Document text
Summary of effectiveness of nirsevimab in infants
Amanda Payne, PhD, MPH
Coronavirus and Other Respiratory Viruses Division
Centers for Disease Control and Prevention
June 28, 2024National Center for Immunization and Respiratory Diseases
•Real -world vaccine/product effectiveness methods
•Effectiveness of nirsevimab in the United States
-RSV-associated emergency department encounters & hospitalization, VISION
-RSV-associated medical encounters and hospitalization, NVSN
•Effectiveness of nirsevimab globally
•ConclusionsAgenda
Real -world vaccine/product effectiveness
context and methods
•Efficacy: the degree to which an immunization prevents disease under
ideal and controlled conditions (i.e., measured in clinical trials)
•Effectiveness: the degree to which an immunization prevents disease
under real -world conditions (i.e., measured in post -licensure observational
studies)
In this presentation,
we’ll discuss product effectiveness (“PE”)
from real -world data.Efficacy ≠ effectiveness
•Limited supply of nirsevimab (100mg and 50mg
formulations) meant clinicians were uncertain
how to ration or prioritize few available doses
•CDC issued an official Health Advisory notice via
the Health Alert Network to prioritize available
doses to high -risk infants and younger infants
•By January, demand had decreased and
additional supply was available allowing return
to original recommendationsInsufficient supply of nirsevimab to meet demand in
2023 -2024 season
Health Alert Network (HAN) - 00499 | Limited Availability of Nirsevimab in the United States —Interim CDC Recommendations to Protect
Infants from Respiratory Syncytial Virus (RSV) during the 2023 –2024 Respiratory Virus Season
Case ControlPerson with acute
respiratory illness
RSV test
RSV immunization
status
Observational effectiveness measured in a
test-negative design (TND) study
Effectiveness = 1 – (odds ratio ) x 100% Odds ratio = 𝑂𝑑𝑑𝑠 𝑜𝑓 𝑖𝑚𝑚𝑢𝑛𝑖𝑧𝑎𝑡𝑖𝑜𝑛 𝑐𝑎𝑠𝑒𝑠
𝑂𝑑𝑑𝑠 𝑜𝑓 𝑖𝑚𝑚𝑢𝑛𝑖𝑧𝑎𝑡𝑖𝑜𝑛 𝑐𝑜𝑛𝑡𝑟𝑜𝑙𝑠Key features of a TND
•Real -world circumstances
•Most heterogenous study population,
often “all comers”
•Reduces bias from health -care seeking behavior
Considerations
•Validity dependent on test performance
•Residual confounding is possible
Slide courtesy of Ruth Link -Gelles, PhD MPH Chua H, Feng S, Lewnard JA, et al. The use of test -negative controls to monitor vaccine effectiveness: a systematic review of methodology. Epidemiology 2020;31:43 -64.
Virtual SARS -CoV-2, Influenza, and Other
respiratory viruses Network (VISION)
•Population: Visiting a participating ED for or hospitalized with RSV -like
illness (RLI)*
•Immunization data: Infant and maternal RSV immunization status
documented by electronic health records, state and city registries, and
claims data (subset of sites)
•Covariate data: Documented in electronic health records
-Underlying medical conditions: ICD -10 discharge diagnosis codes at time of
RLI encounter
-Patient characteristics
•Date of birth
•Census tract of residence
•SexVISION Multi -Site Network of Electronic Health Records (EHRs)
127 emergency rooms and 107 hospitals
VISION 2.0 partners included in this analysis –
ED: Columbia, HealthPartners Institute, Intermountain Healthcare,
KPSC, KPCHR, Regenstrief
Inpatient : Columbia, HealthPartners Institute, Intermountain, KPSC,
KPCHR, Regenstrief
*≥1 ICD -10 discharge diagnosis code indicating RSV -like illness (RLI)
ED = emergency department
ED Encounters and Hospitalizations for RSV -like illness* among infants in their first RSV
season, by immunization and RSV positivity status – VISION, October 2023 – March 2024
ED Encounters and Hospitalizations for RSV -like illness* among infants in their first RSV
season, by immunization and RSV positivity status – VISION, October 2023 – March 2024
ED Encounters and Hospitalizations for RSV -like illness* among infants in their first RSV
season, by immunization and RSV positivity status – VISION, October 2023 – March 2024
ED Encounters and Hospitalizations for RSV -like illness* among infants in their first RSV
season, by immunization and RSV positivity status – VISION, October 2023 – March 2024
•Population:
-Infants aged <8 months as of October 1, 2023, or born after October 1, 2023
-Visiting a participating ED for or hospitalized with RSV -like illness (RLI)
-With RSV test result within 10 days before or 72 hours after encounter
•Cases: RLI with positive RSV antigen or NAAT test*
•Controls: RLI with negative RSV NAAT test
•Study period: October 8, 2023 – March 31, 2024
•Exclusion criteria:
-Children aged <7 days
-Children born after September 22, 2023, without linkage to maternal records
-Evidence of maternal RSV vaccination or palivizumab administration
-Receipt of unrecommended nirsevimab dose(s)†
-<7 days between nirsevimab dose and RLI encounter
-Indeterminate RSV test result
•Statistical Analysis: Adjusted OR comparing odds of immunization‡ among cases vs. controls estimated
using multivariable logistic regression models, adjusting for age, race and ethnicity, sex, calendar day (days
since Oct 8, 2023), and geographic region → PE = (1 -aOR) X 100%Test-negative design (TND) analysis of first season nirsevimab product effectiveness (PE) against
RSV-associated ED encounters and hospitalization – VISION, October 8, 2023 – March 31, 2024
*RSV -positive encounters with positive SARS -CoV -2 and/or influenza test result were (i.e., coinfections) were excluded.
† Unrecommended nirsevimab dose(s) defined as: nirsevimab doses administered on or before October 1, 2023, and receipt of >1 nirsevimab dose. Nirsevimab doses in older children may be
administered as 2 injections on the same day; this was considered one ‘dose’.
‡Immunization defined as one nirsevimab dose ≥7 days prior to encounter index date.
NAAT = nucleic acid amplification test | OR = odds ratio | aOR = adjusted odds ratio | PE = product effectiveness
First season nirsevimab product effectiveness (PE) against RSV-associated ED
encounters and hospitalization – VISION, October 8, 2023 – March 31, 2024
Outcome | Nirsevimab
dosage patternTotal
encountersRSV -positive
encounters
N (Row %)Median days
since dose
(IQR)Adjusted
PE (95% CI)*
RSV -associated ED encounter
No nirsevimab doses4,610 1,988 (43)N/A ref
Nirsevimab , ≥7 days prior 442 63 (14) 53 (27 -84) 77 (69 -83)
RSV -associated hospitalization
No nirsevimab doses927 601 (65)N/A ref
Nirsevimab , ≥7 days prior 93 4 (4) 48 (25 -84) 98 (95 -99)
0 20 40 60 80 100
*Odds ratio used to calculate VE estimate was adjusted for age, race and ethnicity, sex, calendar day (days since Oct 8, 2023), and geographic region
N/A = not applicable | ref = reference groupNirsevimab was effective against RSV-associated ED encounters and
hospitalization among infants in their first RSV season.
New Vaccine Surveillance Network (NVSN)Update to Moline HL, Tannis A, Toepfer AP , et al. Early Estimate of Nirsevimab Effectiveness for Prevention of Respiratory Syncytial
Virus –Associated Hospitalization Among Infants Entering Their First Respiratory Syncytial Virus Season — New Vaccine
Surveillance Network, October 2023 –February 2024. MMWR Morb Mortal Wkly Rep 2024;73:209 –214. DOI:
http://dx.doi.org/10.15585/mmwr.mm7309a4
NVSN is a prospective, population -based surveillance network for
pediatric acute respiratory illness (ARI) at 7 U.S. medical centers.
Children <18 years of age with ARI are enrolled
year -round in the outpatient, urgent care,
emergency department (ED), and hospital settings.
Surveillance Objectives:
–Determine the etiology and burden of laboratory -
confirmed acute viral respiratory diseases in children
–Characterize the clinical and epidemiologic factors of
pediatric ARI and associated syndromes
–Evaluate vaccine effectiveness (VE) using a test -
negative design (TND) and impact of vaccines and
other immunoprophylaxis products.
NVSN Data Collection
•Caregiver interview
-Race and ethnicity, preterm status, date of symptom onset, breastfeeding status
•Specimens
-Mid-turbinate nasal swab collected from all children for RSV testing by reverse -
transcription polymerase chain reaction; results of both clinical and surveillance
testing are collected
-Sequencing of RSV -positive specimens to monitor for substitutions in the
nirsevimab binding site
•Medical chart abstraction
-Age, underlying medical conditions, clinical course of illness, insurance status
•Immunization status ( nirsevimab , palivizumab, and maternal RSV vaccine)
-Ascertained by parent report and confirmed with state immunization information
system, electronic health record, or birth record
During 2023 -2024, RSV prevention products became available in the U.S. after
the RSV season started
ACIP = Advisory Committee on Immunization Practices
NVSN = New Vaccine Surveillance Network
NREVSS = National Respiratory and Enteric Virus Surveillance System Nirsevimab recommended by ACIPPfizer maternal RSV vaccine ( Abrysvo )
recommended by ACIP
All NVSN sites had some
nirsevimab availability by
mid-October
Among 2,383 infants in
their first RSV season
•11.1% received
nirsevimab
•2.2% received
palivizumab
•3.4% (of 1,542
infants <6 months
of age at
enrollment) had
history of maternal
RSV vaccination, April 2023 through April 2024
During 2023 -2024, RSV prevention products became available in the U.S. after
the RSV season started
ACIP = Advisory Committee on Immunization Practices
NVSN = New Vaccine Surveillance Network
NREVSS = National Respiratory and Enteric Virus Surveillance System Nirsevimab recommended by ACIPPfizer maternal RSV vaccine ( Abrysvo )
recommended by ACIP
All NVSN sites had some
nirsevimab availability by
mid-October
Among 2,383 infants in
their first RSV season
•11.1% received
nirsevimab
•2.2% received
palivizumab
•3.4% (of 1,542
infants <6 months
of age at
enrollment) had
history of maternal
RSV vaccination, April 2023 through April 2024
During 2023 -2024, RSV prevention products became available in the U.S. after
the RSV season started
ACIP = Advisory Committee on Immunization Practices
NVSN = New Vaccine Surveillance Network
NREVSS = National Respiratory and Enteric Virus Surveillance System Nirsevimab recommended by ACIPPfizer maternal RSV vaccine ( Abrysvo )
recommended by ACIP
All NVSN sites had some
nirsevimab availability by
mid-October
Among 2,383 infants in
their first RSV season
•11.1% received
nirsevimab
•2.2% received
palivizumab
•3.4% (of 1,542
infants <6 months
of age at
enrollment) had
history of maternal
RSV vaccination, April 2023 through April 2024
Test-negative design (TND) analysis of first season nirsevimab product effectiveness (PE) against
medically attended RSV -associated ARI episodes and RSV -associated hospitalization – NVSN,
October 2023 – March 2024
*Acute respiratory illness (ARI) defined as >1 of the following sign/symptoms: fever, cough, earache, nasal congestion, runn y nose, sore throat, vomiting after coughing, shortness of breath (rapid or
shallow breathing), wheezing, apnea, or apparent life -threatening event or brief resolved unexplained event
†State -level RSV RT -PCR percent positivity thresholds of 3% were used to define the beginning and end weeks of the analysis by si te
‡Immunization defined as one nirsevimab dose ≥7 days prior to symptom onset.
OR = odds ratio | aOR = adjusted odds ratio | PE = product effectiveness
•Population:
-Infants <8 months as of October 1, 2023, or born after October 1, 2023
-Enrolled from participating medical center
-ARI*
•Case patients – children with medically attended ARI who tested positive for RSV by surveillance or clinical testing
•Control patients – children with medically attended ARI who tested negative for RSV by surveillance or clinical testing
•Study period: October 2023 – March 2024†
•Exclusion criteria:
• Chart review incomplete for underlying conditions, preterm status, insurance status, highest level of care, clinical course o f
illness
• Immunization status unverified for nirsevimab and palivizumab receipt and maternal RSV vaccination
• Receipt of palivizumab or history of maternal RSV vaccination during pregnancy
• Unknown or inconclusive RSV test result
• Receipt of nirsevimab <7 days prior to ARI symptom onset
•Statistical Analysis: Adjusted OR comparing odds of immunization‡ among cases vs. controls estimated
using multivariable logistic regression models, adjusting for site, age in months, month of enrollment, and
presence of >1 high -risk medical condition for severe RSV disease → PE = (1 -aOR) X 100%
First season nirsevimab product effectiveness (PE) against medically attended RSV -
associated ARI and RSV -associated hospitalization – NVSN, October 2023 – March 2024*
Outcome | Nirsevimab
dosage patternTotal
encountersRSV -positive
encounters
N (Row %)Median days
since dose
(IQR)Adjusted
PE (95% CI)†
Medically Attended
RSV -associated
ARI episode‡
No nirsevimab doses1,575 755 (48)N/A ref
Nirsevimab, ≥7 days prior§120 9 (8) 42 (21 -73) 89 (77 -94)
RSV -associated hospitalization
No nirsevimab doses807 526 (65)N/A ref
Nirsevimab , ≥7 days prior 63 6 (10) 38 (15 -67) 91 (79 -96)
0 20 40 60 80 100
*State -level RSV RT -PCR percent positivity thresholds of 3% were used to define the beginning and end weeks of the analysis by si te
†Multivariable logistic regression models compared the odds of vaccination among RSV case and control patients while adjusting for site, age in months, month of enrollment, and presence of >1 high -risk
medical condition for severe RSV disease.
§Immunization defined as one nirsevimab dose ≥7 days prior to symptom onset.
ARI = acute respiratory illness | N/A = not applicable | ref = reference groupNirsevimab was effective against medically attended RSV -associated ARI
episodes and RSV -associated hospitalization.
Summary of US data
Outcome/Analysis Vaccine efficacy /effectiveness (%)
Clinical trial, RSV -associated LRTI 79 (69 -86)
Clinical trial, RSV -associated LTRI with hospitalization 81 (62 -90)
Clinical trial, RSV -associated LRTI with ICU admission 90 (16 -99)
VISION, RSV -associated emergency department visits 77 (69 -83)
VISION, RSV -associated hospitalization 98 (95 -99)
NVSN, medically attended RSV -associated ARI episode 89 (77 -94)
NVSN, RSV -associated hospitalization 91 (79 -96)Observational data indicate nirsevimab is working as expected
(vs. RCT results) during the first RSV season after approval
among infants in their first RSV season
https://www.cdc.gov/mmwr/volumes/72/wr/mm7234a4.htm
RCT = randomized clinical trial | ARI = acute respiratory illness0 20 40 60 80 100
Results may not be comparable
across studies due to differences in
outcome definitions, timing, and
other factors.
•High product effectiveness should be interpreted with caution
-Short interval from administration to respiratory illness onset
-Unable to assess duration of protection during the 2023 -2024 RSV season
•Residual confounding was possible
•Misclassification of RSV immunization status was possible
•These results only reflect PE among infants in their first RSV season (not among
children at increased risk in their second RSV season)
•VISION:
-Cases may have sought care for something other than RSV
-All RSV testing was clinician -directed
-EHR data may not fully capture all underlying medical conditions, which may be associated
with likelihood of immunization and risk of severe RSV disease
•NVSN:
-May not be nationally representativeLimitations of test-negative design (TND) analyses of first season
nirsevimab product effectiveness (PE), October 2023 – March 2024
Nirsevimab effectiveness – evidence from
literature
Nirsevimab product effectiveness (PE) among infants in their first RSV season –
Data* from Spain and France
Study Endpoint PE (95% CI)†
RSV -associated hospitalization82 (66 - 90)
88 (82 - 91)
89 (70 - 96)
84 (77 - 90)†
70 (38 - 89) †
81 (61 - 91)
RSV -associated LRTI requiring oxygen87 (69 – 94)
86 (42 - 96)
RSV -associated ICU admission90 (76 – 96)
86 (13 – 98)
76 (49 – 89)
RSV and/or bronchiolitis attended in the ED88 (70 – 95)
55 (48 – 62)
Bronchiolitis or viral pneumonia attended in primary
care setting48 (42 – 53)
61 (24 – 80)
Medically attended RSV infection69 (52 – 80)
74 (65 – 80)
0 20 40 60 80 100
*References provided on backup slide 32.
†PE estimates generated from the same study, using different methods.
LRTI = lower respiratory tract infection | ICU = intensive care unit
Conclusions
•Nirsevimab was effective against RSV -associated ED encounters and hospitalization
among infants in their first RSV season during the
2023 -2024 RSV season
•Due to timing of authorization/recommendation of RSV prevention products and RSV
activity during the 2023 -2024 RSV season:
-US-based analyses may be subject to residual confounding due to prioritization of nirsevimab
doses
-Short time between nirsevimab administration and outcomes, limiting ability to assess duration of
protection
-Limited ability to assess effectiveness of maternal RSV vaccines
•Ongoing monitoring of post -licensure nirsevimab and maternal RSV vaccine
effectiveness will continueConclusions
Acknowledgements
CDC
Amadea Britton
Allison Ciesla
Benjamin Clopper
Fatimah S. Dawood
Monica Dickerson
Katherine Fleming -Dutra
Sascha Ellington
Shikha Garg
Leah Goldstein
Casey Kalman
Amber Kautz
Ruth Link -Gelles
Josephine Mak
Erin McKeever
Meredith McMorrow
Morgan Najdowski
Lakshmi Panagiotakopoulos
Caitlin Ray
Ayzsa Tannis
Mark Tenforde
Ariana Toepfer
Megan Wallace
Ryan WiegandVISION Collaborators
Westat
Sarah Bell
Steph Battan -Wraith
Angela Cheung
Margaret Dunne
Patrick Mitchell
Sarah Reese
Elizabeth Rowley
Janet Watts
Zack Weber
Columbia University
Karthik Natarajan
HealthPartners
Malini B. DeSilva
Intermountain Health
Kristin Dascomb
Kaiser Permanente Center for Health Research
Stephanie A. Irving
Kaiser Permanente Southern California
Sara Tartoff
Regenstrief
Shaun J. Grannis
University of Colorado
Toan C. Ong
+ many more site staff!NVSN Collaborators
Cincinnati Children’s Hospital
Mary Staat
Texas Children’s Hospital
Julie Boom
Leila Sahni
Children’s Mercy Hospital
Jennifer Schuster
Rangaraj Selvarangan
Vanderbilt University Medical Center
Natasha Halasa
UPMC Children’s Hospital
John Williams
Marian Michaels
University of Rochester Medical Center
Geoff Weinberg
Peter Szilagyi
Seattle Children’s Hospital
Jan Englund
Eileen Klein
Hospitalized population comparison for VISION and NVSN
VISION , no. (col %) NVSN , no. (col %)
Characteristic Total no. of
patientsRSV
case -patientsRSV
control -patientsTotal no. of
patientsRSV
case -patientsRSV
control -patients
All hospitalizations 1,020 605 415 870 532 338
Median age, months (IQR) 4 (1-7) 3 (1-6) 4 (1-7) 3 (1-6) 3 (1-5) 3 (1-6)
Gestational age
Preterm (<37 weeks) 133 (13) 59 (10) 74 (18) 180 (21) 102 (19) 78 (23)
Term (≥37 weeks) 508 (50) 323 (53) 185 (45) 687 (79) 428 (81) 259 (77)
Unknown 379 (37) 223 (37) 156 (38) 3 (0) 2 (0) 1 (0)
Race/ethnicity
Black or African American, Non -Hispanic 77 (8) 48 (8) 29 (7) 113 (13) 56 (11) 57 (17)
White, Non -Hispanic 437 (43) 268 (44) 169 (41) 390 (45) 266 (50) 124 (37)
Hispanic or Latino 394 (39) 234 (39) 160 (39) 248 (29) 146 (27) 102 (30)
Other, Non -Hispanic 75 (7) 33 (6) 42 (10) 107 (12) 58 (11) 49 (14)
Unknown 37 (4) 22 (4) 15 (4) 12 (1) 6 (1) 6 (2)
High risk conditions for severe RSV disease
None 796 (78) 529 (87) 267 (64) 832 (96) 520 (99) 281 (83)
≥1 224 (22) 76 (13) 148 (36) 38 (4) 12 (2) 26 (8)
Immunization status
No nirsevimab 927 (91) 601 (99) 326 (79) 807 (93) 526 (99) 281 (83)
Nirsevimab , ≥7 days earlier 93 (9) 4 (1) 89 (21) 63 (7) 6 (1) 57 (17)
Empirical studies* on nirsevimab product effectiveness (PE) among infants in their first RSV season
Citation Country Sample Size
(Number of
Infants)Study Design PE (95% Confidence Interval)
Ares -Gomez et al., 2024 Spain 10,259 Prospective CohortHospitalization for RSV -related LRTI: 82% (95% CI: 66% - 90%)
Severe RSV -related LRTI requiring oxygen support: 87% (95% CI: 69% - 94%)
All-cause LRTI hospitalizations: 69% (56% - 78%)
All-cause hospitalizations: 66% (56% - 74%)
Coma et al., 2024 Spain 26,525Retrospective
CohortHospital admission for RSV -related disease: 88% (95% CI: 82% - 91%)
Hospital ER visits due to bronchiolitis: 55% (95% CI: 48% - 62%)
Medically attended RSV infection: 69% (95% CI: 52% - 80%)
Primary care attended bronchiolitis: 48% (95% CI: 42% - 53%)
Viral pneumonia diagnosed in primary care: 61% (95% CI: 24% - 80%)
ICU admission for RSV -related disease: 90% (95% CI: 76% - 96%)
Estrella -Porter et al., 2024 Spain 27,362Retrospective
CohortMedically attended RSV infection: 74% (95% CI: 65% - 80%)
Ezpeleta et al., 2024 Spain 1,177 Prospective CohortHospitalization due to RSV: 89% (95% CI: 70% - 96%)
RSV infection attended in the ER: 88% (95% CI: 70% - 95%)
RSV ICU admission: 86% (95% CI: 13% - 98%)
Lopez -Lacort et al., 2024 Spain 166Screening and Test
negative case
controlRSV -LRTI hospital admission (pooled data across several regions):
Screening methods: 84% (95% CI: 77% - 90%)
Test negative design: 70% (95% CI: 38% - 89%)
Paireau et al., 2024 France 288Test negative case
controlRSV bronchiolitis hospitalized In the pediatric ICU: 76% (95% CI: 49% - 89%)
Aguera et al., 2024 Spain 181Test negative case
controlHospitalization for RSV -related LRTI: 81% (95% CI: 61% - 91%)
Severe RSV -related LRTI requiring NIV/CMV: 86% (95% CI: 42% - 96%)
*Published during June 20, 2023, through June 21, 2024
LRTI = lower respiratory tract infection | ER = emergency room | ICU = intensive care unit | CI = confidence interval | NIV: noninvasive ventilation | CMV: continuous mandatory ventilation