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Evidence to Recommendations Framework Updates

Pfizer Maternal RSVpreF Vaccine

ACIP General Meeting

September 22, 2023

Katherine E. Fleming-Dutra, MD

Co-lead, Respiratory Syncytial Virus Vaccines – Pediatric/Maternal Work Group

Coronavirus and Other Respiratory Viruses Division

National Center for Immunization and Respiratory Diseases

▪ Should Pfizer RSVpreF vaccine be recommended for pregnant people to be given

during 32 through 36 weeks gestation to prevent RSV lower respiratory tract infection

in infants?

Policy question

RSVpreF is a bivalent recombinant stabilized prefusion F protein subunit vaccine.

Key points that have been updated since the June ACIP presentation are highlighted on the slides.

▪ On August 21, 2023, FDA approved Pfizer RSVpreF vaccine for use in pregnant people

as a single dose to be given at 32 through 36 weeks gestation

▪ In the phase 2b and 3 trials, vaccination was given during 24 through 36 weeks

gestation

▪ Throughout the presentation, these will be denoted as

• Approved dosing interval (32–36 weeks gestation)

• Trial dosing interval (24–36 weeks gestation)

FDA approval for RSVpreF vaccine

FDA Approves First Vaccine for Pregnant Individuals to Prevent RSV in Infants | FDA

Vaccines and Related Biological Products Advisory Committee May 18, 2023 Meeting Briefing Document- FDA

Same Pfizer RSV vaccine, formulation and dose approved for use in adults ages 60 years and older

opulation

Pregnant people

Intervention

Pfizer RSVpreF vaccine given at

32–36 weeks gestation

omparison

No vaccine

utcomes

▪

Medically attended RSV-associated lower respiratory tract infection in infants

▪

Hospitalization for RSV-associated lower respiratory tract infection in infants

▪

Intensive care unit (ICU) admission from RSV hospitalization in infants

▪

Mechanical ventilation from RSV hospitalization in infants

▪

RSV-associated death in infants

▪

All-cause hospitalization for lower respiratory tract infection in infants

▪

All-cause medically attended lower respiratory tract infection in infants

▪

Serious adverse events in pregnant people

▪

Reactogenicity (grade 3+) in pregnant people

▪

Serious adverse events in infants

▪

Preterm birth (<37 weeks gestation)

Evidence to Recommendations (EtR) framework

PICO question

Evidence to Recommendations (EtR) framework

ACIP Evidence to Recommendations Framework (cdc.gov)

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 uncertainty about, or variability in, how much

people value the main outcomes?

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 the problem of public health importance?

▪ Most (68%) infants are infected in the first year of life and

nearly all (97%) by age 2 years

▪ 2–3% of young infants will be hospitalized for RSV

3,4,5

▪ RSV is a common cause of lower respiratory tract infection

in infants

▪ Highest RSV hospitalization rates occur in first months of

life and risk declines with increasing age in early

childhood

3,5

▪ 79% of children hospitalized with RSV aged <2 years had no

underlying medical conditions

RSV is the leading cause of hospitalization in U.S.

infants

Suh et al. JID 2022;

Glezen et al, Arch Dis Child, 1986;

Hall et al, Pediatrics, 2013;

Langley & Anderson, PIDJ, 2011;

CDC NVSN data

Image: Goncalves et al. Critical Care

Research and Practice 2012

▪ Is RSV among infants of public health importance?

Public Health Problem: Work Group interpretation

Probably

Yes

Yes Varies

Don’t

know

EtR Domain: 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?

GRADE outcomes, importance, and data sources: Pfizer

maternal RSVpreF vaccine

RCT = Randomized controlled trial; ICU= intensive care unit

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

2 Among phase 2b trial participants, only those who received the vaccine formulation of the phase 3 trial or placebo were included

Outcome

Importance

Data sources

Benefits

Medically attended RSV

-associated lower respiratory tract infection in infants

Critical

Phase 3 RCT

Hospitalization for RSV

-associated lower respiratory tract infection in infants

Critical

Phase 3 RCT

ICU admission from RSV hospitalization in infants

Important

Phase 3 RCT

Mechanical ventilation from RSV hospitalization in infants

Important

Phase 3 RCT

RSV

-associated death in infants

Important

Phase 3 and phase 2b

RCT

All

-cause medically attended lower respiratory tract infection in infants

Important

Phase 3 RCT

All

-cause hospitalization for lower respiratory tract infection in infants

Important

Phase 3 RCT

Harms

Serious adverse events in pregnant people

Critical

Phase 3 and phase 2b

RCT

Reactogenicity (grade 3+) in pregnant people

Important

Phase 3 and phase 2b

RCT

Serious adverse events in infants

Critical

Phase 3 and phase 2b

RCT

Preterm birth (<37 weeks gestation)

Critical

Phase 3 and phase 2b

RCT

Data available for GRADE and Benefits and Harms

Trial phase

Dosing interval

Number of Participants*

Decision regarding use in GRADE

Phase 2b trial

Trial dosing

interval (24

–36

weeks gestation)

Vaccine (received phase 3 dose

and formulation): 115

Placebo: 117

Yes. Data for GRADE were limited to participants

who received placebo or phase 3 vaccine

formulation and only included for safety

outcomes. Study was not designed to assess

efficacy.

Phase 2b trial

Approved dosing

interval (32

–36

weeks gestation)

Vaccine (received phase 3 dose

and formulation): 45

Placebo: 44

No. Safety data are further limited by small

sample size. Presented as supplemental data.

Phase 3 trial published

analyses

1,2,3

Trial dosing

interval (24

–36

weeks gestation)

Efficacy set / Safety set

Vaccine: 3495 / 3682

Placebo: 3480 / 3675

Yes. Trial was designed and powered using a 24

–

36 weeks dosing interval.

Phase 3 trial, post

-hoc

analysis

Approved dosing

interval (32

–36

weeks gestation)

Efficacy set / Safety set

Vaccine: 1572 / 1653

Placebo: 1539 / 1632

No. Trial was not powered for this interval for

efficacy, and safety data would be limited in

power to detect harms. Presented as

supplemental data.

*For phase 2b trial and phase 3 trial safety set, number of maternal participants are listed. For phase 3 trial efficacy set, number of infants participants are listed.

1 Data provided by Pfizer

2 Kampmann et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants - PubMed (nih.gov)

3 Vaccines and Related Biological Products Advisory Committee May 18, 2023 Meeting Briefing Document- FDA

Effect estimates and concerns in certainty of assessment,

benefits: Pfizer maternal RSVpreF vaccine

RCT= randomized controlled trial; CI= confidence interval; ICU= intensive care unit

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

2 Vaccine efficacy was calculated as 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of cases. The confidence interval was adjusted using the Bonferroni

procedure and accounting for the primary endpoints results. Efficacy is from full phase 3 trial data, using trial dosing interval (24–36 weeks gestation).

3 Serious concern for imprecision due to the width of the confidence interval containing estimates for which different policy decisions might be considered

4 Vaccine efficacy was calculated as 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of cases. Efficacy is from full phase 3 trial data, using trial dosing interval

(24–36 weeks gestation).

5 Very serious concern for imprecision due to the width of the confidence interval containing estimates for which different policy decisions might be considered and fragility of the estimate

6 Among phase 2b trial participants, only those who received the vaccine formulation of the phase 3 trial or placebo were included

Outcome Importance

Data sources Manufacturer

calculated vaccine efficacy

Concerns in certainty

assessment

Benefits

Medically attended RSV-associated lower respiratory tract infection in

infants (0–180 days)

Critical Phase 3 RCT 51.3% (97.58% CI: 29.4, 66.8)

None

Hospitalization for RSV-associated lower respiratory tract infection in

infants (0–180 days)

Critical Phase 3 RCT 56.8% (99.17% CI: 10.1, 80.7)

Imprecision (serious)

ICU admission from RSV hospitalization in infants (0–180 days) Important Phase 3 RCT 42.9% (95% CI: -124.8, 87.7)

Imprecision (very

serious)

Mechanical ventilation from RSV hospitalization in infants (0–180 days) Important Phase 3 RCT 100% (95% CI: -9.1, 100)

Imprecision (very

serious)

RSV-associated death in infants Important Phase 3 and

phase 2b

RCT

1 RSV-associated death occurred in the placebo arm of the

phase 3 trial that was recorded at day 120 after birth. No RSV-

associated deaths were recorded in the phase 2b trial.

All-cause medically attended lower respiratory tract infection in infants

(0–180 days)

Important Phase 3 RCT 2.5% (99.17% CI: -17.9, 19.4)

Imprecision (serious)

All-cause hospitalization for lower respiratory tract infection in infants

(0–180 days)

Important Phase 3 RCT 28.9% (95% CI: -2.0, 50.8)

Imprecision (serious)

Effect estimates and concerns in certainty of assessment,

harms: Pfizer maternal RSVpreF vaccine

RCT = Randomized-controlled trial

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

2 Pooled relative risk estimates were independently calculated using counts of events and participants in the phase 3 trial interim analysis, and phase 2b trial among those who received the

phase 3 vaccine formulation or placebo.

3 Serious concern for indirectness as 55% of the Phase 3 RCT and 62% of the Phase 2b RCT did not receive vaccine or placebo in the approved dosing interval (32–36 weeks gestation). In the

approved dosing interval, there is less opportunity for serious adverse events, including preterm birth/delivery, compared to the trial dosing interval (24–36 weeks gestation).

4 Serious concern for imprecision due to the width of the confidence interval containing estimates for which different policy decisions might be considered

5 Serious concern for indirectness as these data only include systemic reactions. When selecting the a priori harm outcomes, the Work Group defined reactogenicity as both local and systemic

reactions.

6 Very serious concern for imprecision due to the width of the confidence interval containing estimates for which different policy decisions might be considered and not meeting optimal

information size requirements

Outcome

Importance

Data sources

Relative Risk

(95%

confidence interval)

Concerns in certainty

assessment

Harms

Serious adverse events in pregnant people

Critical

Phase 3 and

phase 2b RCT

1.06 (0.95, 1.17)

Indirectness (serious)

and

Imprecision (serious)

Reactogenicity (grade 3+) in pregnant people

Important

Phase 3 and

phase 2b RCT

0.97 (0.72, 1.31)

Indirectness (serious)

Serious adverse events in infants

Critical

Phase 3 and

phase 2b RCT

1.01 (0.91, 1.11)

Indirectness (serious)

and

precision (serious)

Preterm birth (<37 weeks gestation)

Critical

Phase 3 and

phase 2b RCT

1.20 (0.99, 1.46)

Indirectness (serious)

and

Imprecision (very serious)

Summary of GRADE: Pfizer maternal RSVpreF vaccine

Outcome Importance Design (# of

studies)

Findings Evidence Type

Benefits

Medically attended RSV-

associated lower respiratory

infection in infants

Critical RCT (1) Pfizer RSVpreF maternal vaccine is effective in preventing medically

attended RSV-associated lower respiratory infection in infants

High

Hospitalization for RSV-associated lower respiratory

tract infection in infants

Critical RCT (1) Pfizer RSVpreF maternal vaccine may be effective in preventing

hospitalization for RSV-associated lower respiratory tract infection in

infants

Moderate

ICU admission from RSV hospitalization in infants Important RCT (1) Pfizer RSVpreF maternal vaccine may be effective in preventing ICU

admission for RSV hospitalization in infants

Low

Mechanical ventilation from RSV hospitalization in

infants

Important RCT (1) Pfizer RSVpreF maternal vaccine may be effective in preventing

mechanical ventilation for RSV hospitalization in infants

Low

RSV-associated death in infants Important RCT (2) 1 event observed in a placebo recipient among both trials Not evaluated

All-cause medically attended lower respiratory tract

infection in infants

Important RCT (1) Pfizer RSVpreF maternal vaccine is not effective in preventing all-

cause medically attended lower respiratory tract infection in infants

Moderate

All-cause hospitalization for lower respiratory tract

infection in infants

Important RCT (1) Pfizer RSVpreF maternal vaccine may be effective in preventing all-

cause hospitalization for lower respiratory tract infection in infants

Moderate

Harms

Serious adverse events in pregnant people Critical RCT (2) SAEs in pregnant people were balanced between vaccine and placebo

groups

Low

Reactogenicity (grade 3+) in pregnant people Important RCT (2)

Reactogenicity in pregnant people was balanced between vaccine and

placebo groups

Moderate

Serious adverse events in infants Critical RCT (2) SAEs in infants were balanced between vaccine and placebo groups Low

Preterm birth (<37 weeks gestation) Critical RCT (2) Preterm births were unbalanced between vaccine and placebo groups Very low

RCT = Randomized-controlled trial

Summary of GRADE: Pfizer maternal RSVpreF vaccine

The overall evidence type is driven by the lowest quality of evidence for critical outcomes, and here is driven by the evidence rating

for the critical harm of preterm birth being very low.

Overall

evidence type:

Very Low

Effect estimates, benefits: Pfizer maternal RSVpreF vaccine

comparing trial vs approved dosing interval

CI= confidence interval; ICU=Intensive care unit

1 Vaccine efficacy was calculated as 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of cases. Confidence intervals that are not 95% were adjusted using the Bonferroni

procedure and accounting for the primary endpoints results.

2 Vaccine efficacy was calculated as 1-(hP/[1-P]), where P is the number of cases in the RSVpreF group divided by the total number of cases and h is the ratio of number of participants at risk in the placebo group to

the number of participants at risk in the RSVpreF group.

Outcome

Trial dosing interval

(24–36 weeks gestation)

Approved dosing interval

(32–36 weeks gestation)

Manufacturer calculated

vaccine efficacy

(CI)

Manufacturer calculated vaccine

efficacy

(95% CI)

Benefits

Medically attended RSV

-associated lower respiratory tract

infection in infants (0

–180 days)

51.3% (97.58% CI: 29.4, 66.8)

57.3% (95% CI: 29.8, 74.7)

Hospitalization for RSV

-associated lower respiratory tract

infection in infants (0

–180 days)

56.8% (99.17% CI: 10.1, 80.7)

48.2% (

95% CI: -22.9, 79.6)

ICU admission from RSV hospitalization in infants (0

–180 days)

42.9% (95% CI:

-124.8, 87.7)

1 event in the vaccine group

2 events in the placebo group

Mechanical ventilation from RSV hospitalization in infants (0

–

180 days)

100% (95% CI:

-9.1, 100)

0 events in the vaccine group

2 events in the placebo group

All

-cause medically attended lower respiratory tract infection in

infants (0

–180 days)

2.5% (99.17%:

-17.9, 19.4)

7.3% (

95% CI: -15.7, 25.7)

All

-cause hospitalization for lower respiratory tract infection in

infants (0

–180 days)

28.9% (95% CI:

-2.0, 50.8)

34.7% (

95% CI: -18.8, 64.9)

▪ As defined in the Pfizer trial, this outcome

was not included by the Work Group as an

a priori critical or important outcome for

GRADE for vaccine policy decisions

▪ Severe medically-attended RSV-

associated LRTI* required at least 1 of the

following signs/ symptoms:

– Fast breathing (respiratory rate ≥70 (<2 month of

age [60 days]) or ≥60 (≥2 to 12 months of age)

breaths per minute

– SpO2 measured in room air <93%

– High-flow nasal cannula or mechanical

ventilation

– ICU admission for >4 hours

– Unresponsive/unconscious

▪ Included by the Work Group as an a priori

critical outcome for GRADE for vaccine

policy decisions

▪ Medically-attended RSV-associated LRTI*

required at least 1 of the following

signs/symptoms:

– Fast breathing: respiratory rate ≥60 (<2 months

of age [60 days]) or ≥50 (≥2 to 12 months of age)

breaths per minute

– SpO2 measured in room air <95%

– Chest wall indrawing

Severe medically attended RSV-associated lower

respiratory tract infection (LRTI), co-primary trial endpoint

*Medically attended visit includes inpatient and outpatient encounters. Additionally, definition also required RT-PCR or nucleic acid amplification (NAAT) test positive for RSV. Blue text

denotes differences between the two definitions. SpO2= Peripheral capillary oxygen saturation

1. Kampmann et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants - PubMed (nih.gov)

2. Vaccines and Related Biological Products Advisory Committee May 18, 2023 Meeting Briefing Document- FDA

Phase 3 trial vaccine efficacy against severe medically

attended RSV-associated LRTI, co-primary trial endpoint

1 Vaccine efficacy was calculated as 1−(P/[1−P]), where P is the number of cases of illness in the RSVpreF group divided by the total number of cases of illness. At 90 days, 99.5%

confidence intervals (CIs) were used (determined by the alpha-spending function and adjusted with the use of the Bonferroni procedure), and at later intervals, 97.58% CIs were

used (based on a two-sided alpha level of 0.0483 adjusted with the use of the Bonferroni procedure).

2 Vaccine efficacy was calculated as 1-(hP/[1-P]), where P is the number of cases in the RSVpreF group divided by the total number of cases and h is the ratio of number of

participants at risk in the placebo group to the number of participants at risk in the RSVpreF group.

1. Kampmann et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants - PubMed (nih.gov)

2. Vaccines and Related Biological Products Advisory Committee May 18, 2023 Meeting Briefing Document- FDA

Time period

after birth

Trial dosing interval

(24–36 weeks gestation)

Vaccine efficacy

(99.5% or

97.58% CI)

Approved dosing interval

(32–36 weeks gestation)

Vaccine efficacy

(95% CI)

–90 days

after birth

81.8% (40.6, 96.3) 91.1% (38.8, 99.8)

–180 days

after birth

69.4% (44.3, 84.1) 76.5% (41.3, 92.1)

Within 0-180 days after birth

• Among 81 infants with

severe medically attended

RSV LRTI, 50 (62%) were

hospitalized

• Among 63 infants

hospitalized with RSV, 50

(79%) had severe medically

attended RSV LRTI

Effect estimates, harms: Pfizer maternal RSVpreF vaccine

comparing trial vs approved dosing interval

CI= confidence interval

1 Phase 3 and 2b trials

2 Pooled relative risk estimates were independently calculated using counts of events and participants in the phase 3 trial interim analysis, and phase 2b trial among those who

received the phase 3 vaccine formulation

Outcome

Trial dosing interval

(24–36 weeks)

Approved dosing interval

(32–36 weeks)

Relative Risk

(95% CI) Relative Risk

(95% CI)

Harms

Serious adverse events in pregnant people

1.06 (0.95, 1.17) 1.02 (0.87, 1.20)

Reactogenicity (grade 3+) in pregnant people

0.97 (0.72, 1.31) 0.98 (0.62, 1.54)

Serious adverse events in infants

1.01 (0.91, 1.11) 1.04 (0.90, 1.20)

Preterm birth (<37 weeks gestation)

1.20 (0.99, 1.46) 1.15 (0.82, 1.61)

Effect estimates, harms: Pfizer maternal RSVpreF vaccine

comparing trial vs approved dosing interval

CI= confidence interval

1 Phase 3 and 2b trials

2 Pooled relative risk estimates were independently calculated using counts of events and participants in the phase 3 trial interim analysis, and phase 2b trial among those who

received the phase 3 vaccine formulation

Outcome

Trial dosing interval

(24–36 weeks)

Approved dosing interval

(32–36 weeks)

Relative Risk

(95% CI) Relative Risk

(95% CI)

Harms

Serious adverse events in pregnant people

1.06 (0.95, 1.17) 1.02 (0.87, 1.20)

Reactogenicity (grade 3+) in pregnant people

0.97 (0.72, 1.31) 0.98 (0.62, 1.54)

Serious adverse events in infants

1.01 (0.91, 1.11) 1.04 (0.90, 1.20)

Preterm birth (<37 weeks gestation)

1.20 (0.99, 1.46) 1.15 (0.82, 1.61)

▪ Trial of a similar GSK maternal RSV vaccine (stabilized prefusion F protein vaccine without an adjuvant)

was halted due to an imbalance of preterm births with higher numbers in the vaccine vs placebo group

▪ Imbalance of neonatal deaths was a consequence of preterm birth imbalance

▪ Imbalance in preterm births was seen in low and middle-income countries (RR: 1.57, 95% CI: 1.17, 2.10)

but not high-income countries (RR: 1.04, 95% CI: 0.68, 1.58)

▪ Imbalance was observed from April–December 2021, but not consistently after December 2021

▪ Reason for the imbalance remains unclear

GSK maternal RSV vaccine clinical trial and preterm birth

Study vaccine given at 24 0/7 to 34 0/7 weeks gestation

Vaccines and Related Biological Products Advisory Committee February 28 - March 1, 2023 Meeting Briefing Document- Sponsor GSK (fda.gov)

Outcome

Vaccine group, n (%)

N=3,496

Placebo group, n (%)

N=1,739

Relative Risk (95% CI)

Preterm birth (<37 weeks

gestation)

238 (6.81%) 86 (4.95%) 1.38 (1.08, 1.75)

Neonatal death

13 (0.37%) 3 (0.17%) 2.16 (0.62, 7.55)

Preterm birth in Pfizer RSVpreF vaccine phase 3 trial data,

comparing trial vs approved dosing interval

Trial dosing interval

(24–36 weeks gestation)

Approved dosing interval

(32–36 weeks gestation)

1,2

RSVpreF vaccine

group

N=3,568

Placebo group

N=3,558

RSVpreF vaccine

group

N=1,628

Placebo group

N=1,604

n % (95% CI) n % (95% CI) n % (95% CI) n % (95% CI)

Preterm birth

(<37 weeks

gestation)

202 5.7%

(4.9%, 6.5%)

169 4.7%

(4.1%, 5.5%)

68 4.2%

(3.3%, 5.3%)

59 3.7%

(2.8%, 4.7%)

1. Package Insert - ABRYSVO (STN 125768) (fda.gov)

2. Pfizer response to ACIP, unpublished data, August 2023. In package insert, approved dosing interval reported as: 4.2% (68/1,631) in the RSVpreF group and 3.7% (59/1,610) in

the placebo group.

Low birth weight and neonatal jaundice outcomes in Pfizer

RSVpreF vaccine phase 3 trial data, trial vs approved dosing

interval

Trial dosing interval

(24–36 weeks gestation)

1,2

Approved dosing interval

(32–36 weeks gestation)

RSVpreF vaccine

group

N=3,568

Placebo group

N=3,558

RSVpreF vaccine

group

N=1,628

Placebo group

N=1,604

n % (95% CI) n % (95% CI) n % (95% CI) n % (95% CI)

Low birth

weight

(≤2500 g)

181 5.1%

(4.4%, 5.8%)

155 4.4%

(3.7%, 5.1%)

67 4.1%

(3.2%, 5.2%)

54 3.4%

(2.5%, 4.4%)

Neonatal

jaundice

257 7.2%

(6.4%, 8.1%)

240 6.7%

(5.9%, 7.6%)

102 6.3%

(5.1%, 7.6%)

107

6.7%

(5.5, 8.0%)

1. Vaccines and Related Biological Products Advisory Committee May 18, 2023 Meeting Presentation- Review of Efficacy and Safety of Respiratory Syncytial Virus Vaccine (ABRYSVO) (fda.gov)

2. Package Insert - ABRYSVO (STN 125768) (fda.gov)

3. Pfizer response to ACIP, unpublished data, August 2023

▪ Rate of preterm birth by calendar month of birth

▪ Birth by week of gestational age

▪ Percent of births that were preterm by country

▪ Adverse pregnancy outcomes

In June, ACIP requested additional data regarding the

Pfizer maternal RSV vaccine

Preterm birth rate for vaccine and placebo recipients by

calendar time—Pfizer Phase 3 trial, trial dosing interval (24–

36 weeks gestation)

GSK signal was present from

April–December 2021

Data source: Pfizer response to ACIP, unpublished data, July 2023

Preterm birth rate for vaccine and placebo recipients by

calendar time—Pfizer Phase 3 trial, approved dosing

interval (32–36 weeks gestation)

GSK signal was present from April–

December 2021

Data source: Pfizer response to ACIP, unpublished data, September 2023

Number of births by gestational age: Pfizer phase 3 trial,

trial dosing interval (24–36 weeks gestation)

1 1

125

336

764

1262

738

243

349

755

1321

680

251

200

400

600

800

1000

1200

1400

≥27 to <28 weeks

≥28 to <29 weeks

≥29 to <30 weeks

≥30 to <31 weeks

≥31 to <32 weeks

≥32 to <33 weeks

≥33 to <34 weeks

≥34 to <35 weeks

≥35 to <36 weeks

≥36 to <37 weeks

≥37 to <38 weeks

≥38 to <39 weeks

≥39 to <40 weeks

≥40 to <41 weeks

≥41 to <42 weeks

≥42 to <43 weeks

≥43 to <44 weeks

≥44 to <45 weeks

Number of Births

Gestational Age at Birth

Vaccine Placebo

Preterm birth: <37 weeks gestation

Data source: Pfizer response to ACIP, unpublished data, July 2023

Number of births by gestational age, preterm births (<37

weeks gestation) only: Pfizer phase 3 trial, trial dosing

interval (24–36 weeks gestation)

1 1

125

100

120

≥27 to <28 weeks

≥28 to <29 weeks

≥29 to <30 weeks

≥30 to <31 weeks

≥31 to <32 weeks

≥32 to <33 weeks

≥33 to <34 weeks

≥34 to <35 weeks

≥35 to <36 weeks

≥36 to <37 weeks

Number of Births

Gestational Age at Birth

Vaccine Placebo

Imbalance begins

at 33 weeks

Preterm birth: <37 weeks gestation

Data source: Pfizer response to ACIP, unpublished data, July 2023

Number of births by gestational age: Pfizer phase 3 trial,

approved dosing interval (32–36 weeks gestation)

Preterm birth: <37 weeks gestation

Data source: Pfizer unpublished data, August 2023

148

374

567

338

120

11 1

156

334

603

325

112

100

200

300

400

500

600

≥32 to <33 weeks

≥33 to <34 weeks

≥34 to <35 weeks

≥35 to <36 weeks

≥36 to <37 weeks

≥37 to <38 weeks

≥38 to <39 weeks

≥39 to <40 weeks

≥40 to <41 weeks

≥41 to <42 weeks

≥42 to <43 weeks

≥43 to <44 weeks

Number of Births

Gestational Age at Birth

Vaccine Placebo

Number of births by gestational age, preterm births (<37

weeks gestation) only: Pfizer Phase 3 trial, approved

dosing interval (32–36 weeks gestation)

1 1

≥32 to <33 weeks

≥33 to <34 weeks

≥34 to <35 weeks

≥35 to <36 weeks

≥36 to <37 weeks

Number of Births

Gestational Age at Birth

Vaccine Placebo

Preterm birth: <37 weeks gestation

Data source: Pfizer unpublished data, August 2023

Number births and percent preterm by country–Pfizer phase 3 trial

Trial dosing interval (24–36 weeks gestation) Approved dosing interval (32–36 weeks gestation)

RSVpreF recipients

N=3568

Placebo recipients

N=3558

RSVpreF recipients

N=1628

Placebo recipients

N=1604

Country

No. births % preterm No. births % preterm No. births % preterm No. births % preterm

Argentina

423 6.4% 416 4.1% 230 4.8% 230 4.3%

Australia

11 0.0% 13 7.7% 8 0.0% 8 12.5%

Brazil

35 8.6% 37 2.7% 22 9.1% 23 4.3%

Canada

27 0.0% 28 3.6% 20 0.0% 27 3.7%

Chile

86 8.1% 85 7.1% 47 6.4% 50 2.0%

Denmark

30 3.3% 31 0.0% 21 4.8% 17 0.0%

Finland

75 2.7% 73 1.4% 44 0.0% 40 2.5%

Gambia

78 2.6% 79 2.5% 32 3.1% 24 0.0%

Japan

218 3.2% 216 6.0% 111 2.7% 94 2.1%

Korea

7 0.0% 4 25.0% 6 0.0% 1 100.0%

Mexico

37 8.1% 37 5.4% 13 7.7% 13 0.0%

Netherlands

97 3.1% 95 3.2% 43 2.3% 44 0.0%

New Zealand

49 4.1% 47 6.4% 29 3.4% 28 3.6%

Philippines

32 3.1% 34 5.9% 0 0.0% 1 0.0%

South Africa

469 8.3% 471 4.0% 150 6.7% 127 2.4%

Spain

117 3.4% 123 2.4% 73 2.7% 88 3.4%

Taiwan

123 4.9% 125 5.6% 58 5.2% 57 3.5%

United States

1654 5.7% 1644 5.3% 721 4.0% 732 4.4%

Data source: Pfizer response to ACIP, unpublished data, July and August 2023. Trial included 480 sites across 18 countries. Number of births is the total number of births regardless of gestational age.

Blue indicates higher percent of preterm birth among RSVpreF vs. placebo in trial dosing interval, red in approved dosing interval, and purple in both dosing intervals. Black indicates either balanced

preterm birth rates or a higher percent of preterm births among placebo vs RSVpreF recipients. Caution should be used in interpreting rates based on small numbers; some differ by very small counts.

Number births and percent preterm by country–Pfizer phase 3 trial

Trial dosing interval (24–36 weeks gestation) Approved dosing interval (32–36 weeks gestation)

RSVpreF recipients

N=3568

Placebo recipients

N=3558

RSVpreF recipients

N=1628

Placebo recipients

N=1604

Country

No. births % preterm No. births % preterm No. births % preterm No. births % preterm

Argentina

423 6.4% 416 4.1% 230 4.8% 230 4.3%

Australia

11 0.0% 13 7.7% 8 0.0% 8 12.5%

Brazil

35 8.6% 37 2.7% 22 9.1% 23 4.3%

Canada

27 0.0% 28 3.6% 20 0.0% 27 3.7%

Chile

86 8.1% 85 7.1% 47 6.4% 50 2.0%

Denmark

30 3.3% 31 0.0% 21 4.8% 17 0.0%

Finland

75 2.7% 73 1.4% 44 0.0% 40 2.5%

Gambia

78 2.6% 79 2.5% 32 3.1% 24 0.0%

Japan

218 3.2% 216 6.0% 111 2.7% 94 2.1%

Korea

7 0.0% 4 25.0% 6 0.0% 1 100.0%

Mexico

37 8.1% 37 5.4% 13 7.7% 13 0.0%

Netherlands

97 3.1% 95 3.2% 43 2.3% 44 0.0%

New Zealand

49 4.1% 47 6.4% 29 3.4% 28 3.6%

Philippines

32 3.1% 34 5.9% 0 0.0% 1 0.0%

South Africa

469 8.3% 471 4.0% 150 6.7% 127 2.4%

Spain

117 3.4% 123 2.4% 73 2.7% 88 3.4%

Taiwan

123 4.9% 125 5.6% 58 5.2% 57 3.5%

United States

1654 5.7% 1644 5.3% 721 4.0% 732 4.4%

preterm birth rates or a higher percent of preterm births among placebo vs RSVpreF recipients. Caution should be used in interpreting rates based on small numbers; some differ by very small counts.

Select pregnancy-related serious adverse events at any

time following vaccination

1,2

: Pfizer phase 3 trial, trial

dosing interval (24–36 weeks gestation)

1 Table 3 ABRYSVO package insert Package Insert - ABRYSVO (STN 125768) (fda.gov)

2 Includes all SAEs from vaccination to 6 months post-delivery (up to approximately 10 months, depending on the gestational age at the time of vaccination). In the phase 3 RCT,

eclampsia occurred in 5 participants (3 in the RSVpreF group and 2 in the placebo group) and HELLP syndrome occurred in 5 participants (2 in the RSVpreF group and 3 in the

placebo group).

3 There was one maternal death in the vaccine group due to postpartum hemorrhage that was not likely to be associated with vaccination.

4 A total of 18 intrauterine deaths were reported for the index pregnancy: 10 intrauterine deaths in the vaccine group (0.3%) and 8 intrauterine deaths in the placebo group

(0.2%). The intrauterine deaths represented various clinical conditions and presentations resulting in fetal demise without clear evidence of a common pathophysiology.

RSVpreF Vaccine

N= 3,682

Placebo

N= 3,675

Serious Adverse Reaction

n (%) 95% CI n (%) 95% CI

All Maternal Serious Adverse Events (SAEs)

598 (16.2) (15.1, 17.5) 558 (15.2) (14.0, 16.4)

Pre

-eclampsia 68 (1.8) (1.4, 2.3) 53 (1.4) (1.1, 1.9)

Gestational hypertension

41 (1.1) (0.8, 1.5) 38 (1.0) (0.7, 1.4)

Premature rupture of membranes

15 (0.4) (0.2, 0.7) 16 (0.4) (0.2, 0.7)

Preterm premature rupture of membranes

15 (0.4) (0.2, 0.7) 10 (0.3) (0.1, 0.5)

Hypertension

13 (0.4) (0.2, 0.6) 6 (0.2) (0.1, 0.4)

Maternal death

1 (<0.1) (0.0, 0.2) 0 (0.0, 0.1)

Fetal death

10 (0.3) (0.1, 0.5) 8 (0.2) (0.1, 0.4)

▪ Same Pfizer RSV vaccine, formulation and dose approved for use in adults ages 60

years and older

▪ Within the trials for this product among adults ages 60 years and older, a potential

safety signal of inflammatory neurologic events was identified

▪ A total of 3 cases of interest were recorded among 20,255 investigational vaccine

recipients aged 60 years and older. No cases were observed among placebo

recipients.

– 1 case of Guillain-Barré Syndrome (GBS)

– 1 case of Miller Fisher syndrome (a GBS variant)

– 1 case of undifferentiated motor-sensory axonal polyneuropathy (with

worsening of preexisting symptoms)

Other considerations: Inflammatory neurologic events and

Pfizer RSVpreF Vaccine

Melgar et al. Use of Respiratory Syncytial Virus Vaccines in Older Adults: Recommendations of the Advisory Committee on Immunization Practices — United States, 2023 |

MMWR (cdc.gov)

▪ No Guillain-Barré syndrome (GBS) or other demyelinating events were

reported in the phase 2b or 3 trials among pregnant people

▪ Background rate of GBS in pregnant people is much lower than among

older adults

2,3

▪ Incidence rate of GBS in pregnant people in the Vaccine Safety Datalink

during 2004–2015: 2.8 (95% CI 0.5–9.3) per million person-years (based on

2 cases)

Other considerations: Inflammatory neurologic events and

Pfizer RSVpreF Vaccine (cont.)

1. Vaccines and Related Biological Products Advisory Committee May 18, 2023 Meeting Briefing Document- FDA

2. Myers TR, McCarthy NL, Panagiotakopoulos L, Omer SB. Estimation of the Incidence of Guillain-Barré Syndrome During Pregnancy in the United States. Open Forum Infect Dis.

2019 Mar 15;6(3):ofz071. doi: 10.1093/ofid/ofz071.

3. Sejvar JJ, Baughman AL, Wise M, Morgan O. Population Incidence of Guillain-Barré Syndrome: A Systematic Review and Meta-Analysis. Neuroepidemiology 2011;36:123–133

▪ Efficacious vaccine that can prevent RSV lower respiratory tract

infection in young infants

▪ No consensus among Work Group regarding clinical importance

of preterm birth imbalance observed in clinical trials

Summary of Benefits and Harms

▪ Though not statistically significant, imbalance in preterm births was seen in the full

trial population

▪ Trial powered for efficacy outcomes and not designed or powered to detect 20%

increase in preterm birth

▪ There may have been less precise dating of gestational age in some sites and

countries in the trial, but there is no reason this should bias towards a preterm birth

imbalance among vaccinated compared to placebo participants

▪ Preterm birth signal in the GSK maternal RSV vaccine trial (also a stabilized prefusion

F protein vaccine) adds to concern

Work Group members found the following points

concerning regarding preterm birth

▪ When using the full trial dosing interval (24–36 weeks gestation), most preterm births (60%)

were >30 days after vaccination, and no known biologic mechanism for vaccines to cause

preterm birth, particularly >30 days after vaccination

▪ When assessed among those vaccinated during the approved interval (32–36 weeks

gestation), data on preterm birth were reassuring to the Work Group

– Imbalance in preterm birth was still present but lessened

– Most infants born preterm in the vaccine group (72%, 49/68) were born at 36 weeks

– In the United States (largest contributing country in the trial), imbalance in preterm births

reversed:

• Trial dosing interval: 5.7% in vaccine vs. 5.3% in placebo recipients

• Approved dosing interval: 4.0% in vaccine vs. 4.4% in placebo recipients

▪ Majority of the Work Group felt the approved dosing interval (32–36 weeks gestation) reduces

the potential risk of preterm birth and the potential for complications from preterm birth,

which is their major safety concern

Work Group members found the following data reassuring

regarding preterm birth imbalance

▪ How substantial are the desirable anticipated effects?

– How substantial are the anticipated effects for:

• Medically attended RSV-associated lower respiratory infection in infants

• Hospitalization for RSV-associated lower respiratory tract infection in infants

• ICU admission from RSV hospitalization in infants

• Mechanical ventilation from RSV hospitalization in infants

• RSV-associated death in infants

• All-cause hospitalization for lower respiratory tract infection in infants

• All-cause medically attended lower respiratory tract infection in infants

Benefits and Harms - Pfizer maternal RSVpreF vaccine,

given as a single dose at 32–36 weeks gestation

Minimal Small Moderate Large Varies

Don’t know

Minority OpinionMajority Opinion

▪ How substantial are the undesirable anticipated effects?

– How substantial are the anticipated effects for:

• Serious adverse events in pregnant people

• Reactogenicity (3+ or higher) in pregnant people

• Serious adverse events in infants

• Preterm birth

Benefits and Harms - Pfizer maternal RSVpreF vaccine,

given as a single dose at 32–36 weeks gestation

Minimal Small Moderate Large Varies

Don’t know

Majority Opinion

▪ Do the desirable effects outweigh the undesirable effects?

– What is the balance between the desirable effects relative to the

undesirable effects?

Benefits and Harms - Pfizer maternal RSVpreF vaccine,

given as a single dose at 32–36 weeks gestation

Favors intervention (Pfizer Maternal RSVpreF

Vaccine)

Favors comparison (No intervention)

Favors both

Favors neither

Unclear

Majority Opinion

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?

▪ Values survey of pregnant and recently pregnant people conducted from December

21, 2022–January 2, 2023 by University of Iowa, RAND, and CDC

– 68% of respondents had knowledge of RSV prior to taking survey

– 61% of respondents said they ‘definitely’ or ‘probably’ would get an RSV vaccine while pregnant

– Among those who did not respond that they “definitely would” get an RSV vaccine while pregnant, safety

concerns, lack of RSV knowledge, and concerns about vaccination causing or intensifying RSV infection

were the top reasons for not wanting an RSV vaccine during pregnancy

▪ In the US, coverage for recommended vaccines among pregnant people has decreased

during the pandemic and varies by race and ethnicity

– Tdap vaccination coverage was 53.5% in 2020–21 season and 45.8% in 2021–22 season

– Rates of Tdap coverage were higher in White, non-Hispanic women than among Black, non-Hispanic women

during the 2020–21 and 2021–22 seasons

Summary of values domain

1 CDC and University of Iowa/RAND survey, unpublished

2 Flu, Tdap, and COVID-19 Vaccination Coverage Among Pregnant Women – United States, April 2022 | FluVaxView | Seasonal Influenza (Flu) | CDC

▪ Criterion 1: Do pregnant people feel that the desirable effects

are large relative to undesirable effects?

Values

Probably No

Probably Yes

Yes Varies

Don’t know

Majority Opinion

▪ Criterion 2: Is there important uncertainty about, or variability in,

how much pregnant people value the main outcomes?

Values

Important uncertainty or variability

Probably important uncertainty or variability

Probably not important uncertainty or variability

No important uncertainty or variability

No known undesirable outcomes

Most common answers

EtR Domain: Acceptability

Is the intervention acceptable to key stakeholders?

▪ Obstetrician and midwife support of RSV vaccine, if it was routinely

recommended:

– 47% definitely

– 34% likely

– 14% not sure

– 4% unlikely

– 0.5% very unlikely

Maternity healthcare professionals survey—England, 2019

Wilcox CR, Calvert A, Metz J, et al. Attitudes of Pregnant Women and Healthcare Professionals Toward Clinical Trials and Routine Implementation of Antenatal Vaccination Against

Respiratory Syncytial Virus: A Multicenter Questionnaire Study. The Pediatric Infectious Disease Journal. 2019 Sept;38(9):944-951. DOI: 10.1097/INF.0000000000002384

▪ Is RSV prevention with Pfizer maternal RSVpreF vaccine

acceptable to key stakeholders?

Acceptability

Probably No

Probably Yes

Yes Varies

Don’t know

Minority OpinionMajority Opinion

EtR Domain: Feasibility

Is the intervention feasible to implement?

▪ Storage and handling requirements

– Supplied as single 0.5 mL dose, or as a 5-pack or 10-pack of single-dose kits

– Reconstitution required: single dose vial of lyophilized powder, reconstitution

supplies included in kit

– Product should be refrigerated (2–8°C) in original container, protected from light

– After reconstitution, the product should be administered within 4 hours, otherwise

discarded

▪ Most pregnant patients receive Tdap vaccine in an obstetrician's or midwife’s office

– Likely pregnant patients would also most often receive RSV vaccine at their prenatal

care provider’s office

Storage and handling

Package Insert - ABRYSVO (STN 125769/26) (fda.gov)

Flu, Tdap, and COVID-19 Vaccination Coverage Among Pregnant Women – United States, April 2022 | FluVaxView | Seasonal Influenza (Flu) | CDC

▪ Pregnant people may potentially be eligible to receive RSV, Tdap, COVID-19, and

influenza vaccines at same visit

▪ Pfizer Phase 2b study in healthy non-pregnant women ages 18–49 years on

simultaneous administration of Tdap and Pfizer RSVpreF found decreased immune

response to pertussis components (i.e., non-inferiority criteria were not met)

▪ Given lack of correlates of protection for pertussis, it is unclear how this might impact

protection against pertussis from maternal Tdap when simultaneously administered

with RSVpreF vaccine

Simultaneous administration of RSV vaccine with other

vaccines in pregnant people

1 Peterson et al. Safety and Immunogenicity of a Respiratory Syncytial Virus Prefusion F Vaccine When Coadministered With a Tetanus, Diphtheria, and Acellular Pertussis

Vaccine.The Journal of Infectious Diseases. 2022 June 15; 225(12): 2077–2086. doi: 10.1093/infdis/jiab505

▪ Tdap recommended every pregnancy, preferably during the early part of gestational

weeks 27 through 36

▪ Tdap would be preferably given before 32 weeks (based on recommendation) and RSV

vaccine would be given at or after 32 weeks

▪ In MarketScan data from 2018–2021, about half of captured Tdap doses were given

before 32 weeks gestation

RSV vaccine and Tdap dosing timing

1 CDC, https://www.cdc.gov/vaccines/vpd/dtap-tdap-td/hcp/recommendations.html

2 MarketScan data, 2018-2021

▪ Either RSV vaccination during pregnancy or nirsevimab administration for the infant

can be used to prevent RSV lower respiratory tract infection in infants

▪ Work Group felt both products are not needed for most infants

▪ Pregnant person and prenatal care provider will need to make the decision during

pregnancy regarding which RSV prevention product to use

▪ Many prenatal care providers may not have time to discuss options for RSV prevention

with their patients

▪ Prenatal care providers may not feel equipped to discuss nirsevimab, as this product

will be given to the infant after birth

RSVpreF vaccine is one of two available preventive

products for RSV in infants

▪ Maximizes cost-effectiveness

▪ Maximizes benefits for infants

▪ Targets dosing to infants who will be in the first months of life during RSV season

▪ Another product (nirsevimab) is available for infants who are born out of season— for

whom maternal vaccine protection would have waned by RSV season

Work Group unanimously supported use of a seasonal

dosing strategy for maternal RSV vaccine

▪ Work Group supported seasonal dosing during September through January in most

of the continental US based on typical (pre-pandemic) RSV seasonality

– Aligns with implementation of influenza vaccine and thus would simplify

implementation for prenatal care providers

▪ Work Group felt that jurisdictions in which RSV seasonality differs from most of the

continental US should have flexibility regarding start and stop of administration of

RSVpreF vaccine in pregnant people

• Alaska

• Tropical climates: parts of Florida, Puerto Rico, U.S. Virgin Islands, Hawaii, Guam,

and U.S.-affiliated Pacific Islands

Seasonal dosing for RSVpreF vaccine

▪ Is Pfizer Maternal RSVpreF vaccine feasible to implement among

pregnant people at 32–36 weeks gestation?

Feasibility

Probably No

Probably Yes

Yes Varies

Don’t know

Minority OpinionMajority Opinion

EtR Domain: Resource Use

Is the intervention a reasonable and efficient allocation of

resources?

Scenarios for cost-effectiveness by months of RSVpreF

vaccine dosing during the calendar year

ICER: Incremental cost-effectiveness ratio

QALY: Quality-Adjusted Life-Year

Cost-effectiveness model assumes typical RSV seasonality (based on pre-pandemic years) in most of the continental United States.

$400,304

$363,344

$322,594

$282,498

$186,256

$167,280

$141,806

$50,000

$100,000

$150,000

$200,000

$250,000

$300,000

$350,000

$400,000

$450,000

Base Apr-Feb May-Feb Jun-Feb Aug-Jan Sep-Jan Sep-Dec

ICER ($.QALY)

Months of RSV vaccine dosing

ICER: RSVpreF vs. Natural History

▪ RSVpreF vaccine may improve RSV outcomes but will also increase costs

– Base case incremental cost-effectiveness (ICER) ratio : $400,304/QALY

• Year-round dosing

• Typical RSV seasonality (based on pre-pandemic years) in most of the continental United

States

– Work group felt that this vaccine would not be cost-effective under the base case conditions

▪ Cost-effectiveness would improved by using a seasonal dosing strategy

– September through January in most of the continental US based on typical (pre-pandemic)

RSV seasonality

▪ Work Group unanimously supported use of a seasonal dosing strategy

WG interpretations: Resource Use

QALY: Quality-Adjusted Life-Year

Cost-effectiveness model assumes typical RSV seasonality (based on pre-pandemic years) in most of the continental United States.

▪ Is Pfizer Maternal RSVpreF vaccine use among pregnant people

at 32–36 weeks gestation a reasonable and efficient allocation of

resources?

▪ Work Group responses were based on seasonal dosing for RSVpreF vaccine (i.e.,

September-January in most of the continental United States)

Resource Use

Probably No

Probably Yes

Yes Varies

Don’t know

Minority OpinionMajority Opinion

EtR Domain: Equity

What would be the impact of the intervention on health equity?

▪ National studies of death certificates found higher rates of RSV-

associated deaths among non-Hispanic Black children compared with

non-Hispanic White infants and children aged 1–4 years

▪ ICU admission rates for RSV among Non-Hispanic Black infants <6

months old were 1.2–1.6x higher than among Non-Hispanic White infants

▪ RSV hospitalization rates 4–10x higher among Alaska Native and

American Indian children ages <24 months than the rate in the general

population

– This study was limited to specific populations and might not be broadly

representative of risk in all Alaska Native and American Indian children

Equity summary: Incidence of RSV disease by race and

ethnicity in infants and children

1. Hansen et al. The Use of Death Certificate Data to Characterize Mortality Associated With Respiratory Syncytial Virus, Unspecified Bronchiolitis, and Influenza in the United

States, 1999-2018 J Infect Dis. 2022 Aug 15;226(Supplement 2): S255–S266.

2 Unpublished data from RSV-NET, CDC.

3 Atwell et al. RSV Among American Indian and Alaska Native Children: 2019 to 2020 Pediatrics. 2023 Aug 1;152(2):e2022060435

▪ By federal law, all states provide Medicaid coverage for pregnancy-related services to

pregnant women with incomes up to 138% of the federal poverty level

▪ In 2021, 41.0% of mothers had Medicaid at the time of birth

▪ If recommended, ACIP will vote on a Vaccines for Children resolution for the Pfizer

RSV vaccine for pregnant people <19 years of age

▪ After October 1, 2023, when the Inflation Reduction Act provisions become effective,

state Medicaid agencies will be required to cover vaccines and their administration

without cost-sharing for nearly all full-benefit adult beneficiaries covered under

traditional Medicaid, if the CDC/ACIP recommendations apply

Equity summary: Medicaid coverage for pregnant people

and vaccines during pregnancy

1 Medicaid Coverage for Women | KFF

2 2023 Medicaid and CHIP Beneficiary Profile: Enrollment, Expenditures, Characteristics, Health Status, and Experience

▪ Under the Affordable Care Act and its implementing regulations, ACIP

recommendations that have been adopted by CDC “with respect to the individual

involved” and are “listed on the Immunization Schedules of the Centers for Disease

Control and Prevention” generally are required to be covered by group health plans

and health insurance issuers offering group or individual health insurance coverage

without imposing any cost-sharing requirements (such as a copayment, coinsurance,

or deductible)

Equity summary: Other insurance coverage for vaccines

during pregnancy

ACIP Shared Clinical Decision-Making Recommendations | CDC

▪ What would be the impact of Pfizer Maternal RSVpreF vaccine

on health equity? Answers ranged, no majority

Equity

Reduced

Probably reduced

Probably no impact

Probably increased

Increased

Varies

Don’t know

most common Most common

3rd most common

Summary

Evidence to Recommendations (EtR) framework

EtR Domain

Question(s)

Work Group Judgements

Public Health Problem

Is the problem of public health importance?

Yes

Benefits and Harms

How substantial are the desirable anticipated effects?

Large

How substantial are the undesirable anticipated effects?

Small

Do the desirable effects outweigh the undesirable effects?

Favors intervention

Values

Does the target population feel the desirable effects are large

relative to the undesirable effects?

Probably yes

Is there important uncertainty about, or variability in, how

much people value the main outcomes?

Probably not important

uncertainty or variability/

Probably important

uncertainty or variability

Acceptability

Is the intervention acceptable to key stakeholders?

Yes

Feasibility

Is the intervention feasible to implement?

Yes

Resource Use

Is the intervention a reasonable and efficient allocation of

resources?

Probably yes, with seasonal

dosing

Equity

What would be the impact of the intervention on health

equity?

Ranged from probably no

impact to increased

Evidence to Recommendations framework

Summary: Work Group interpretations

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

Minority OpinionMajority Opinion

Evidence to Recommendations framework

Summary: Work Group interpretations

Type of

Recommendation

We do not

recommend the

intervention

We recommend the

intervention for

individuals based on

shared clinical

decision-making

We recommend the

intervention

Minority OpinionMajority Opinion

▪ Majority of Work Group was supportive of intervention with Pfizer maternal RSVpreF

vaccine for pregnant people with dosing during the approved dosing interval (32–36

weeks gestation)

– Found the data on preterm birth when assessed among those vaccinated during the

approved dosing interval (32–36 weeks gestation) to be reassuring

– Felt the approved dosing interval (32–36 weeks gestation) reduces the potential risk

of preterm birth and the potential for complications from preterm birth, which is

their major safety concern

▪ All Work Group members endorsed the importance of post-introduction vaccine safety

monitoring

Work Group considerations: Benefit and harms

▪ Unanimously supported use of a seasonal dosing strategy which would maximize

benefits and cost-effectiveness

▪ Supported that RSVpreF vaccine dosing should occur during September–January in

most of the continental United States

▪ Felt that jurisdictions in which RSV seasonality differs from most of the continental US

should have flexibility regarding start and stop of administration of RSVpreF vaccine in

pregnant people

Work Group considerations: Seasonal dosing

▪ Pregnant people should have options for RSV prevention

– Nirsevimab may not be readily available in all settings

– Pregnant people and their providers may have preferences regarding these two

products

▪ Pregnant people should be made aware that they can either receive RSVpreF vaccine

during pregnancy or nirsevimab can be given to the infant, but most infants will not

need both

▪ Pregnant people should be informed regarding the risks and benefits of both products

before making a decision

Work Group considerations: RSVpreF vaccine is one of two

available preventive products for RSV in infants

▪ Most work group members support a full recommendation

– Approved dosing interval (32–36 weeks) reduces the potential risk of and complications from preterm birth

– Importance of clear vaccine recommendations

– Providers who will help pregnant people decide which product to receive generally have less familiarity with the

data than ACIP

– SCDM can be confusing to providers, hard to implement for providers, can lead to lower vaccine confidence and

uptake of vaccination, and could potentially influence support for the vaccine in lower and middle income

countries

▪ Minority supported a recommendation with SCDM

– Without SCDM, a full recommendation could result in some providers recommending RSVpreF vaccine during

pregnancy without discussing with pregnant patients that nirsevimab is an option

– Potential risk for preterm birth (and neuroinflammatory events)

– Same vaccine is recommended under SCDM for adults ages 60 years and older

▪ ACIP generally makes SCDM recommendations when individuals may benefit from

vaccination, but broad vaccination of people in that group is unlikely to have

population-level impacts

Work Group considerations: Full vs shared clinical decision making

(SCDM) recommendation for Pfizer maternal RSVpreF vaccine during

the approved dosing interval (32–36 weeks gestation)

▪ Currently there are no data available on:

– Efficacy of the first lifetime dose during subsequent pregnancies

– Safety of additional doses given in subsequent pregnancies

▪ Work Group felt that it was too early to decide whether additional doses should be

given in subsequent pregnancies given the lack of data

▪ Additional data are needed to inform whether additional doses in subsequent

pregnancies would be indicated, and recommendations can be updated in the future

Work Group considerations: Additional vaccine doses in

subsequent pregnancies

▪ Maternal RSV vaccine is recommended for pregnant people during 32

through 36 weeks gestation, using seasonal administration, to prevent

RSV lower respiratory tract infection in infants

Proposed voting language

Jefferson Jones

Lauren Roper

Meredith McMorrow

Mila Prill

Monica Godfrey

Michael Melgar

Amadea Britton

Amanda Payne

Megan Wallace

Danielle Moulia

Morgan Najdowski

David Hutton

Jamison Pike

Andrew Leidner

Ismael Ortega-Sanchez

Karen Broder

Naomi Tepper

Heidi Moline

Amber Winn

Monica Patton

Jenny Milucky

Fiona Havers

Rebecca Morgan

Doug Campos-Outcalt

Patricia Wodi

Sascha Ellington

Megan Lindley

Fangjun Zhou

Sarah Meyer

David Hutton

Barbara Mahon

Aron Hall

Coronavirus and Other

Respiratory Viruses Division

Immunization Services

Division

Acknowledgements

▪ We acknowledge that not every person who can become pregnant identifies as a

woman. Although we try to use gender-neutral language as often as possible, much of

the research available currently refers only to “women” when discussing the ability to

become pregnant. When citing research, we refer to the language used in the study. In

these cases, “woman” refers to someone who was assigned female at birth. For clarity

in terminology, “maternal” is used to identify the person who is pregnant or

postpartum throughout this presentation; the authors are aware that pregnancy is not

equated with the decision to parent nor do all parents who give birth identify as

mothers.

Note

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.

Photographs and images included in this presentation are licensed solely for CDC/NCIRD online and presentation

use. No rights are implied or extended for use in printing or any use by other CDC CIOs or any external audiences.

Centers for Disease Control and Prevention

National Center for Immunization and Respiratory Diseases

Photographs and images included in this presentation are licensed solely for CDC/NCIRD online and presentation

use. No rights are implied or extended for use in printing or any use by other CDC CIOs or any external audiences.

Grading of Recommendations, Assessment, Development,

and Evaluation (GRADE):

Pfizer Maternal RSVpreF Vaccine

Update: September 6, 2023

Evidence Retrieval, conducted as of April 10, 2023

*Medline (OVID), Embase (OVID), Cochrane Library, CINAHL (EbscoHost), Scopus, clinicaltrials.gov

Records screened*

(n=161)

Duplicates removed

(n=7)

Studies irrelevant

(n=139)

Full text studies

assessed for

eligibility

(n=12)

Studies excluded

(n=10)

7 wrong intervention

3 wrong patient population

Records included

in evidence

synthesis

(n=2)

▪ High certainty: We are very confident that the true effect lies close to that of the

estimate of the effect.

▪ Moderate certainty: We are moderately confident in the effect estimate: The true

effect is likely to be close to the estimate of the effect, but there is a possibility that it

is substantially different.

▪ Low certainty: Our confidence in the effect estimate is limited: The true effect may be

substantially different from the effect estimate.

▪ Very low certainty: We have very little confidence in the effect estimate: The true

effect is likely to be substantially different from the estimate of the effect.

GRADE Evidence Type

NOTE: Evidence type is not measuring the quality of individual studies, but how much certainty we

have in the estimates of effect across each outcome.

▪ Initial evidence type (certainty level) determined by study design

– Initial evidence high certainty: A body of evidence from randomized

controlled trials

– Initial evidence low certainty: A body of evidence from observational

studies

▪ The certainty of evidence may be downgraded due to risk of bias,

inconsistency, indirectness, imprecision, or publication bias. For non-

randomized studies, the certainty may be rated up for presence of dose-

response gradient, large or very large magnitude of effect, and opposing

residual confounding.

GRADE Evidence Type

NOTE: Evidence type is not measuring the quality of individual studies, but how much certainty we

have in the estimates of effect across each outcome.

Benefits

Vaccine efficacy methods

*8 participants (3 in the vaccine group and 5 in the placebo group) received injection at >36 weeks gestation and were included in the analysis

Dosing interval

Number of

Participants

VE Formula

Outcomes

Reference

Phase 3 trial, Trial

dosing interval

(24

–36 weeks)*

Vaccine: 3495

Placebo: 3480

–(P/[1–P]), where P is the number of

cases in the RSVpreF group divided by

the total number of cases

•

Medically attended RSV-associated lower

respiratory tract infection in infants

•

Hospitalization for RSV-associated lower

respiratory tract infection in infants

•

All-cause medically attended lower

respiratory tract infection in infants

Kampmann et al. and

VRBPAC briefing

document

Phase 3 trial, Trial

dosing interval

(24

–36 weeks)*

Vaccine: 3495

Placebo: 3480

–(P/[1–P]), where P is the number of

cases in the RSVpreF group divided by

the total number of cases

• ICU admission from RSV hospitalization in

infants

•

Mechanical ventilation from RSV

hospitalization in infants

•

All-cause hospitalization for lower

respiratory tract infection in infants

Post

-hoc analysis,

data provided by the

manufacturer for

GRADE

Phase 3 trial,

Approved dosing

interval (32

–36

weeks)

Vaccine: 1572

Placebo: 1539

-(hP/[1-P]), where P is the number of

cases in the RSVpreF group divided by

the total number of cases and h is the

ratio of number of participants at risk in

the placebo group to the number of

participants at risk in the RSVpreF group

All efficacy outcomes

Post

-hoc analysis,

data provided by the

manufacturer

▪ Pfizer phase 3 randomized controlled trial (RCT), MATISSE

▪ Trial locations: Argentina, Australia, Brazil, Canada, Chile, Denmark, Finland, Gambia, Japan, Republic of

Korea, Mexico, Netherlands, New Zealand, Philippines, South Africa, Spain, Taiwan, United States

– 45% of participants from United States

▪ Study enrollment and efficacy follow-up occurred June 17, 2020, to October 2, 2022

▪ Data evaluated: data cut-off September 30, 2022; mean follow-up in infant participants 11.97 months

after birth (range: 0.0, 24.3)

▪ Infant evaluable efficacy set: 3,495 in vaccine arm; 3,480 in placebo arm

▪ Exclusion criteria of certain conditions may not represent all pregnant people and their infants in the

United States

▪ Placebo was not a saline placebo, but a lyophile match to the vaccine consisting of excipients matched

to those used in the RSVpreF vaccine formulation, minus the active ingredients

Outcome 1: Medically attended RSV-associated lower

respiratory tract infection in infants (n=1 study)

Kampmann B, Madhi SA, Munjal I, et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. N Engl J Med. 2023 Apr 5. doi: 10.1056/NEJMoa2216480.

▪ Medically attended visit (inclusive of inpatient and outpatient encounters)

and ≥1:

– Fast breathing: respiratory rate ≥60 bpm (<2 months of age [60 days]) or

≥50 bpm (≥2 to 12 months of age)

– SpO2 measured in room air <95%

– Chest wall indrawing

▪ RSV RT-PCR–positive test result by Pfizer central laboratory or by

certified laboratory with NAAT for RSV

▪ Confirmed by endpoint adjudication committee (EAC)

Outcome 1: Medically attended RSV-associated lower

respiratory tract infection in infants (n=1 study)

Outcome 1: Medically attended RSV-associated lower

respiratory tract infection in infants (n=1 study)

RR= relative risk, CI=confidence interval

Vaccine efficacy was calculated as 1−(P/[1−P]), where P is the number of cases of illness in the RSVpreF group divided by the total number of cases of illness. At 90 days, 99.5%

confidence intervals (CIs) were used (determined by the alpha-spending function and adjusted with the use of the Bonferroni procedure), and at later intervals, 97.58% CIs were

used (based on a two-sided alpha level of 0.0483 adjusted with the use of the Bonferroni procedure). Efficacy is from full phase 3 trial data, using trial dosing interval (24–36 weeks

gestation).

This outcome did not meet success criterion using manufacturer calculated VE (lower bound of CI was <20%)

Time period

after birth

Events/Vaccine

(n/N)

Events/Placebo

(n/N)

Vaccine efficacy (1

– RR)

(95% CI)

Manufacturer calculated

vaccine efficacy

(99.5%

or 97.58% CI)

–90 days after

birth

24/3495

56/3480

57.3% (31.3, 73.5)

57.1% (14.7, 79.8)

–

120 days after

birth

35/3495

81/3480

57.0% (36.2, 71.0)

56.8% (31.2, 73.5)

–

150 days after

birth

47/3495

99/3480

52.7% (33.3, 66.5)

52.5% (28.7, 68.9)

–

180 days after

birth

57/3495

117/3480

51.5% (33.7, 64.5)

51.3% (29.4, 66.8)

▪ Medically attended visit (inclusive of inpatient and outpatient encounters)

and ≥1:

– Fast breathing (respiratory rate ≥70 (<2 month of age [60 days]) or ≥60 (≥2

to 12 months of age)

– SpO2 measured in room air <93%

– High-flow nasal cannula or mechanical ventilation

– ICU admission for >4 hours

– Unresponsive/unconscious

▪ RSV RT-PCR–positive test result by Pfizer central laboratory or by

certified laboratory with NAAT for RSV

▪ Confirmed by EAC

Outcome 1: Severe medically attended RSV-associated

lower respiratory tract infection in infants (n=1 study)

SpO2= Peripheral capillary oxygen saturation; RT-PCR = Real-time polymerase chain reaction; NAAT= nucleic acid amplification technology; EAC= endpoint adjudication committee

Blue text denotes differences between definitions of severe medically attended RSV-associated lower respiratory tract infection and medically attended RSV-associated lower

respiratory tract infection.

Outcome 1: Severe medically attended RSV-associated

lower respiratory tract infection in infants (n=1 study)

RR= relative risk, CI= confidence interval

Vaccine efficacy was calculated as 1−(P/[1−P]), where P is the number of cases of illness in the RSVpreF group divided by the total number of cases of illness. At 90 days, 99.5%

confidence intervals (CIs) were used (determined by the alpha-spending function and adjusted with the use of the Bonferroni procedure), and at later intervals, 97.58% CIs were

used (based on a two-sided alpha level of 0.0483 adjusted with the use of the Bonferroni procedure).

Efficacy is from full phase 3 trial data, using trial dosing interval (24–36 weeks gestation).

Time period

after birth

Events/Vaccine

(n/N)

Events/Placebo

(n/N)

Vaccine efficacy (1

– RR)

(95% CI)

Manufacturer calculated

vaccine efficacy

(99.5% or

97.58% CI)

–90 days

after birth

6/3495

33/3480

81.9% (56.8, 92.4)

81.8% (40.6, 96.3)

–120 days

after birth

12/3495

46/3480

74.0% (51.1, 86.2)

73.9% (45.6, 88.8)

–150 days

after birth

16/3495

55/3480

71.0% (49.6, 83.4)

70.9% (44.5, 85.9)

–180 days

after birth

19/3495

62/3480

69.5% (49.1, 81.7)

69.4% (44.3, 84.1)

▪ Measures of effect

– Relative Risk: 0.487 (97.58% CI: 0.332, 0.706)

– Absolute Risk

: 1,725 fewer per 100,000 (988 to 2,246 fewer); NNV: 58 (45, 101)

– Absolute Risk

: 11,850 fewer per 100,000 (6,791 to 15,431 fewer); NNV: 8 (6, 15)

– Absolute Risk

: 5,643 fewer per 100,000 (3,234 to 7,348 fewer); NNV: 18 (14, 31)

▪ Concerns in certainty assessment:

– None

▪ Evidence type: High

GRADE: Medically attended RSV-associated lower

respiratory infection in infants (n=1 study)

Calculated using the observed outcomes in the placebo arm during the clinical trial follow-up (3.4%)

Calculated using rate from Lively 2019 JPIDS, 2004-2009 from 3 New Vaccine Surveillance Network (NVSN) sites from Nov-Apr season, included if with acute respiratory infection

(ARI), not restricted to lower respiratory tract infection (LRTI).

Calculated assuming 47.5% of ARI from Lively et al paper were LRTI (Rainisch 2020 Vaccine)

NNV= Number needed to vaccinate

▪ Phase 3 RCT, MATISSE

▪ A respiratory tract infection due to RSV that results in hospitalization

▪ Confirmed by endpoint adjudication committee (EAC)

Outcome 2: Hospitalization for RSV-associated lower

respiratory tract infection in infants (n=1 study)

Kampmann B, Madhi SA, Munjal I, et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. N Engl J Med. 2023 Apr 5. doi: 10.1056/NEJMoa2216480.

Outcome 2: Hospitalization for RSV-associated lower

respiratory tract infection in infants (n=1 study)

RR= relative risk, CI= confidence interval

Vaccine efficacy was calculated as 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of cases. The confidence interval was adjusted

using the Bonferroni procedure and accounting for the primary endpoints results. As a secondary endpoint, the criterion for vaccine efficacy was a

lower bound of the confidence interval >0%.

This outcome did not meet success criterion using manufacturer calculated VE (lower bound of CI was <0%)

Efficacy is from full phase 3 trial data, using trial dosing interval (24–36 weeks gestation).

Time period after

birth

Events/Vaccine

(n/N)

Events/Placebo

(n/N)

Vaccine efficacy

– RR) (95% CI)

Manufacturer calculated

vaccine efficacy

(99.17% CI)

–90 days after birth

10/3495

31/3480

67.9% (34.6, 84.2)

67.7% (15.9, 89.5)

–120 days after birth

15/3495

37/3480

59.6% (26.6, 77.8)

59.5% (8.3, 83.7)

–150 days after birth

17/3495

39/3480

56.6% (23.4, 75.4)

56.4% (5.2, 81.5)

–180 days after birth

19/3495

44/3480

57.0% (26.5, 74.8)

56.8% (10.1, 80.7)

–360 days after

birth

38/3495

57/3480

33.6% (0.2, 55.8)

33.3% (

-17.6, 62.9)

▪ Measures of effect

– Relative risk: 0.432 (99.17% CI: 0.193, 0.899)

– Absolute risk

: 718 fewer per 100,000 (128 to 1,020 fewer); NNV: 139 (98, 781)

– Absolute risk

: 1,051 fewer per 100,000 (187 to 1,493 fewer); NNV: 95 (67, 535)

▪ Concerns in certainty assessment:

– Serious concern for imprecision due to the width of the confidence interval

containing estimates for which different policy decisions might be considered

▪ Evidence type: Moderate

GRADE: Hospitalization for RSV-associated lower

respiratory tract infection in infants (n=1 study)

Absolute risk was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up.

Calculated using the rate of acute respiratory infection (ARI) hospitalizations for infants 0-5 months (2016-2020 NVSN, unpublished)

Outcome 3: ICU admission from RSV hospitalization in

infants (n=1 study)

RR= relative risk, CI= confidence interval

Vaccine efficacy was calculated as 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of cases.

Efficacy is from full phase 3 trial data, using trial dosing interval (24–36 weeks gestation).

Time period after

birth

Events/Vaccine

(n/N)

Events/Placebo

(n/N)

Vaccine efficacy

– RR) (95% CI)

Manufacturer calculated

vaccine efficacy

(95% CI)

–90 days after birth

2/3495

6/3480

66.8% (

-64.3, 93.3)

66.7% (

-86.4, 96.7)

–150 days after

birth

4/3495

6/3480

33.6% (

-135, 81.3)

33.3% (

-181.1, 86.2)

–180 days after

birth

4/3495

7/3480

43.1% (

-94.2, 83.3)

42.9% (

-124.8, 87.7)

▪ Measures of effect

– Relative risk: 0.571 (95% CI: 0.123, 2.248)

– Absolute risk

: 86 fewer per 100,000 (from 176 fewer to 251 more)

– Absolute risk

: 285 fewer per 100,000 (from 583 fewer to 830 more)

▪ Concerns in certainty assessment:

– Very serious concern for imprecision due to the width of the confidence interval

containing estimates for which different policy decisions might be considered and

fragility of the estimate

▪ Evidence type: Low

Outcome 3: ICU admission from RSV hospitalization in

infants (n=1 study)

Absolute risk was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up.

Calculated using the rate of ICU admissions in hospitalizations from Arriola 2019 JPIDS and acute respiratory infection (ARI) hospitalizations for infants 0-5 months (2016-2020

NVSN, unpublished)

Outcome 4: Mechanical ventilation

from RSV

hospitalization in infants (n=1 study)

RR= relative risk, CI= confidence interval

Efficacy is from full phase 3 trial data, using trial dosing interval (24–36 weeks gestation)

1 Invasive or non-invasive mechanical ventilation

2 Using 0.5 offset to account for zero events in the vaccine arm

3 Vaccine efficacy was calculated as 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of cases

Time period after

birth

Events/Vaccine

(n/N)

Events/Placebo

(n/N)

Vaccine efficacy

– RR) (95% CI)

Manufacturer calculated

vaccine efficacy

(95% CI)

–90 days after

birth

0/3495

4/3480

88.9% (

-105.4, 99.4)

100% (

-51.5, 100)

–150 days after

birth

0/3495

4/3480

88.9% (

-105.4, 99.4)

100% (

-51.5, 100)

–180 days after

birth

0/3495

5/3480

90.0% (

-63.6, 99.5)

100% (

-9.1, 100)

▪ Measures of effect

– Relative risk: 0.001 (95% CI: 0.001, 1.091)

– Absolute risk

: 144 fewer per 100,000 (144 fewer to 13 more)

– Absolute risk

: 209 fewer per 100,000 (209 fewer to 19 more)

▪ Concerns in certainty assessment:

– Very serious concern for imprecision due to the width of the confidence interval

containing estimates for which different policy decisions might be considered and

fragility of the estimate

▪ Evidence type: Low

Outcome 4: Mechanical ventilation from RSV

hospitalization in infants (n=1 study)

Absolute risk was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up

Calculated using the rate of mechanical ventilations in hospitalizations from Arriola 2019 JPIDS and acute respiratory infection (ARI) hospitalizations for infants 0-5 months (2016-

2020 NVSN, unpublished)

▪ Phase 3 RCT, MATISSE and Phase 2b RCT (unpublished, data obtained from

manufacturer)

▪ Phase 2b RCT

1,2

– Pregnant people ages 18–49 in Argentina, Chile, South Africa and United States

• Infant safety set: 114 in vaccine arm (phase 3 formulation); 116 in placebo arm

▪ 1 RSV-associated death occurred in an infant in the placebo group recorded at day 120

after birth in the Phase 3 study, no RSV-associated deaths occurred in the RSVpreF

group

▪ No RSV-associated deaths were recorded in the Phase 2b study among those who

received the phase 3 formulation or placebo

▪ Outcome not included in GRADE

Outcome 5: RSV-associated death in infants (n=2 studies)

Simões EAF, Center KJ, Tita ATN, et al. Prefusion F Protein–Based Respiratory Syncytial Virus Immunization in Pregnancy. N Engl J Med. 2022 Apr 28. doi:

10.1056/NEJMoa2106062.

https://www.clinicaltrials.gov/ct2/show/study/NCT04032093

▪ Phase 3 RCT, MATISSE

▪ Infant with any medically attended-RTI visit (inpatient or outpatient) AND

– Fast breathing (respiratory rate ≥60 bpm for <2 months of age [<60 days of

age] or ≥50 bpm for ≥2 to <12 months of age) OR

– SpO2 <95% OR

– Chest wall indrawing

Outcome 6: All-cause medically attended lower respiratory

tract infection in infants (n=1 study)

100

Outcome 6: All-cause medically attended lower respiratory

tract infection in infants (n=1 study)

RR= relative risk, CI= confidence interval

Vaccine efficacy was calculated as 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of cases. The confidence interval was adjusted

using the Bonferroni procedure and accounting for the primary endpoints results. As a secondary endpoint, the criterion for vaccine efficacy was a

lower bound of the confidence interval >0%. Efficacy is from full phase 3 trial data, using trial dosing interval (24–36 weeks gestation).

This outcome did not meet success criterion (lower bound of CI was <0%)

Time period

after birth

Events/Vaccine

(n/N)

Events/Placebo

(n/N)

Vaccine efficacy

– RR) (95% CI)

Manufacturer calculated

vaccine efficacy

(99.17% CI)

–90 days after

birth

186/3495

200/3480

7.4% (

-12.4, 23.7)

7.0% (

-22.3, 29.3)

–

120 days after

birth

261/3495

278/3480

6.5% (

-10, 20.5)

6.1% (

-18.3, 25.5)

–

150 days after

birth

331/3495

349/3480

5.6% (

-8.9, 18.1)

5.2% (

-16.5, 22.8)

–180 days

after birth

392/3495

402/3480

2.9% (

-10.7, 14.8)

2.5% (

-17.9, 19.4)

–360 days

after birth

504/3495

531/3480

5.5% (

-5.8, 15.5)

5.1% (

-12.1, 19.6)

101

▪ Measures of effect

– Relative risk: 0.975 (99.17% CI: 0.806, 1.179)

– Absolute risk*: 289 fewer per 100,000 (2,241 fewer to 2,068 more)

▪ Concerns in certainty assessment

– Serious concern for imprecision due to the width of the confidence interval

containing estimates for which different policy decisions might be considered

▪ Evidence type: Moderate

GRADE: All-cause medically attended lower respiratory

tract infection in infants (n=1 study)

*Absolute risk was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute risk estimates should be interpreted in this

context.

102

Outcome 7: All-cause hospitalization for lower respiratory

tract infection in infants (n=1 study)

RR= relative risk, CI= confidence interval

1 Vaccine efficacy was calculated as 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of cases.

Efficacy is from full phase 3 trial data, using trial dosing interval (24–36 weeks gestation).

Time period

after birth

Events/Vaccine

(n/N)

Events/Placebo

(n/N)

Vaccine efficacy

– RR) (95% CI)

Manufacturer calculated

vaccine efficacy

(95% CI)

–90 days

after birth

35/3495

55/3480

36.6% (3.4, 58.4)

36.4% (1.0, 59.6)

–150 days

after birth

47/3495

67/3480

30.2% (

-1.10, 51.8)

29.9% (

-3.4, 52.7)

–180 days

after birth

54/3495

76/3480

29.3% (0, 49.9)

28.9% (

-2.0, 50.8)

103

▪ Measures of effect

– Relative risk: 0.711 (95% CI: 0.492, 1.020)

– Absolute risk*: 631 fewer per 100,000 (from 1,109 fewer to 44 more)

▪ Concerns in certainty assessment

– Serious concern for imprecision due to the width of the confidence interval

containing estimates for which different policy decisions might be considered

▪ Evidence type: Moderate

Outcome 7: All-cause hospitalization for lower respiratory

tract infection in infants (n=1 study)

*Absolute risk was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute risk estimates should be interpreted in this

context.

104

Harms

105

▪ Phase 3 RCT, MATISSE (unpublished, data obtained directly from

manufacturer)

– Maternal safety set: 3,682 participants in vaccine arm; 3,675 in placebo arm

▪ Phase 2b RCT (unpublished, data obtained directly from manufacturer)

– Maternal safety set: 115 participants in vaccine arm (phase 3 formulation);

117 in placebo arm

▪ Follow up times for serious adverse events reported by maternal

participants were from vaccination through 6 months after delivery

(Phase 3) or throughout the study (Phase 2b)

Outcome 8: Serious adverse events in pregnant people (n=2

studies)

106

Outcome 8: Serious adverse events in pregnant people (n=2

studies)

CI= confidence interval

Vaccines and Related Biological Products Advisory Committee May 18, 2023 Meeting Briefing Document- FDA

Trial

Events/Vaccine

(n/N)

Events/Placebo

(n/N)

Relative Risk (95% CI)

Phase 3

598/3682 (16.2%)

558/3675 (15.1%)

1.07 (0.96, 1.19)

Phase 2b

7/115 (6.1%)

14/117 (12.0%)

0.51 (0.21, 1.21)

Serious adverse events in four vaccine recipients (pain in an arm followed by bilateral lower extremity pain,

premature labor, systemic lupus erythematosus, and eclampsia) and in one placebo recipient (premature placental

separation) were assessed by the investigator as being related to the injection. Based on review of the event

narratives and temporal association of these events to vaccination, FDA agreed with the investigator’s

assessments that there was a reasonable possibility that these events were related to the study intervention.

107

▪ Measures of effect

– Relative risk: 1.06 (95% CI: 0.95, 1.17)

– Absolute risk*: 905 more per 100,000 (754 fewer to 2,564 more)

▪ Concerns in certainty assessment

– Serious concern for imprecision due to the width of the confidence interval

containing estimates for which different policy decisions might be considered

– Serious concern for indirectness as 55% of the Phase 3 RCT and 62% of the Phase 2b

RCT did not receive vaccine or placebo in the approved dosing interval (32–36 weeks

gestation). In the approved dosing interval, there is less opportunity for serious

adverse events, including preterm birth/delivery, compared to the trial dosing

interval (24–36 weeks gestation).

▪ Evidence type: Low

GRADE: Serious adverse events in pregnant people (n=2

studies)

*Absolute risk was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute risk estimates should be interpreted in this

context. CI= confidence interval

108

▪ Phase 3 RCT, MATISSE and Phase 2b (unpublished, data obtained directly

from manufacturer)

▪ Participants reported local and systemic reactions up to 7 days after

vaccination

Outcome 9: Reactogenicity (grade 3+) in pregnant people

(n=2 studies)

109

Outcome 9: Reactogenicity (grade 3+) in pregnant people

Trial Outcome Events/Vaccine

(n/N)

Events/Placebo

(n/N)

Relative Risk (95% CI)

Phase 3 Local events (grade 3+) 11/3663 (0.3%) 0/3639 (0%) 21.86 (1.29, 371.74)

Systemic events (grade 3+) 83/3663 (2.3%) 83/3640 (2.3%) 0.99 (0.74, 1.34)

Phase 2b Local events (grade 3+) 0/114 (0%) 0/117 (0%) 1.03 (0.02, 51.28)*

Systemic events (grade 3+) 2/114 (1.8%) 4/117 (3.4%) 0.51 (0.10, 2.75)

Grade 3: prevents daily routine activity. For redness or swelling is >10 cm. For vomiting, requires intravenous hydration. For

diarrhea, includes 6 or more loose stools in 24 hours. Grade 4: requires emergency room visit or hospitalization; for redness

included necrosis or exfoliative dermatitis; for swelling included necrosis.

*Using 0.5 offset to account for zero events

CI= confidence interval

110

▪ Measures of effect

– Relative risk: 0.97 (95% CI: 0.72, 1.31)

– Absolute risk*: 69 fewer per 100,000 (648 fewer to 718 more)

▪ Concerns in certainty assessment:

– Serious concern for indirectness as this data only includes systemic

reactions. When selecting the a priori harm outcomes, the Work Group

defined reactogenicity as both local and systemic reactions.

▪ Evidence type: Moderate

Outcome 9: Reactogenicity (grade 3+) in pregnant people

(n=2 studies)

*Absolute risk was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute risk estimates should be interpreted in this

context. CI= confidence interval

111

▪ Phase 3 RCT, MATISSE (unpublished, data obtained directly from

manufacturer)

– Infant safety set: 3,568 in vaccine arm; 3,558 in placebo arm

▪ Phase 2b RCT (unpublished, data obtained directly from manufacturer)

– Infant safety set: 114 in vaccine arm (phase 3 formulation); 116 in placebo

arm

Outcome 10: Serious adverse events in infants (n=2 studies)

112

Outcome 10: Serious adverse events in infants (n=2 studies)

Vaccines and Related Biological Products Advisory Committee May 18, 2023 Meeting Briefing Document- FDA, CI= confidence interval

Trial

Events/Vaccine

(n/N)

Events/Placebo

(n/N)

Relative Risk (95% CI)

Phase 3

625/3568 (17.5%)

623/3558 (17.5%)

1.00 (0.90, 1.11)

Phase 2b

41/114 (36.0%)

38/116 (32.8%)

1.10 (0.77, 1.57)

No serious adverse events in infants were considered by the investigators to be related to the vaccine. For infant deaths in the

RSVpreF group, the FDA agreed with the investigator’s conclusions for 4 out of 5 of the infant deaths; however, for 1 case of

extreme prematurity in an infant born to an 18-year-old mother at 10 days after vaccination who died from prematurity-related

complications, FDA was unable to exclude the possibility of the extreme prematurity and subsequent death being related to

receipt of the investigational product. No non-fatal SAEs in infant participants were considered related to maternal vaccination by

FDA.

113

▪ Measures of effect

– Relative risk: 1.01 (95% CI: 0.91, 1.11)

– Absolute risk*: 180 more per 100,000 (1,619 fewer to 1,979 more)

▪ Concerns in certainty assessment

– Serious concern for imprecision due to the width of the confidence interval

containing estimates for which different policy decisions might be considered

– Serious concern for indirectness as 55% of the Phase 3 RCT and 62% of the Phase 2b

RCT did not receive vaccine or placebo in the approved dosing interval (32–36 weeks

gestation). In the approved dosing interval, there is less opportunity for serious

adverse events, including preterm birth/delivery, compared to the trial dosing

interval (24–36 weeks gestation)

▪ Evidence type: Low

GRADE: Serious adverse events in infants (n=2 studies)

CI= confidence interval

114

▪ Phase 3 RCT, MATISSE and Phase 2b (unpublished, data obtained directly

from manufacturer)

– Gestational age at birth <37 weeks and <34 weeks

Outcome 11: Preterm births (n=2 studies)

115

Outcome: Preterm births (n=2 studies), Pfizer maternal

RSVpreF vaccine

*When reported as an adverse event of special interest, 202 preterm births occurred in the vaccine arm; the relative risk is minimally changed at 1.19 (0.98, 1.45) when using this

count

**Using 0.5 offset to account for zero events in the vaccine arm

CI= confidence interval

Publication

Definition

Events/Vaccine

(n/N)

Events/Placebo

(n/N)

Relative Risk (95% CI)

Phase 3

<34 weeks

21/3568

12/3558

1.75 (0.86, 3.54)

<37 weeks

201*/3568

169/3558

1.19 (0.97, 1.45)

Phase 2b

<34 weeks

0/115

1/117

0.34 (0.01, 8.24)**

<37 weeks

6/115

3/117

2.03 (0.52, 7.94)

116

▪ Measures of effect

– Relative risk: 1.20 (0.99, 1.46)

– Absolute risk*: 936 more per 100,000 (from 47 fewer to 2,153 more)

▪ Concerns in certainty assessment:

– Very serious concern for imprecision due to the width of the confidence interval

containing estimates for which different policy decisions might be considered and

not meeting optimal information size requirements

– Serious concern for indirectness as 55% of the Phase 3 RCT and 62% of the Phase 2b

RCT did not receive vaccine or placebo in the approved dosing interval (32–36 weeks

gestation). In the approved dosing interval, there is less opportunity for serious

adverse events, including preterm birth/delivery, compared to the trial dosing

interval (24–36 weeks gestation)

▪ Evidence type: Very low

Outcome: Preterm births (n=2 studies)

*Absolute risk was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute risk estimates should be interpreted in this

context. CI= confidence interval

117

GRADE additional slides

118

Inclusion/exclusion criteria for pregnant people-Phase 3 Trial

Inclusion Exclusion

Healthy women ≤49 years of age who are

between 24 0/7 and 36 0/7 weeks of gestation on

the day of planned vaccination, with an

uncomplicated, singleton pregnancy, who are at

no known increased risk for complications.

Willing and able to comply with scheduled

visits, treatment plan, laboratory tests, and

other study procedures.

Receiving prenatal standard of care based on

country requirements.

Had a fetal anomaly ultrasound examination

performed at ≥18 weeks of pregnancy with no

significant fetal abnormalities observed.

Determined by medical history, physical

examination, and clinical judgment to be

appropriate for inclusion in the study.

Documented negative HIV antibody test,

syphilis test, and hepatitis B virus (HBV) surface

antigen test during this pregnancy and prior to

randomization (Visit 1).

Intention to deliver at a hospital or birthing

facility where study procedures can be

obtained.

Expected to be available for the duration of the

study and can be contacted by telephone during

study participation.

Participant is willing to give informed consent

for her infant to participate in the study.

Capable of giving signed informed consent

which includes compliance with the

requirements and restrictions listed in the

informed consent document (ICD) and in this

protocol OR If the maternal participant is

illiterate, a thumbprinted informed consent

must be obtained, which must be signed and

dated by an impartial witness who was present

throughout the entire informed consent process

confirming that the maternal participant has

been informed of all pertinent aspects of the

study.

Prepregnancy body mass index (BMI) of >40 kg/m2. If prepregnancy BMI is not available, the BMI at the time of the first obstetric visit during the current pregnancy may be used.

Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection.

History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g., anaphylaxis) to any component of the investigational product or any related vaccine.

Current pregnancy resulting from in vitro fertilization.

Current pregnancy complications or abnormalities at the time of consent that will increase the risk associated with the participation in and completion of the study, including but not

limited to the following:

Preeclampsia, eclampsia, or uncontrolled gestational hypertension.

Placental abnormality.

Polyhydramnios or oligohydramnios.

Significant bleeding or blood clotting disorder.

Endocrine disorders, including untreated hyperthyroidism or untreated hypothyroidism. This also includes disorders of glucose intolerance (e.g., diabetes mellitus type 1 or 2) antedating

pregnancy or occurring during pregnancy if uncontrolled at the time of consent.

Any signs of premature labor with the current pregnancy or having ongoing intervention (medical/surgical) in the current pregnancy to prevent preterm birth.

Prior pregnancy complications or abnormalities at the time of consent, based on the investigator's judgment, that will increase the risk associated with the participation in and completion

of the study, including but not limited to the following:

Prior preterm delivery ≤34 weeks' gestation.

Prior stillbirth or neonatal death.

Previous infant with a known genetic disorder or significant congenital anomaly.

Major illness of the maternal participant or conditions of the fetus that, in the investigator's judgment, will substantially increase the risk associated with the maternal or infant participant's

participation in, and completion of, the study or could preclude the evaluation of the maternal participant's response (includes positive serologic testing for regional endemic conditions

assessed during routine maternal care, as per local standards of care and obstetric recommendations).

Congenital or acquired immunodeficiency disorder, or rheumatologic disorder or other illness requiring chronic treatment with known immunosuppressant medications, including

monoclonal antibodies, within the year prior to enrollment.

Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk

associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make

the participant inappropriate for entry into this study.

Participation in other studies involving investigational drug(s) within 28 days prior to consent and/or during study participation.

Receipt of monoclonal antibodies within the year prior to enrollment or the use of systemic corticosteroids for >14 days within 28 days prior to study enrollment. Permitted treatments

include the receipt of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies, prednisone doses of <20 mg/day for ≤14 days and, inhaled/nebulized, intra-

articular, intrabursal, or topical (skin or eyes) corticosteroids.

Current alcohol abuse or illicit drug use. Note: Marijuana use is not considered an exclusion criterion for the study when elicited in participant screening, though it may be considered illicit

in some locales.

Receipt of blood or plasma products or immunoglobulin (Ig), from 60 days before investigational product administration, or planned receipt through delivery, with 1 exception, Rho(D)

immune globulin (e.g., RhoGAM), which can be given at any time.

Previous vaccination with any licensed or investigational RSV vaccine or planned. Note: Licensed COVID-19 vaccines or COVID-19 vaccines authorized for temporary or emergency use will

not be prohibited during the course of this study.

Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or Pfizer employees,

including their family members, directly involved in the conduct of the study.

Participants who are breastfeeding at the time of enrollment.

119

Inclusion/exclusion criteria for infants-Phase 3 Trial

Inclusion

Exclusion

Evidence of a signed and dated informed consent document signed by

the parent(s)/legal guardian(s) OR If the infant participant's maternal

participant/parent(s)/legal guardian(s) is illiterate, a thumbprinted

informed consent must have been obtained, which must have been

signed and dated by an impartial witness who was present throughout the

entire informed consent process confirming that the maternal

participant/parent(s)/legal guardian(s) has been informed of all pertinent

aspects of the study for herself (maternal participant) and her fetus/infant

prior to taking part in the study.

Parent(s)/legal guardian(s) willing and able to comply with scheduled

visits, treatment plan, laboratory tests, and other study procedures.

Infant who is a direct descendant (e.g., child or

grandchild) of the study personnel.

120

Inclusion/exclusion criteria for pregnant people-Phase 2b

Inclusion-Pregnant people Exclusion-Pregnant people

Healthy women 18 to 49 years of age between 24

and 36 weeks of gestation on the day of planned

vaccination, with an uncomplicated pregnancy, who

are at no known increased risk for complications, and

whose fetus has no significant abnormalities

observed on ultrasound.

Willing and able to comply with scheduled visits,

treatment plan, laboratory tests, and other study

procedures.

Receiving prenatal standard of care.

Had an ultrasound performed at >=18 weeks of

pregnancy.

Had a negative urinalysis for protein and glucose at

the screening visit. Trace protein in the urine is

acceptable if the blood pressure is also normal.

Determined by medical history, physical

examination, screening laboratory assessment, and

clinical judgment to be appropriate for inclusion in

the study.

Documented negative human immunodeficiency

virus antibody, hepatitis B virus surface antigen,

hepatitis C virus antibody, and syphilis tests at the

screening visit.

Body mass index of </=40 kg/m2 at the time of the

screening visit.

Capable of giving signed informed consent, which

includes compliance with the requirements and

restrictions listed in the informed consent document

and in this protocol.

Expected to be available for the duration of the

study and willing to give informed consent for her

infant to participate in the study.

Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate

intramuscular injection.

History of severe adverse reaction associated with a vaccine and/or severe allergic reaction to any component of the investigational product

or any related vaccine.

History of latex allergy.

History of any severe allergic reaction.

Participants with known or suspected immunodeficiency.

Current pregnancy resulting from in vitro fertilization or other assisted reproductive technology.

A prior history of or known current pregnancy complications or abnormalities that will increase the risk associated with the participant's

participation in and completion of the study.

Major illness of the mother or conditions of the fetus that, in the investigator's judgment, will substantially increase the risk associated with

the participant's participation in, and completion of, the study or could preclude the evaluation of the participant's response.

Participant with a history of autoimmune disease or an active autoimmune disease requiring therapeutic intervention including but not

limited to systemic or cutaneous lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré syndrome, multiple

sclerosis, Sjögren's syndrome, idiopathic thrombocytopenia purpura, glomerulonephritis, autoimmune thyroiditis, giant cell arteritis

(temporal arteritis), psoriasis, and insulin-dependent diabetes mellitus (type 1).

Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or

laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may

interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for

entry into this study.

Participation in other studies involving investigational drug(s) within 28 days prior to study entry and/or during study participation.

Participants who receive treatment with immunosuppressive therapy including cytotoxic agents or systemic corticosteroids (such as for

cancer or an autoimmune disease), or planned receipt of such treatment or agents during study participation. If systemic corticosteroids

have been administered short term (<14 days) for treatment of an acute illness, participants should not be enrolled into the study until

corticosteroid therapy has been discontinued for at least 30 days before investigational product administration. Inhaled/nebulized, intra

articular, intrabursal, or topical (skin or eyes) corticosteroids are permitted.

Current alcohol abuse or illicit drug use.

Receipt of blood or plasma products or immunoglobulin, from 60 days before investigational product administration, or planned receipt

through delivery, with 1 exception, Rho(D) immune globulin (eg, RhoGAM), which can be given at any time.

Previous vaccination with any licensed or investigational RSV vaccine or planned receipt during study participation.

Laboratory test results at the screening visit outside the normal reference value for pregnant women according to their trimester in

pregnancy.

Participants who are breastfeeding at the time of the screening visit.

121

Inclusion/exclusion criteria for infants-Phase 2b

Inclusion-Infants Exclusion-Infants

Evidence of a signed and dated informed consent document

signed by the parent(s).

Parent(s) willing and able to comply with scheduled visits,

treatment plan, laboratory tests, and other study procedures.

Infant who is a direct descendant (eg, child or grandchild) of the

study personnel.

122

Figure 1. Enrollment,

Randomization,

Administration of Vaccine or

Placebo, and Follow-up

Kampmann B, Madhi SA, Munjal I, et al.

Bivalent Prefusion F Vaccine in

Pregnancy to Prevent RSV Illness in

Infants. N Engl J Med. 2023 Apr 5. doi:

10.1056/NEJMoa2216480.

123

Table 1. Demographics of phase 3 trial

Kampmann B, Madhi SA, Munjal I, et al.

Bivalent Prefusion F Vaccine in Pregnancy to

Prevent RSV Illness in Infants. N Engl J Med.

2023 Apr 5. doi: 10.1056/NEJMoa2216480.

124

Severity scale for local reactions and systemic events

(maternal participants)

Kampmann B, Madhi SA, Munjal I, et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. N Engl J Med. 2023 Apr 5. doi: 10.1056/NEJMoa2216480.

125

Studies Included in the Review of Evidence

Last name first

author, Publication

year

Study

design

Country Age

mean

(SD),

years

Total Population N intervention N comparison Outcomes Funding

Source

Kampmann B,

et al. plus unpublished

data obtained directly

from the manufacturer

RCT Argentina, Australia,

Brazil, Canada, Chile,

Denmark, Finland,

Gambia, Japan,

Republic of Korea,

Mexico, Netherlands,

New Zealand,

Philippines, South

Africa, Spain, Taiwan,

United States

29.0

(5.7)

7,357 3,682 3,675 Medically attended

RSV-associated lower

respiratory infection in

infants; Hospitalization

for RSV-associated

lower respiratory tract

infection in infants;

RSV-associated death

in infants; All cause

medically attended

lower respiratory tract

infection in infants;

Serious adverse events

in pregnant people;

Reactogenicity in

pregnant people;

Serious adverse events

in infants; Preterm

birth

Pfizer

Pfizer, Phase 2 Trial

plus unpublished data

obtained directly from

the manufacturer

RCT Argentina, Chile,

South Africa and the

United States

27.1

(5.2)

232 115 (phase 3

formulation)

117 RSV-associated death

in infants; Serious

adverse events in

pregnant people;

Reactogenicity in

pregnant people;

Serious adverse events

in infants; Preterm

birth;

Pfizer

126

Summary of Studies Reporting Outcome 1: Medically

attended RSV-associated lower respiratory infection in

infants

Absolute difference was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute difference estimates should be

interpreted in this context.

Last name

first author,

Publication

year

Age

mean

(SD),

years

intervention

comparison

Comparator

Vaccine

Absolute

difference/effect

estimate

(97.58% CI)

Study

limitations

(Risk of Bias)

Kampmann B,

et al.

29.0

(5.7)

3495

3480

Placebo

1,725 fewer per

100,000 (988 to

2,246 fewer)

None

127

Summary of Studies Reporting Outcome 2:

Hospitalization for RSV-associated lower respiratory

tract infection in infants

Absolute difference was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute difference estimates should be

interpreted in this context.

Last name first

author,

Publication

year

Age

mean

(SD),

years

interventio

comparison

Comparato

r Vaccine

Absolute

difference/effect

estimate

(99.17% CI)

Study

limitations

(Risk of Bias)

Kampmann

et al.

29.0

(5.7)

3495

3480

Placebo

718 fewer per

100,000 (128 to

1,020 fewer)

None

128

Summary of Studies Reporting Outcome 3: ICU

admission from RSV hospitalization in infants

Absolute difference was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute difference estimates should be

interpreted in this context.

Last name first

author,

Publication

year

Age

mean

(SD),

years

intervention

comparison

Comparator

Vaccine

Absolute

difference/effect

estimate (95% CI)

Study

limitations

(Risk of Bias)

Data received

directly from

the

manufacturer

29.0

(5.7)

3495

3480

Placebo

86 fewer per

100,000 (176

fewer to 251

more)

None

129

Summary of Studies Reporting Outcome 4: Mechanical

ventilation from RSV hospitalization in infants

Absolute difference was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute difference estimates should be

interpreted in this context.

Last name first

author,

Publication

year

Age

mean

(SD),

years

interventio

comparison

Comparato

r Vaccine

Absolute

difference/effect

estimate (95%

CI)

Study

limitations

(Risk of Bias)

Data received

directly from

the

manufacturer

29.0

(5.7)

3495

3480

Placebo

144 fewer per

100,000 (144

fewer to 13 more)

None

130

Summary of Studies Reporting Outcome 5: RSV-associated

death in infants

Last name first

author,

Publication

year

Age

mean

(SD),

years

intervention

compariso

Comparator

Vaccine

Absolute

difference/eff

ect estimate

Study

limitations

(Risk of Bias)

Kampmann

et al.

29.0

(5.7)

3495

3480

Placebo

Not estimable

1 death in a

placebo

recipient

None

Phase 2b RCT,

unpublished

-49

(range)

114

116

Placebo

Not estimable

0 deaths in trial

None

131

Summary of Studies Reporting Outcome 6: All-cause

medically attended lower respiratory tract infection in

infants

Absolute difference was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute difference estimates should be

interpreted in this context.

Last name first

author,

Publication

year

Age

mean

(SD),

years

interventio

comparison

Comparator

Vaccine

Absolute

difference/effect

estimate

(99.17% CI)

Study

limitations

(Risk of Bias)

Kampmann

et al.

29.0

(5.7)

3495

3480

Placebo

289 fewer per

100,000 (2,241

fewer to 2,068

more)

None

132

Summary of Studies Reporting Outcome 7: All-cause

hospitalization for lower respiratory tract infection in

infants

Absolute difference was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute difference estimates should be

interpreted in this context.

Last name first

author,

Publication

year

Age

mean

(SD),

years

interventio

comparison

Comparator

Vaccine

Absolute

difference/effect

estimate (95%

CI)

Study

limitations

(Risk of Bias)

Data received

directly from

the

manufacturer

29.0

(5.7)

3495

3480

Placebo

631 fewer per

100,000 (1,109

fewer to 44

more)

None

133

Summary of Studies Reporting Outcome 8: Serious adverse

events in pregnant people

Last name first

author,

Publication

year

Age

mean

(SD),

years

intervention

compariso

Comparato

r Vaccine

Relative

difference/effect

estimate

Study

limitations

(Risk of Bias)

Kampmann

et al.

29.0

(5.7)

3682

3675

Placebo

RR: 1.07 (0.96,

1.19)

None

Phase 2b RCT

27.1

(5.2)

115

117

Placebo

RR: 0.51 (0.21,

1.21)

None

134

Summary of Studies Reporting Outcome 9: Reactogenicity

(grade 3+) in pregnant people

Last name

first author,

Publication

year

Age

mean

(SD),

years

interventio

comparison

Comparato

r Vaccine

Relative

difference/effect

estimate

Study

limitations

(Risk of Bias)

Kampmann B,

et al.

29.0

(5.7)

3663

3640

Placebo

RR: 0.99 (0.74,

1.34)

None

Phase 2b RCT

27.1

(5.2)

114

117

Placebo

RR: 0.51 (0.10,

2.75)

None

135

Summary of Studies Reporting Outcome 10: Serious

adverse events in infants

Last name first

author,

Publication year

Age median

(range)

N intervention N comparison

Comparator

Vaccine

Relative

difference/effect

estimate

Study

limitations

(Risk of Bias)

Kampmann

et al.

11.97

months

(0.0, 24.3)

3568

3558

Placebo

RR: 1.00 (0.90,

1.11)

None

Phase 2b RCT

114

116

Placebo

RR: 1.10 (0.77,

1.57)

None

136

Summary of Studies Reporting Outcome 11: Preterm birth

Last name first

author,

Publication year

Age mean

(SD)

N intervention N comparison

Comparator

Vaccine

Relative

difference/effect

estimate

Study

limitations

(Risk of Bias)

Kampmann B,

et al.

11.97

months

(0.0, 24.3)

3568

3558

Placebo

RR: 1.19 (0.97,

1.45)

None

Phase 2b RCT

115

117

Placebo

RR: 2.03 (0.52,

7.94)

None

137

Grade Summary of Findings Table- Benefits

№ of

studies

Study design

Risk of

bias

Inconsistency Indirectness Imprecision

Other

considerations

Intervention Comparison

Relative

(CI)

Absolute

(CI)

Importance

Certainty

Medically attended RSV

-associated lower respiratory infection in infants

Randomized

studies

Not

serious

Not serious Not serious Not serious None

57/3495 (1.6%)

117/3480

(3.4%)

0.487

(97.58% CI:

0.332, 0.706)

1,725 fewer per

100,000 (988 to

2,246 fewer)

Critical High

23.1% 11,850 fewer per

100,000 (6,791 to

15,431 fewer)

11.0% 5,643 fewer per

100,000 (3,234 to

7,348 fewer)

Hospitalizations RSV

-associated lower respiratory infection in infants

Randomized

studies

Not

serious

Not serious Not serious Serious None

19/3495 (0.5%)

44/3480 (1.3%)

0.432

(99.17% CI:

0.193,

0.899)

718 fewer per

100,000 (128 to

1,020 fewer)

Critical Low

1.9% 1,051 fewer per

100,000 (187 to

1,493 fewer)

ICU admission from RSV hospitalization

Randomized

studies

Not

serious

Not serious Not serious Very serious None 4/3495 (0.1%) 7/3480 (0.2%)

0.571 (95%

CI: 0.123,

2.248)

86 fewer per

100,000 (176 fewer

to 251 more)

Important Low

0.7% 285 fewer per

100,000 (583 fewer

to 830 more)

138

Grade Summary of Findings Table- Benefits

№ of

studies

Study

design

Risk of

bias

Inconsistency Indirectness Imprecision

Other

considerations

Intervention Comparison

Relative

(CI)

Absolute

(95% CI)

Importance

Certainty

Mechanical ventilation from RSV hospitalization

Randomized

studies

Not

serious

Not serious Not serious Very serious None

0/3495 (0.0%)

5/3480 (0.1%) 0.001

(95% CI:

0.001,

1.091)

144 fewer

per 100,000

(144 fewer

to 13 more)

Important Low

0.2%

209 fewer

per 100,000

(209 fewer

to 19 more)

All

-cause medically attended lower respiratory tract infection in infants

Randomized

studies

Not

serious

Not serious Not serious Serious None 392/3495

(11.2%)

402/3480

(11.6%)

0.975

(99.17% CI:

0.806,

1.179)

289 fewer

per 100,000

(2,241 fewer

to 2,068

more)

Important Moderate

All

-cause hospitalization for lower respiratory tract infection in infants

Randomized

studies

Not

serious

Not serious Not serious Serious None

54/3495 (1.5%)

76/3480 (2.2%)

0.711 (95%

CI: 0.492,

1.010)

631 fewer

per 100,000

(1,109 fewer

to 44 more)

Important Moderate

139

Grade Summary of Findings Table- Harms

№ of

studies

Study design

Risk of

bias

Inconsistency

Indirectness Imprecision

Other

considerations

Intervention comparison

Relative

(95% CI)

Absolute

(95% CI)

Importance

Certainty

Serious adverse events in pregnant women

2 Randomized

studies

Not

serious

Not serious Serious Serious None 605/3797

(15.9%)

572/3792

(15.1%)

1.06

(0.95,

1.17)

905 more

per 100,000

(754

fewer to

2,564 more)

Critical Low

Reactogenicity (3+ or higher) in pregnant women

2 Randomized

studies

Not

serious

Not serious Serious

Not serious

None 85/3777

(2.3%)

87/3757 (2.3%)

0.97

(0.72,

1.31)

69 fewer per

100,000

(648 fewer

to 718 more)

Important

Moderate

Serious adverse events in infants

2 Randomized

studies

Not

serious

Not serious Serious Serious None 666/3682

(18.1%)

661/3674

(18.0%)

1.01

(0.91,

1.11)

180 more

per 100,000

(1,619 fewer

to 1,979

more)

Critical Low

Preterm birth

2 Randomized

studies

Not

serious

Not serious Serious

Very serious

None 207/3683

(5.6%)

172/3675

(4.7%)

1.20

(0.99,

1.46)

936 more

per 100,000

(47 fewer to

2,153 more)

Critical Very low