended in August 2023 for all infants younger than 8 months who were born during or entering their first RSV season. Nirsevimab was also recommended for some children aged 8 to 19 months at increased risk for severe RSV disease and entering their second RSV season.¹³ In September 2023, a maternal RSV F protein vaccine (Abrysvo; Pfizer) was recommended using seasonal administration for pregnant people during 32 to 36 weeks of pregnancy to prevent RSV lower respiratory tract illness in young infants.¹⁴ Either maternal RSV vaccination during pregnancy or infant nirsevimab administration is recommended to prevent RSV-associated lower respiratory tract illness among infants, but both are not needed for most infants. These new RSV prevention products are expected to have a notable impact on hospitalizations and medically attended care visits among young children, and postlicensure studies are needed to assess their effectiveness and impact.

The New Vaccine Surveillance Network (NVSN) conducts prospective, population-based surveillance for acute respiratory illness (ARI) in children with systematic testing for respiratory viruses, including RSV, at 7 US pediatric academic medical centers. Using data from NVSN, we compare the epidemiology and disease burden of RSV among children younger than 5 years, including RSV seasonality, hospitalization incidence rates, and in-hospital outcomes during the 2023-2024 RSV season with 3 prepandemic RSV seasons (2017-2020). We also estimate the effectiveness of nirsevimab to prevent medically attended RSV-associated ARI and characterize the genomic features of circulating RSV subtypes during the 2023-2024 season.

Methods

Study activities during 2017-2020 were reviewed and approved by the institutional review boards at CDC and each site. Study activities during 2023-2024 were reviewed by CDC, were deemed not research, and were conducted consistent with applicable federal law and CDC policy. This analysis adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for observational studies.

NVSN Study Design and Data Collection

The NVSN includes 7 academic medical centers. Sites enrolled children meeting a standard case definition for ARI who received medical care in the outpatient, urgent care, or emergency department setting or were hospitalized (eMethods in Supplement 1).¹⁵ Demographic, clinical, and immunization data were systematically collected through parent/guardian interviews, medical record abstraction, outpatient records, and state immunization information systems. RSV prevention product receipt status was determined using a hierarchical approach based on documentation in the state immunization information system, electronic medical record (including outpatient and birth hospital records), or plausible self-report.

Children were included in this analysis if they were younger than 5 years and received care for ARI in a surveillance outpatient clinic, urgent care, emergency department, or hospital from September 1, 2023, through April 30, 2024 (2023-2024 season), or during the same calendar months during the 2017-2020 RSV seasons. The 2017-2020 RSV seasons were chosen to represent recent typical RSV seasons in the United States because previous analyses have documented that RSV circulation changed during the COVID-19 pandemic.⁷ The populations for each analysis are shown in eFigure 1 in Supplement 1.

Laboratory Methods

Midturbinate nasal, oropharyngeal, or tracheal (intubated patients only) specimens were collected from enrolled children and tested for RSV at each site by commercial or institution-specific in-house reverse transcription–polymerase chain reaction (RT-PCR) assays. RSV-positive specimens were typed as RSV-A or RSV-B. When available, RSV detections from clinical RT-PCR testing were also used.

Statistical Analysis

Seasonality, Prevention Product Uptake, and Hospitalization Outcomes

Time trends in RSV detection among all children with medically attended ARI were characterized by calculating a 3-week moving average RSV percent positivity among weekly ARI detections in all care settings by season. For the 2023-2024 season, percent positivity and the distribution of RSV-A and RSV-B subtypes were also calculated by site.

Participant characteristics and in-hospital outcomes among all hospitalized children with RSV-associated ARI were summarized with descriptive statistics. RSV prevention product receipt was also summarized among children with medically attended ARI in their first or second RSV season. Parent-reported race and ethnicity data were summarized to characterize the representativeness of the analytic population and identify patient characteristics associated with prevention product uptake. In-hospital outcomes were compared by period (2023-2024 vs 2017-2020) using χ² tests for categorical variables and Wilcoxon rank sum for continuous variables.

RSV-Associated Hospitalization Incidence Rates

NVSN methods for estimation of incidence rates have been previously described.^5,6 Hospitalizations in residents of defined catchment area counties for the 7 sites were included in numerators. Numerators were adjusted for enrollment rates, weeks with less than 7 days of surveillance, test sensitivity, and market share (eMethods in Supplement 1). County-specific denominators were obtained from US bridged-race population estimates. Rates were calculated per 1000 children and 95% bootstrap percentile CIs were determined based on 1000 bootstrap samples for each rate. Bootstrap rate ratios with 95% bootstrap percentile CIs were calculated to compare age-based RSV-associated hospitalization rates from September through April 2023-2024 to average age-based rates for the 2017-2020 RSV seasons.

Nirsevimab Effectiveness

A test-negative design was used to estimate the effectiveness of nirsevimab among infants in their first RSV season (eMethods in Supplement 1). Infants were included if they were younger than 8 months as of October 1, 2023, or born after October 1, 2023. Infants were excluded if they received nirsevimab less than 7 days before symptom onset, they received palivizumab, or their birth parent received maternal RSV vaccine during pregnancy. Cases and controls were infants with positive and negative RT-PCR tests for RSV, respectively. State-level RSV RT-PCR percent positivity thresholds of 3% were used to define the beginning and end weeks of the analysis by site (eTable 1 in Supplement 1).^8,16 Nirsevimab effectiveness was estimated using multivariable logistic regression models, comparing the odds of nirsevimab receipt between cases and controls while adjusting for site, age in months, month of enrollment, and presence of 1 or more high-risk medical condition for severe RSV disease.¹⁷ Effectiveness was calculated as (1- adjusted odds ratio) × 100%.

Genomic Sequencing

A nested matched case-control design was used to compare the genomic features of RSV infections among infants who received nirsevimab 7 or more days before symptom onset to infections among infants without nirsevimab receipt. Specimens were eligible for sequencing if they had PCR cycle threshold values of 28 or lower and the child had not received palivizumab or maternal vaccine. Sequencing was performed via twist capture probe method and Illumina NovaSeq S4 flow cell or by hybridization capture using the Illumina NextSeq 2000 or NovaSeq 6000 (eMethods in Supplement 1).¹⁸

All analyses were performed in SAS version 9.4 (SAS Institute). Statistical significance was set a priori at P < .05.

Results

Participant Enrollment and RSV Seasonality

Overall, 28 689 children younger than 5 years with medically attended ARI were enrolled, including 9536 during September 1, 2023, through April 30, 2024, and 19 153 during the same calendar period of 2017-2020 (eFigure 1 in Supplement 1). Among 28 643 children with documented highest level of care, the proportion with RSV among children in all settings was 26% (7504/28 643) and 36% (4507/12 684) among hospitalized children (eTable 2 in Supplement 1). Of these children, 16 196 (57%) were male, and 12 444 (43.4%) were female; the median (IQR) age was 15 (6-29) months. A total of 7297 (26%) were Hispanic/Latino, 8484 (30%) were non-Hispanic Black or African American, and 9442 (33%) were non-Hispanic White (eTable 3 in Supplement 1).

The 2023-2024 RSV season occurred earlier than during the 2017-2020 seasons with RSV detection increasing by September or October at all sites during 2023-2024 (Figure 1A-G). RSV detections peaked in November and December during the 2023-2024 season compared with December and January during the 2017-2020 seasons (eFigure 2 in Supplement 1). Nirsevimab became available at each site within 2 weeks before or some time after state-level RSV RT-PCR percent positivity exceeded 3%, indicating the start of RSV season. Maternal RSV vaccine became available by recommendation after the start of the RSV season at 2 sites. Of 2037 medically attended episodes with successful RSV typing, 904 (44%) were RSV-A and 1133 (56%) RSV-B (Figure 1H).

Figure 1. — Availability is shown by epidemiologic week and site (A-G) and RSV subtype distribution by site (H). NREVSS indicates National Respiratory and Enteric Surveillance System.

During 2023-2024, among enrolled infants with ARI in their first RSV season, 402 of 2989 infants (14%) received nirsevimab, 16 of 2989 (1%) received palivizumab, and 70 of 1737 (4%) younger than 6 months at enrollment were born to maternal RSV vaccine recipients (eTable 3 in Supplement 1). Infants whose mothers received maternal RSV vaccine were younger at enrollment and more frequently had private or self-pay insurance status compared with infants whose mothers did not receive maternal RSV vaccine. Receipt of maternal RSV vaccine also varied by parent-reported race and ethnicity of the infant and by site (eTable 4 in Supplement 1). Among children entering their second RSV season, 40 of 2620 (2%) received nirsevimab and 33 of 2620 (1%) received palivizumab (eTable 3 in Supplement 1).

RSV-Associated Hospitalization Characteristics, Outcomes, and Incidence Rates

Among 4507 children hospitalized with RSV-associated ARI during the 2023-2024 and 2017-2020 RSV seasons, the median age was 7 months IQR, 2-17 months), 2897 (64%) were younger than 12 months with 1286 (29%) aged 0 to 2 months, and 961 children (21%) had underlying medical conditions. Compared with the 2017-2020 seasons, the age distribution was older during the 2023-2024 RSV season (median age, 9 months vs 6 months), and the frequency of underlying medical conditions was similar (Table 1).

Table 1. Baseline Characteristics of Children Younger Than 5 Years Hospitalized With Respiratory Syncytial Virus–Associated Acute Respiratory Illness: New Vaccine Surveillance Network, September Through April 2023-2024 and 2017-2020 (N = 4507).

Characteristic	No. (%)
Characteristic	Total	2017-2020	2023-2024
Total enrolled (row %)	4507	3265 (72.4)	1242 (27.6)
Age, median (IQR), mo	7 (2-17)	6 (2-15)	9 (3-21)
Age group, mo
0-2	1286 (28.5)	991 (30.4)	295 (23.8)
3-5	779 (17.3)	588 (18.0)	191 (15.4)
6-11	832 (18.5)	597 (18.3)	235 (18.9)
12-23	842 (18.7)	599 (18.4)	243 (19.6)
24-59	768 (17.0)	490 (15.0)	278 (22.4)
Sex
Female	1982 (44.0)	1426 (43.7)	556 (44.8)
Male	2524 (56.0)	1838 (56.3)	686 (55.2)
Unknown	1 (0.02)	1 (0.03)	0
Race and ethnicity^a
American Indian/Alaska Native, non-Hispanic	41 (0.9)	31 (1.0)	10 (0.8)
Asian, non-Hispanic	207 (4.6)	111 (3.4)	96 (7.7)
Black or African American, non-Hispanic	743 (16.5)	576 (17.6)	167 (13.5)
Hispanic/Latino	1118 (24.8)	805 (24.7)	313 (25.2)
Multiple race or other nonspecified, non-Hispanic	210 (4.7)	160 (4.9)	50 (4.0)
Native Hawaiian/Other Pacific Islander, non-Hispanic	35 (0.8)	22 (0.7)	13 (1.1)
White, non-Hispanic	2119 (47.0)	1539 (47.1)	580 (46.7)
Unknown	34 (0.8)	21 (0.6)	13 (1.1)
Insurance status
Public	2545 (56.5)	1931 (59.1)	614 (49.4)
Private	1635 (36.3)	1126 (34.5)	509 (41.0)
Public and private	41 (0.9)	27 (0.8)	14 (1.1)
Self-pay (none)	218 (4.8)	150 (4.6)	68 (5.5)
Unknown	68 (1.5)	31 (1.0)	37 (3.0)
Site
Cincinnati, OH	416 (9.2)	343 (10.5)	73 (5.9)
Houston, TX	922 (20.5)	691 (21.2)	231 (18.6)
Kansas City, MO	404 (9.0)	309 (9.5)	95 (6.6)
Nashville, TN	526 (11.7)	418 (12.8)	108 (8.7)
Pittsburgh, PA	1135 (25.2)	820 (25.1)	315 (25.4)
Rochester, NY	521 (11.6)	381 (11.7)	140 (11.3)
Seattle, WA	583 (12.9)	303 (9.3)	280 (22.5)
Comorbid condition
None	3546 (78.7)	2608 (79.9)	938 (75.5)
Respiratory condition^b	468 (10.4)	306 (9.4)	162 (13.0)
Cardiovascular condition^c	229 (5.1)	154 (4.7)	75 (6.0)
Neurologic condition^d	180 (4.0)	126 (3.9)	54 (4.4)
Immunocompromised^e	59 (1.3)	47 (1.4)	12 (1.0)
History of prematurity (among children aged <2 y)^f	771 (20.6)	567 (20.8)	204 (21.4)

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^{^a}

Race and ethnicity were self-reported during the parent interview.

^{^b}

Asthma, reactive airway disease, cystic fibrosis, bronchopulmonary dysplasia, chronic lung disease of prematurity, or other chronic lung condition.

^{^c}

Congenital heart malformation or other heart condition.

^{^d}

Cerebral palsy, seizure disorder, or other neurologic or neuromuscular disorder.

^{^e}

Immune condition, transplant recipient (peripheral blood stem cells, bone marrow, cord blood, or organ), cancer, and sickle cell anemia.

^{^f}

Prematurity was defined as birth at less than 37 weeks’ gestation.

Among the 4507 children with RSV-associated hospitalizations during the 2023-2024 and 2017-2020 RSV seasons, 3030 (67%) received supplemental oxygen, 1022 (23%) received intensive care, 161 (4%) received mechanical ventilation, and 1 child died (Table 2). Controlling for age and underlying medical conditions, children hospitalized with RSV during the 2023-2024 RSV season were more likely to receive supplemental oxygen and intensive care but had no difference in median length of stay and were less likely to require mechanical ventilation compared with children hospitalized during the 2017-2020 seasons (Table 2).

Table 2. In-Hospital Outcomes and Length of Stay Among Children Younger Than 5 Years Hospitalized With Respiratory Syncytial Virus–Associated Acute Respiratory Illness: New Vaccine Surveillance Network, September Through April 2023-2024 and 2017-2020 (N = 4507).

Outcome	No. (%)			aOR (95%CI)^a	P value
Outcome	Total	2017-2020	2023-2024	aOR (95%CI)^a	P value
Total enrolled (row %)	4507	3265 (72.4)	1242 (27.6)	NA	NA
Outcome
Supplemental oxygen receipt	3030 (67.2)	2075 (63.6)	955 (76.9)	1.90 (1.63-2.20)	<.001
Intensive care unit admission	1022 (22.7)	713 (21.8)	309 (24.9)	1.25 (1.07-1.46)	.005
Mechanical ventilation	161 (3.6)	132 (4.0)	29 (2.3)	0.63 (0.41-0.94)	.035
Death	1 (0.0)	0	1 (0.1)	NA	NA
Length of stay, median (IQR), d	2 (1-4)	2 (1-4)	2 (1-3)	NA	NA
Length of stay, d
0-1	1578 (35.0)	1152 (35.3)	426 (34.3)	1.0 [Reference]	NA
2	1136 (25.2)	805 (24.7)	331 (26.7)	1.12 (0.94-1.33)	.19
3-4	986 (21.9)	702 (21.5)	284 (22.9)	1.15 (0.96-1.37)	.14
≥5	807 (17.9)	606 (18.6)	201 (16.2)	0.95 (0.78-1.15)	.57

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Abbreviations: aOR, adjusted odds ratio; NA, not applicable.

^{^a}

Odds ratios were calculated using logistic regression adjusting for age and underlying condition.

During the 2023-2024 season, RSV-associated hospitalization rates were 5.0 (95% CI, 4.6-5.3) per 1000 children younger than 5 years, with the highest incidence rates among children aged 0 to 2 months (26.6; 95% CI, 23.0-30.2), followed by children aged 3 to 5 months (16.2; 95% CI, 13.5-19.0) (Figure 2 and eTable 5 in Supplement 1). Incidence rates varied by site (eTable 6 in Supplement 1). RSV-associated hospitalization incidence rates were similar during the 2023-2024 season compared with average seasonal rates from the 2017-2020 seasons among children aged 0 to 11 months.

Nirsevimab Effectiveness

Of 2989 infants younger than 8 months as of October 1, 2023, or born after October 1, 1616 infants (54%) were included in the analysis of nirsevimab effectiveness, including 875 hospitalized infants, 523 with emergency department visits, and 218 with outpatient/urgent care visits (eTable 7 in Supplement 1). Overall, 10 of 765 case patients (1%) and 126 of 851 control patients (15%) received nirsevimab. Receipt of nirsevimab was more frequent among infants with high-risk medical conditions vs without (22/55 infants [40%] vs 114/1561 [7%]; P < .001) but similar by preterm and insurance status (eTable 7 in Supplement 1). Median (IQR) interval from nirsevimab receipt to ARI symptom onset was 44 (21-73) days (eFigure 3 in Supplement 1). Nirsevimab effectiveness was 89% (95% CI, 79%-94%) against any medically attended RSV-associated ARI and 93% (95% CI, 82%-97%) against RSV-associated hospitalization (eTable 8 in Supplement 1). Of the 10 infants with RSV infections with symptom onset 7 or more days after receiving nirsevimab, the median age was 4 months (range, 0-6 months), and 5 had no underlying high-risk medical conditions or history of prematurity; RSV infections occurred a mean of 5.1 weeks after nirsevimab receipt (range, 1.1-11 weeks) (eTable 9 in Supplement 1).

RSV Genomic Features

Overall, 240 samples from children younger than 2 years underwent whole-genome sequencing, including 21 samples from nirsevimab recipients, 56 age- and site-matched samples from children without nirsevimab receipt, and 163 samples from other children without nirsevimab or maternal RSV vaccine receipt (eTable 10 in Supplement 1). Overall, 229 samples (95%) were successfully sequenced and genotyped, including 16 samples from nirsevimab-recipients. All genomes were genotype GA2.3.5 (RSV-A, n = 110) or GB5.0.5a (RSV-B, n = 119). RSV-A genomes belonged to at least 4 distinct clades, and RSV-B genomes, 2 distinct clades (eFigure 4A and B in Supplement 1). Substitutions in the nirsevimab binding site (antigenic site Ø) were not detected in RSV-A viruses. Among 119 RSV-B viruses, 3 known substitutions were detected in the nirsevimab binding site, including I206M (119/119, 100%), Q209R (118/119, 99%), and S211N (117/119, 98%). We also identified 1 additional mutation, L204S, with almost 50% frequency of 1 nucleotide (T 41%, /C 59%) at position 611 in a sample from a nirsevimab recipient.

Discussion

In this multicenter analysis of more than 28 000 children less than 5 years of age, RSV seasonality and the contribution of RSV to overall medically attended ARI burden was similar during the 2023-2024 season and recent prepandemic seasons (2017-2020) with RSV infection associated with more than a quarter of all medically attended ARI episodes. RSV-associated hospitalization incidence rates were also similar among children aged 0 to 11 months during the 2 time periods. Nirsevimab was 89% effective (95% CI, 79%-94%) at preventing medically attended RSV-associated ARI and 93% effective (95% CI, 82%-97%) against RSV-associated hospitalization. However, only a small fraction of infants in their first RSV season had received nirsevimab or were born to mothers who received maternal RSV vaccine.

For several seasons since the COVID-19 pandemic began in 2020, RSV circulation in the US was atypical with unusually early circulation during the 2021-2022 and 2022-2023 seasons.⁷ Some reports also suggested a shift in age distribution of RSV-associated hospitalization with higher burden among children aged 24 to 59 months, possibly because of delayed RSV exposure during the COVID-19 pandemic.^6,10,19 Our analysis suggests that RSV circulation may be returning to prepandemic patterns with respect to timing, the distribution of RSV-A and RSV-B subtypes, and incidence rates of hospitalization by age.²⁰ Predictable seasonality will facilitate RSV prevention product implementation and effectiveness assessment efforts that depend on anticipating season onset. The 2023-2024 RSV season occurred earlier than prepandemic seasons across NVSN sites and demonstrates geographic variability in the onset of RSV circulation, which may be an important consideration for local and regional product administration guidelines.

Given the short median interval from nirsevimab receipt to symptom onset of 44 days in our analysis, our estimate of nirsevimab effectiveness likely reflects the expected maximum protection from nirsevimab early after administration when serum monoclonal antibody titers are at their highest. A pooled analysis of 2 prelicensure trials of nirsevimab effectiveness among 2579 infants in their first RSV season followed up through 150 days after injection found that nirsevimab was 81% effective (95% CI, 62%-90%) against RSV-associated hospitalization.¹³ Limited postlicensure data from European countries have found nirsevimab effectiveness of 83% (95% CI, 68%-92%), 82% (95% CI, 66%-90%), and 70% (95% CI, 38%-89%) against hospitalization with RSV-associated lower respiratory tract infection in infants in their first RSV season.^21,22,23 Additional studies are needed to assess nirsevimab effectiveness under real-world conditions for longer intervals from receipt in seasons when prevention products are received by more infants ahead of RSV circulation, by dose, and among young children with high-risk medical conditions entering their second RSV season.

We found low uptake of the Pfizer maternal RSV vaccine (Abrysvo) among children with medically attended ARI at study sites during the 2023-2024 season. Although the maternal RSV vaccine became available in September 2023, the narrow eligibility window for administration to pregnant persons (32-36 weeks’ gestation), low uptake likely resulting from a variety of factors in the first season of introduction, and the early onset of RSV circulation during the 2023-2024 season precluded assessment of maternal RSV vaccine effectiveness for preventing severe RSV disease in young infants. Data on maternal RSV vaccine effectiveness are important to inform policy decisions about optimal strategies for prevention of RSV in young infants, especially in settings where introduction of multiple prevention strategies is less feasible.

We sequenced RSV specimens from infants who received nirsevimab to identify naturally occurring binding site changes on the F protein, which may reduce or increase nirsevimab susceptibility.^24,25 We found no nirsevimab binding site substitutions in RSV-A viruses, while nearly all RSB-B viruses contained 3 previously observed substitutions that are not known to disrupt nirsevimab binding. Notably, I206M and Q209R became dominant in the 2017-2018 RSV season while S211N emerged and has predominated since 2020.^9,26 Genomic surveillance of circulating RSV remains important to monitor binding site changes as nirsevimab use increases over time.^27,28

Strengths and Limitations

Strengths of this analysis include the use of multisite population-based surveillance with systematic molecular testing for RSV over multiple seasons among a geographically and demographically diverse population and assessment of nirsevimab effectiveness among more than 1600 children using the test-negative design, which has been used extensively to evaluate other respiratory virus vaccines and validated for estimating RSV prevention product effectiveness.²⁹ However, several limitations should be considered when interpreting findings. First, NVSN sites are academic pediatric health systems with catchment areas and hospitalization acuity that may not be nationally representative. Nevertheless, RSV incidence rates and in-hospital severity in this analysis are similar to previous reports from other US studies.^2,3 Second, nirsevimab became available at most sites after RSV circulation began, which resulted in a relatively short interval from administration to respiratory illness onset. Nirsevimab effectiveness over the course of a full RSV season is expected to be somewhat lower than our estimate because of antibody decay.

Conclusions

During the first season with RSV prevention products recommended for all US infants, limited product availability and low coverage during peak RSV circulation likely limited prevention product impact. However, results from this analysis document the continued high burden of RSV disease among infants and young children in the US and suggest the potential for substantial public health impact with increased and equitable prevention product coverage in future seasons. Additional studies are needed to evaluate the effectiveness and impact of these products over the course of a full RSV season and to monitor how the epidemiology of RSV in children evolves with further availability and uptake of pediatric RSV prevention products.

Supplement 1.

eMethods

eTable 1. Analytic time periods by site for nirsevimab effectiveness analyses

eTable 2. Percentage of medically attended acute respiratory illness episodes positive for respiratory syncytial virus by reverse-transcription polymerase chain reaction testing by highest level of care and season

eTable 3. Baseline characteristics of children <5 years of age with medically attended acute respiratory illness

eTable 4. Characteristics at enrollment of infants aged <6 months with medically attended acute respiratory illness by maternal RSV vaccination status

eTable 5. Incidence rates of RSV-associated hospitalizations per 1,000 children by age group and season among children <5 years of age

eTable 6. Incidence rates of RSV-associated hospitalizations per 1,000 children by site among children <5 years of age

eTable 7. Infants born during or entering their first respiratory syncytial virus (RSV) season with medically attended acute respiratory illness, by RSV test result and nirsevimab receipt

eTable 8. Nirsevimab effectiveness in preventing RSV-associated hospitalization and any medically attended illness among infants entering or born during their first RSV season

eTable 9. Characteristics of infants with respiratory syncytial virus infections >7 days after receipt of nirsevimab

eTable 10. Characteristics of children with RSV-associated medically-attended ARI with sequenced respiratory samples by nirsevimab receipt status

eFigure 1. Enrollment and analytic population flow

eFigure 2. Respiratory syncytial virus (RSV) percent positivity by season among children <5 years of age with medically attended acute respiratory illness

eFigure 3. Time from receipt of nirsevimab to acute respiratory illness symptom onset among infants born during or entering their first respiratory syncytial virus (RSV) season

eFigure 4. Phylogenetic diversity and distribution of RSV-A and RSV-B viruses

eReferences

jamapediatr-e245572-s001.pdf^{(1.6MB, pdf)}

Supplement 2.

Nonauthor collaborators

jamapediatr-e245572-s002.pdf^{(124.4KB, pdf)}

Supplement 3.

Data sharing statement

jamapediatr-e245572-s003.pdf^{(14.9KB, pdf)}

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Supplementary Materials