About
CDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.
Overview
A Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) review of the evidence for benefits and harms for Pfizer Respiratory Syncytial Virus (RSV) preF vaccine was presented to the Advisory Committee on Immunization Practices (ACIP) on June 21, 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 questions were, “Should vaccination with Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose administered intramuscularly [IM]), rather than no vaccine, be recommended in persons aged ≥65 years?” and “Should vaccination with Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose IM), rather than no vaccine, be recommended in persons aged 60–64 years?” The benefits chosen by the ACIP RSV Vaccines Work Group (Work Group) as critical or important to policy decisions were prevention of RSV lower respiratory tract illness/disease (LRTI/LRTD) (critical), medically attended RSV LRTI/LRTD (critical), hospitalization for RSV respiratory illness (important), severe RSV respiratory illness requiring supplemental oxygen (O2) or other respiratory support (important), and death due to RSV respiratory illness (important). The harms chosen by the Work Group as critical or important to policy decisions were serious adverse events (critical), inflammatory neurologic events* (important) and reactogenicity grade ≥3 (important).
A systematic review of evidence on the efficacy and safety of Pfizer RSVpreF vaccine among persons aged 60 years and older was conducted. The quality of evidence from one Phase 3 randomized controlled trial (RCT) and one Phase 1/2 RCT were assessed using the GRADE approach.234
A lower risk of RSV LRTI† was observed with vaccination compared to placebo (incidence rate ratio [IRR] 0.156, 95% confidence interval [CI]: 0.048, 0.404, evidence certainty: moderate), corresponding to a vaccine efficacy of 84.4% (95% CI: 59.1%, 95.2%)§. This was observed over one complete RSV season (Season 1) and one partial second RSV season (Season 2). A lower risk of medically attended RSV LRTI¶ was also observed (IRR 0.191; 95% CI: 0.047, 0.563; evidence certainty: moderate), corresponding to a vaccine efficacy of 81.0% (95% CI: 43.5%, 95.2%)§. The trial was not powered to detect a lower risk of hospitalization for RSV respiratory illness (IRR 0.333; 95% CI: 0.006, 4.143; evidence certainty: very low) nor a lower risk for severe RSV respiratory illness requiring supplemental oxygen or other respiratory support** (IRR 0.000; 95% CI: 0.013, 78.33; evidence certainty: very low), corresponding to a vaccine efficacy of 66.7% (95% CI: -315%, 99.4%) and 0% (-7750%, 98.7%) for the outcomes, respectively. No deaths due to RSV respiratory illness were identified among vaccine recipients or placebo recipients.
In terms of harms, the pooled available data from the Phase 3 and Phase 1/2 RCTs indicated that serious adverse events (SAEs)†† were balanced between the vaccine and placebo arms (risk ratio [RR] 1.041; 95% CI: 0.944, 1.148; evidence certainty: high). Reactogenicity grade ≥3§§ was similar between the vaccine and placebo arms of the trials (RR 1.43; 95% CI: 0.852, 2.385; evidence certainty: moderate), with 1.0% of vaccine recipients and 0.7% of placebo recipients reporting any grade ≥3 local or systemic reactions following injection. Three participants in the intervention group of the Phase 3 trial were reported to have inflammatory neurologic events within 42 days after vaccination (one case of Guillain-Barré syndrome [GBS], one case of Miller Fisher syndrome [a GBS variant], and one case of undifferentiated motor-sensory axonal polyneuropathy with worsening of pre-existing symptoms), compared with zero participants in the placebo group. No inflammatory neurologic events were reported in the phase 1/2 RCT.¶¶
Introduction
On May 31, 2023, the U.S. Food and Drug Administration (FDA) approved the Biologics License Application (BLA) for a single dose Pfizer RSV vaccine (ABRYSVO) for administration in adults 60 and older for prevention of RSV-associated lower respiratory tract disease.5 Pfizer RSVpreF is a bivalent (RSV A and B) stabilized prefusion F protein subunit vaccine. As part of the process employed by the ACIP, a systematic review and GRADE evaluation of the evidence for Pfizer RSVpreF vaccine was conducted and presented to ACIP. The 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 and Work Group members involved in the GRADE analysis.
The policy questions were, “Should vaccination with Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose IM), rather than no vaccine, be recommended in persons aged ≥65 years?” and “Should vaccination with Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose IM), rather than no vaccine, be recommended in persons aged 60–64 years?” (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 August 2022 to June 2023.
Members were asked to pre-specify and rate the importance of relevant patient-important outcomes (including benefits and harms) before the GRADE assessment. Outcomes of interest included individual benefits and harms (Table 2). The critical benefits of interest selected by the Work Group were prevention of RSV lower respiratory tract illness/disease (LRTI/LRTD) and medically attended RSV LRTI/LRTD. Other important benefits of interest included hospitalization for RSV respiratory illness, severe RSV respiratory illness requiring supplemental oxygen or other respiratory support, and death due to RSV illness. Pre-specified harms of interest were serious adverse events (critical) and reactogenicity grade ≥3 (important). Inflammatory neurologic events were added as an additional important harm for consideration after the Work Group was made aware of GBS cases in Season 1 safety data (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 persons aged ≥60 years 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 January 31, 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.
Incident rate ratios (IRR) were calculated using event counts and total person-time available from Pfizer’s pivotal phase 3 clinical trial. IRRs include follow-up time in two RSV seasons (August 2021 – October 2022 and July 2022 – January 2023) and are estimates of the ratio of the cumulative rates during this time. Vaccine efficacy estimates were defined as 100% x (1-IRR). Risk ratios used in the safety profile were calculated using counts of events and total participants available in the body of evidence, including both the phase 3 RCT and a phase 1/2 trial (estimates were pooled using R version 4.1.2).
Results
The results of the GRADE assessment were presented to ACIP on Jun 21, 2023. Data were reviewed from one published Phase 3 RCT and one published Phase 1/2 RCT, including additional unpublished data provided by the manufacturer and FDA.2346 Characteristics of the included studies are shown in Appendix 1.
For evaluation of benefit outcomes, mean follow-up time was 10.6 months per participant. Due to a gap in surveillance for RSV illness between season one and season two, this represents a mean of 12 months per participant from beginning to end of efficacy follow-up. During this follow-up period, the Pfizer RSVpreF vaccine reduced the risk of RSV LRTI (vaccine efficacy: 84.4% [95% CI: 59.6%, 95.2%]) (Table 3a). Pfizer RSVpreF also reduced the risk of medically attended RSV LRTI (vaccine efficacy: 81.0% (95% CI: 43.5%, 95.2%) (Table 3b). The trial was not powered to detect a lower risk of hospitalization for RSV respiratory illness (vaccine efficacy: 66.7% [95% CI: -315%, 99.4%]) (Table 3c). The trial was also not powered to detect a lower risk of severe RSV respiratory illness requiring supplemental oxygen or other respiratory support (vaccine efficacy: 0% ([95% CI: -7750%, 98.7%]) (Table 3d). No deaths due to RSV respiratory illness were recorded among vaccine recipients or placebo recipients.
For evaluation of potential harms, proportions of participants with SAEs were comparable between the vaccine group and the placebo group (RR: 1.041; 95% CI: 0.944, 1.148) (Table 3e). Three participants experienced SAEs that were considered by FDA to be possibly related to the vaccine: these were reported as hypersensitivity, GBS and Miller Fisher syndrome (a variant of GBS).6 Three phase 3 participants in the intervention group were reported to have inflammatory neurologic events within 42 days of vaccination (one case of GBS, one case of Miller Fisher syndrome [a variant of GBS], and one case reported by the investigator as undifferentiated motor-sensory axonal polyneuropathy in a participant with pre-existing symptoms), compared with zero participants in the placebo group (Table 3f). No inflammatory neurologic events were reported in the phase 1/2 RCT. Grade ≥3, or severe, local or systemic reactions following vaccination, were reported by 1.0% of vaccine recipients and 0.7% of placebo recipients (pooled RR: 1.426; 95% CI 0.852, 2.385) (Table 3g, Table 4).
GRADE Summary
The initial GRADE evidence level was type 1 (high) for each outcome because the body of evidence consisted of randomized controlled trials (Table 4). In terms of critical benefits, the available data indicated that the vaccine was effective for preventing RSV LRTI and medically attended LRTI with moderate certainty. Certainty was downgraded once due to serious concern for indirectness (limited number of adults 80 and older included in the trial and exclusion of persons with immune compromise).
The certainty in the effect estimate for hospitalization for RSV respiratory illness and severe RSV respiratory illness requiring supplemental oxygen or other respiratory support were both downgraded three times to very low certainty (once for serious concern for indirectness [again due to number of adults aged 80 years and older included in the trial and exclusion of persons with immune compromise] and twice for very serious concern for imprecision due to the 95% confidence interval for the measure of absolute risk including potential for both benefit and harm, and fragility of the estimates). No concerns impacted the certainty in the estimate for serious adverse events (high certainty). The outcome of inflammatory neurologic events had low certainty (downgraded twice for very serious concern for imprecision due to inability to calculate a measure of absolute risk). The outcome of reactogenicity (Grade ≥3) had moderate certainty (downgraded once for serious imprecision due to the 95% confidence interval for absolute risk including both the potential for harm as well as no meaningful difference) (Table 4).
Footnotes
* Inflammatory neurologic events were defined as Guillain-Barre syndrome (including variants thereof), chronic inflammatory demyelinating polyneuropathy, and acute central nervous system inflammation (e.g., transverse myelitis, acute disseminated encephalomyelitis) occurring within 42 days after vaccination.
† The Pfizer phase 3 trial had two co-primary endpoints, defined as RSV lower respiratory tract illness (LRTI) with ≥2 or ≥3 lower respiratory signs or symptoms. In GRADE, only LRTI with ≥3 lower respiratory signs or symptoms was considered. Lower respiratory signs and symptoms included new or worsened cough, new or worsened sputum production, new or worsened wheezing, new or worsened shortness of breath, and new or worsened tachypnea.
§ Efficacy was calculated as 1 – incidence rate ratio x 100. Estimates are from the manufacturer and are unadjusted; CDC was able to replicate estimates using event counts and person-time provided by the manufacturer with only minor rounding differences.
¶ Medically attended RSV LRTI included LRTI prompting any health care visit (including any outpatient or inpatient visit such as hospitalization, ER visit, urgent care visit, home healthcare services, primary care physician office visit, pulmonologist office visit, specialist office visit, other visit, or telehealth contact).
**Events requiring respiratory support were defined as RSV-associated acute respiratory illness with new or increased oxygen supplementation or mechanical ventilation.
††Serious adverse events were defined as any untoward medical occurrence (during all available follow-up time [safety follow-up through February 2023] after injection in the phase 3 trial and 60 days for the phase 1/2 trial) that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability or incapacity, or was a congenital anomaly or birth defect.
§§Severe reactogenicity events were defined as grade 3 or higher injection site reaction (pain at injection site, redness and swelling) or systemic reaction (fever, fatigue/tiredness, headache, nausea, muscle pain, joint pain, vomiting, diarrhea, and other systemic event) during days 0–7 after vaccination. For injection site redness and swelling, grade 3 corresponded to a diameter >10.0 cm from e-diary or severe grade from adverse event case report form. For fever, grade 3 corresponded to a temperature >38.9°C from e-diary or severe grade from adverse event case report form. For all other reactions, grade 3 corresponded to reactions that prevented normal, everyday activities. Grade 4 event is only applicable to fever >40℃.
¶¶Across all RSVpreF clinical trials, inflammatory neurologic events were reported in three of 20,255 adults aged ≥60 years within 42 days after vaccination with RSVpreF. All cases occurred in the phase 3 clinical trial. The first case was reported as GBS in a 66 year-old participant from the United States with onset of symptoms 14 days post-vaccination. The second case was reported as Miller Fisher syndrome (a GBS variant) in a 66 year-old participant from Japan with symptom onset 10 days post-vaccination. The third case was reported as undifferentiated motor-sensory axonal polyneuropathy in a 68 year-old participant from Argentina with worsening of pre-existing symptoms 21 days post vaccination. Available from: www.cdc.gov/acip/downloads/slides-2023-06-21-23/06-RSV-Adults-Melgar-508.pdf.
Tables
Table 1: Policy Question and PICO
Abbreviations: RSV= respiratory syncytial virus; IM = intramuscular; LRTD= lower respiratory tract disease; LRTI= lower respiratory tract illness
Table 2: Outcomes and Rankings
| Outcome | Importance | Included in evidence profile |
|---|---|---|
| RSV LRTI/LRTD | Critical | Yes |
| Medically attended RSV LRTI/LRTD | Critical | Yes |
| Hospitalization for RSV respiratory illness | Important | Yes |
| Severe RSV respiratory illness requiring O2/respiratory support | Important | Yes |
| Death due to RSV respiratory illness | Important | Noa |
| Serious adverse events | Critical | Yes |
| Inflammatory neurologic events | Important | Yes |
| Reactogenicity (grade ≥3) | Important | Yes |
Abbreviations: RSV= respiratory syncytial virus; LRTD= lower respiratory tract disease; LRTI= lower respiratory tract illness; O2= Oxygen
a No events occurred in the single study with this outcome included in the review of evidence.
Table 3a: Summary of Studies Reporting RSV Lower Respiratory Tract Illness (LRTI)a
| Authors last name, pub year | Age or other characteristic of importance | n/N interventionb,c | n/N comparisonb | Comparator | Vaccine Efficacyd (95% CI) | Study limitations (Risk of Bias) |
|---|---|---|---|---|---|---|
| Walsh EE, et al. 2023 plus unpublished data provided directly by the manufacturer[2,4] | LRTI ≥ 3 signs/symptomsa | 5/18,056 (16,010 person years observation) | 32/18,071 (15,976 person years observation) | Placebo | 84.4% (59.6%, 95.2%) | Not serious |
Abbreviations: RSV= respiratory syncytial virus; LRTI= lower respiratory tract illness; CI = confidence interval.
a RSV LRTI defined as ≥3 lower respiratory signs and symptoms (new or worsened cough, new or worsened sputum production, new or worsened wheezing, new or worsened shortness of breath, and new or worsened tachypnea) lasting >1 day.
b Based on data cutoff January 31, 2023.
c Intervention was a single dose of Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose IM).
d Efficacy was calculated as 1 – incidence rate ratio x 100. Estimates are from the manufacturer and are unadjusted; CDC was able to replicate estimates using event counts and person-time provided by the manufacturer with only minor rounding differences. VE is for first episode of RSV-LRTI from Day 15 (14 days after vaccination) through the end of follow-up time. Includes the full 2021-2022 RSV season (August 2021 – October 2022; exact dates were site-dependent) in both the Northern and Southern hemispheres and part of the 2022-2023 RSV season (July 2022 – January 2023; exact dates were site-dependent) in the Northern hemisphere. Estimates represent a mean follow-up time under surveillance for RSV illness of 10.6 months per participant. Due to a gap in surveillance for RSV illness between seasons one and two, this corresponds to a mean of 12 months from beginning to end of efficacy follow up, per participant.
Table 3b: Summary of Studies Reporting Medically Attended RSV LRTIa
References in this table:4
| Authors last name, pub year | Age or other characteristic of importance | 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] | Medically attended RSV LRTIa | 4/18,056 (16,010 person years observation) | 21/18,071 (15,976 person years observation) | Placebo | 81.0% (43.5%, 95.2%) | Not serious |
Abbreviations: RSV= respiratory syncytial virus; LRTI= Lower Respiratory Tract Illness;CI = confidence interval.
a Medically attended RSV LRTI defined as LRTI prompting any health care visit (any outpatient or inpatient visit such as hospitalization, emergency department visit, urgent care visit, home health care services, primary care physician office visit, pulmonologist office visit, specialist office visit, other visit, or telehealth contact). Estimates were not included in per-protocol assessments.
b Based on data collected from August 31, 2021 to data cutoff January 31, 2023.
c Intervention was a single dose of Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose IM)
d Efficacy was calculated as 1 – incidence rate ratio x 100. Estimates are from the manufacturer and are unadjusted; CDC was able to replicate estimates using event counts and person-time provided by the manufacturer with only minor rounding differences. VE is for first episode of medically attended RSV LRTI from Day 15 (14 days after vaccination) through the end of follow-up time. Includes the full 2021-2022 RSV season (August 2021-October 2022; exact dates were site-dependent) in both the Northern and Southern hemispheres and part of the 2022-2023 RSV season (July 2022-January 2023; exact dates were site-dependent) in the Northern hemisphere. Estimates represent a mean follow-up time under surveillance for RSV illness of 10.6 months per participant. Due to a gap in surveillance for RSV illness between seasons one and two, this corresponds to a mean of 12 months from beginning to end of efficacy follow up, per participant.
Table 3c: Summary of Studies Reporting Hospitalization for RSV Respiratory Illnessa
References in this table:4
| 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 by the manufacturer [4] | Hospitalization for RSV respiratory illnessa | 1/18,056 (16,010 person years observation) | 3/18,071 (15,976 person years observation) | Placebo | 66.7% (-315%, 99.4%) | Not Serious |
Abbreviations: CI = confidence interval; IRR = Incidence rate ratio.
a RSV-associated acute respiratory illness plus an associated hospitalization.
b Based on data collected from August 31, 2021 to data cutoff January 31, 2023.
c Intervention was vaccination with Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose IM)
d Efficacy was calculated as 1 – incidence rate ratio x 100. Estimates are from the manufacturer and are unadjusted; CDC was able to replicate estimates using event counts and person-time provided by the manufacturer with only minor rounding differences. VE is for first episode of hospitalization from Day 15 (14 days after vaccination) through the end of follow-up time. Includes the full 2021-2022 RSV season (August 2021-October 2022; exact dates were site-dependent) in both the Northern and Southern hemispheres and part of the 2022-2023 RSV season (July 2022-January 2023; exact dates were site-dependent) in the Northern hemisphere. Estimates represent a mean follow-up time under surveillance for RSV illness of 10.6 months per participant. Due to a gap in surveillance for RSV illness between seasons one and two, this corresponds to a mean of 12 months from beginning to end of efficacy follow up, per participant.
Table 3d: Summary of Studies Reporting Severe RSV Respiratory Illness requiring Oxygen/Respiratory Supporta
References in this table: 4
| Authors last name, pub year | Age or other characteristic of importance | n/N interventionb,c | n/N comparisonb | Comparator | Vaccine Efficacyd (95% CI) | Study limitations (Risk of Bias) |
|---|---|---|---|---|---|---|
| Unpublished data provided directly by the manufacturer [4] | RSV respiratory illness requiring oxygen/respiratory supporta | 1/18,056 (16,010 person years observation) | 1/18,071 (15,976 person years observation) | Placebo | 0% (-7750%, 98.7%) | Not Serious |
Abbreviations: CI = confidence interval; IRR = Incidence rate ratio.
a RSV-associated acute respiratory illness with new or increased oxygen supplementation or mechanical ventilation.
b Based on data collected from August 31, 2021 to data cutoff January 31, 2023.
c Intervention was a single dose of Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose IM)
d Efficacy was calculated as 1 – incidence rate ratio x 100. Estimates are from the manufacturer and are unadjusted; CDC was able to replicate estimates using event counts and person-time provided by the manufacturer with only minor rounding differences. VE is for first episode of hospitalization from Day 15 (14 days after vaccination) through the end of follow-up time. Includes the full 2021-2022 RSV season (August 2021-October 2022; exact dates were site-dependent) in both the Northern and Southern hemispheres and part of the 2022-2023 RSV season (July 2022-January 2023; exact dates were site-dependent) in the Northern hemisphere. Estimates represent a mean follow-up time under surveillance for RSV illness of 10.6 months per participant. Due to a gap in surveillance for RSV illness between seasons one and two, this corresponds to a mean of 12 months from beginning to end of efficacy follow up, per participant.
Table 3e: Summary of Studies Reporting Serious Adverse Eventsa
| 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) |
|---|---|---|---|---|---|---|
| Walsh EE, et al. 2023 plus unpublished data provided directly from the manufacturer[2,4] | Phase 3 RCT, persons aged ≥60 years | 790/18,574 participantsc,d (4.3%) | 746/18,288 participantsd (4.1%) | Placebo | 1.04 (0.95, 1.15) | Not Serious |
| Falsey et al., 2022 plus additional unpublished data provided directly from the manufacturer [3,4] |
Phase 1/2 RCT, persons aged 65-85 years | 2/45 participantse (4.4%) | 3/46 participantse (6.5%) | Placebo | 0.68 (0.12, 3.89) | Not Serious |
Abbreviations: RR = relative risk; CI = confidence interval; RCT = randomized controlled trial.
a Serious adverse events were defined as any untoward medical occurrence (during all available follow-up time [safety follow-up through February 2023] after injection in the phase 3 trial and 60 days for the phase 1/2 trial) that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability or incapacity, or was a congenital anomaly or birth defect.
b Intervention was a single dose of Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose IM)
c Three participants in the intervention group had SAEs which were assessed by FDA as possibly related to study vaccination: Guillain-Barre Syndrome reported 7 days after vaccination, Miller Fisher Syndrome reported 8 days after vaccination, and hypersensitivity reported 8 hours after vaccination.
d All events up to end of available follow-up time February 6, 2023 (note this is different than efficacy follow-up date of January 31, 2023).
e All events after dose 1, but before dose 2 (day 61).
Table 3f: Summary of Studies Reporting Inflammatory Neurologic Eventsa
| 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) |
|---|---|---|---|---|---|---|
| Walsh EE, et al. 2023 plus unpublished data provided directly from the manufacturer[2,4] | Phase 3 RCT, persons aged ≥60 years | 3/18,574 participants (0.02%)c | 0/18,228 participants (0%) | Placebo | Not estimable | Not Serious |
| Falsey et al., 2022 plus additional unpublished data provided directly from the manufacturer [3,4] |
Phase 1/2 RCT, persons aged 65-85 years | 0/48 participants (0%) | 0/47 participants (0%) | Placebo | Not estimable | Not Serious |
Abbreviations: RR = relative risk; CI = confidence interval.
a Guillain-Barre Syndrome (including variants thereof), chronic inflammatory demyelinating polyneuropathy, and acute central nervous system inflammation (e.g., transverse myelitis, acute disseminated encephalomyelitis) occurring within 42 days after injection.
b Intervention was a single dose of Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose IM)
c In the phase 3 RCT there were a total of three cases of inflammatory neurologic events occurring within 42 days after injection reported by investigators. All occurred in the intervention arm. These included GBS (14 days post-vaccination), Miller Fisher syndrome (a variant of GBS; 10 days post-vaccination), and undifferentiated motor-sensory axonal polyneuropathy (site investigator reported this case as not associated with vaccination; participant had worsening of pre-existing symptoms 21 days post-vaccination).
Table 3g: Summary of Studies Reporting Reactogenicitya
| 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) |
|---|---|---|---|---|---|---|
| Walsh EE, et al. 2023 plus unpublished data provided directly from the manufacturer [2,4] | Phase 3 RCT, persons aged ≥60 years; events occurring within 7 days of injection | 35/3628 participants (1.0%) | 22/3446 participants (0.6%) | Placebo | 1.51 (0.89, 2.57) | Not Serious |
| Falsey et al., 2022 plus additional unpublished data provided directly from the manufacturer [3,4] |
Phase 1/2 RCT, persons aged 65-85 years; events occurring within 7 days of injection | 1/45 participants (2.2%) | 2/45 participants (4.4%) | Placebo | 0.50 (0.05, 5.32) | Not Serious |
Abbreviations: RR = relative risk; CI = confidence interval.
a Severe reactogenicity events were defined as grade 3 or higher injection site reaction (pain at injection site, redness and swelling) or systemic reaction (fever, fatigue/tiredness, headache, nausea, muscle pain, joint pain, vomiting, diarrhea, and other systemic event) during days 0–7 after vaccination. For injection site redness and swelling, grade 3 corresponded to a diameter >10.0 cm from e-diary or severe grade from adverse event case report form. For fever, grade 3 corresponded to a temperature >38.9°C from e-diary or severe grade from adverse event case report form. For all other reactions, grade 3 corresponded to reactions that prevented normal, everyday activities. Grade 4 event is only applicable to fever >40℃.
b Intervention was a single dose of Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose IM)
c All events within 7 days of injection.
Table 4: Grade Summary of Findings Table
| Certainty assessment | № of patients | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| № of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | Pfizer RSVPreF Vaccine | Placebo | Relative (95% CI) |
Absolute (95% CI) |
||
| RSV Lower Respiratory Tract Illness (LRTI) with ≥3 symptoms | ||||||||||||
| 1 | randomized trials | not serious | not serious | seriousa,b | not serious | none | 5/18056 | 32/18071 | Rate ratio 0.156 (0.048 to 0.404)c |
not estimabled | ⨁⨁⨁◯ Moderate |
CRITICAL |
| Medically Attended RSV LRTI with ≥3 symptoms | ||||||||||||
| 1 | randomized trials | not serious | not serious | seriousa,b | not serious | none | 4/18056 | 21/18071 | Rate ratio 0.190 (0.048 to 0.565)c |
274 fewer per 100,000 patient(s) per RSV season (from 322 fewer to 148 fewer)f |
⨁⨁⨁◯ Moderate |
CRITICAL |
| 0.3%e | ||||||||||||
| Hospitalization for RSV respiratory illness | ||||||||||||
| 1 | randomized trials | not serious | not serious | seriousa,b | very seriousg | none | 1/18056 | 3/18071 | Rate ratio 0.333 (0.006 to 4.150)c |
108 fewer per 100,000 patient(s) per RSV season (from 161 fewer to 509 more)i |
⨁◯◯◯ Very low |
IMPORTANT |
| 0.2%h | ||||||||||||
| Severe RSV respiratory illness requiring supplemental oxygen or other respiratory support | ||||||||||||
| 1 | randomized trials | not serious | not serious | seriousa,b | very seriousg | none | 1/18056 | 1/18071 | Rate ratio 0.000 (0.013 to 78.500)c |
0 fewer per 100,000 patient(s) per RSV season (from 203 fewer to 15,965 more)k |
⨁◯◯◯ Very low |
IMPORTANT |
| 0.2%j | ||||||||||||
| Death due to RSV respiratory illness | ||||||||||||
| 1 | randomized trials | 0/18056 | 0/18071 | not estimablel | not estimablel | – | IMPORTANT | |||||
| Serious Adverse Events | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | not serious | none | 792/18619 (4.3%) | 749/18334 (4.1%) | RR 1.041 (0.944 to 1.148)m |
167 more per 100,000 (from 229 fewer to 605 more) |
⨁⨁⨁⨁ High |
CRITICAL |
| Inflammatory neurologic events within 42 days after injection | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | very seriousn | none | 3/18622 (0.0%) | 0/18335 (0.0%) | not estimableo | not estimableo | ⨁⨁◯◯ Low |
IMPORTANT |
| Reactogenicity (Grade 3 or higher) | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | seriousp | none | 36/3673 (1.0%) | 24/3491 (0.7%) | RR 1.426 (0.852 to 2.385)m |
285 more per 100,000 (from 99 fewer to 926 more) |
⨁⨁⨁◯ Moderate |
IMPORTANT |
- Concern for indirectness was noted due to the limited number of adults 80 and older included in the trial. Only 6% of the study population was aged ≥80 years; of the U.S. population aged ≥60 years, 16% is aged ≥80 years.
- Concern for indirectness was noted due exclusion of persons with immune compromise from the trial.
- Manufacturer-reported rate ratio estimates are presented in the table and used to calculate measures of absolute risk (CDC was able to replicate manufacturer rate ratio and vaccine efficacy estimates using trial case counts and person-time with only minor differences in rounding). Rate ratio estimates include follow-up time from the full 2021-2022 RSV season (August 2021-October 2022; exact dates were site-dependent) in both the Northern and Southern hemispheres and part of the 2022-2023 RSV season (July 2022-January 2023; exact dates were site-dependent) in the Northern hemisphere. Estimates represent a mean follow-up time under surveillance for RSV illness of 10.6 months per participant. Due to a gap in surveillance for RSV illness between seasons one and two, this corresponds to a mean of 12 months from beginning to end of efficacy follow up, per participant.
- An absolute effect could not be calculated for this outcome because there were no reliable data to estimate the true baseline rate of this outcome in the general population. The baseline rate captured in the placebo arm of the trial was felt to underestimate the true population-based incidence due to atypical RSV burden and seasonality during the COVID-19 pandemic. There were no estimates of rate of ≥3 symptom RSV LRTI available in the literature that included non-medically attended cases.
- This represents a control rate of 338 cases of medically attended RSV LRTI with ≥3 symptoms per 100,000 adults aged ≥60 years per RSV season (139 cases of medically attended RSV illness over one RSV season per 10,000 adults aged ≥60 years, of which 24.3% are RSV LRTI with ≥3 symptoms). Control rate data are from Belongia EA, et al. Clinical Features, Severity, and Incidence of RSV Illness During 12 Consecutive Seasons in a Community Cohort of Adults ≥60 Years Old. Open Forum Infect Dis. 2018 Nov 27;5(12):ofy316).
- For calculation of absolute effect, the baseline number of events was not taken from the placebo arm of the trial given concerns that the incidence in the trial placebo arm underestimated the population-based incidence from surveillance studies. Instead, the calculation uses the control rate described in footnote e.
- Very serious concern for imprecision was noted due to the small number of events observed in the trial. Certainty of evidence was downgraded twice, once because the 95% confidence interval for measure of absolute risk included potential for both benefit and harm and a second time because the rate ratio estimate was fragile (even one additional event in either arm would have significantly changed the estimate).
- This represents a control rate of 162 cases of RSV-associated hospitalization over one RSV season per 100,000 adults aged ≥65 years. Control rate data are unpublished data from CDC's RSV-NET, aggregated in a cost effectiveness analysis presented at the June 2023 ACIP meeting: www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-06-21-23/05-RSV-Adults-Ortega-Sanchez-508.pdf
- For calculation of absolute effect, the baseline number of events was not taken from the placebo arm of the trial given concerns that the incidence in the trial placebo arm underestimated the population-based incidence from surveillance studies. Instead the calculation uses the control rate described in footnote h.
- This represents a control rate of 206 cases of severe RSV illness requiring supplemental oxygen or other respiratory support per 100,000 adults aged ≥60 years per RSV season (139 cases of medically attended RSV illness over one RSV season per 10,000 adults aged ≥60 years, of which 14.8% require supplemental oxygen in the 28 days after medical attention). Control rate data are from Belongia EA, et al. Clinical Features, Severity, and Incidence of RSV Illness During 12 Consecutive Seasons in a Community Cohort of Adults ≥60 Years Old. Open Forum Infect Dis. 2018 Nov 27;5(12):ofy316).
- For calculation of absolute effect, the baseline number of events was not taken from the placebo arm of the trial given concerns that the incidence in the trial placebo arm underestimated the population-based incidence from surveillance studies. Instead the calculation uses the control rate described in footnote j.
- Measures of relative and absolute effect could not be estimated due to zero events.
- Pooled relative risk estimates were independently calculated using counts of events and participants in the pivotal phase 3 trial, as well as from the placebo-controlled phase 1/2 dosing selection study.
- Very serious concern for imprecision was noted due to the small number of events during the observation period. Certainty of evidence was downgraded twice due to inability to calculate a measure of absolute risk.
- Measures of relative and absolute effect could not be estimated due to zero events in the placebo arm.
- Serious concern for imprecision was noted due to the 95% confidence interval for measure of absolute risk including the potential for harm as well as no meaningful difference.
Appendix 1. Studies Included in the Review of Evidence
| Last name first author, Publication year | Study design | Country (or more detail, if needed) | Participant age | Total population | N Intervention | N comparison | Outcomes | Funding source |
|---|---|---|---|---|---|---|---|---|
| Walsh EE, et. al. 2023, plus unpublished data provided directly from the manufacturer 2,4] | RCT Phase 3 | Argentina, Canada, Finland, Japan, Netherlands, South Africa, United States | ≥60 years Mean: 68.3 years (SD: 6.14 years) |
36,862 | 18,574 | 18,288 | RSV Lower Respiratory Tract Infection (LTRI)
Hospitalization for RSV respiratory illness Severe RSV respiratory illness requiring oxygen/respiratory support Medically attended RSV LRTI |
Pfizer |
| Falsey et al., 2022, plus unpublished data provided directly from the manufacturer [3,4] | RCT Phase 1/2 | United States | 65-85 years | 91 | 45 | 46 | Serious adverse events Inflammatory neurologic events Reactogenicity (grade ≥3) |
Pfizer |
Abbreviations: SD = standard deviation; RCT = randomized controlled trial
Appendix 2. Databases and strategies used for systematic reviewa,b
| Database | Strategy |
|---|---|
| Medline (OVID) 1946- |
(Respiratory Syncytial Virus Vaccines/ OR ((RSV OR Respiratory Syncytial Virus) AND vaccin*)) AND (Viral Fusion Proteins/ OR Viral Proteins/ OR (fusion OR prefusion OR pre-fusion OR F protein* OR protein F OR RSV F OR PreF OR pre-f OR F subunit OR RSVpreF OR F vaccin* OR glycoprotein F OR F glycoprotein OR Ad26* OR adenovector 26 OR adenoviral vector* OR adenovirus vector*)) AND exp adult/ OR (adult* OR elder* OR senior* OR aged OR geriatric*).mp. |
| Embase (OVID) 1974- |
(Respiratory Syncytial Virus Vaccine/ OR ((RSV OR Respiratory Syncytial Virus) AND vaccin*)) AND (Virus Fusion Protein/ OR Viral Protein/ OR (fusion OR prefusion OR pre-fusion OR F protein* OR protein F OR RSV F OR PreF OR pre-f OR F subunit OR RSVpreF OR F vaccin* OR glycoprotein F OR F glycoprotein OR Ad26* OR adenovector 26 OR adenoviral vector* OR adenovirus vector*))AND exp adult/ OR (adult* OR elder* OR senior* OR aged OR geriatric*).mp. NOT pubmed/medline |
| Cochrane Library | ([mh “Respiratory Syncytial Virus Vaccines”] OR ((RSV OR “Respiratory Syncytial Virus”) AND vaccin*)) AND ([mh “Viral Fusion Proteins”] OR [mh “viral proteins”] OR (fusion OR prefusion OR pre-fusion OR “F protein*” OR “protein F” OR “RSV F” OR PreF OR pre-f OR “F subunit” OR RSVpreF OR “F vaccin*” OR “glycoprotein F” OR “F glycoprotein” OR Ad26* OR “adenovector 26” OR “adenoviral vector*” OR “adenovirus vector*”)) AND [mh adult] OR (adult* OR elder* OR senior* OR aged OR geriatric*) |
| CINAHL (EbscoHost) |
((MH “Respiratory Syncytial Virus Vaccines”) OR ((RSV OR “Respiratory Syncytial Virus”) AND vaccin*)) AND ((MH “Viral Fusion Proteins”) OR (fusion OR prefusion OR pre-fusion OR “F protein*” OR “protein F” OR “RSV F” OR PreF OR pre-f OR “F subunit” OR RSVpreF OR “F vaccin*” OR “glycoprotein F” OR “F glycoprotein” OR Ad26* OR “adenovector 26” OR “adenoviral vector*” OR “adenovirus vector*”)) AND (MH adult+) OR (adult* OR elder* OR senior* OR aged OR geriatric*) Exclude Medline records |
| Scopus | TITLE-ABS-KEY((RSV OR “Respiratory Syncytial Virus”) AND vaccin*) AND TITLE-ABS-KEY(fusion OR prefusion OR pre-fusion OR “F protein*” OR “protein F” OR “RSV F” OR PreF OR pre-f OR “F subunit” OR RSVpreF OR “F vaccin*” OR “glycoprotein F” OR “F glycoprotein” OR Ad26* OR “adenovector 26” OR “adenoviral vector*” OR “adenovirus vector*”) AND TITLE-ABS-KEY (adult* OR elder* OR senior* OR aged OR geriatric*) AND NOT INDEX(medline) |
| Clinicaltrials.gov | Respiratory Syncytial Virus Prefusion F Protein OR RSVPreF OR RSVPreF3 OR AD26.RSV.preF| Adult, Older Adult |
a. Most recent search conducted January 31, 2023.
b. Initial literature search was performed for multiple RSV vaccine products in older adults
View the complete list of GRADE evidence tables
- Ahmed F. U.S. Advisory Committee on Immunization Practices (ACIP) Handbook for Developing Evidence-based Recommendations.
- Walsh EE, Pérez Marc G, Zareba AM, et al. Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults. 2023. 388(16): 1465-1477. https://doi.org/10.1056/NEJMoa2213836
- Falsey AR, Walsh EE, Scott DA, et al. Phase 1/2 Randomized Study of the Immunogenicity, Safety, and Tolerability of a Respiratory Syncytial Virus Prefusion F Vaccine in Adults with Concomitant Inactivated Influenza Vaccine. The Journal of Infectious Diseases. 225(12): 2056-2066. https://doi.org/10.1093/infdis/jiab611
- Pfizer, 2023 personal communication, August 2022 – June 2023.
- Food and Drug Administration (FDA). Approval letter: Abrysvo. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2023. https://www.fda.gov/media/168890/download
- Food and Drug Administration (FDA). FDA Briefing Document Pfizer RSV vaccine. Vaccines and Related Biological Products Advisory Committee February 28 – March 1, 2023 Meeting Briefing Document- FDA: Applicant Pfizer