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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Pfizer Maternal RSV Vaccine						Print
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			OverviewIntroductionMethodsResultsGRADE Summary
		
Overview
A Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) review of the evidence for benefits and harms for Pfizer Respiratory Syncytial Virus (RSV) vaccine (RSVpreF, Abrysvo, Pfizer Inc.) was presented to the Advisory Committee on Immunization Practices (ACIP) on June 22, 2023 and September 22, 2023. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from high certainty to very low certainty [*1*].
The policy question was, “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?” The benefits chosen by the ACIP Maternal/Pediatric RSV Work Group (Work Group) as critical or important to policy decisions were prevention of: medically attended RSV-associated lower respiratory tract infection (LRTI) in infants (critical); hospitalization for RSV-associated LRTI in infants (critical); intensive care unit (ICU) admission from RSV hospitalization in infants (important); mechanical ventilation from RSV hospitalization in infants (important); RSV-associated death in infants (important); all-cause medically attended LRTI in infants (important); and all-cause hospitalization for LRTI in infants (important). The harms chosen by the Work Group as critical or important to policy decisions were serious adverse events in pregnant people (critical), reactogenicity (grade ≥3) in pregnant people (important); serious adverse events in infants (critical) and preterm birth (<37 weeks) (important). A systematic review of evidence on the efficacy and safety of Pfizer RSVpreF vaccine among pregnant persons identified one phase 3 randomized controlled trial (RCT) and one phase 2b RCT; these two RCTs, plus additional data provided by the sponsor and FDA, were assessed using the GRADE approach [*2-4*].
A lower risk of medically attended RSV-associated LRTI* in infants† was observed with vaccination compared with placebo (relative risk [RR] 0.487, 97.58%§ confidence interval [CI]: 0.332, 0.706, evidence certainty: high), vaccine efficacy of 51.3% (97.58% CI: 29.4%, 66.8%). A lower risk of hospitalization for RSV-associated LRTI in infants was also observed (RR 0.432; 99.17% CI: 0.193, 0.899; evidence certainty: moderate), vaccine efficacy 56.8% (99.17% CI: 10.1%, 80.7%). A possible lower risk of ICU admission from RSV hospitalization in infants was observed with vaccination compared with placebo (RR: 0.571 95% CI: 0.123, 2.248; evidence certainty low), vaccine efficacy 42.9% (95% CI: -124.8%, 87.7%). A lower risk of mechanical ventilation from RSV hospitalization was also observed (RR: 0.001 95% CI: 0.001, 1.091, evidence certainty low), vaccine efficacy 100% (95% CI: -9.1%, 100%). A lower risk of all-cause medically attended LRTI in infants was not observed (RR 0.975; 99.17% CI 0.806, 1.179; evidence certainty: moderate), vaccine efficacy 2.5% (99.17% CI: -17.9, 19.4). A possible lower risk of all-cause hospitalization for LRTI in infants was observed (RR: 0.711 95% CI: 0.492, 1.020, evidence certainty moderate), vaccine efficacy 28.9% (95% CI: -2.0%, 50.8%). The trial was not powered to detect a lower risk of death due to RSV.¶
In terms of harms, available data was pooled from the phase 3 and phase 2b RCTs.  The evidence indicated that serious adverse events (SAEs)** in pregnant people were balanced between the vaccine and placebo arms (RR 1.06; 95% CI: 0.95, 1.17; evidence certainty: low). Reactogenicity grade ≥3†† was similar between the vaccine and placebo arms of the trials (RR 0.97; 95% CI: 0.72, 1.31; evidence certainty: moderate), with 2.3% of vaccine recipients and 2.3% of placebo recipients reporting any systemic reactions grade ≥3 following injection. For infants, SAEs were balanced between the vaccine and placebo arms (RR 1.01; 95% CI: 0.91, 1.11; evidence certainty: low). Preterm births§§ were unbalanced between the vaccine and placebo arms, with more preterm births among RSVpreF vaccine recipients than placebo recipients (RR 1.20; 95% CI: 0.99, 1.46; evidence certainty: very low).
Introduction
On August 21, 2023, the U.S. Food and Drug Administration (FDA) approved the Biologics License Application (BLA) for a single dose of RSV vaccine (Abrysvo, Pfizer Inc.) for administration in pregnant people at 32 through 36 weeks for prevention of RSV in infants [*5*]. Pfizer RSV vaccine is a bivalent (RSV A and B) stabilized prefusion F protein subunit vaccine (RSVpreF).  As part of the process employed by the ACIP, a systematic review and GRADE evaluation of the evidence for Pfizer RSV vaccine was conducted and presented to ACIP. ACIP adopted a modified GRADE approach in 2010 as the framework for evaluating the scientific evidence that informs recommendations for vaccine use. Evidence of benefits and harms were reviewed based on the GRADE approach [*1*]. No conflicts of interest were reported by CDC or Work Group members involved in the GRADE analysis.
In the Pfizer phase 2b and 3 trials, vaccination was given during 24 through 36 weeks gestation. In both the phase 2b and phase 3 trials, a numerical imbalance in preterm births in RSV vaccine recipients was observed compared with placebo recipients, with more preterm births among RSVpreF vaccine recipients than placebo recipients. However, available data were insufficient to establish or exclude a causal relationship between preterm birth and Pfizer RSV vaccine. FDA approved the use of the Pfizer RSV vaccine in pregnant people at 32 through 36 weeks gestation to reduce the potential risk of preterm birth and complications from preterm birth [*6*]. For the GRADE assessment, data were included from phase 2b and phase 3 trials using the trial dosing interval of 24–36 weeks gestation window, as per the original trial design. Utilizing all available data from the trial dosing interval increased power to allow better detection of potential benefits and harms. The policy question was, “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? (Table 1).
Methods
We conducted a systematic review of evidence on the efficacy and safety of Pfizer bivalent RSVpreF vaccine. We assessed outcomes and evaluated the quality of evidence using the GRADE approach from February–September 2023.
The Work Group was asked to pre-specify and rate the importance of relevant patient-important outcomes before the GRADE assessment. Outcomes of interest included individual benefits and harms (Table 2). The critical benefits of interest for infants selected by the Work Group were medically attended RSV-associated LRTI and hospitalization for RSV-associated LRTI. Important benefits of interest in infants were ICU admissions from RSV hospitalization, mechanical ventilation from RSV hospitalization, RSV-associated death, all-cause medically attended LRTI, and all-cause hospitalization for LRTI. Harm outcomes rated by the workgroup as critical were SAEs in both pregnant people and infants as well as preterm birth. The outcome of reactogenicity (grade ≥3) in pregnant people was rated as important.
A systematic literature search was completed to review all available evidence on the efficacy and safety of Pfizer RSVpreF vaccine. Records of relevant observational studies as well as randomized controlled trials were included if they 1) provided data on pregnant persons vaccinated with RSVpreF; 2) involved human subjects; 3) reported primary data; and 4) included data relevant to the efficacy and safety outcomes being measured. We identified relevant studies through Medline, Embase, Cochrane Library, CINAHL, Scopus, and clinicaltrials.gov. Relevant observational studies were restricted to the defined population, intervention, comparison, and outcome outlined in the policy question, or related outcomes if direct data were not available. In addition, unpublished relevant data were obtained through direct communication with the vaccine manufacturer. The systematic review was conducted through April 2023. Characteristics of all included studies are shown in Appendix 1 and evidence retrieval methods are found in Appendix 2.
The evidence certainty assessment addressed risk of bias, inconsistency, indirectness, imprecision, and other characteristics. The GRADE assessment across the body of evidence for each outcome was presented in an evidence profile; evidence could be assessed as certainty of high, moderate, low, or very low certainty.
For benefit outcomes of medically attended RSV-associated LRTI, hospitalization for RSV-associated LRTI, and all-cause medically attended LRTI, vaccine efficacy was published by Kampmann et al. 2023 and 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 [*2*]. Risk ratios for GRADE were estimated by 1-(Vaccine Efficacy/100). 95% confidence intervals were calculated unless different confidence intervals were specifically agreed upon by the sponsor and FDA. Data on the outcomes of ICU admission from RSV hospitalization in infants, mechanical ventilation from RSV hospitalization, and all-cause hospitalization for LRTI in infants were provided directly from the manufacturer as a post-hoc analysis using the same method for calculating vaccine efficacy as the Kampmann publication [2]. For the harm outcomes, risk ratios were calculated using counts of events and total participants available in the body of evidence, including both the phase 3 and phase 2b RCTs (estimates were pooled using R version 4.1.2).
Results
The results of the GRADE assessment were presented to ACIP on June 22, 2023 and September 22, 2023. Data were reviewed from one published phase 3 RCT, one published phase 2b RCT, plus additional data provided by the sponsor and FDA [2-4, 6].
For benefit outcomes, the Pfizer RSV vaccine reduced the risk of medically attended RSV LRTI in infants 0–180 days after birth (vaccine efficacy: 51.3% [97.58% CI: 29.4%, 66.8%]) (Table 3a). Pfizer RSVpreF also reduced the risk of hospitalization for RSV-associated LRTI in infants 0–180 days after birth (vaccine efficacy: 56.8% [99.17% CI: 10.1%, 80.7%]) (Table 3b). Pfizer RSVpreF may be effective in preventing ICU admission for RSV hospitalization in infants 0–180 days after birth (vaccine efficacy: 42.9% [95% CI: -124.8, 87.7]) (Table 3c). Pfizer RSVpreF may be effective in preventing mechanical ventilation for RSV hospitalization in infants 0–180 days after birth (vaccine efficacy: 100% [95% CI: -9.1, 100]) (Table 3d). The vaccine was not effective in preventing all-cause medically attended LRTI in infants 0–180 days after birth (vaccine efficacy: 2.5% [99.17% CI: -17.9%, 19.4%]) (Table 3e). Pfizer RSVpreF may be effective in preventing all-cause hospitalization for LRTI in infants 0–180 days after birth (vaccine efficacy: 28.9% [95% CI: -2.0, 50.8]) (Table 3f). One RSV-associated death occurred in the placebo arm of the phase 3 RCT that was recorded at day 120 after birth. No RSV-associated deaths were recorded in the phase 2b trial.
For evaluation of potential harms, SAEs in pregnant people were similar between the vaccine group and the placebo group (RR: 1.06; 95% CI: 0.95, 1.17) (Table 3g). SAEs 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 [*5*].  Grade ≥3 systemic reactogenicity events in pregnant people were reported by 2.3% of vaccine recipients and 2.3% of placebo recipients (RR: 0.97; 95% CI: 0.72, 1.31) (Table 3h). SAEs in infants were similar between the vaccine and placebo groups (RR: 1.01; 95% CI: 0.91, 1.11) (Table 3i). No serious adverse events in infants were considered by the investigators to be related to the vaccine. The FDA agreed with the investigator’s conclusions for 4 out of 5 of the infant deaths in the RSVpreF group. 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 [*5*]. Preterm births were unbalanced between the vaccine and placebo arms, with more preterm births among RSVpreF vaccine recipients than placebo recipients (RR: 1.20; 95% CI: 0.99, 1.46) (Table 3j).
GRADE Summary
The initial GRADE evidence level was high for each outcome because the body of evidence consisted of randomized controlled trials [*1*]. Of note, these trials were conducted during the COVID-19 pandemic which did impact RSV incidence, but outcomes were not downgraded for indirectness because this was judged to be not a serious concern of bias.
In terms of critical benefits, the available data indicated that the vaccine was effective at preventing medically attended RSV-associated LRTI with no concerns in the certainty assessment. The available data indicated that the vaccine was effective at preventing hospitalization for RSV-associated LRTI with moderate certainty. Certainty was downgraded once for serious concern for imprecision due to the width of the confidence interval containing estimates for which different policy decisions might be considered.
The available data showed that RSVpreF vaccine may be effective at preventing the important outcomes of ICU admission from RSV hospitalization and mechanical ventilation from RSV hospitalization with low certainty. Certainty in estimates of both of these outcomes of ICU admission from RSV hospitalization and mechanical ventilation from RSV hospitalization were downgraded twice for imprecision due to the width of the confidence interval containing estimates for which different policy decisions might be considered as well as fragility of the estimates.
The data available for the important benefit of all-cause medically attended LRTI, showed that the vaccine was not effective at preventing the outcome with moderate certainty. Certainty was downgraded once for serious concern for imprecision due to the width of the confidence interval containing estimates for which different policy decisions might be considered.
The data available for the important benefit of all-cause hospitalization for LRTI, showed that the vaccine was effective at preventing the outcome with moderate certainty. Certainty was downgraded once for serious concern for imprecision due to the width of the confidence interval containing estimates for which different policy decisions might be considered.
For the critical harm outcomes of SAEs in both pregnant people and infants, the available data showed that SAEs were balanced between the vaccine and placebo groups with low certainty. Certainty was downgraded once for serious concern for imprecision due to the width of the confidence interval containing estimates for which different policy decisions might be considered and once for 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 with the trial dosing interval (24–36 weeks gestation).
The data available on the critical harm of preterm birth showed that preterm births were unbalanced between the vaccine and placebo groups, with more preterm births among RSVpreF vaccine recipients than placebo recipients, with very low evidence certainty. Certainty was downgraded twice for 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; certainty was additionally downgraded once for 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 preterm birth compared with the trial dosing interval (24–36 weeks gestation).
The data available on the important harm of reactogenicity (grade ≥3) in pregnant people showed that reactogenic events were balanced between the vaccine and placebo groups with moderate certainty. Certainty was downgraded once for 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 events (Table 4).Footnotes
* Medically-attended LRTI was defined as a medical encounter (inclusive of both outpatient and inpatient settings) with ≥1 symptom of fast breathing (respiratory rate ≥60 bpm [<2 months of age] or ≥50 bpm [≥2 to 12 months of age]), peripheral blood oxygen saturation measured in room air <95%, or chest wall indrawing, plus a positive validated reverse transcription-polymerase chain reaction in central laboratory or by a certified laboratory with nucleic acid amplification test, and confirmation by endpoint adjudication committee
†0–180 days after birth
§Confidence intervals that are not 95% were adjusted using the Bonferroni procedure and accounting for the primary endpoints results.
¶ There was 1 RSV-associated death in a placebo recipient in the phase 3 trial. There were no RSV-associated deaths recorded in the Phase 2b study.
** Serious adverse event is defined as any untoward medical occurrence that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability or incapacity, or is a congenital anomaly or birth defect.
††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.
§§Footnote: Preterm birth was defined as birth at <37 weeks gestational age
References
Ahmed F. U.S. Advisory Committee on Immunization Practices (ACIP) Handbook for Developing Evidence-based Recommendations.
Kampmann B, Madhi SA, Munjal I, et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants.*New England Journal of Medicine.* 388(16): 1451-1464. https://doi.org/10.1056/NEJMoa2216480
Simões EAF, Center KJ, Tita ATN, et al. Prefusion F Protein–Based Respiratory Syncytial Virus Immunization in Pregnancy.*New England Journal of Medicine*. 2022. 386(17): 1615-1626. https://doi.org/10.1056/NEJMoa2106062
Fleming-Dutra KE. Evidence to Recommendations Updates. Presentation to ACIP September 2023. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-09-22/06-Mat-Peds-Fleming-Dutra-508.pdf
Food and Drug Administration (FDA). FDA Approves First Vaccine for Pregnant Individuals to Prevent RSV in Infants. Press briefing. https://www.fda.gov/news-events/press-announcements/fda-approves-first-vaccine-pregnant-individuals-prevent-rsv-infants
Food and Drug Administration (FDA). Abrysvo package insert. https://www.fda.gov/media/171482/download?attachment
Food and Drug Administration (FDA). FDA Briefing Document Pfizer RSV vaccine. https://www.fda.gov/media/168185/downloadTable 1: Policy Question and PICO

Table 1: Policy Questions and PICO
Policy question:
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?Population
Pregnant peopleIntervention
Pfizer RSVPreF vaccine (120μg antigen, 1 dose IM) at 32–36 weeks gestationComparison
No RSV vaccine (placebo)Outcomes
Medically attended RSV-associated LRTI in infants
Hospitalization for RSV-associated LRTI in infants
ICU admission from RSV hospitalization in infants
Mechanical ventilation from RSV hospitalization in infants
RSV-associated death in infants
All-cause medically attended LRTI in infants
All-cause hospitalization for LRTI in infants
Serious adverse events in pregnant people
Reactogenicity (grade 3+) in pregnant people
Serious adverse events in infants
Preterm birth (<37 weeks gestation)**Abbreviations**: RSV= respiratory syncytial virus; IM = intramuscular; LRTI= lower respiratory tract infection; ICU= intensive care unitTable 2: Outcomes and Rankings
Table 2: Outcomes and Rankings
Outcome
Importance
Included in evidence profileMedically attended RSV-associated LRTI in infants
Critical
YesHospitalization for RSV-associated LRTI in infants
Critical
YesICU admission from RSV hospitalization in infants
Important
YesMechanical ventilation from RSV hospitalization in infants
Important
YesRSV-associated death in infants
Important
NoaAll-cause medically attended LRTI in infants
Important
YesAll-cause hospitalization for LRTI in infants
Important
YesSerious adverse events in pregnant people
Critical
YesReactogenicity (grade 3+) in pregnant people
Important
YesSerious adverse events in infants
Critical
YesPreterm birth (<37 weeks gestation)
Critical
Yes**Abbreviations:**RSV= respiratory syncytial virus; LRTI= lower respiratory tract infection; ICU= intensive care unit
a1 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.Table 3a. Summary of studies reporting RSV medically attended RSV-associated LRTI in infantsa
Table 3a. Summary of studies reporting RSV medically attended RSV-associated LRTI in infantsa
Authors last name, pub year
Age or other characteristic of importance
n/N interventionb,c
n/N comparisonb
Comparator
Vaccine Efficacyd (97.58% CIe)
Study limitations (Risk of Bias)Kampmann B, et al. 2023 [2]
Medically attended visitf + ≥1 symptomg + RSV RT-PCR–positive test result by Pfizer central laboratory or by certified laboratory with NAAT for RSV + confirmation by endpoint adjudication committee
57/3495
117/3480
Placebo
51.3% (29.4%, 66.8%)
Not serious
**Abbreviations:** LRTI= Lower Respiratory Tract Infection;****CI = confidence interval; RT-PCR = Reverse transcriptase-polymerase chain reaction; NAAT= nucleic acid amplification technologya0–180 days after birthbBased on data cutoff September 30, 2022cIntervention was a single dose of Pfizer bivalent RSVpreF vaccine (120μg antigen, 1 dose IM).dEfficacy was calculated 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of cases.eThe confidence interval was adjusted using the Bonferroni procedure and accounting for the primary endpoints results.fInclusive of inpatient and outpatient encountersgFast breathing (respiratory rate ≥60 bpm [<2 months of age] or ≥50 bpm [≥2 to 12 months of age]), peripheral blood oxygen saturation measured in room air <95%, or chest wall indrawingTable 3b: Summary of studies reporting hospitalization for RSV-associated LRTI in infantsa
Table 3b: Summary of studies reporting hospitalization for RSV-associated LRTI in infants
Authors last name, pub year
Age or other characteristic of importance
n/N interventionb,c
n/N comparisonb
Comparator
Vaccine Efficacyd (99.17% CI)e
Study limitations (Risk of Bias)Kampmann B, et al. 2023 [2]
Respiratory tract infection due to RSV that results in hospitalization + confirmation by endpoint adjudication committee
19/3495
44/3480
Placebo
56.8% (10.1%, 80.7%)
Not serious
**Abbreviations:** LRTI= Lower Respiratory Tract Infection;****CI = confidence intervala0–180 days after birthbBased on data cutoff September 30, 2022cIntervention was a single dose of Pfizer bivalent RSVpreF vaccine (120μg antigen, 1 dose IM).dEfficacy was calculated 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of cases.eThe confidence interval was adjusted using the Bonferroni procedure and accounting for the primary endpoints results.Table 3c: Summary of studies reporting ICU admission from RSV hospitalization in infantsa
Table 3c: Summary of studies reporting ICU admission from RSV hospitalization in infants
Authors last name, pub year
Age or other characteristic of importancea
n/N interventionb,c
n/N comparisonb
Comparator
Vaccine Efficacyd (95% CI)e
Study limitations (Risk of Bias)Unpublished data provided directly from the manufacturer[4]
ICU admission during hospitalization due to RSV
4/3495
7/3480
Placebo
42.9% (-124.8%, 87.7%)
**Abbreviations:** ICU= intensive care unit; RSV= respiratory syncytial virus;****CI = confidence intervala0–180 days after birthbBased on data cutoff September 30, 2022cIntervention was a single dose of Pfizer bivalent RSVpreF vaccine (120μg antigen, 1 dose IM).dEfficacy was calculated as 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of casesTable 3d: Summary of studies reporting mechanical ventilation from RSV hospitalization in infantsa
Table 3d: Summary of studies reporting mechanical ventilation from RSV hospitalization in infants
Authors last name, pub year
Age or other characteristic of importancea
n/N interventionb,c
n/N comparisonb
Comparator
Vaccine Efficacyd (95% CI)
Study limitations (Risk of Bias)Unpublished data provided directly from the manufacturer[4]
Mechanical ventilatione during hospitalization due to RSV
0/3495
5/3480
Placebo
100% (-9.1%, 100%)
None
**Abbreviations:** LRTI= Lower Respiratory Tract Infection;****CI = confidence intervala0–180 days after birthbBased on data cutoff September 30, 2022cIntervention was a single dose of Pfizer bivalent RSVpreF vaccine (120μg antigen, 1 dose IM).dEfficacy was calculated as 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of caseseInclusive of invasive or non-invasive mechanical ventilationTable 3e: Summary of studies reporting all-cause medically attended LRTI in infantsa
Table 3e: Summary of studies reporting all-cause medically attended lower respiratory tract infection in infants
Authors last name, pub year
Age or other characteristic of importancea
n/N interventionb,c
n/N comparisonb
Comparator
Vaccine Efficacyd (99.17% CI)e
Study limitations (Risk of Bias)Kampmann B, et al. 2023 [2]
Medically attended visitf + ≥1 symptomg
392/3495
402/3480
Placebo
2.5% (-17.9%, 19.4%)
Not Serious
**Abbreviations:** LRTI= Lower Respiratory Tract Infection;****CI = confidence intervala0–180 days after birthbBased on data cutoff September 30, 2022cIntervention was a single dose of Pfizer bivalent RSVpreF vaccine (120μg antigen, 1 dose IM).dEfficacy was calculated 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of cases.eThe confidence interval was adjusted using the Bonferroni procedure and accounting for the primary endpoints results.f Inclusive of inpatient and outpatient encounterg Fast breathing (RR ≥60 bpm for <2 months of age [<60 days of age], ≥50 bpm for 2–<12 months of age, or ≥40 bpm for 12–24 months of age), SpO2 <95%, or chest wall indrawingTable 3f: Summary of studies reporting all-cause hospitalizations for LRTI in infantsa
Table 3f: Summary of studies reporting all-cause hospitalizations for LRTI in infants
Authors last name, pub year
Age or other characteristic of importancea
n/N interventionb,c
n/N comparisonb
Comparator
Vaccine Efficacyd (95% CI)
Study limitations (Risk of Bias)Unpublished data provided directly from the manufacturer[4]
Hospitalization + ≥1 symptome
54/3495
76/3480
Placebo
28.9% (-2.0%, 50.8%)
None
**Abbreviations:** LRTI= Lower Respiratory Tract Infection;****CI = confidence intervala0–180 days after birthbBased on data cutoff September 30, 2022cIntervention was a single dose of Pfizer bivalent RSVpreF vaccine (120μg antigen, 1 dose IM).dEfficacy was calculated as 1–(P/[1–P]), where P is the number of cases in the RSVpreF group divided by the total number of caseseFast breathing (RR ≥60 bpm for <2 months of age [<60 days of age], ≥50 bpm for 2–<12 months of age, or ≥40 bpm for 12–24 months of age), SpO2 <95%, or chest wall indrawingTable 3g: Summary of studies reporting serious adverse eventsa in pregnant people
Table 3g: Summary of studies reporting serious adverse events in pregnant people
Authors last name, pub year
Age or other characteristic of importance
n/N (%) interventionb
n/N (%) comparison
Comparator
RR (95% CI)
Study limitations (Risk of Bias)Kampmann B, et al. 2023 plus unpublished data provided directly from the manufacturer[2,4]
Phase 3 RCT in pregnant people
598/3682 participantsc,d (16.2%)
558/3675 participantsd (15.1%)
Placebo
1.07 (0.96, 1.19)
Not SeriousUnpublished data provided directly from the manufacturer [4]
Phase 2b RCT in pregnant people
7/115 participantsd (6.1%)
14/117 participantsd (12.0%)
Placebo
0.51 (0.21, 1.21)
Not Serious
**Abbreviations:**RR = relative risk; CI = confidence interval; RCT = randomized controlled trial.a Serious adverse event is defined as any untoward medical occurrence that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability or incapacity, or is a congenital anomaly or birth defect.b Intervention was a single dose of Pfizer bivalent RSVpreF vaccine (120μg antigen, 1 dose IM)c 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.d Based on data cutoff September 2, 2022Table 3h: Summary of studies reporting reactogenicitya (grade ≥3)b in pregnant people
Table 3h: Summary of studies reporting reactogenicity (grade ≥3) in pregnant people
Authors last name, pub year
Age or other characteristic of importance
n/N (%) interventionc
n/N (%) comparison
Comparator
RR (95% CI)
Study limitations (Risk of Bias)Kampmann B, et al. 2023 plus unpublished data provided directly from the manufacturer [2,4]
Phase 3 RCT in pregnant people
83/3663 participants (2.3%)
83/3640 participants (2.3%)
Placebo
0.99 (0.74, 1.34)
Not SeriousUnpublished data provided directly from the manufacturer [4]
Phase 2b RCT in pregnant people
2/114 participants (1.8%)
4/117 participants (3.4%)
Placebo
0.51 (0.10, 2.75)
Not Serious
**Abbreviations:**RR = relative risk; CI = confidence interval; RCT = randomized controlled trial.a Reported within 7 days of injectionb Systemic reactions only included. Grade 3: prevents daily routine activity. For vomiting, requires intravenous hydration. For diarrhea, includes 6 or more loose stools in 24 hours. Grade 4: requires emergency room visit or hospitalizationc Intervention was a single dose of Pfizer bivalent RSVpreF vaccine (120μg antigen, 1 dose IM)Table 3i: Summary of studies reporting serious adverse eventsa in infants
Table 3i: Summary of studies reporting serious adverse events in infants
Authors last name, pub year
Age or other characteristic of importance
n/N (%) interventionb,c
n/N (%) comparisonc
Comparator
RR (95% CI)
Study limitations (Risk of Bias)Kampmann B, et al. 2023 plus unpublished data provided directly from the manufacturer [2,4]
Phase 3 RCT, infants
625/3568 participants (17.5%)
623/3558 participants (17.5%)
Placebo
1.00 (0.90, 1.11)
Not SeriousUnpublished data provided directly from the manufacturer [4]
Phase 2b RCT, infants
41/114 participants (36.0%)
38/116 participants (32.8%)
Placebo
1.10 (0.77, 1.57)
Not Serious
**Abbreviations:**RR = relative risk; CI = confidence interval; RCT = randomized controlled trial.aSerious adverse event is defined as any untoward medical occurrence that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability or incapacity, or is a congenital anomaly or birth defect.b Intervention was a single dose of Pfizer bivalent RSVpreF vaccine (120μg antigen, 1 dose IM)c Based on data cutoff September 2, 2022Table 3j: Summary of studies reporting preterm birthsa
Table 3j: Summary of studies reporting preterm births
Authors last name, pub year
Age or other characteristic of importance
n/N (%) interventionb,c
n/N (%) comparisonc
Comparator
RR (95% CI)
Study limitations (Risk of Bias)Kampmann B, et al. 2023 plus unpublished data provided directly from the manufacturer [2,4]
Phase 3 RCT, infants born at <37 weeks gestation
201/3568 participants (5.6%)
169/3558 participants (4.7%)
Placebo
1.19 (0.97, 1.45)
Not SeriousUnpublished data provided directly from the manufacturer [4]
Phase 2b RCT, infants born at <37 weeks gestation
6/115 participants (5.2%)
3/117 participants (2.6%)
Placebo
2.03 (0.52, 7.94)
Not Serious
a Infant born at <37 weeks gestational agebIntervention was a single dose of Pfizer bivalent RSVpreF vaccine (120μg antigen, 1 dose IM)c Based on data cutoff September 2, 2022Table 4. Grade Summary of Findings Table
Table 4. Grade Summary of Findings Table
Certainty assessment
No of patients
Effect
Certainty
ImportanceNo of studies
Study design
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations
Pfizer RSVpreF vaccine
placebo
Relative
(CI)
Absolute
(CI)Medically attended RSV-associated lower respiratory infection in infants1
randomized trials
not serious
not serious
not seriousa,b
not serious
none
57/3495 (1.6%)
117/3480 (3.4%)
**RR 0.487**
(97.58% CI: 0.332 to 0.706)
**1,725 fewer per 100,000**
(97.58% CI: from 988 to 2,246 fewer)c
⨁⨁⨁⨁
High
CRITICAL23.1%d
**11,850 fewer per 100,000**
(97.58% CI: from 6,791 to 15,431 fewer)11.0%e
**5,643 fewer per 100,000**
(97.58% CI: from 3,234 to 7,348 fewer)Hospitalization for RSV-associated lower respiratory tract infection in infants1
randomized trials
not serious
not serious
not seriousf
seriousg
none
19/3495 (0.5%)
44/3480 (1.3%)
**RR 0.432**
(99.17% CI: 0.193 to 0.899)
**718 fewer per 100,000**
(99.17% CI from 218 to 1,020 fewer)c
⨁⨁⨁◯
Moderate
CRITICAL1.9%h
**1,051 fewer per 100,000**
(99.17% CI: from 187 to 493 fewer)ICU admission from RSV hospitalization1
randomized trials
not serious
not serious
not serious
very seriousi
none
4/3495 (0.1%)
7/3480 (0.2%)
**RR 0.571**
(95% CI: 0.123 to 2.248)
**86 fewer per 100,000**
(95% CI: from 176 fewer to 251 more)c
⨁⨁◯◯
Low
IMPORTANT0.7%j
**285 fewer per 100,000**
(95% CI: from 583 fewer to 830 more)Mechanical ventilation from RSV hospitalization1
randomized trials
not serious
not serious
not serious
very seriousi
none
0/3495 (0.0%)
5/3480 (0.1%)
**RR 0.001**
(95% CI: 0.001 to 1.091)
**144 fewer per 100,000**
(95% CI: from 144 fewer to 13 more)c
⨁⨁◯◯
Low
IMPORTANT0.2%k
**209 fewer per 100,000**
(95% CI: from 209 fewer to 19 more)All-cause medically attended lower respiratory tract infection in infants1
randomized trials
not serious
not serious
not seriousf
seriousg
none
392/3495 (11.2%)
402/3480 (11.6%)
**RR 0.975**
(99.17% CI: 0.806 to 1.179)
**289 fewer per 100,000**
(99.17% CI: from 2,241 fewer to 2,068 more)c
⨁⨁⨁◯
Moderate
IMPORTANTAll-cause hospitalization for lower respiratory tract infection in infants1
randomized trials
not serious
not serious
not serious
seriousg
none
54/3495 (1.5%)
76/3480 (2.2%)
**RR 0.711**
(95% CI: 0.492 to 1.020)
**631 fewer per 100,000**
(95% CI: from 1,109 fewer to 44 more)c
⨁⨁⨁◯
Moderate
IMPORTANTSerious adverse events in pregnant people2m
randomized trials
not serious
not serious
seriousf,m
seriousg
none
605/3797 (15.9%)
572/3792 (15.1%)
**RR 1.06**
(95% CI: 0.95 to 1.17)
**905 more per 100,000**
(95% CI: from 754 fewer to 2,564 more)c
⨁⨁◯◯
Low
CRITICALReactogenicity (3+ or higher) in pregnant people2m
randomized trials
not serious
not serious
seriousn
not serious
none
85/3777 (2.3%)
87/3757 (2.3%)
**RR 0.97**
(95% CI: 0.72 to 1.31)
**69 fewer per 100,000**
(95% CI: from 648 fewer to 718 more)c
⨁⨁⨁◯
Moderate
IMPORTANTSerious adverse events in infants2m
randomized trials
not serious
not serious
seriousf,m
seriousg
none
666/3682 (18.1%)
661/3674 (18.0%)
**RR 1.01**
(95% CI: 0.91 to 1.11)
**180 more per 100,000**
(95% CI: from 1,619 fewer to 1,979 more)c
⨁⨁◯◯
Low
CRITICALPreterm birth2m
randomized trials
not serious
not serious
seriousf,n
very seriouso
none
207/3683 (5.6%)
172/3675 (4.7%)
**RR 1.20**
(95% CI: 0.99 to 1.46)
**936 more per 100,000**
(95% CI: from 47 fewer to 2,153 more)c
⨁◯◯◯
Very low
CRITICAL
**CI:** confidence interval; **RR:** risk ratio
Explanations
The effects noted are from a per protocol analysis. In a modified intention to treat analysis there were 60 cases among 3568 persons in the vaccine arm and 118 cases among 3558 persons in the placebo arm (RR = 0.51 [0.37 to 0.69])
The clinical trial participants consisted of healthy people ≤49 years of age with an uncomplicated, singleton pregnancy, who were at no known increased risk for complications. The clinical trial population may not be representative of all pregnant people and their infants in the United States.
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.
Rate used from Lively JY, Curns AT, Weinberg GA, et al. Respiratory Syncytial Virus–Associated Outpatient Visits Among Children Younger Than 24 Months, Journal of the Pediatric Infectious Diseases Society, Volume 8, Issue 3, July 2019, Pages 284–286, https://doi.org/10.1093/jpids/piz011
Rate calculated from Lively et al study, assuming 47.5% of ARI cases are LRTI. Rainisch G, Adhikari B, Meltzer MI, Langley G. Estimating the impact of multiple immunization products on medically attended respiratory syncytial virus (RSV) infections in infants. 2020. Vaccine 38(2): 251-257. ISSN 0264-410X. https://doi.org/10.1016/j.vaccine.2019.10.023.
The clinical trial excluded pregnant persons with certain conditions and therefor may not represent all pregnant people and their infants in the United States
Serious concern for imprecision due to the width of the confidence interval containing estimates for which different policy decisions might be considered.
Rate of acute respiratory infection (ARI) hospitalizations for infants 0-5 months (2016-2020 NVSN, unpublished)
Very serious concern for imprecision due to the confidence interval containing estimates for which different policy decision might be considered and fragility of the estimate.
ICU admission rate of hospitalizations of 35% from Arriola CS, Kim L, Langley G, et al. Estimated Burden of Community-Onset Respiratory Syncytial Virus–Associated Hospitalizations Among Children Aged <2 Years in the United States, 2014–15, Journal of the Pediatric Infectious Diseases Society, Volume 9, Issue 5, November 2020, Pages 587–595, https://doi.org/10.1093/jpids/piz087. Using NVSN hospitalization rate (unpublished)
Mechanical ventilation rate of 11% of hospitalizations from Arriola CS, Kim L, Langley G, et al. Estimated Burden of Community-Onset Respiratory Syncytial Virus–Associated Hospitalizations Among Children Aged <2 Years in the United States, 2014–15, Journal of the Pediatric Infectious Diseases Society, Volume 9, Issue 5, November 2020, Pages 587–595, https://doi.org/10.1093/jpids/piz087. Using NVSN hospitalization rate (unpublished)
Data were pooled from one phase 2B trial and one phase 3 trial
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 with the trial dosing interval (24–36 weeks gestation).
Serious concern for indirectness as this measure only contains information on systemic reactogenicity. Phase 3 local reactogenicity grade ≥3: 11/3660 vaccine arm;| 0/3639 placebo arm. Phase 2b local reactogenicity grade ≥3: 0/114 vaccine arm; 0/117 placebo arm.
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.Appendices
Appendix 1. Studies Included in the Review of Evidence
Appendix 1. Studies Included in the Review of Evidence
Last name first
author, Publication year
Study design
Country (or more detail, if needed)
Population Age mean (SD), years
Total population
N
Intervention
N
comparison
Outcomes
Funding sourceKampmann B, et al. plus unpublished data obtained directly from the manufacturer
Phase 3 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; ICU admission from RSV hospitalization in infants; Mechanical ventilation from RSV hospitalization in infants; RSV-associated death in infants; All-cause medically attended lower respiratory tract infection in infants;  All-cause hospitalization for lower respiratory tract infection in infants; Serious adverse events in pregnant people; Reactogenicity in pregnant people; Serious adverse events in infants; Preterm birth
PfizerPfizer, Phase 2b trial plus unpublished data obtained directly from the manufacturer
Phase 2b RCT
Argentina, Chile, South Africa, and the United States
27.1 (5.2)
232
115 (phase 3 vaccine 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
aAdditional data provided by sponsor.
**Abbreviations:** SD = standard deviation; RCT = randomized controlled trial; ICU = intensive care unitAppendix 2. Databases and strategies used for systematic reviewa
Appendix 2. Databases and strategies used for systematic reviewa
Database
Strategy**Medline
(OVID)
1946-**
(Prefusion F AND (RSV OR Respiratory Syncytial Virus)) OR RSV preF OR RSVpreF**Embase
(OVID)
1974-**
(Prefusion F AND (RSV OR Respiratory Syncytial Virus)) OR RSV preF OR RSVpreF**Cochrane Library**
((“Prefusion F” AND (RSV OR “Respiratory Syncytial Virus”)) OR “RSV preF” OR RSVpreF ):ti,ab**CINAHL
(EbscoHost)**
(“Prefusion F” AND (RSV OR “Respiratory Syncytial Virus”)) OR “RSV preF” OR RSVpreF**Scopus**
TITLE-ABS-KEY((“Prefusion F” AND (RSV OR “Respiratory Syncytial Virus”)) OR “RSV preF” OR RSVpreF )**Clinicaltrials.gov**
(“Prefusion F” AND (RSV OR “Respiratory Syncytial Virus”)) OR “RSV preF” OR RSVpreF
a. Most recent search conducted April 2023.Top of Page
							
					
							Last Reviewed:  September 28, 2023						Source: 	National Center for Immunization and Respiratory Diseases
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