Centers for Disease Control and Prevention

Evidence to Recommendations Framework: 

Nirsevimab

Jefferson Jones MD MPH FAAP, CDR USPHS

ACIP General Meeting

February 23, 2023
Evidence to Recommendations Framework
71

Nirsevimab is a form of passive immunization

 Active immunity results from infection or vaccination, which triggers 

an immune 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
72

Evidence 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?
73

Evidence 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
74

Evidence to Recommendations (EtR) Framework

EtR Domain 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?
EtR Domain: 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? 
76

Changes 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

1 Displayed 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.
77

Each year among U.S. children aged less than 5 years, 

RSV is associated with...

~1,500,0003

outpatient visits

~520,0003

emergency department visits

58,000-80,0003,4,5

hospitalizations

100-3001,2

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) 
78

Epidemiology 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
79

Public 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? 

No Probably 

No

Probably 

Yes Yes Varies Don’t 

know
EtR Domain: Benefits and Harms

Do the desirable effects outweigh the undesirable effects?
81

Outcomes, importance, and data sources

Outcome Importancea Data 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

Harms

Serious Adverse Events (SAEs) Important Phase 3 and phase 2b RCTb

a Three options: Critical; Important but not critical; Not important for decision making

b Includes 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 determined to be too low to be efficacious for this 

weight

LRTI: Lower respiratory tract infection, RCT: randomized control trial, ICU: intensive care unit 
82

Efficacy 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 

illness

None recorded N/A

All-cause medically attendedLRTI34.8% (95% CI: 23.0–44.7%) Not serious (indirectness)

All-cause LRTI-associated 

hospitalization

44.9% (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
83

Efficacy 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 

illness

None recorded N/A

All-cause medically attendedLRTI34.8% (95% CI: 23.0–44.7%) Not serious (indirectness)

All-cause LRTI-associated 

hospitalization

44.9% (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
84

Efficacy 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 

illness

None recorded N/A

All-cause medically attendedLRTI34.8% (95% CI: 23.0–44.7%) Not serious (indirectness)

All-cause LRTI-associated 

hospitalization

44.9% (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
85

Relative risk of SAEs and concerns in certainty of 

assessment

Outcome Relative risk1 Concerns in certainty of assessment

Harms

Serious Adverse Events 

(SAEs)2

0.73 (95% CI: 0.59–0.89) Serious (imprecision)

1 Pooled phase 2b and phase 3 estimate comparing nirsevimab arm to placebo arm

2 Adverse event resulting in death, hospitalization, significant disability, or requiring medical intervention. 

Adverse events include respiratory symptoms.
86

Summary of GRADE for nirsevimab

OutcomeImportance Design

(# of studies)

FindingsLevel of 

certainty

Benefits

Medically attended RSV 

LRTI Critical RCT (2) Nirsevimab is effective in preventing medically attended RSV LRTI High

RSV LRTI with 

hospitalization Critical RCT (2) Nirsevimab is effective in preventing medically attended RSV LRTI with hospitalization High

RSV LRTI with ICU 

admission Critical RCT (2) Nirsevimab is likely effective in preventing medically 

attended RSV LRTI with ICU admission Moderate

Death due to RSV Critical RCT (2) No deaths reported -

All-cause medically 

attended -LRTI Important RCT (2) Nirsevimab is effective in preventing all cause medically 

attended LRTI High

All-cause LRTI-associated 

hospitalization Important RCT (2) Nirsevimab is effective in preventing all cause hospitalization with respiratory disease High

Harms

Serious adverse eventsCritical RCT (1) SAEs were likely not more common in intervention group 

than placebo group Moderate

1 1: High certainty; 2: Moderate certainty. 3: Low certainty; 4: Very low certainty. 
87

Summary of GRADE for nirsevimab

OutcomeImportance Design

(# of studies)

FindingsLevel of 

certainty

Benefits

Medically attended RSV 

LRTI Critical RCT (2) Nirsevimab is effective in preventing medically attended RSV LRTI High

RSV LRTI with 

hospitalization Critical RCT (2) Nirsevimab is effective in preventing medically attended RSV LRTI with hospitalization High

RSV LRTI with ICU 

admission Critical RCT (2) Nirsevimab is likely effective in preventing medically 

attended RSV LRTI with ICU admission Moderate

Death due to RSV Critical RCT (2) No deaths reported -

All-cause medically 

attended -LRTI Important RCT (2) Nirsevimab is effective in preventing all cause medically 

attended LRTI High

All-cause LRTI-associated 

hospitalization Important RCT (2) Nirsevimab is effective in preventing all cause hospitalization with respiratory disease High

Harms

Serious adverse eventsCritical RCT (1) SAEs were likely not more common in intervention group 

than placebo group Moderate

1 1: High certainty; 2: Moderate certainty. 3: Low certainty; 4: Very low certainty. 
88

Summary of GRADE for nirsevimab

OutcomeImportance Design

(# of studies)

FindingsLevel of 

certainty

Benefits

Medically attended RSV 

LRTI Critical RCT (2) Nirsevimab is effective in preventing medically attended RSV LRTI High

RSV LRTI with 

hospitalization Critical RCT (2) Nirsevimab is effective in preventing medically attended RSV LRTI with hospitalization High

RSV LRTI with ICU 

admission Critical RCT (2) Nirsevimab is likely effective in preventing medically 

attended RSV LRTI with ICU admission Moderate

Death due to RSV Critical RCT (2) No deaths reported -

All-cause medically 

attended -LRTI Important RCT (2) Nirsevimab is effective in preventing all cause medically 

attended LRTI High

All-cause LRTI-associated 

hospitalization Important RCT (2) Nirsevimab is effective in preventing all cause hospitalization with respiratory disease High

Harms

Serious adverse eventsCritical RCT (1) SAEs were likely not more common in intervention group 

than placebo group Moderate

1 1: High certainty; 2: Moderate certainty. 3: Low certainty; 4: Very low certainty. 
89

Overall 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
90

Benefits 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
91

Benefits 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
92

Benefits 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
EtR Domain: 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?
94

About 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 

get RSV

Unsure

Definitely or 

probably would 

not get 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
96

63% 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

Worried about 

both

Worried about 

bad disease 

symptoms

CDC and University of Iowa/RAND survey, unpublished
97

Parent 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
98

Values

 Criterion 1: Does the target population feel that the desirable effects 

are large relative to undesirable effects?

No Probably 

No

Probably 

Yes Yes Varies Don’t 

know
99

Values

 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
EtR Domain: Acceptability

Is immunization with nirsevimab acceptable to key stakeholders?
101

Provider 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_Jan-2023.pdf
102

Importance 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
103

Acceptability

 Is immunization with nirsevimab acceptable to key stakeholders?

No Probably 

No

Probably 

Yes Yes Varies Don’t know
EtR Domain: 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?
105

Administration 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 2nd RSV 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 

Beyfortussummary of product characteristics. European Medicines Agency https://www.ema.europa.eu/en/documents/product -information/beyfortus -epar-product-information_en.pdf
106

ACIP 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
107

Considerations 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
108

Feasibility

 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 

No

Probably 

Yes

Yes Varies Don’t know
EtR Domain: 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?
110

Cost-effectiveness results

Cost of nirsevimab per infant 1 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.
111

Resource Use

 Is nirsevimab immunuization 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?

At $300 per infant

At $500 per infant

No Probably 

No

Probably 

Yes

Yes Varies Don’t know

No Probably 

No

Probably 

Yes

Yes Varies Don’t know
EtR Domain: Equity

What would be the impact of nirsevimab on health equity?
113

Equity 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
114

Seasonal 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, RSV2022 12th International Symposium, Belfast 9/29/2022-10/2/2022;Atwell et al. (manuscript submitted, under peer-review) SuNA= RSV Surveillance 

among Native American Persons

**Incidence of RSV-associated hospitalization in 2019-2020 from Curns et al. (unpublished manuscript in preparation) included for comparison. NVSN = New Vaccine 

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)
115

RSV rates of severe disease by race and ethnicity

 National studies of death certificates found higher rates among nonHispanic 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):e341-8

4. Hall NEJM 2009;360(6):588–598

5. IwanePediatrics 2004 Jun;113(6):1758-64, findings differed by age group

6. Rha Pediatrics 2020 Jul;146(1):e20193611, findings differed by age group
116

Equity

 What would be the impact of nirsevimab on health equity?

Reduced

Probably reduced

Probably no impact

Probably increased

Increased

Varies

Don’t know
117

EtR Summary: All infants 1st RSV season

EtR Domain Question(s) Work Group Judgments

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?

Yes

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?

Moderate to large

Minimal to small

Yes

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?

Yes/probably yes

No consensus

Acceptability  Is nirsevimab acceptable to key stakeholders? Yes/probably yes

Feasibility  Is the intervention feasible to implement? Probably yes

Resource Use  Is the intervention a reasonable and efficient allocation of 

resources?

Yes/probably yes 

(depends on price)

Equity  What would be in the impact of the intervention on health 

equity? —
118

Evidence to Recommendations Framework

Summary: Work Group Interpretations

All infants 1st RSV season 

Balance of

consequences

Undesirable

consequences

clearly

outweigh

desirable

consequences

in most settings

Undesirable

consequences

probably

outweigh

desirable

consequences

in most settings

The balance

between

desirable 

and undesirable

consequences

is closely

balanced or

uncertain

Desirable

consequences

probably

outweigh

undesirable

consequences

in most settings

Desirable

consequences

clearly

outweigh

undesirable

consequences

in most settings

There 

is insufficient

evidence 

to determine 

the balance of

consequences
119

Evidence to Recommendations Framework

Summary: Work Group Interpretations

All infants 1st RSV season 

Type of

recommendation

We do not 

recommend the 

intervention

We recommend 

the intervention for 

individuals based on 

shared 

clinical decisionmaking

We recommend 

the intervention
2nd indication

Should one dose of nirsevimab be recommended for children <20 months 

of age with increased risk of severe disease entering their second RSV 

season?
121

Evidence 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
EtR Domain: 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

.0

5.0

10.0

15.0

20.0

25.0

Hospitalization Rate per 1000
124

Relative risk in 1st RSV season compared with 2nd RSV 

season

CDC, unpublished data

Figure: 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

0

1

2

3

4

5

6

7

8

0-2 vs. 12-23 3-5 vs. 12-23 6-11 vs. 12-23

Rate Ratio

Comparison (age in months)
125

High-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 hemodynamicallysignificant CHD and CLD were included
126

Chronic conditions recommended by American Academy of Pediatrics 

(AAP) to qualify for palivizumab when entering 2nd RSV 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. 
127

WG 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. 
128

Public 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?

No Probably 

No

Probably 

Yes Yes Varies Don’t 

know
EtR Domain: Benefits and Harms

Do the desirable effects outweigh the undesirable effects?
130

MEDLEY study: Dose for children ≤24 months with 

CLD/CHD entering their second RSV season

130

Domachowske et al. https://www.nejm.org/doi/full/10.1056/NEJMc2112186, https://clinicaltrials.gov/ct2/show/NCT03959488
131

Outcomes, 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

Harms

Serious Adverse Events (SAEs) Important MEDLEY, Domachowske et al.

a Three options: Critical; Important but not critical; Not important for decision making
132

Medically 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
133

Pharmacokinetic 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
134

GRADE: 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 
135

Available 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 with

CLD/CHD Cohort

Palivizumab/ 

Palivizumab1

(N=42)

N (%)

Palivizumab / 

Nirsevimab1

(N=40)

N (%)

Nirsevimab / 

Nirsevimab1

(N=180)

N (%)

At least one adverse event2 29 (69.0) 29 (72.5) 126 (70.0)

At least one serious event3 0 ( 0.0) 4 (10.0) 17 ( 9.4)

At least one investigational product-related 

event 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Any adverse event with outcome of death 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

1 Palivizumab/ 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

2 Any untoward medical occurrence (e.g., unintended abnormal laboratory, symptom, or disease temporally associated with product, whether or not considered 

associated);3AE resulting in death, hospitalization, significant disability, or required medical intervention.

Data from Sanofi/AstraZeneca
136

GRADE: 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 

1 Relative risk of an serious adverse event among children who received nirsevimab in their 2nd RSV season compared with childr en who 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.
137

Summary of GRADE for nirsevimab dose for second season

OutcomeImportance Design

(# of studies)

FindingsLevel of 

certainty

Benefits

Medically attended (MA) 

RSV LRTI Critical 3 Nirsevimab might be effective in preventing MA RSV LRTI Low

RSV LRTI with 

hospitalization Critical No available data

RSV LRTI with ICU 

admission Critical No available data

RSV-associated death Critical No available data

All cause medically 

attended LRTI Important

No available data

All cause hospitalization 

with respiratory disease Important No available data

Harms

Serious adverse events 

(SAEs) Critical 1 SAEs might not be more common in intervention group than placebo group Very low

137
138

Overall 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
139

Benefits 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
140

Benefits 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
141

Benefits 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
EtR Domains: Values, Acceptability, and 

Feasibility
143

Values

 Criterion 1: Does the target population feel that the desirable effects 

are large relative to undesirable effects?

No Probably 

No

Probably 

Yes Yes Varies Don’t 

know
144

Values

 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
145

Acceptability

 Is RSV prevention with nirsevimab acceptable to key stakeholders?

No Probably 

No

Probably 

Yes

Yes Varies Don’t know
146

Feasibility

 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 

No

Probably 

Yes

Yes Varies Don’t know
EtR Domain: Resource Use
148

Resource Use

 Is nirsevimab use among all high-risk children aged <20 months of age 

entering their second RSV season a reasonable and efficient allocation 

of resources?

$600 per child

$1000 per child

No Probably 

No

Probably 

Yes

Yes Varies Don’t know

No Probably 

No

Probably 

Yes

Yes Varies Don’t know
EtR Domain: Equity
150

Equity

 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 Birth Defects Res 2019 Nov 1;111(18):1420-1435
151

Equity

 What would be the impact of nirsevimab on health equity among highrisk children entering their 2nd RSV season?

Reduced

Probably reduced

Probably no impact

Probably increased

Increased

Varies

Don’t know
152

Summary: Children at high risk entering 2nd RSV season

EtR Domain Question(s) Work Group Judgments

Public Health 

Problem

 Is RSV disease among children <20 months who are at high 

risk of severe disease of public health importance? Yes

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?

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?

-
153

Evidence to Recommendations Framework

Summary: Work Group Interpretations

Children at high risk entering 2nd RSV season

Balance of

consequences

Undesirable

consequences

clearly

outweigh

desirable

consequences

in most settings

Undesirable

consequences

probably

outweigh

desirable

consequences

in most settings

The balance

between

desirable 

and undesirable

consequences

is closely

balanced or

uncertain

Desirable

consequences

probably

outweigh

undesirable

consequences

in most settings

Desirable

consequences

clearly

outweigh

undesirable

consequences

in most settings

There 

is insufficient

evidence 

to determine 

the balance of

consequences
154

Evidence to Recommendations Framework

Summary: Work Group Interpretations

Children at high risk entering 2nd RSV season

Type of

recommendation

We do not 

recommend the 

intervention

We recommend 

the intervention for 

individuals based on 

shared 

clinical decisionmaking

We recommend 

the intervention
Summary
156

1st 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
157

2nd RSV season

 WG would like more time to consider which infants and children would be 

sufficiently high risk to warrant nirsevimab in their 2nd RSV season

– Limited efficacy and safety data

– Limited data to measure the risk of severe disease in the 2nd RSV 

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
158

ACIP 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?
159

Acknowledgements 

Meredith McMorrow

Lauren Roper

Katherine Fleming-Dutra

Mila Prill

Amanda Payne

Danielle Moulia

Morgan Najdowski

David Hutton

Jamie Pike

Ismael Ortega-Sanchez

Andrew Leidner

Sara Oliver

Monica 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.