
==== Front
eClinicalMedicine
EClinicalMedicine
eClinicalMedicine
2589-5370
Elsevier

S2589-5370(24)00369-9
10.1016/j.eclinm.2024.102790
102790
Articles
An evaluation of 2015–2019 United States respiratory syncytial virus hospitalizations as a framework to develop potential strategies for the preventiosn of the hospital burden among infants
Suss Robert J. a
Simões Eric A.F. eric.simoes@cuanschutz.edu
ab∗
a Department of Paediatric Infectious Diseases, University of Colorado School of Medicine and Children's Hospital Colorado Aurora, CO, USA
b Centre for Global Health, Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA
∗ Corresponding author. University of Colorado School of Medicine, 12123 E 16th Ave, Aurora, CO 80045, USA. eric.simoes@cuanschutz.edu
22 8 2024
9 2024
22 8 2024
75 1027903 6 2024
30 7 2024
30 7 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Summary

Background

New options for RSV prevention are available for the 2023/2024 RSV season, nirsevimab, a monocolonal antibody, and RSVpreF maternal vaccine, that target infants entering their first RSV season. Countries vary in implementation of one or both strategies to reduce the RSV burden among infants.

Methods

This study utilized retrospective cohort data from 47 children's hospitals in the United States Pediatric Health Information Systems (PHIS) database between 2015 and 2019. Patients hospitalized with RSV or bronchiolitis aged 0–15 months were included based on birth timing relative to the RSV season. Annualized hospitalization rates per 100,000 were calculated from extrapolated population estimates. Recommended prevention strategies were applied to age cohorts to compare protection afforded by nirsevimab and maternal immunization strategies.

Findings

72,209 RSV hospitalizations were included in the study. Compared to those born nine months prior to the season (n = 2116; 375/100,000 per year), those born at the start of the season were 9.44 (9.02–9.89) times as likely to be hospitalized for RSV (n = 19,979; 3542/100,000 per year). Both strategies would prevent most of these hospitalizations. Maternal immunization would not prevent hospitalizations of infants aged two or 3 months at season start, who were respectively 2.95 (2.80–3.10) and 2.22 (2.11–2.34) times as likely to be hospitalized. Proportionally more preterm infants were hospitalized in their second RSV season, resulting in less protection (up to 40% to >80% unprotected).

Interpretation

These findings suggest without a more narrowly targeted strategy, current nirsevimab recommendations may not be as cost efficient for infants born further outside of the RSV season, and those born later in the season who are more likely to be hospitalized in subsequent seasons. Conversely, it may be more beneficial to begin maternal immunization further in advance of the season. Immunization strategies should be based on the RSV seasons within specific regions.

Funding

None.

Keywords

Acute lower respiratory infection (ALRI)
Prophylaxis
RSV
Public health
==== Body
pmc Research in context

Evidence before this study

Epidemiological studies, clinical trial data, and any other relevant scholarly publications were identified by searches of Elsevier, EBSCO and PubMed databases. Relevant findings regarding the epidemiology and disease burden of respiratory syncytial virus (RSV), as well as safety and efficacy findings for nirsevemab and the maternal RSVpreF vaccine were included. Search terms such as “nirsevimab”, “RSV hospitalization”, “maternal immunization RSV”, and “RSV seasonality of birth” were used. The most recently published data on both immunizations were included, given that both have recently received the approval of various regulatory bodies. Searches favored the most recent epidemiological findings from the pre-pandemic era (e.g., prior to 2020, but no earlier than 2010). Disease burden of RSV, especially among infants under one year of age, has been well-established in the literature. The safety and efficacy profiles of both nirsevimab and the RSVpreF vaccine have also been demonstrated internationally by recent clinical trial data. The magnitude of impact, and the cost effectiveness of both immunization strategies have not been as extensively studied thus far. Recent cost effective analyses by the sanofi group have used static models with modeled estimates of the burden of disease. None have used large databases to study the impact of varying ages at the start of the RSV season on the monthly risk of hospitalization for that cohort based on actual data.

Added value of this study

This is one of the first studies to examine in detail the potential impact of current recommendations for the newly available RSV prophylaxis options, using pre COVID 19 pandemic data. The data show that protection varies between strategies and is partly dependent on birth timing relative to the RSV season; globally, the most protective and most cost-effective approach may be tailored depending on the epidemiology of RSV in a specific geographic region, using these data.

Implications of all the available evidence

Current recommendations for nirsevimab prophylaxis may not be as useful as anticipated for older infants, particularly those born more than four months prior to the RSV season. Additionally, recommendations for maternal immunization may fall short in protecting infants born more than only one month prior to the start of the season. The magnitude of preventable hospitalization at a given age when administering prophylaxis to most of the infant population, should be a key consideration in deciding policy regarding these new products. Data should be tailored to individual country, and in some countries, regions, and local data on the seasonality of the RSV season rather than broad recommendations.

Introduction

In the last several months, two different prevention strategies–nirsevimab, a monocolonal antibody treatment, and Pfizer's RSVpreF–have received approval in many countries for RSV prophylaxis in healthy infant populations. Nirsevimab was approved by the EMA in the European Union at the end of October 2022, the MHRA in the United Kingdom in November 2022, Health Canada in April 2023, and the FDA in the United States in July 2023; it is additionally awaiting approval in China and Japan.1 In August 2023, RSV PreF was approved for maternal immunization in the US, all 27 member states in the EU, Iceland, Liechtenstein, and Norway, for the prevention of severe RSV LRTI in infants from birth through 6 months; it was later approved in many other countries, including the UK, Canada and Australia in late 2023 to early 2024.2, 3, 4, 5

In August 2023, the Advisory Committee on Immunization Practices (ACIP) in the US recommended nirsevimab for all infants under eight months of age during their first week of life during or shortly before the RSV season.6 The RSV PreF maternal immunization is recommended between September and January at 32–36 weeks gestation. These recommendations were based on vaccine efficacies of 76.5% against severe medically attended RSV-LRTI, 57.3% against medically attended RSV-LRTI, and 48.2% against RSV-LRTI hospitalizations, within this interval.7 For nirsevimab, recent findings have demonstrated a 71.1–79.5% reduced risk of medically-attended RSV-LRTI, as well as potential risk reductions in RSV-LRTI hospital admissions of over 75%, relative to placebo.8

Overall, the burden of RSV in the US is primarily carried by hospitalization, particularly in infants aged under one year.9 An estimated 58,000 to 80,000 RSV hospitalizations occur annually in children under five years of age in the United States, with overall rates estimated at three-to-five per 1000 children, and an approximate four-to-fivefold increase in these rates among children under 1 year.10,11

One area of interest is the impact of new prevention modalities on preterm infants, who are at increased risk of RSV. Griffin et al. have demonstrated that single-dose nirsevimab reduced both RSV infection incidence and hospitalization in healthy preterm infants up to one year of age.12 Other findings suggest a higher risk of RSV hospitalization, ICU admission and mechanical ventilation use among those born preterm at 29–34 wGA, relative to full term infants.13

Due to variations in approval for both modalities among countries, recommendations also vary. In this retrospective analysis, hypothetical scenarios using recommendations for nirsevimab and RSVpreF were applied to RSV-associated hospitalizations in US children's hospitals. Strategies were compared between term and preterm infants, and between regional and classically defined seasonality for the continental US. It was hypothesized that (1) infants born during or within one month of the start of the RSV season would have the highest risk of hospitalization; (2) the monoclonal antibody (nirsevimab) strategy would provide potential protection against most hospitalizations, regardless of age; and (3) the maternal immunization (RSVpreF) strategy would provide potential protection against most hospitalizations within the first six months of life.

Methods

Patient cohorts were identified using the Pediatric Health Information Systems (PHIS) database from the Children's Hospital Association, which contains billing records from US member hospitals. In the PHIS Cohort Builder, two cohorts were identified by ICD-9/10 diagnostic codes: the RSV cohort (ICD codes 466.11, 079.6, 480.1, J21.0, J12.1, B97.4, and J20.5); and the bronchiolitis cohort (ICD codes 466.0, 466.19, J20.8, J20.9, J21.1, J21.8, and J21.9). Bronchiolitis patients without RSV codes were used as a sensitivity analysis because RSV causes most bronchiolitis in the RSV season. In comparison with chart data at Children's Hospital Colorado, identification of RSV hospitalizations with this method demonstrated overestimation in PHIS by 6.8% for all encounters, and underestimation of hospitalizations by −2.7%, between 2016 and 2019 (Supplemental Table S1). All patients were 15 months or younger at admission. This allowed comparison of those born nine months before the start of the season, who would be 15 months old by the end of the season, to other ages for the same duration. Hospitals with data for at least two full, consecutive calendar years between 2015 and the first quarter of 2023 (31 March 2023) were initially included. Encounters at Florida hospitals were excluded from the analysis, due to the seasonal irregularity of RSV activity.14,15 One hospital that only reported to PHIS after 2020 was excluded. Ultimately, 47 continental US children's hospitals with encounters between June 2015 and December 2019 were included. This time range provided data for the five most recent years of typical RSV seasonality, prior to Covid-19 pandemic disruption.14,16

RSV seasons in 2015–2019 were defined as starting on the first of three consecutive weeks with more than six RSV hospitalizations and ending on the first of three consecutive weeks with six or fewer. This strategy was used previously to define seasonality within Colorado, in which 0.9% of inter-seasonal weeks (i.e., June to October) contained six or more weekly RSV hospitalizations.17 Using this strategy, 130 of 11,620, or 1.1% of all weeks observed, had more than six weekly RSV hospitalizations in the inter-seasonal period (Supplemental Table S2). Furthermore, there was substantial to almost perfect agreement between Children's Hospital Colorado chart and PHIS records in the number of seasonal weeks that meet this cutoff (kappa = 0.81, 95% CI 0.60–1.00). As such, the authors have also applied this methodology to a more recent analysis.18 Hospitalizations were also categorized according to the US Department of Health and Human Services (HHS)-defined regions that the CDC has used for RSV surveillance since 2007.14 Regional seasonality was defined by the mean start and end dates among hospitals. Hospital data by HHS region are summarized in Supplemental Tables S3 and S4.

Hospitalized RSV patients born from nine months prior to, through six months following, the start of the RSV season were categorized into birth cohorts by age at season start. To avoid counting birth timing with respect to more than one season, patients hospitalized in July or later were categorized by their age with respect to the upcoming season. Population-based estimates of RSV hospitalization incidence were calculated for each birth cohort.

An annual hospitalization rate per 100,000 was calculated by age for each birth cohort, and further by age of admission within each cohort. To estimate population at risk of RSV hospitalization, a population estimate per month of birth between 2015 and 2019 was extrapolated from the estimated rates of RSV hospitalization by month of age published by Rha et al.11 The mean population estimate for all ages 0–15 months was used as a constant denominator for all birth cohorts because patients could be admitted between 0 and 15 months of age for any season starting age. We did not account for the seasonality of birth.

Because both prophylaxis recommendations assume an RSV season from October through the end of March for most of the continental US,7,15 standard and regional seasonality were compared. Four hypothetical scenarios were applied as prevention strategies: (1) nirsevimab strategy with universal seasonality (as currently recommended); (2) maternal immunization with universal seasonality (as currently recommended); (3) nirsevimab strategy with regional seasonality; and (4) maternal immunization strategy with regional seasonality. Hospitalization counts were used to estimate the proportion of hospitalizations preventable for each modality. Scenarios assume the maximum potential coverage of each strategy: that all eligible children receive prophylaxis with six months of protection.

Eligibility for all scenarios was based on the recommendations from the American Academy of Pediatrics and ACIP as of 2023.7,15 Thus the nirsevimab strategy was applied to all hospitalizations at younger than eight months, beginning one month prior to the start of the season, or at birth during the season. Additionally, a relative risk (RR) of hospitalization was calculated for all birth cohorts, with regional seasonality, relative to the oldest cohort, which would not be eligible for nirsevimab, assuming six-months of protection. This analysis used the Benjamini-Hochberg method to account for multiple comparisons. The maternal immunization strategy covered hospitalizations of infants at gestational ages 32–36 weeks, between September and January. We also examined strategies among preterm infants using WHO preterm classifications.19 This provides hypothetical scenarios for countries that have approval for immunization at earlier preterm gestational ages (e.g., the UK and countries in the EU).

Patient demographic characteristics (i.e., sex, race, age distribution, ethnicity, use of Medicaid, median household income [based on 2010 census zip code estimates], preterm birth, presence of comorbidity, care unit of admission, and median length of stay) were compared between cohorts. Sociodemographic variables are provided by PHIS so are based on claims data. To compare RSV and bronchiolitis patient characteristics, significance tests (i.e., χ2-squared test, independent two-sample t-test, Mann–Whitney test, as appropriate) were performed. All analyses were conducted using Stata/SE 17.0 and R 4.3.0. This study received approval with institutional exemption from the Colorado Multiple Institutional Review Board (COMIRB) of the University of Colorado and Children's Hospital Colorado because it is secondary research. The study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for observational studies.

Role of the funding source

There was no funding for this study.

Results

For the defined time period between 2015 and 2019, a total of 72,209 RSV cases and 72,592 bronchiolitis-only cases were identified, for a total of 144,801 patients in the combined cohort. Data on gestational age was available for 35.8% of RSV (n = 25,875), 39.8% of bronchiolitis (n = 28,882), and 37.8% (n = 54,757) of combined total hospitalizations for each respective cohort. Medicaid use data was available for 98.9% of all cohorts, and income data for greater than 97.9%. Data for all other patient characteristics summarized in Table 1 was complete. There was a statistically significant difference in all patient characteristics between RSV and bronchiolitis patient encounters (p < 0.0001) (Table 1).Table 1 Patient Characteristics of RSV and Bronchiolitis Hospitalizations Ages 0–15 months, 2015–2019.

	RSV (N = 72,209)	Bronchiolitis (N = 72,592)	Total (N = 144,801)	
N (%)/mean (SD)	
Sex∗∗∗				
 Male	40,786 (56.5)	44,367 (61.1)	85,153 (58.8)	
 Female	31,394 (43.5)	28,221 (38.9)	59,615 (41.2)	
 Unknown	29 (.04)	4 (.01)	33 (.02)	
Age (Months)∗∗∗				
 0–3	40,274 (54.5)	20,667 (28.1)	60,941 (41.3)	
 4–6	13,421 (18.2)	16,050 (21.8)	29,471 (20.0)	
 7–9	8312 (11.3)	13,810 (18.8)	22,122 (15.0)	
 10–15	11,866 (16.1)	23,019 (31.3)	34,885 (23.7)	
Race∗∗∗				
 White	42,197 (58.4)	37,608 (51.8)	79,805 (55.1)	
 Black	13,337 (18.5)	19,507 (26.9)	32,844 (22.7)	
 Asian	2041 (2.8)	2184 (3.0)	4225 (2.9)	
 AI/AN	393 (.5)	296 (.4)	689 (.5)	
 NH/PI	490 (.7)	590 (.8)	1080 (.8)	
 Other	9975 (13.8)	9302 (12.8)	19,277 (13.3)	
 Missing/NA	3776 (5.2)	3105 (4.3)	6881 (4.8)	
Ethnicity∗∗∗				
 Hispanic or Latino	15,044 (20.8)	15,618 (21.5)	30,662 (21.2)	
 Not Hispanic or Latino	51,831 (71.8)	52,596 (72.5)	104,427 (72.1)	
 Unknown	5334 (7.4)	4378 (6.0)	9712 (6.7)	
ICU Admission∗∗∗	30,933 (42.8)	22,624 (31.2)	53,557 (37.0)	
LOS (days) Median [IQR]∗∗∗	4 [2, 6]	3 [2, 4]	3 [2, 5]	
Comorbidity∗∗∗	14,879 (20.6)	18,444 (25.4)	33,323 (23.0)	
Preterm∗∗∗	(N = 25,875)	(N = 28,882)	(N = 54,757)	
7568 (29.3)	9989 (34.6)	17,557 (32.1)	
Medicaid∗∗∗	(N = 71,534)	(N = 71,726)	(N = 143,260)	
43,126 (60.3)	46,022 (64.2)	89,148 (62.2)	
Median Household Income (USD)∗∗∗	(N = 70,653)	(N = 71,158)	(N = 141,811)	
44,540 (16,587)	43,399 (16,101)	43,968 (16,355)	
∗∗∗p < 0.0001.

Across regions, the season start ranged between late September and early December, and the season end ranged between March and early May (Supplemental Table S4). Hospital admissions, and rates per 100,000 hospitalizations, per year by birth cohort and admission age are presented in Supplemental Tables S5 and S6, respectively. Population estimates and hospitalization rates for ages 0–15 months are shown in Table 2. All admissions are presented using regionally-defined RSV seasonality.Table 2 RSV hospitalization rates and relative risk, 2015–2019, 0–15 months.

Age admitted (months)	Population estimate	Percent	Hospitalized	Rate/1000	Relative risk	
0	629,752	15.6	10,139	16.1	3.6	
1	544,900	21.1	13,677	25.1	5.6	
2	593,846	14.3	9264	15.6	3.5	
3	475,373	9.8	6370	13.4	3.0	
4	529,192	8.1	5239	9.9	2.2	
5	510,120	6.5	4234	8.3	1.8	
6	447,439	5.7	3669	8.2	1.8	
7	612,292	4.5	2939	4.8	1.1	
8	586,667	4.1	2640	4.5	1.0	
9	639,487	3.8	2494	3.9	0.9	
10	783,333	3.3	2115	2.7	0.6	
11	452,889	3.1	2038	4.5	REF	
12	590,833	3.3	2127	3.6	0.8	
13	533,333	3.0	1920	3.6	0.8	
14	484,000	2.6	1694	3.5	0.8	
15	611,111	2.5	1650	2.7	0.6	
All	9,024,568	100.0	64,818	7.2	1.6	
All <6 m	3,283,184	36.4	48,923	14.9	3.3	

RSV hospitalization rates per 100,000 by birth cohort were highest during the first five months of the RSV season, and for those born within four months (i.e., −2 to +2 months) of the start of the season (Table 3). Specifically, consistent with the first hypothesis, hospitalization rates at ages 0–15 months were highest among those born at the start of the season (3542 per 100,000, RR = 9.44, 95% CI 9.02–9.89), followed by those born one month after (1566 per 100,000, RR = 4.17 [ 3.98–4.38]) and one month before (1455 per 100,000, RR = 3.88 [3.69 4.07]) season start (Corresponding findings for bronchiolitis patients are shown in Supplemental Table S7.) RSV hospitalization rates with birth timing are summarized in Table 4. This table can be used to identify trends among children of various ages born at different times throughout the season. The time from season start added to the age at season start provides the age of admission. For example, the highest incidence of hospitalization is seen among those born at the start of the season at one month of age–1327 per 100,000, which comprises over one-third of the total 3542 per 100,000 stated above.Table 3 Relative risk (RR) of RSV hospitalization by birth timing, all ages 0–15 Months and during protection period, 2015–2019.

Age at season start (months)	Population estimate	All 0–15 months	During Protection Perioda	
N	Rate/100 K	RR	95% CI	padjb	N	Rate/100 K	RR	95% CI	padjb	
−6	564,036	87	15	0.04	0.03	0.05	0.034	87	15	0.04	0.04	0.05	0.034	
−5	564,036	239	42	0.11	0.10	0.13	0.031	239	42	0.12	0.11	0.14	0.028	
−4	564,036	590	105	0.28	0.25	0.31	0.025	590	105	0.30	0.27	0.33	0.022	
−3	564,036	1388	246	0.66	0.61	0.70	0.041	1388	246	0.70	0.66	0.75	0.041	
−2	564,036	5512	977	2.60	2.47	2.74	0.016	3525	625	1.78	1.69	1.88	0.025	
−1	564,036	8832	1566	4.17	3.98	4.38	0.003	7024	1245	3.55	3.38	3.73	0.003	
0	564,036	19,979	3542	9.44	9.02	9.89	0.003	18,201	3227	9.20	8.79	9.64	0.003	
1	564,036	8208	1455	3.88	3.69	4.07	0.003	6769	1200	3.42	3.26	3.60	0.003	
2	564,036	6236	1106	2.95	2.80	3.10	0.003	5225	926	2.64	2.51	2.78	0.013	
3	564,036	4695	832	2.22	2.11	2.34	0.022	4076	723	2.06	1.95	2.17	0.019	
4	564,036	3761	667	1.78	1.68	1.88	0.028	3369	597	1.70	1.61	1.80	0.031	
5	564,036	3152	559	1.49	1.41	1.58	0.038	2873	509	1.45	1.37	1.54	0.037	
6	564,036	2757	489	1.30	1.23	1.38	0.044	2531	449	1.28	1.21	1.36	0.044	
7	564,036	2414	428	1.14	1.08	1.21	0.047	2215	393	1.12	1.05	1.19	0.047	
8	564,036	2243	398	1.06	1.00	1.13	0.050	2067	366	1.04	0.98	1.11	0.050	
9	564,036	2116	375	REF	1978	351	REF	
All	9,024,568	72,209	800	2.13	2.04	2.23	0.019	62,157	735	2.09	2.00	2.19	0.016	
a The number and proportion of hospitalized infants per birth cohort that could receive protection with nirsevimab under current recommendations, assuming six months of protection: all infants eight months or younger (or at birth), during and one month prior to the start of the RSV season.

b Benjamini-Hochberg adjusted p-value.

Table 4 Monthly RSV hospitalizations/100,000 by birth timing, ages 0–15 months, 2015–2019.a

	

Using both regional and standard seasonality, the nirsevimab strategy could prevent most hospitalizations across all eligible birth cohorts, as hypothesized. With regional seasonality, it could prevent up to 40,744 hospitalizations among those born 2 months prior to two months after the start of the season, which accounts for over half (56%) of hospitalizations (i.e., 451 of 800 per 100,000 within the entire population). Among children six months or older at the start of the season, nirsevimab could prevent up to 6,813, or 9% of all hospitalizations within the population depending on the strategy (Table 5, Supplemental Table S8). Among all hospital admissions between 0 and 15 months of age, the greatest potential impact of maternal immunization was in those born between a month prior through two months after the start of the RSV season, where it can prevent up to 49% of hospitalizations with either strategy (Supplemental Table S8). In general, the impact of each strategy was similar between seasonality definitions (Table 5, Supplemental Table S8). As hypothesized, within the first 6 months of life, maternal immunization could cover 77% or 88% of hospitalizations using the regional or standard seasonality definitions, respectively (Supplemental Tables S5 and S8). Because maternal immunization would not address hospitalizations that occurred between 2 and 6 months of age in months 0–4 of the RSV season, this subset of birth cohorts was compared between the two seasonality definitions: HHS regions such as Atlanta and Dallas, showed greater coverage by maternal immunization using regional seasonality, compared to the October–March seasonality (Supplemental Table S4).Table 5 Prevention strategies for monthly RSV hospitalizations/100,000 by birth timing, ages 0–15 months, ICU + Inpatient 2015–2019.a

	

When comparing coverage of each strategy among gestational age groups, both strategies demonstrate increased protection with an increase in gestational age. For example, 58% vs 86% of extremely preterm (<28wGA) vs full-term (37–42 wGA) hospitalizations, respectively, could be prevented using a regional nirsevimab strategy (Supplemental Table S9). Using the regional maternal immunization strategy, 84% of extremely preterm RSV hospitalizations remain unprotected, compared to 39% of full-term hospitalizations (Supplemental Table S11). Strategy comparisons by preterm classification are shown in Supplemental Tables S9–S12.

Discussion

The current findings suggest that births at the start of the RSV season through the following two months are the most likely to have an RSV hospitalization. Additionally, infants who are older at the start of the RSV season—particularly those who were born in the second half of the prior season (i.e., early in the calendar year)—are more likely to be hospitalized in the subsequent season than the second half of their first season (i.e., later in the calendar year) (Table 4). It should be noted that using July to define the cutoff between seasonal assignments for birth timing may have impacted the resulting distribution of hospitalizations. However, July was selected due to the low RSV circulation at this time for all regions, and to keep seasons distinct. As the relative risk was compared for all birth cohorts relative to those born nine months prior to the start of the season, this would suggest that prophylaxis should prioritize infants born (1) within the first few months of the start of the RSV season; and (2) up to six months prior to the start of the season, as these birth cohorts are more likely to be hospitalized for RSV than those born three or more months into the RSV season (Table 3). This suggests there may be greater benefit and cost-effectiveness for maternal immunization of infants born one month or more prior to the RSV season (i.e., prior to September under current recommendations), than those born three or more months into the season.

Similarly, the broad application of nirsevimab may provide diminishing returns amongst the oldest eligible age groups (i.e., six to 8 months at season start), in which relatively few hospitalizations—in some cases, there was an approximately 10-fold reduction in hospitalization rates from births close to season start—are preventable. This group accounted for only up to 9% of all hospitalizations 0–15 months. On the other hand, nirsevimab may have an advantage among those born three-to-six months prior to the start of the season (Table 5).

It should be noted that the conclusions above result from the decision to assume six months of protection for both nirsevimab and maternal immunization. For nirsevimab, this was a more conservative assumption based on clinical trial data in which the endpoint efficacy for MALRI was studied up to 150 days,8 although the authors acknowledge there have been findings to suggest protection lasting up to one year.20 Similarly, modeling and vaccine efficacy analyses of maternal vaccination have shown neutralizing antibody response to suggest continued efficacy from five to six months after administration21,22 as well as incremental efficacies of 46% for MALRI and 67% for severe MALRI, respectively, from ages five to six months.23 These findings were the basis for the defined protection period of up to six months for both modalities.

While the model by Kieffer's team assumes that infants up to 6 months of age are at highest risk of hospitalization and severe disease due to RSV,24 the impact appears to be less dramatic more than three months outside of the RSV season. While Voirin et al. modeled RSV hospitalization risk and the expected impact of nirsevimab using a disease transmission model,25 our analysis demonstrates the risk of RSV hospitalization within similar, stratified birth cohorts using real data. All these studies and other prior ones6, 7, 8,26 suggest that the risk of RSV hospitalization is highest within the first few months of season start, and in the earliest months of life (Table 5).

The role of timing of birth on RSV hospitalization is well known. We found that higher hospitalization rates occurred among births occurring one-to-two months after the start of the season. In contrast, a study from the UK27 found that laboratory-confirmed RSV risk was higher in infants born in September through November, compared to those born in January, during their first month of life. A study from Croatia also more closely resembles those of the UK study, with infants born two-to-three months prior having the highest risk of hospitalization.28 This variability further lends to the need to tailor prevention strategies to local and/or national regional RSV epidemiology.

Among the preterm cohorts in this analysis, a greater proportion of hospitalizations occurred during the patients’ second RSV season. For this reason, both prevention strategies appeared to be less protective with decreasing gestational age, with maternal immunization notably leaving most extremely preterm infants unprotected (Supplemental Tables S9–S12). This warrants further study, given that current recommendations target prophylaxis during the first RSV season and/or first year of life. Palivizumab administration during the observation period may have impacted the number of hospitalizations observed in preterm groups. Particularly in the EU and Australia, and in the UK, where maternal immunization is approved beginning at 24 and 28wGA, respectively, these results represent an additional, potentially more cost-effective modality than palivizumab for these infants. For both modalities, the results may represent an additional benefit if there is greater uptake than for palivizumab.

There are several limitations to the current study. First, only the specified PHIS hospitals were included, thus the findings may not generalize to other hospitals. While there was an observable time trend demonstrating increased RSV hospitalizations each season, calculations were based on a mean annual hospitalization rate over the five seasons analyzed.18 Similarly, while the current analysis did not include modeling to account for random effects or multivariate adjustments (e.g., for demographics), such methods may be useful in future studies to refine results. For example, there is known disparity in RSV disease burden in the US among racial and ethnic minorities as well as Medicaid recipients,9 and the majority of cohorts included in this analysis were in fact Medicaid recipients (Table 1). Also notable with respect to age distribution is that the bronchiolitis cohort is overall older and experiences less ICU admission and a shorter length of stay. This may reflect differences in testing strategies and other untested viral etiologic agents of bronchiolitis, such as human metapneumovirus.

A further limitation of our analysis is that gestational age could not be assessed for most subjects, and we did not account for the differential recommendations by gestational age of the EMA or FDA for the maternal PreF vaccine. For this reason, these findings have more limited generalizability for the impact of either strategy on preterm infants. However, nirsevimab is currently indicated for all infants, regardless of gestational age; conversely, under current FDA recommendations, maternal immunization would not protect infants born before 34wGA.29 For the data that was available, preterm infants less than 34wGA that would be unprotected account for 13% of all hospitalizations.20 This would include recipients of palivizumab; therefore, in a scenario of maternal vaccination alone, this proportion would likely increase.

The data presented in this analysis, using a very large database, considers age-specific attack rates for RSV hospitalization accounting for the month of birth before the start of the RSV season. At the country level, recommendations for either strategy should consider the seasonality of RSV, the individual country recommendations for use of both modalities, the efficacy of each modality and these age-specific hospitalization rates, which can be used in individual country cost effective evaluations.

This study has several unique strengths. Utilization of the PHIS database allowed for large sample sizes, while still specifying regional variation in seasonality, as well as variation among individual hospitals. This allowed for birth timing specifically defined in relation to regional seasonality. The methodology used to define RSV seasonality provides general guidelines for other countries. Furthermore, RSV cases were identified using claims-based data rather than active surveillance, the latter of which tends to result in under-reporting.10 Finally, diagnostic codes were specific to RSV, and excluded similar lower respiratory diagnoses with similar presentation (e.g., acute bronchiolitis), which present with a different age distribution as shown (Supplemental Table S5).

The potential reduction of burden from nirsevimab has been evaluated in recent years, as well as the cost-effectiveness of various strategies. A recent modeling study estimates a 53% reduction in hospital admissions, a 52% reduction in ICU admissions, and a 49% reduction in medical costs when implementing a universal nirsevimab immunization strategy, as compared to the current standard of care.22 In 2021, a similar study assumed 5 months of protection with nirsevimab for all infants during the first RSV season, estimating a 49.7% reduction among patients under six months, and a 34.9% reduction among patients 6–12 months, in RSV-associated MALRI. Assuming an effect of nirsevimab on viral shedding, these reductions increased to 51.9% and 36.8%, respectively.23 However, this effect of nirsevimab on shedding has never been studied nor is to be expected.

The scenarios proposed here suggest that current nirsevimab recommendations may not be the most cost-effective, given the number of infants that would need to receive the immunization to prevent relatively few hospitalizations. Conversely, the current ACIP recommendations for maternal immunization leave some out-of-season births (i.e., prior to August/September) potentially unprotected. However, maternal immunization may be less impactful among those born 3 or more months after the start of the RSV season. While cost-effectiveness studies are limited, it has been proposed in the US that nirsevimab may be cost-effective using a seasonal administration strategy.30 It is likely that a combination of strategies will maximize both cost-effectiveness and public health benefit for many countries.

Contributors

EAFS conceived the study concept and design. RJS collected the data, did the statistical analysis and wrote the first draft of the report with input from EAFS. EAFS and RJS had access to the study data, contributed to the analysis and interpretation of the data, and reviewed and approved the final manuscript.

Data sharing statement

Individuals who wish to access Pediatric Health Information Systems (PHIS) data must be affiliated with a member hospital of the Children's Hospital Association, receive PHIS sponsor approval and complete a Direct Access Agreement. De-identified and aggregated participant data and a data dictionary may be made available to such individuals on request with publication. Requests for data can be initiated by contacting eric.simoes@cuanschutz.edu. The specific data and associated documents to be shared will be dependent on the nature of the individual request.

Declaration of interests

EAFS reports grants to the institution from AstraZeneca, Bill and Melinda Gates Foundation, Enanta Pharmaceuticals, Johnson and Johnson, Merck, Pfizer, and Roche, advisory board participation for AbbVie, Bill and Melinda Gates Foundation, and GSK, and consulting fees paid to the institution from Adagio, Cidara, GlaxoSmithKline, Merck, Nuance, Pfizer and Sanofi Pasteur. RJS reports no disclosures.

Appendix A Supplementary data

Supplementary Tables

Appendix A Supplementary data related to this article can be found at https://doi.org/10.1016/j.eclinm.2024.102790.
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