Document text
Centers for Disease Control and Prevention
Evidence to Recommendations Framework:
Nirsevimab
Jefferson Jones MD MPH FAAP , CDR USPHS
ACIP General MeetingFebruary 23, 2023
Evidence to Recommendations Framework
71Nirsevimab is a form of passive immunization
Active immunity results from infection or vaccination, which triggers
animmune response
Passive immunity is when a person receives antibodies from an external source
–From mother to baby through transplacental or breastmilk transfer
–Direct administration of antibodies, such as IVIG or monoclonal antibodies
https://www.cdc.gov/vaccines/vac -gen/immunity -types.htm
72Evidence to Recommendations (EtR ) Framework
Policy Questions
Should one dose of nirsevimab be recommended a) at birth for all
infants born during October to March and b) when entering first RSV
season and <8 months of age for all infants born during April through
September?
Should one dose of nirsevimab be recommended for children <20 months of age with increased risk of severe disease entering their
second RSV season?
73Evidence to Recommendations (EtR ) Framework
PICO Question 1
Population All infants born during Apr -Sept who are <8 months of age when
entering their first RSV season and infants born during Oct- Mar
Intervention Nirsevimab (1 injection prior to start of RSV season or at birth if born
during season, 50 mg if <5 kg or 100 mg if ≥5 kg)
Comparison No nirsevimab prophylaxis
Outcomes Medically -attended RSV- associated lower respiratory tract
infection (MA -LRTI)
RSV-associated LRTI with hospitalization
RSV-associated LRTI with ICU admission
RSV-associated death
All-cause MA -LRTI
All-cause LRTI- associated hospitalization
Serious adverse events
74Evidence to Recommendations (EtR ) Framework
EtRDomain Question(s)
Public Health Problem Is the problem of public health importance?
Benefits and Harms How substantial are the desirable anticipated effects?
How substantial are the undesirable anticipated effects?
Do the desirable effects outweigh the undesirable effects?
Values Does the target population feel the desirable effects are large relative
to the undesirable effects?
Is there important variability in how patients value the outcome?
Acceptability Is the intervention acceptable to key stakeholders?
Feasibility Is the intervention feasible to implement?
Resource Use Is the intervention a reasonable and efficient allocation of resources?
Equity What would be the impact of the intervention on health equity?
EtRDomain: Public Health Problem
Is RSV -associated disease among infants <8 months of age entering their
first RSV season and infants born during the RSV season of public health
importance?
76Changes in seasonality of RSV transmission following
SARS -CoV2 introduction —NREVSS1, 2016 –2023
2016- 17
1017- 18
2018- 19
2019- 20
2020- 21
2021- 22
2022- 23
1Displayed results are among ~200 commercial, hospital, and
state/local public health laboratories which consistently report RSV
PCR tests at an annual average of ≥10 PCR tests and ≥30 weeks of the
12-month surveillance year. Testing is clinician -directed and results
include all ages.
77Each year among U.S. children aged less than 5 years,
RSV is associated with…
~1,500,0003
outpatient visits~520,0003
emergency department visits58,000 -80,0003,4,5
hospitalizations100-3001,2
deaths
1Thompson et al, JAMA, 2003; 2Hansen et al, JAMA Network Open, 2022; 3Hall et al, NEJM, 2009; 4Rha et al., Peds, 2020; 5McLaughlin et al, J
Infect Dis, 2022; (*estimate 80,000 hospitalizations in infants <1y)
78Epidemiology of RSV
Pre-pandemic RSV seasonality is well defined with limited geographic
variability in most of the U.S.
RSV is the most common cause of hospitalization in U.S. infants
–Highest hospitalization rates in first months of life
–Risk declines by month with increasing age in infancy and early childhood
Prematurity and other chronic diseases increase risk of RSV -associated
hospitalization, but most hospitalizations are in healthy, term infants
79Public Health Problem- Work Group Interpretation
Is RSV -associated disease among infants <8 months of age entering
their first RSV season and infants born during the RSV season of
public health importance?
NoProbably
NoProbably
YesYes VariesDon’t
know
EtRDomain: Benefits and Harms
Do the desirable effects outweigh the undesirable effects?
81Outcomes, importance, and data sources
Outcome ImportanceaData sources
Benefits
Medically attended RSV LRTI Critical Phase 3 and phase 2b RCTb
RSV LRTI with hospitalization Critical Phase 3 and phase 2b RCTb
RSV LRTI with ICU admission Critical Phase 3 and phase 2b RCTb
Death due to RSV respiratory illness Critical No RSV deaths in trials
All-cause medically attended -LRTI Important Phase 3 and phase 2b RCTb
All-cause LRTI -associated hospitalization Important Phase 3 and phase 2b RCTb
HarmsSerious Adverse Events (SAEs) Important Phase 3 and phase 2b RCT
b
a Three options: Critical; Important but not critical; Not important for decision making
bIncludes 3012 participants in the phase 3 trials (born >34 weeks gestational age [GA]) and 860 participants in phase 2b trial (born 29- 34 weeks GA). Among phase 2b trial
participants, only those who received the recommended dose were included: infants ≥5 kg received a dose (50mg) that was deter mined to be too low to be efficacious for this
weightLRTI: Lower respiratory tract infection, RCT: randomized control trial, ICU: intensive care unit
82Efficacy estimates and concerns in certainty of
assessment
Outcome Efficacy estimate* Concerns in certainty of assessment
Benefits
Medically attended RSV LRTI 79.0% (95% CI: 68.5% –86.1%) Not serious (indirectness)
RSV LRTI with hospitalization 80.6% (95% CI: 62.3% –90.1%) Not serious (indirectness)
RSV LRTI with ICU admission 90.0% (95% CI: 16.4% –98.8%) Serious (imprecision): Too few events
Not serious (indirectness)
Death due to RSV respiratory
illnessNone recorded N/A
All-cause medically attended -
LRTI34.8% (95% CI: 23.0– 44.7%) Not serious (indirectness)
All-cause LRTI -associated
hospitalization44.9% (95% CI: 24.9% –59.6%) Not serious (indirectness)
*Pooled phase 2b (excluding underdosed) and phase 3 trial estimate comparing nirsevimab arm to placebo arm
83Efficacy estimates and concerns in certainty of
assessment
Outcome Efficacy estimate* Concerns in certainty of assessment
Benefits
Medically attended RSV LRTI 79.0% (95% CI: 68.5% –86.1%) Not serious (indirectness)
RSV LRTI with hospitalization 80.6% (95% CI: 62.3% –90.1%) Not serious (indirectness)
RSV LRTI with ICU admission 90.0% (95% CI: 16.4% –98.8%) Serious (imprecision): Too few events
Not serious (indirectness)
Death due to RSV respiratory
illnessNone recorded N/A
All-cause medically attended -
LRTI34.8% (95% CI: 23.0– 44.7%) Not serious (indirectness)
All-cause LRTI -associated
hospitalization44.9% (95% CI: 24.9% –59.6%) Not serious (indirectness)
*Pooled phase 2b (excluding underdosed) and phase 3 trial estimate comparing nirsevimab arm to placebo arm
84Efficacy estimates and concerns in certainty of
assessment
Outcome Efficacy estimate* Concerns in certainty of assessment
Benefits
Medically attended RSV LRTI 79.0% (95% CI: 68.5% –86.1%) Not serious (indirectness)
RSV LRTI with hospitalization 80.6% (95% CI: 62.3% –90.1%) Not serious (indirectness)
RSV LRTI with ICU admission 90.0% (95% CI: 16.4% –98.8%) Serious (imprecision): Too few events
Not serious (indirectness)
Death due to RSV respiratory
illnessNone recorded N/A
All-cause medically attended -
LRTI34.8% (95% CI: 23.0– 44.7%) Not serious (indirectness)
All-cause LRTI -associated
hospitalization44.9% (95% CI: 24.9% –59.6%) Not serious (indirectness)
*Pooled phase 2b (excluding underdosed) and phase 3 trial estimate comparing nirsevimab arm to placebo arm
85Relative risk of SAEs and concerns in certainty of
assessment
Outcome Relative risk1Concerns in certainty of assessment
Harms
Serious Adverse Events
(SAEs)20.73 (95% CI: 0.59– 0.89) Serious (imprecision)
1Pooled phase 2b and phase 3 estimate comparing nirsevimab arm to placebo arm
2Adverse event resulting in death, hospitalization, significant disability, or requiring medical intervention.
Adverse events include respiratory symptoms.
86Summary of GRADE for nirsevimab
Outcome Importance Design
(# of studies)Findings Level of certainty
Benefits
Medically attended RSV
LRTICritical RCT (2)Nirsevimab is effective in preventing medically attended
RSV LRTIHigh
RSV LRTI with
hospitalizationCritical RCT (2)Nirsevimab is effective in preventing medically attended
RSV LRTI with hospitalizationHigh
RSV LRTI with ICU
admissionCritical RCT (2)Nirsevimab is likely effective in preventing medically
attended RSV LRTI with ICU admissionModerate
Death due to RSV Critical RCT (2) No deaths reported -
All-cause medically
attended -LRTIImportant RCT (2)Nirsevimab is effective in preventing all cause medically
attended LRTIHigh
All-cause LRTI -associated
hospitalizationImportant RCT (2)Nirsevimab is effective in preventing all cause hospitalization with respiratory diseaseHigh
Harms
Serious adverse events Critical RCT (1)SAEs were likely not more common in intervention group
than placebo groupModerate
11: High certainty; 2: Moderate certainty. 3: Low certainty; 4: Very low certainty.
87Summary of GRADE for nirsevimab
Outcome Importance Design
(# of studies)Findings Level of certainty
Benefits
Medically attended RSV
LRTICritical RCT (2)Nirsevimab is effective in preventing medically attended
RSV LRTIHigh
RSV LRTI with
hospitalizationCritical RCT (2)Nirsevimab is effective in preventing medically attended
RSV LRTI with hospitalizationHigh
RSV LRTI with ICU
admissionCritical RCT (2)Nirsevimab is likely effective in preventing medically
attended RSV LRTI with ICU admissionModerate
Death due to RSV Critical RCT (2) No deaths reported -
All-cause medically
attended -LRTIImportant RCT (2)Nirsevimab is effective in preventing all cause medically
attended LRTIHigh
All-cause LRTI -associated
hospitalizationImportant RCT (2)Nirsevimab is effective in preventing all cause hospitalization with respiratory diseaseHigh
Harms
Serious adverse events Critical RCT (1)SAEs were likely not more common in intervention group
than placebo groupModerate
11: High certainty; 2: Moderate certainty. 3: Low certainty; 4: Very low certainty.
88Summary of GRADE for nirsevimab
Outcome Importance Design
(# of studies)Findings Level of certainty
Benefits
Medically attended RSV
LRTICritical RCT (2)Nirsevimab is effective in preventing medically attended
RSV LRTIHigh
RSV LRTI with
hospitalizationCritical RCT (2)Nirsevimab is effective in preventing medically attended
RSV LRTI with hospitalizationHigh
RSV LRTI with ICU
admissionCritical RCT (2)Nirsevimab is likely effective in preventing medically
attended RSV LRTI with ICU admissionModerate
Death due to RSV Critical RCT (2) No deaths reported -
All-cause medically
attended -LRTIImportant RCT (2)Nirsevimab is effective in preventing all cause medically
attended LRTIHigh
All-cause LRTI -associated
hospitalizationImportant RCT (2)Nirsevimab is effective in preventing all cause hospitalization with respiratory diseaseHigh
Harms
Serious adverse events Critical RCT (1)SAEs were likely not more common in intervention group
than placebo groupModerate
11: High certainty; 2: Moderate certainty. 3: Low certainty; 4: Very low certainty.
89Overall evidence rating
Overall evidence rating: moderate certainty
Downgraded based on imprecision for protection against ICU admissions
because of few recorded events and imprecision of SAEs because rare
events are unlikely to be detected
90Benefits and Harms
How substantial are the desirable anticipated effects?
–How substantial are the anticipated effect for each main outcome
for which there is a desirable effect?
Minimal Small Moderate Large Varies Don’t know
91Benefits and Harms
How substantial are the undesirable anticipated effects?
–How substantial are the anticipated effect for each main outcome
for which there is an undesirable effect?
Minimal Small Moderate Large Varies Don’t know
92Benefits and Harms
Do the desirable effects outweigh the undesirable effects?
–What is the balance between the desirable effects relative to the
undesirable effects?
Favors intervention ( Nirsevimab )
Favors comparison (No intervention)
Favors both
Favors neither
Unclear
EtRDomain: Values
Criterion 1: Does the target population feel that the desirable effects are
large relative to undesirable effects?
Criterion 2: Is there important uncertainty about, or variability in, how
much people value the main outcomes?
94About one-third (33%) of respondents thought their baby ‘definitely’ or
‘probably’ would get an RSV infection within one year after being born*
Definitely or
probably would g e t RSV
Unsure
Definitely or probably would not
g e t RSV
*CDC and University of Iowa/RAND survey, unpublished, of 523 people who were actively pregnant or pregnant within last
12 months; conducted during 12/2022–1/2023; 68% of respondents had previously heard of RSV.
95
70% of respondents said they ‘definitely’ or ‘probably’ would get an
RSV antibody injection for their baby if safe and effective*
‘Definitely’ or
‘ Probably’ would get antibody
Unsure
‘Definitely’ or ‘ Probably’ would not
get antibody
*If antibody injection was approved by FDA and recommended by CDC. CDC and University of Iowa/RAND survey, unpublished
9663% of respondents said they were more worried or equally worried
about their baby experiencing side effects from an RSV antibody
injection vs. symptoms if sick with RSV
Worried about
bad side effects from antibodies
W orried about both
W orried about bad disease symptoms
CDC and University of Iowa/RAND survey, unpublished
97Parent attitudes about RSV
38% of respondents believe that their baby would have no symptoms or
mild symptoms if they got sick with RSV
24% expressed uncertainty about the disease severity or treatability if their
baby got sick with RSV
Despite being unsure or perceiving RSV risk to be low, respondents were
worried their baby would need to be hospitalized if they got sick with RSV
(mean response 4 of 5 with 5 being most worried)
CDC and University of Iowa/RAND survey, unpublished
98Values
Criterion 1: Does the target population feel that the desirable effects
are large relative to undesirable effects?
NoProbably
NoProbably
YesYes VariesDon’t
know
99Values
Criterion 2: Is there important uncertainty about, or variability in, how
much people value the main outcomes?
Important uncertainty or variability
Probably important uncertainty or variability
Probably not important uncertainty or
variability
No important uncertainty or variability
No known undesirable outcomes
EtRDomain: Acceptability
Is immunization with nirsevimab acceptable to key stakeholders?
101Provider survey
In survey by Alliance for Patient Access and National Coalition for Infant
Health of 175 providers using YouGov to poll U.S. physicians
–99% agree that parents need more information about RSV
–86% report including RSV education as part of routine care
–97% said immunizations could help prevent RSV
–92% agreed that RSV immunization policy should ensure all children
get access
https://admin.allianceforpatientaccess.org/wp -content/uploads/2023/01/AfPA -and-NCfIH_The -Indirect -Impact -of-RSV_Survey -Report_Ja n-2023.pdf
102Importance of RSV prevention recognized by relevant
national organizations
AAP states that development of safe and effective RSV immunization is a
priority
National Foundation for Infectious Disease roundtable agreed on the
importance of rapid adoption and deployment of evidence -based RSV
prevention
–Included National Association of County and City Health Officials
AAP COID BGC Pediatrics 2014 Aug;134(2):415 -20.
https://www.nfid.org/wp -content/uploads/2022/04/NFID -RSV-Call-to-Action.pdf
103Acceptability
Is immunization with nirsevimab acceptable to key stakeholders?
NoProbably
NoProbably
YesYes Varies Don’t know
EtRDomain: Feasibility
Is nirsevimab feasible to implement among all infants <8 months of age
entering their first RSV season and infants born during the RSV season?
105Administration and storage
Administered as intramuscular injection using pre -filled, single -use syringe
available in the following doses for infants born during or entering 1st RSV
season:
–50mg (0.5mL) for infants weighing <5 kg or
–100mg (1.0 mL) for infants ≥5 kg
For high -risk infants and children entering 2ndRSV season, dosing is 200mg
(two 100 mg doses administered at the same time
One dose of nirsevimab per season
Storage at refrigerator temperatures (2 °C -8°C)
May be kept at room temperature (20 °C -25°C) when protected from light
for a maximum of 8 hours
Beyfortus summary of product characteristics. European Medicines Agency https://www.ema.europa.eu/en/documents/product -information/beyfortus -epar-product -information_en.pdf
106ACIP considerations
Nirsevimab would be first passive immunization product to be
independently included in CDC immunization schedule
Proposed indication is for all infants and would result in population -level
impacts
Nirsevimab inclusion in Vaccines For Children (VFC) program undetermined
107Considerations related to nirsevimab being classified
as a drug
Certain types of health care workers (e.g., medical assistants) can
administer vaccines but might not be able to administer a monoclonal
antibody depending on jurisdiction
Adverse events would be reported to FDA Adverse Event Reporting
System rather than the Vaccine Adverse Event Reporting System
Billing and administration codes for nirsevimab have not been finalized
Some state immunization information systems might not be able to include products that are considered drugs and not vaccines
108Feasibility
Is immunization with nirsevimab feasible to implement among all
infants <8 months of age entering their first RSV season and infants
born during the RSV season?
No Probably
NoProbably
YesYes Varies Don’t know
EtRDomain: Resource Use
Is nirsevimab immunization among all infants <8 months of age entering
their first RSV season and infants born during the RSV season a
reasonable and efficient allocation of resources?
110Cost -effectiveness results
Cost of nirsevimab per infant1 ICER ($/QALY)2
$300 $ 102,805
$500 $ 244,677
ICER: Incremental cost effectiveness ratio, QALY: quality -adjusted life year
1 Cost includes cost of administration.
2 Restricted to lower respiratory tract infection (i.e., upper respiratory infections from RSV excluded). Incorporated costs of
outpatient, ED, inpatient, and death from RSV LRTI. Incidence of RSV -associated outpatient, ED, and inpatient events based on
published and unpublished NVSN estimates. Nirsevimab efficacy based on phase 2b and phase 3 trial results. Other model
assumptions from published literature. Cost of palivizumab not incorporated.
111Resource Use
Is nirsevimab immunuization among a ll infants <8 months of age
entering their first RSV season and infants born during the RSV season a
reasonable and efficient allocation of resources?
At $300 per infant
At $500 per infantNo Probably
NoProbably
YesYes Varies Don’t know
No Probably
NoProbably
YesYes Varies Don’t know
EtRDomain: Equity
What would be the impact of nirsevimab on health equity?
113Equity and payment
Nirsevimab inclusion in Vaccines For Children (VFC) program undetermined
If not included in VFC, state Medicaid, Medicaid expansion (Children’s
Health Insurance Programs), and private insurance would likely cover
nirsevimab
–Underinsured and uninsured would likely have reduced access
114Seasonal incidence per 1,000 children of RSV -associated hospitalizations
among American Indian and Alaska Native children <5 years of age, Nov
2019 -May 2020 ( SuNA )*
*Hartman et al, R SV 2022 12thInternational Symposium, B elfast 9/29/2022- 10/2/2022; A twell et al. (manuscript submitted, under peer -review) SuNA = RSV Surveillance
among Native A merican Persons
**In cid e n ce o f RSV -associated hosp italization in 2019 -2020 from Curns et al. (unp ub lished manuscrip t in p rep aration) included fo r comp arison. NVSN = New V accine
Surveillance Network.Age Chinle, Arizona Whiteriver,
Arizona Anchorage, Alaska Yukon -Kuskokwim
Delta, Alaska NVSN** for
comparison
0-5 Months 83.0 (52.0, 132.5) 70.4 (36.3, 136.6) 35.7 (20.4, 62.6) 132.3 (98.2, 178.1) 21.6 (20.0 , 23.3)
6-11 Months 61.6 (35.9, 105.8) 90.1 (50.0, 162.3) 0.0 (0.0, 10.8) 91.6 (64.0, 131.0) 8.2 (7.1 , 9.3)
0-11 Months 71.8 (50.4, 102.4) 80.6 (51.9, 125.2) 19.2 (11.2, 33.0) 112.2 (89.3, 141.0) 14.9 (13.9 , 16.0)
12-23 Months 42.1 (27.2, 65.3) 38.7 (22.0, 68.1) 15.6 (8.7, 27.7) 26.4 (16.6, 41.8) 4.5 (3.9 , 5.2)
24-59 Months 10.9 (6.8, 17.4) 8.2 (4.2, 16.0) 1.1 (0.3, 3.8) 5.9 (3.2, 10.9) 1.2 (1.2 , 1.5)
0-59 Months 27.2 (21.4, 34.4) 25.4 (18.7, 34.5) 7.7 (5.3, 11.1) 32.7 (26.9, 39.7) 4.6 (4.3, 4.8)
115RSV rates of severe disease by race and ethnicity
National studies of death certificates found higher rates among non -
Hispanic black compared with non -Hispanic White children1
Hospitalization rates using New Vaccine Surveillance Network (NVSN) data
have shown mixed results2
–Several studies have shown no differences by race or ethnicity3-5
–Even when significant, relative risk for non -Hispanic Black and Hispanic
children mildly increased (e.g., relative risk of 1.2 -2.2)5-6
1. Hansen J Infect Dis 2022 Aug 15;226(Suppl 2):S255 -S266
2. NVSN analyses compared incidence rates of non -Hispanic Black, non -Hispanic White,
and Hispanic children
3. Hall Pediatrics 2013 Aug;132(2):e341 -84. Hall NEJM 2009;360(6):588 –598
5. Iwane Pediatrics 2004 Jun;113(6):1758 -64, findings differed by age group
6. Rha Pediatrics 2020 Jul;146(1):e20193611, findings differed by age group
116Equity
What would be the impact of nirsevimab on health equity?
Reduced
Probably reduced
Probably no impact
Probably increased
Increased
Varies
Don’t know
117EtRSummary: All infants 1st RSV season
EtRDomain Question(s) Work Group Judgments
Public Health
ProblemIs RSV -associated disease among infants <8 months of age
entering their first RSV season and infants born during the
RSV season of public health importance?Ye s
Benefits and
HarmsHow substantial are the desirable anticipated effects?
How substantial are the undesirable anticipated effects?
Do the desirable effects outweigh the undesirable effects?Moderate to large
Minimal to small
Ye s
Values Does the target population feel the desirable effects are
large relative to the undesirable effects?
Is there important variability in how patients value the outcome?Y es/probabl y yes
No consensus
Acceptability Is nirsevimab acceptable to key stakeholders? Y es/probabl y yes
Feasibility Is the intervention feasible to implement? Probabl y yes
Resource Use Is the intervention a reasonable and efficient allocation of resources? Y es/probabl y yes
(depends on price)
Equity What would be in the impact of the intervention on health equity?—
118Evidence to Recommendations Framework
Summary: Work Group Interpretations
All infants 1st RSV season
Balance of
consequencesUndesirable
consequences
clearly
outweigh
desirable
consequences
in most settingsUndesirable
consequences
probably
outweigh
desirable
consequences
in most settingsThe balance
between
desirable
and undesirable
consequences
isclosely
balanced or
uncertainDesirable
consequences
probably
outweigh
undesirable
consequences
in most settingsDesirable
consequences
clearly
outweigh
undesirable
consequences
in most settingsThere
isinsufficient
evidence
todetermine
thebalance of
consequences
119Evidence to Recommendations Framework
Summary: Work Group Interpretations
All infants 1st RSV season
Type of
recommendationWe do not
recommend the
interventionWe recommend
theintervention for
individuals based on
shared
clinical decision -
makingWe recommend
theintervention
2ndindication
Should one dose of nirsevimab be recommended for children <20 months
of age with increased risk of severe disease entering their second RSV
season?
121Evidence to Recommendations (EtR ) Framework
PICO Question
Population Children age <20 months who are at increased risk of severe disease
with RSV and who are entering their second RSV season
Intervention Nirsevimab (200 mg [2 x 100 mg] injection prior to start of second
RSV season)
Comparison No nirsevimab prophylaxis
Outcomes Medically attended RSV associated lower respiratory tract
infection (LRTI)
Medically attended RSV associated LRTI with hospitalization
Medically attended RSV associated LRTI with ICU admission
RSV-associated death
All-cause MA LRTI
All-cause LRTI associated hospitalization
Serious adverse events
EtRDomain: Public Health Problem
Is RSV disease among children who are at high risk of severe disease in
their 2nd RSV season of public health importance?
RSV-associated hospitalization rates in children aged <5 years,
New Vaccine Surveillance Network, 2016 -2020
0-5 months 6-11 months 12-23 months 24-59 months 0-59 months
2016-2020 18.5 7.5 3.9 1.0 3.9.05.010.015.020.025.0Hospitalization Rate per 1000
124Relative risk in 1st RSV season compared with 2nd RSV
season
CDC, unpublished dataFigure: RSV hospitalization rate ratios by age in months among children <2 years old, New Vaccine
Surveillance Network, December 2016 through September 2020.
6.1
3.4
1.9
012345678
0-2 vs. 12-23 3-5 vs. 12-23 6-11 vs. 12-23Rate Ratio
Comparison (age in months)
125High- risk second season indications proposed by
manufacturer
Children up to 24 months of age who remain vulnerable to severe RSV
disease through their second RSV season, which may include but is not
limited to children with:
– Chronic lung disease of prematurity (CLD)
– Hemodynamically significant congenital heart disease (CHD)
– Immunocompromised states
– Down syndrome
– Cystic fibrosis
– Neuromuscular disease
– Congenital airway anomalies
In MEDLEY study, palivizumab -eligible children with hemodynamically -
significant CHD and CLD were included
126Chronic conditions recommended by American Academy of Pediatrics
(AAP) to qualify for palivizumab when entering 2ndRSV season
Group recommended for palivizumab
–CLD of prematurity if require medical support (chronic corticosteroid
therapy, diuretic therapy, or supplemental oxygen) during the 6 -month
period before the start of the second RSV season
Groups that can be considered for palivizumab
–Profoundly immunocompromised
–Cystic fibrosis if manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or
abnormalities on chest XR or CT that persist when stable) or weight for
length < 10th percentile.
American Academy of Pediatrics Committee on Infectious Diseases and Bronchiolitis Guidelines Committee. Updated guidance for palivizumab prophylaxis among
infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics. 2014 A ug;134(2):415 -20.
127WG considerations for conditions and populations to
be considered “high risk”
Same children eligible for palivizumab when entering 2nd RSV season per American
Academy of Pediatrics recommendations
–Children with chronic lung disease of prematurity if require medical support (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) during the 6- month period before the start of the second RSV season
–Children who are profoundly immunocompromised
–Children with cystic fibrosis with manifestations of severe lung disease
(previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest XR or CT that persist when stable) or weight for length < 10th percentile
Other conditions are under review
American Academy of Pediatrics Committee on Infectious Diseases and Bronchiolitis Guidelines Committee. Updated guidance for palivizumab prophylaxis among
infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics. 2014 A ug;134(2):415 -20.
128Public Health Problem- Work Group Interpretation
Is RSV disease among children who are at high risk of severe disease
in their 2nd RSV season of public health importance?
NoProbably
NoProbably
YesYes VariesDon’t
know
EtRDomain: Benefits and Harms
Do the desirable effects outweigh the undesirable effects?
130MEDLEY study: Dose for children ≤24 months with
CLD/CHD entering their second RSV season
130
Domachowske e t a l. https://www.nejm.org/doi/full/10.1056/NE JMc2112186 , https://clinicaltrials.gov/ct2/show/NCT03959488
131Outcomes, importance, and data sources
Outcome Importancea Data sources
Benefits
Medically attended RSV LRTI Critical MEDLEY , Domachowske et al.
RSV LRTI with hospitalization Critical No available data
RSV LRTI with ICU admission Critical No available data
Death due to RSV respiratory illness Critical No available data
All-cause medically attended -LRTI Important No available data
All-cause LRTI -associated hospitalization Important No available data
HarmsSerious Adverse Events (SAEs) Important MEDLEY , Domachowske et al.
a Three options: Critical; Important but not critical; Not important for decision making
132Medically attended (MA)* RSV LRTI
MEDLEY designed as safety and pharmacokinetics (PK) study
No clinical efficacy data available for children <24 months at high risk of
severe RSV disease entering their second RSV season
PK data from Phase 2b, Phase 3, and MEDLEY studies (i.e., among infants
<12 months of age) were analyzed using population modelling
Area under the curve (AUC0-∞) was derived using individual estimates as a
measure of exposure to nirsevimab
AUC0-∞was then correlated to efficacy for prevention of the first episode of
MA RSV LRTI in infants age <12 months from Phase 2b, Phase 3 and
MEDLEY trials
*Medically attended means presented for medical care, either outpatient or inpatient
133Pharmacokinetic data for children ≤24 months with
CLD/CHD entering their second RSV season who
received 200 mg of nirsevimab
Dashed black line is the AUC Exposure -Response
threshold (12.8 day*mg/mL)
Notes: black points are individual AUC predictions.
AUC = area under the serum concentration- time curve
derived from dose and post -hoc clearance values at
baseline from the final population PK model; CHD =
congenital heart disease; CL = clearance; CLD = chronic lung disease; GA = gestational age
Pre-determined threshold of
80% meeting PK criteria met
Data from Sanofi/AstraZeneca
134GRADE: medically attended RSV LRTI (n=1 study)
Measures of effect:
–Pharmacokinetic extrapolation from efficacy in infants <12 months of
age for prevention of the first MA RSV LRTI to pharmacokinetic levels in
children ≤24 months with CLD/CHD entering their second RSV season
Concerns in certainty assessment:
–Very serious (indirectness due to surrogate outcome, outcome
established in 1st season, and population that does not match proposed indication)
Evidence type:
–Low certainty
135Available safety data from children ≤24 months with
CLD/CHD entering their second RSV season who
received nirsevimab (200 mg) or palivizumab (15 mg/kg)
Subjects withCLD/CHD Cohort
Palivizumab/
Palivizumab1
(N=42)
N (%)Palivizumab / Nirsevimab
1
(N=40)N (%)Nirsevimab / Nirsevimab
1
(N=180)N (%)
At least one adverse event229 (69.0) 29 (72.5) 126 (70.0)
At least one serious event30 ( 0.0) 4 (10.0) 17 ( 9.4)
At least one investigational product -related
event0 ( 0.0) 0 ( 0.0) 0 ( 0.0)
Any adverse event with outcome of death 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)
1Palivizumab / Palivizumab = Palivizumab in season 1 / Palivizumab in season 2; Palivizumab / Nirsevimab = Palivizumab in season 1 /Nirsevimab in season 2;
Nirsevimab / Nirsevimab = Nirsevimab in season 1 / Nirsevimab in season 2
2A ny untoward medical occurrence (e.g., unintended abnormal laboratory , symptom, or disease temporally associated with product , whether or not considered
associated);3AE resulting in death, hosp italization, significant disab ility, or required medical intervention.
Data from Sanofi/A straZeneca
136GRADE: Serious adverse events (n=1 study)
Measures of effect
–Relative Risk: 8.4 (95% CI: 0.52 -135.50)1
–Absolute risk: 176 more cases per 1,000 immunized (95% CI: 11 fewer
to 1,000 more)
Concerns in certainty assessment
–Serious (indirectness because comparison group is palivizumab
recipients rather than placebo)
–Very serious (imprecision)
Evidence type:
–Very low certainty
1Relative risk of an serious adverse event among children who received nirsevimab in their 2nd RSV season compared with childr enwho received palivizumab their 2nd
RSV season. Because no SAEs were reported in palivizumab group, 0.5 was added to both the nirsevimab and the palivizumab groups t o calculate relative risk.
137Summary of GRADE for nirsevimab dose for second season
Outcome Importance Design
(# of studies)Findings Level of certainty
Benefits
Medically attended (MA) RSV LRTICritical 3 Nirsevimab might be effective in preventing MA RSV LRTI Low
RSV LRTI with
hospitalizationCriticalNo available data
RSV LRTI with ICU
admissionCriticalNo available data
RSV-associated deathCriticalNo available data
All cause medically attended LRTI ImportantNo available data
All cause hospitalization with respiratory diseaseImportantNo available data
Harms
Serious adverse events
(SAEs)Critical 1SAEs might not be more common in intervention group
than placebo groupVery low137
138Overall evidence rating
Overall evidence rating: Very low certainty
Downgraded based on indirectness because pharmacokinetic data used as
surrogate for efficacy, population did not include children that matches
proposed indication, study small in size, and no placebo group was
included for comparison
139Benefits and harms of nirsevimab
How substantial are the desirable anticipated effects?
–How substantial are the anticipated effects for each main outcome
for which there is a desirable effect?
Minimal Small Moderate Large Varies Don’t know
140Benefits and harms of nirsevimab
How substantial are the undesirable anticipated effects?
–How substantial are the anticipated effect for each main outcome
for which there is an undesirable effect?
Minimal Small Moderate Large Varies Don’t know
141Benefits and harms of nirsevimab
Do the desirable effects outweigh the undesirable effects?
–What is the balance between the desirable effects relative to the
undesirable effects?
Favors intervention (Nirsevimab)
Favors comparison (No intervention)
Favors both
Favors neither
Unclear
EtRDomains: Values, Acceptability, and
Feasibility
143Values
Criterion 1: Does the target population feel that the desirable effects
are large relative to undesirable effects?
NoProbably
NoProbably
YesYes VariesDon’t
know
144Values
Criterion 2: Is there important uncertainty about, or variability in, how
much people value the main outcomes?
Important uncertainty or variability
Probably important uncertainty or variability
Probably not important uncertainty or
variability
No important uncertainty or variability
No known undesirable outcomes
145Acceptability
Is RSV prevention with nirsevimab acceptable to key stakeholders?
No Probably
NoProbably
YesYes Varies Don’t know
146Feasibility
Additional visit to provider might be needed for administration of
nirsevimab prior to beginning of 2nd RSV season
Is nirsevimab feasible to implement among high -risk children
<20 months of age entering their second RSV season?
No Probably
NoProbably
YesYes Varies Don’t know
EtRDomain: Resource Use
148Resource Use
Is nirsevimab use among a ll high-risk children aged < 20months of age
entering their second RSV season a reasonable and efficient allocation
of resources?
$600 per child
$1000 per childNo Probably
NoProbably
YesYes Varies Don’t know
No Probably
NoProbably
YesYes Varies Don’t know
EtRDomain: Equity
150Equity
Equity issues differ by chronic condition among infants and young children
Non -Hispanic Black populations experience higher rates of preterm birth
than non -Hispanic White population1
For children with cystic fibrosis, the majority are from non -Hispanic white
populations2
Hispanic populations may have higher prevalence of Down syndrome than
non-Hispanic White populations3
Hispanic and non -Hispanic American Indian and Alaska Native populations
may have higher prevalence of neuromuscular disorders than non -Hispanic
White populations3
1.https: //www.cdc.gov/reproductivehealth/maternalinfanthealth/pretermbirth.htm
2.McGarry Pediatr Pulmonol 2021 Jun;56(6):1496- 1503
3.Mai B irth Defects R es 2019 Nov 1;111(18):1420- 1435
151Equity
What would be the impact of nirsevimab on health equity among high -
risk children entering their 2ndRSV season?
Reduced
Probably reduced
Probably no impact
Probably increased
Increased
Varies
Don’t know
152Summary: Children at high risk entering 2nd RSV season
EtRDomain Question(s) Work Group Judgments
Public Health
ProblemIs RSV disease among children <20 months who are at high risk of severe disease of public health importance? Yes
Benefits and
HarmsHow substantial are the desirable anticipated effects?
How substantial are the undesirable anticipated effects?
Do the desirable effects outweigh the undesirable effects?Moderate
Minimal
Favors nirsevimab
Values Does the target population feel the desirable effects are
large relative to the undesirable effects?
Is there important variability in how patients value the outcome?Probably yes
Probably no
Acceptability Is nirsevimab acceptable to key stakeholders? Probably yes
Feasibility Is the intervention feasible to implement? Probably yes
Resource Use Is the intervention a reasonable and efficient allocation of
resources?$600: Probably yes
$1000: Probably yes or probably no
Equity What would be in the impact of the intervention on health
equity?-
153Evidence to Recommendations Framework
Summary: Work Group Interpretations
Children at high risk entering 2nd RSV season
Balance of
consequencesUndesirable
consequences
clearly
outweigh
desirable
consequences
in most settingsUndesirable
consequences
probably
outweigh
desirable
consequences
in most settingsThe balance
between
desirable
and undesirable
consequences
isclosely
balanced or
uncertainDesirable
consequences
probably
outweigh
undesirable
consequences
in most settingsDesirable
consequences
clearly
outweigh
undesirable
consequences
in most settingsThere
isinsufficient
evidence
todetermine
thebalance of
consequences
154Evidence to Recommendations Framework
Summary: Work Group Interpretations
Children at high risk entering 2nd RSV season
Type of
recommendationWe do not
recommend the
interventionWe recommend
theintervention for
individuals based on
shared
clinical decision -
makingWe recommend
theintervention
Summary
1561st RSV season
The WG recommends nirsevimab a) at birth for all infants born during
October to March and b) when entering first RSV season and <8 months of age for all infants born during April through September?
Many expressed concerns about feasibility and equity, particularly because inclusion in VFC is unknown
Some WG expressed concern that at higher prices, nirsevimab may not be a reasonable and efficient allocation of resources
1572nd RSV season
WG would like more time to consider which infants and children would be
sufficiently high risk to warrant nirsevimab in their 2ndRSV season
–Limited efficacy and safety data
–Limited data to measure the risk of severe disease in the 2ndRSV
season
–At this time, WG recommended nirsevimab for those who are eligible for palivizumab in their 2nd RSV season, since assumed to be cost effective
–WG will continue to evaluate other conditions
158ACIP Policy Questions
Should one dose of nirsevimab be recommended a) at birth for all infants
born during October to March and b) when entering first RSV season and
<8 months of age for all infants born during April through September?
Should one dose of nirsevimab be recommended for children <20 months
of age entering their second RSV season who are eligible for palivizumab in
their second RSV season?
159Acknowledgements
Meredith McMorrow
Lauren RoperKatherine Fleming -Dutra
Mila PrillAmanda Payne
Danielle Moulia
Morgan NajdowskiDavid Hutton
Jamie PikeIsmael Ortega- Sanchez
Andrew Leidner
Sara OliverMonica Godfrey
Evelyn Twentyman
Rebecca Morgan
Doug Campos -Outcalt
For more information, contact CDC
1-800- CDC-INFO (232- 4636)
TTY: 1 -888- 232-6348 www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.