Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Protein subunit RSV vaccines (GSK Arexvy and Pfizer Abrysvo) in older adults

Overview

A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence of benefits and harms from protein subunit RSV vaccination (GSK Arexvy and Pfizer Abrysvo) in adults aged ≥60 years was presented to the Advisory Committee on Immunization Practices (ACIP) on June 26, 2024. 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 all adults aged ≥75 years be recommended to receive a single dose of RSV vaccination?" and "Should adults aged 60–74 years at increased risk of severe RSV disease be recommended to receive a single dose of RSV vaccination?" These policy questions were not specific to RSV vaccine product, but GRADE review was separated by vaccine type* (protein subunit vaccines, mRNA vaccine). On this webpage GRADE for the protein subunit vaccine products (GSK Arexvy and Pfizer Abrysvo) is reviewed.

The ACIP Work Group for RSV prevention in adults (Work Group) chose the following benefits outcomes as critical or important to policy decisions: prevention of RSV lower respiratory tract disease (LRTD) (important), medically attended RSV LRTD (critical), hospitalization for RSV respiratory illness (critical), severe RSV respiratory illness requiring supplemental oxygen 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 (critical), and reactogenicity grade ≥3 (important).

A systematic review of evidence of the efficacy and safety of protein subunit RSV vaccines among persons aged 60 years and older was conducted. The quality of evidence from two phase 3 randomized controlled trials (RCT) and two phase 1/2 RCTs were assessed using the GRADE approach.2345678 Efficacy findings were based on analyses of data collected during May 2021–September 2023 for GSK Arexvy and August 2021–November 2023 for Pfizer Abrysvo.

In adults aged ≥75 years, using the pooled available data from both phase 3 trials, a lower rate^† of RSV LRTD^§,¶ was observed with vaccination compared with placebo (incidence rate ratio [IRR] 0.31 [95% confidence interval (CI): 0.15, 0.63]; evidence certainty: high) corresponding to a vaccine efficacy of 69.4% (95% CI: 36.6%, 85.3%). A lower rate of medically attended RSV LRTD**^,†† was also observed in adults aged ≥75 years (IRR 0.23 [95% CI: 0.13, 0.42]; evidence certainty: moderate) corresponding to a vaccine efficacy against medically attended RSV LRTD of 76.6% (95% CI: 58.5%, 86.8%). Using person-time from all trial participants aged ≥60 years (i.e. not limited only to adults aged ≥75 years), there were insufficient cases to detect a lower rate of hospitalization for RSV respiratory illness (IRR 0.24 [95% CI: 0.05, 1.13]; evidence certainty: low) or severe RSV respiratory illness requiring supplemental oxygen or other respiratory support (IRR 0.37 [95% CI: 0.07, 1.89]; evidence certainty: very low). Vaccine efficacy against hospitalization for RSV respiratory illness or severe RSV respiratory illness requiring supplemental oxygen or other respiratory support were 75.7% (95% CI: -12.5%, 94.8%) and 62.7% (95% CI: -88.7%, 92.6%), respectively. No deaths due to RSV respiratory illness were identified among vaccine recipients or placebo recipients in either trial.

For adults aged 60–74 years at increased risk of severe RSV disease,^§§,¶¶ using pooled data available from both the GSK and Pfizer phase 3 trials, a lower rate of RSV LRTD was observed with vaccination compared with placebo (IRR 0.27 [95% CI: 0.18, 0.41]; evidence certainty: high) corresponding to a vaccine efficacy of 73.1% (95% CI: 58.7%, 82.4%). A lower rate of medically attended RSV LRTD was also observed (IRR 0.27 [95% CI: 0.16, 0.47], evidence certainty: high); vaccine efficacy against medically attended RSV LRTD was 72.7% (95% CI: 52.9%, 84.2%). As for adults aged ≥75 years, GRADE assessment of hospitalization for RSV respiratory illness, severe RSV respiratory illness requiring supplemental oxygen or other respiratory support, and death due to RSV respiratory illness included data from all trial participants aged ≥60 years (rather than those 60-74 at increased risk of severe disease only). Therefore, the effect estimates and certainty assessments were the same as for adults aged ≥75 years.

In terms of harms, data were included from all trial participants aged ≥60 years, so effect estimates and certainty assessments were the same for both policy questions (pertaining to adults aged ≥75 years, and adults aged 60–74 years at increased risk of severe RSV disease). The pooled data available from both phase 3 RCTs and from the two additional phase 1/2 RCTs indicated that serious adverse events (SAEs)***^{, †††} were balanced between participants in the vaccine and placebo arms (risk ratio [RR] 1.01; 95% CI: 0.93, 1.10; evidence certainty: moderate). Reactogenicity grade ≥3^{§§§,¶¶¶} may be increased with vaccine compared to placebo (RR 1.92; 95% CI: 0.78, 4.70; evidence certainty: low). Protein subunit vaccination may increase inflammatory neurologic events,**** but the effect is very uncertain (RR: 1.76; 95% CI: 0.29, 10.77; evidence certainty: very low).

Importantly, GRADE includes only data from studies identified during systematic review. At the June 2024 ACIP meeting, additional unpublished post-licensure data on RSV vaccines from CDC and FDA systems on vaccine effectiveness and safety were also reviewed. A summary of these additional considerations may be found in the Evidence to Recommendation (EtR) profile ACIP Evidence to Recommendations for Use of Protein Subunit RSV vaccines (GSK Arexvy or Pfizer Abrysvo) in All Adults Aged ≥75 years and in Adults Aged 60–74 at Increased Risk of Severe RSV Disease.

Introduction

In 2023, the U.S. Food and Drug Administration (FDA) approved the Biologics License Application (BLA) for use of GSK's Arexvy and Pfizer's Abrysvo RSV vaccines in adults aged ≥60 years. In June 2023, the Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP), recommended that adults aged ≥60 years may receive RSV vaccination, using shared clinical decision-making (SCDM). Following a year of implementation of SCDM, CDC received feedback that this type of recommendation was challenging for providers to implement and was not always implemented as ACIP had intended. In addition, new data on RSV vaccine safety and vaccine effectiveness became available from post-licensure studies. Taking into account the challenges of SCDM, along with the updated evidence on balance of benefits and risks, two new proposed recommendations were brought to ACIP in June 2024: 1) a universal recommendation in adults aged ≥75 years and 2) a risk-based recommendation in adults aged 60–74 years. As part of the process employed by the ACIP, a systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) assessment of the evidence was conducted and presented to ACIP.1 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 ACIP RSV Vaccines Work Group members involved in the GRADE analysis.

The policy questions under consideration were, "Should all adults aged ≥75 years be recommended to receive a single dose of RSV vaccination?" and "Should adults aged 60–74 years at increased risk of severe RSV disease be recommended to receive a single dose of RSV vaccination?" (Table 1).

Methods

During August 2023 to June 2024, CDC conducted a systematic review of evidence on the efficacy and safety of protein subunit RSV vaccines (GSK Arexvy and Pfizer Abrysvo). We assessed outcomes and evaluated the quality of evidence using the GRADE approach.

Work Group members were asked to pre-specify and rate the importance of relevant patient-important outcomes (including benefits and harms) before the GRADE assessment (Table 2). The benefits of interest selected by the Work Group were prevention of: RSV lower respiratory tract disease (LRTD) (important), medically attended RSV LRTD (critical), hospitalization for RSV respiratory illness (critical), severe RSV respiratory illness requiring supplemental oxygen or other respiratory support (important), and death due to RSV illness (important). Pre-specified harms of interest were serious adverse events (critical), inflammatory neurologic events (critical), and reactogenicity (grade ≥3) (important).

A systematic literature search was completed to review all available evidence on the efficacy and safety of protein subunit RSV vaccines. 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 any protein subunit vaccine; 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 from the identified studies were obtained through personal communication with the vaccine manufacturers. The systematic review was conducted as of August 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 certainty was assigned as high, moderate, low, or very low.

To assess efficacy, incidence rate ratios (IRR) were calculated using pooled event counts and total person-time available from the phase 3 clinical trials. IRRs included follow-up time up to 2 calendar years and were estimates of the ratio of the cumulative incidence during this time. Vaccine efficacy estimates were defined as 100% x (1-IRR). Efficacy estimates in this assessment correspond only to a single dose of RSV vaccine, compared with placebo In the GSK phase 3 trial, some participants who received the RSV vaccine were re-randomized to receive a second dose 12 months after the first dose. Among those participants, efficacy follow up time after the second dose of RSV vaccine was excluded from this GRADE assessment. To assess safety, risk ratios were calculated using counts of events and total participants available in the body of evidence, including both the phase 3 RCTs and both phase 1/2 RCTs. All analyses were performed using R version 4.4.0.

Results

The results of the GRADE assessment were presented to ACIP on June 26, 2024. Data were reviewed from two published phase 3 RCTs and two published phase 1/2 RCTs, including additional unpublished data from each trial provided by the manufacturers.2345678 Characteristics of the included studies are shown in Appendix 1.

In evaluation of benefits, mean follow up from the Pfizer phase 3 RCT was 16 months post-vaccination per participant (median 17) and mean follow up from the GSK phase 3 RCT was 19 months post-vaccination per participant (median 23).

For the policy question in adults aged ≥75 years, protein subunit RSV vaccines reduced RSV LRTD (vaccine efficacy: 69.4% [95% CI: 36.6%, 85.3%]) (Table 3a). Protein subunit RSV vaccines also reduced medically attended RSV LRTD (vaccine efficacy: 76.6% [95% CI: 58.5%, 86.8%]) (Table 3b). The trials had insufficient events to detect a lower rate of hospitalization for RSV respiratory illness and severe RSV respiratory illness requiring supplemental oxygen or other respiratory support (vaccine efficacy: 75.7% [95% CI: -12.5%, 94.8%] and 62.7% [95% CI: -88.7, 92.6], respectively) (Table 3c, Table 3d). No deaths due to RSV respiratory illness were identified among vaccine recipients or placebo recipients in either phase 3 trial.

For the policy question in adults aged 60–74 years at increased risk of severe RSV disease, protein subunit RSV vaccines reduced RSV LRTD (pooled vaccine efficacy: 73.1% [95% CI: 58.7%, 82.4%]) (Table 4a). Protein subunit RSV vaccines also reduced medically attended RSV LRTD (pooled vaccine efficacy: 72.7% [95% CI: 52.9%, 84.2%]) (Table 4b). The trials had insufficient events to detect a lower rate of hospitalization for RSV respiratory illness and severe RSV respiratory illness requiring supplemental oxygen or other respiratory support (pooled vaccine efficacy: 75.7% [95% CI: -12.5%, 94.8%] and 62.7% [95% CI: -88.7, 92.6], respectively) (Table 3c, Table 3d). No deaths due to RSV respiratory illness were identified among vaccine recipients or placebo recipients in either phase 3 trial.

Harms data were available from the Pfizer phase 3 RCT as well as an earlier phase 1/2 trial and from the GSK phase 3 RCT as well as an earlier phase 1/2 trial. Evidence for harm outcomes included all adults aged ≥60 years, so effect estimates were the same for both policy questions (pertaining to adults aged ≥75 years, and adults aged 60–74 years at increased risk of severe RSV disease). Proportions of participants with SAEs were comparable between the vaccine and the placebo groups (pooled RR: 1.01 [95% CI: 0.93, 1.10]) (Table 3e). The pooled RR for neurological events following vaccination was 1.76 (95% CI: 0.29, 10.77) (Table 3f). The pooled relative risk for reactogenicity (grade ≥3) was 1.92 (0.78, 4.70) (Table 3g).

GRADE Summary

The initial GRADE evidence certainty level was high for each outcome because the body of evidence consisted of randomized controlled trials (Table 5a and 5b).

Regarding critical benefits outcomes in adults aged ≥75 years, the available data indicated that protein subunit RSV vaccination likely reduces medically attended RSV LRTD with moderate certainty. Certainty was downgraded once due to serious concern for indirectness due to inclusion of adults aged 60–74 years in effect estimates (data from GSK). The available data indicated that protein subunit RSV vaccination may reduce RSV hospitalization with low certainty. Certainty for hospitalization was downgraded twice: once due to serious concern for indirectness due to inclusion of adults aged 60–74 years, and once for imprecision due to the confidence intervals containing absolute risk reduction estimates for which different policy decisions might be considered.

For important benefits outcomes in adults aged ≥75 years, the available data indicated that protein subunit RSV vaccination reduces RSV LRTD with high certainty, and may reduce severe RSV respiratory illness requiring supplemental oxygen or other respiratory support certainty with very low certainty (downgraded once for serious concern for indirectness [again due to inclusion of adults 60–74], once for serious concern for imprecision [due to the confidence intervals containing absolute risk reduction estimates for which different policy decisions might be considered], and once for inconsistency [point estimates between the studies differed substantially]).

In terms of critical benefits outcomes in adults aged 60–74 years at increased risk of severe RSV disease, the available data indicated that protein subunit RSV vaccination reduces medically attended RSV LRTD with high certainty and may reduce RSV hospitalization with low certainty. Evidence certainty for RSV hospitalization was downgraded once for serious concern for indirectness due to inclusion of adults without chronic medical conditions as well as once for imprecision due to the confidence intervals containing absolute risk reduction estimates for which different policy decisions might be considered.

For important benefits outcomes in adults aged 60–74 years at increased risk of severe RSV disease, the available data indicated that protein subunit RSV vaccination reduces RSV LRTD with high certainty, and may reduce severe RSV respiratory illness requiring supplemental oxygen or other respiratory support with very low certainty (downgraded once for serious concern for indirectness [again due to inclusion of adults without chronic medical conditions], once for serious concern for imprecision [due to the confidence intervals containing absolute risk reduction estimates for which different policy decisions might be considered], and once for inconsistency [point estimates between the studies differed substantially]).

For harms in both adults aged ≥75 years and 60–74 years at increased risk of severe RSV disease, all outcomes were downgraded at least once for indirectness due to inclusion of adults aged 60–74 years (when evaluating the policy question in adults aged ≥75 years), or inclusion of adults without comorbidities (when evaluating the policy question in adults aged 60–74 years at increased risk of severe RSV disease). Available data indicated that protein subunit RSV vaccination likely results in little to no difference in serious adverse events, with moderate certainty. Protein subunit RSV vaccination may increase severe reactogenicity events, with low certainty. In addition to the indirectness downgrade, this outcome was also downgraded once for imprecision (due to the width of the confidence interval containing estimates for which different policy decisions might be considered). Protein subunit RSV vaccination may increase inflammatory neurologic events, with very low certainty. In addition to the indirectness downgrade, this outcome was also downgraded twice for imprecision (due to the width of the confidence interval containing estimates for which different policy decisions might be considered and due to fragility of the estimate).

Footnotes

*For details on the GRADE assessment for mRNA RSV vaccine (Moderna mRESVIA) please see Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Moderna mRNA RSV Vaccine (mResvia) in older adults.

† Incidence rate ratios and efficacy estimates were independently calculated by CDC using counts of events ≥14 days after injection and total person-time available from the phase 3 trials (Efficacy= 1 – incidence rate ratio x 100%).

^§ GSK phase 3 trial: RSV lower respiratory tract disease (LRTD) was defined by the presence of ≥2 lower respiratory symptoms or signs for ≥24 hours including ≥1 lower respiratory sign, or ≥3 lower respiratory symptoms ≥24 hours. Lower respiratory symptoms included new or increased sputum, new or increased cough, and new or increased dyspnea. Lower respiratory signs included new or increased wheezing, new or increased crackles or rhonchi based on chest auscultation, respiratory rate ≥20 respirations per minute, low or decreased oxygen saturation (<95% or ≤90% if baseline was <95%), and need for oxygen supplementation.

^¶ Pfizer phase 3 trial: 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.

** GSK phase 3 trial: Medically attended LRTD was defined as attention at ≥1 inpatient or outpatient health care service. These estimates were not included in per-protocol assessments.

^†† Pfizer phase 3 trial: Medically attended RSV lower respiratory tract illness (LRTI) with ≥3 signs or symptoms 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).

^§§ GSK phase 3 trial: Adults aged ≥60 years with pre-existing comorbidities of interest includes adults with chronic obstructive pulmonary disease (COPD), asthma, any chronic respiratory/pulmonary disease, chronic heart failure, diabetes mellitus Type 1 or Type 2, or advanced liver or renal disease.

^¶¶ Pfizer phase 3 trial: Adults aged ≥60 years with pre-specified significant conditions includes adults with current tobacco use, diabetes, lung disease [including COPD], heart disease [including congestive heart failure], liver disease, or renal disease.

*** GSK trials: Serious adverse events were defined as any untoward medical occurrence (during six months after injection in the phase 3 trials and 60 days after injection in the phase 1/2 trials) 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.

^†† Pfizer trials: Serious adverse events were defined as any untoward medical occurrence (through day 182 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.

^§§§ GSK trials: Severe reactogenicity events were defined as grade 3 solicited local reactions (injection site pain, redness and swelling) or systemic reactions (fatigue, fever, headache, gastrointestinal symptoms [nausea, vomiting, diarrhea or abdominal pain], arthralgia, myalgia and shivering) recorded during days 0–4 after vaccination in the phase 3 trial and days 0–7 after vaccination in the phase 1/2 trial. For injection site erythema and swelling, grade 3 corresponded to a diameter >100 mm. For fever, grade 3 corresponded to a temperature >39°C. For all other reactions, grade 3 corresponded to reactions that prevented normal, everyday activities. Grade 4 events were not defined in these trials.

^¶¶¶ Pfizer trials: Severe reactogenicity events were defined as grade 3 or higher solicited 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℃.

**** 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.

Tables

Table 1: Policy Questions and Population, Intervention, Comparison, Outcome (PICO)

Table 1a: Policy Question and PICO for Adults Aged ≥75 Years

Table 1b: Policy Question and PICO for Adults Aged 60–74 Years at Increased Risk of Severe RSV Disease

Table 2: Outcomes and Rankings

^a Three options: 1. Critical; 2. Important but not critical; 3. Not important for decision-making

^b No events were recorded in included studies, so the outcome could not be evaluated.

Table 3: Summary of Studies Reporting Outcomes in Adults Aged ≥75 Years

Table 3a: Summary of Studies Reporting RSV LRTD

References in this table:23568

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^a ≥2 lower respiratory trace disease symptoms or signs for ≥24 hours including ≥1 lower respiratory sign, or ≥3 lower respiratory symptoms for ≥24 hours. Lower respiratory symptoms included new or increased sputum, new or increased cough, and new or increased dyspnea. Lower respiratory signs included new or increased wheezing, new or increased crackles or rhonchi based on chest auscultation, respiratory rate ≥20 respirations per minute, low or decreased oxygen saturation (<95% or ≤90% if baseline was <95%), and need for oxygen supplementation.

^b ≥3 lower respiratory trace disease signs or symptoms. 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.

^c Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel fixed-effect model.

Table 3b: Summary of Studies Reporting Medically Attended RSV LRTD

References in this table:23568

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^a Medically attended RSV LRTD was defined as RSV LRTD with attention at ≥1 inpatient or outpatient health care service.

^b Medically attended RSV lower respiratory tract illness (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).

^c Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel fixed-effect model.

Table 3c: Summary of Studies Reporting Hospitalization for RSV Respiratory Illness

References in this table:23568

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^a Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel fixed-effect model.

Table 3d: Summary of Studies Reporting Severe RSV Respiratory Illness Requiring O2/Respiratory Support

References in this table:23568

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^a Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel fixed-effect model.

Table 3e: Summary of Studies Reporting Serious Adverse Events

References in this table:2345678

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^a Serious adverse events were defined as any untoward medical occurrence (during six months after injection in the phase 3 trial and 60 days after injection in 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 GSK Arexvy (120µg antigen + AS01_E adjuvant, 1 dose IM).

^c Includes all events for 6 months after injection.

^d Includes all events after dose 1, but before dose 2 (day 61) in a placebo-controlled phase 1/2 dosing selection study.

^e Serious adverse events were defined as any untoward medical occurrence (through day 182 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.

^f Intervention was a single dose of Pfizer Abrysvo (120µg antigen, 1 dose IM).

^g All events reported from vaccination through day 182.

^h Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel random-effect model.

Table 3f: Summary of Studies Reporting Inflammatory Neurologic Events^a

References in this table:2345678

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^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 GSK Arexvy (120µg antigen + AS01_E adjuvant, 1 dose IM).

^c Calculated using 0.5 correction factor to account for zero events.

^d Intervention was a single dose of Pfizer Abrysvo (120µg antigen, 1 dose IM).

^e In the Pfizer phase 3 RCT there were a total of three cases of inflammatory neurologic events initially identified as 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). After further investigation, the case of undifferentiated motor-sensory axonal polyneuropathy was excluded. This is a revision since the June 2023 GRADE.

^f Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel random-effect model.

Table 3g: Summary of Studies Reporting Severe Reactogenicity

References in this table:2345678

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^a Severe reactogenicity events were defined as grade 3 solicited local reactions (injection site pain, redness and swelling) or systemic reactions (fatigue, fever, headache, gastrointestinal symptoms [nausea, vomiting, diarrhea or abdominal pain], arthralgia, myalgia and shivering) recorded during days 0–4 after vaccination in the phase 3 trial and days 0–7 after vaccination in the phase 1/2 trial. For injection site erythema and swelling, grade 3 corresponded to a diameter >100 mm. For fever, grade 3 corresponded to a temperature >39°C. For all other reactions, grade 3 corresponded to reactions that prevented normal, everyday activities. Grade 4 events were not defined in these trials.

^b Intervention was a single dose of GSK Arexvy (120µg antigen + AS01_E adjuvant, 1 dose IM).

^c All events within 4 days of injection.

^d All events within 7 days of injection.

^e 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℃.

^f Intervention was a single dose of Pfizer Abrysvo (120µg antigen, 1 dose IM).

^g Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel random-effect model.

Table 4 Summary of Studies Reporting Outcomes in Adults Aged 60–74 Years at Increased Risk of Severe RSV Disease

Table 4a Summary of Studies Reporting RSV LRTD

References in this table:23568

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

a Pre-existing comorbidities of interest ("specific medical conditions") includes adults with chronic obstructive pulmonary disease (COPD), asthma, any chronic respiratory/pulmonary disease, chronic heart failure, diabetes mellitus Type 1 or Type 2, or advanced liver or renal disease.

b Pre-specified significant condition includes adults with current tobacco use, diabetes, lung disease [including COPD], heart disease [including congestive heart failure], liver disease, or renal disease.

c Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel fixed-effect model.

Table 4b Summary of Studies Reporting Medically Attended RSV LRTD

References in this table:23568

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^a Pre-existing comorbidities of interest ("specific medical conditions") includes adults with chronic obstructive pulmonary disease (COPD), asthma, any chronic respiratory/pulmonary disease, chronic heart failure, diabetes mellitus Type 1 or Type 2, or advanced liver or renal disease.

^b Pre-specified significant condition includes adults with current tobacco use, diabetes, lung disease [including COPD], heart disease [including congestive heart failure], liver disease, or renal disease.

^c Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel fixed-effect model.

Table 4c: Summary of Studies Reporting Hospitalization for RSV Respiratory Illness

References in this table:23568

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^a Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel fixed-effect model.

Table 4d: Summary of Studies Reporting Severe RSV Respiratory Illness Requiring O2/Respiratory Support

References in this table:23568

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^a Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel fixed-effect model.

Table 4e: Summary of Studies Reporting Serous Adverse Events

References in this table:2345678

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^a Serious adverse events were defined as any untoward medical occurrence (during six months after injection in the phase 3 trial and 60 days after injection in 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 GSK Arexvy (120µg antigen + AS01_E adjuvant, 1 dose IM).

^c Includes all events for 6 months after injection.

^d Includes all events after dose 1, but before dose 2 (day 61) in a placebo-controlled phase 1/2 dosing selection study.

^e Serious adverse events were defined as any untoward medical occurrence (through day 182 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.

^f Intervention was a single dose of Pfizer Abrysvo (120µg antigen, 1 dose IM).

^g All events reported from vaccination through day 182.

^h Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel random effect model.

Table 4f: Summary of Studies Reporting Inflammatory Neurologic Events^a

References in this table:2345678

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^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 GSK Arexvy (120µg antigen + AS01_E adjuvant, 1 dose IM).

^c Calculated using 0.5 correction factor to account for zero events.

^d Intervention was a single dose of Pfizer Abrysvo (120µg antigen, 1 dose IM).

^e In the Pfizer phase 3 RCT there were a total of three cases of inflammatory neurologic events initially identified as 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). After further investigation, the case of undifferentiated motor-sensory axonal polyneuropathy was excluded. This is a revision since the June 2023 GRADE.

f Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel random-effect model.

Table 4g: Summary of Studies Reporting Severe Reactogenicity

References in this table:2345678

Abbreviations: CI = confidence interval; RCT = randomized controlled trial.

^a Severe reactogenicity events were defined as grade 3 solicited local reactions (injection site pain, redness and swelling) or systemic reactions (fatigue, fever, headache, gastrointestinal symptoms [nausea, vomiting, diarrhea or abdominal pain], arthralgia, myalgia and shivering) recorded during days 0–4 after vaccination in the phase 3 trial and days 0–7 after vaccination in the phase 1/2 trial. For injection site erythema and swelling, grade 3 corresponded to a diameter >100 mm. For fever, grade 3 corresponded to a temperature >39°C. For all other reactions, grade 3 corresponded to reactions that prevented normal, everyday activities. Grade 4 events were not defined in these trials.

^b Intervention was a single dose of GSK Arexvy (120µg antigen + AS01_E adjuvant, 1 dose IM).

^c All events within 4 days of injection.

^d All events within 7 days of injection.

^e 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℃.

^f Intervention was a single dose of Pfizer Abrysvo (120µg antigen, 1 dose IM).

^g Pooled estimate using data from all studies for this outcome generated using Mantel-Haenszel random-effect model.

Table 5: Summary of Evidence for Outcomes of Interest

Table 5a Summary of Evidence for Outcomes of Interest in Adults Aged ≥75 Years

Table 5b: Summary of Evidence for Outcomes of Interest in Adults Aged 60–74 Years at Increased Risk of Severe RSV Disease

Table 6: Grade Summary of Findings

Table 6a: Grade Summary of Findings Table in Adults aged ≥75 years

a. 7,358 person-years of observation.

b. 8,416 person-years of observation.

c. Pooled rate ratio and the corresponding 95% CIs were calculated as 1- vaccine efficacy observed in the manufacturers’ phase 3 clinical trials for the specified outcome using all available follow-up time. The input vaccine efficacy was calculated by CDC using reported case counts and person-time without adjustment for covariates.

d. 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 also no estimates of rate of ≥3 symptom RSV LRTD available in the literature.

e. Serious concern for indirectness due to inclusion of adults aged 60–74 years.

f. 20,774 person-years of observation.

g. 25,706 person-years of observation.

h. This represents a control rate of 476 cases of medically attended RSV LRTI with ≥3 symptoms per 100,000 adults aged ≥60 years per RSV season (196 cases of medically attended RSV illness over one RSV season per 10,000 adults aged ≥60 years with chronic cardiopulmonary conditions [as a proxy for those 75 years and older], 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).

i. For calculation of absolute effect, the baseline number of events was not taken from the placebo arm of the trial given concerns that the baseline captured in the trial underestimated the true population-based incidence. Instead the calculation uses the control rate described in footnote h.

j. Serious concern for imprecision due to the confidence intervals containing measures of absolute risk for which different policy decisions might be considered.

k. 39,323 person-years of observation.

l. 41,962 person-years of observation.

m. This represents a control rate of 314 cases of RSV-associated hospitalization over one RSV season per 100,000 adults aged 75 and older. Control rate data are unpublished data from CDC’s RSV-NET. Available here: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2024-06-26-28/08-RSV-Adult-Hutton-508.pdf.

n. For calculation of absolute effect, the baseline number of events was not taken from the placebo arm of the trial given concerns that the baseline captured in the trial underestimated the true population-based incidence. Instead the calculation uses the control rate described in footnote m.

o. Serious concern for inconsistency because the point estimates between the studies differed substantially, although the confidence intervals overlapped.

p. 39,322 person-years of observation.

q. This represents a control rate of 290 cases of severe RSV illness requiring supplemental oxygen or other respiratory support per 100,000 adults aged ≥60 years per RSV season (196 cases of medically attended RSV illness over one RSV season per 10,000 adults aged ≥60 years with chronic cardiopulmonary conditions [as a proxy for those 75 years and older], 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

r. For calculation of absolute effect, the baseline number of events was not taken from the placebo arm of the trial given concerns that the baseline captured in the trial underestimated the true population-based incidence. Instead the calculation uses the control rate described in footnote q.

s. 34,167 person-years of observation.

t. 43,696 person-years of observation.

u. Measures of relative and absolute effect could not be estimated due to zero events.

v. Pooled relative risk estimates were independently calculated using counts of events and participants in the pivotal phase 3 trials, as well as from earlier the phase 1/2 trials.

w. For calculation of absolute effect, the baseline number of events was taken from the rates observed in the placebo arm.

x. 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 in the estimate.

y. Absolute risk was unable to be calculated due to zero events in the placebo arm and no reliable data to estimate the true baseline rate of this outcome in the general population.

z. Differences in the risk of grade ≥3 reactogenicity between GSK and Pfizer vaccines are not unexpected given that one of the products is adjuvanted and one is not; therefore inconsistency was felt to be not serious, as we would expect that the risk of grade ≥3 reactogenicity is different between the vaccine products.

Table 6b: Grade Summary of Findings Table in Adults aged 60–74 Years at Increased Risk of Severe RSV Disease

a. 19,516 person-years of observation.

b. 21,340 person-years of observation.

c. Pooled rate ratio and the corresponding 95% CIs were calculated as 1- vaccine efficacy observed in the manufacturers’ phase 3 clinical trials for the specified outcome using all available follow-up time. The input vaccine efficacy was calculated by CDC using reported case counts and person-time without adjustment for covariates.

d. 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 also no estimates of rate of ≥3 symptom RSV LRTD available in the literature.

e. 19,524 person-years of observation.

f. 21,372 person-years of observation.

g. This represents a control rate of 476 cases of medically attended RSV LRTI with ≥3 symptoms per 100,000 adults aged ≥60 years per RSV season (196 cases of medically attended RSV illness over one RSV season per 10,000 adults aged ≥60 years with chronic cardiopulmonary conditions, 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).

h. For calculation of absolute effect, the baseline number of events was not taken from the placebo arm of the trial given concerns that the baseline captured in the trial underestimated the true population-based incidence. Instead the calculation uses the control rate described in footnote g.

i. Serious concern for indirectness as this outcome was assessed for all adults 60-74 years, not only those at increased risk of severe RSV disease.

j .Serious concern for imprecision due to the confidence intervals containing measures of absolute risk estimates for which different policy decisions might be considered.

k. 39,323 person-years of observation.

l. 41,962 person-years of observation.

m. This represents a control rate of 198 cases of RSV-associated hospitalization over one RSV season per 100,000 adults aged 60-74 at increased risk of severe RSV disease. Control rate data are unpublished data from CDC’s RSV-NET with at least one condition among: COPD, asthma, CAD, diabetes, obesity (>40 kg/m2), or CKD. Available here: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2024-06-26-28/08-RSV-Adult-Hutton-508.pdf.

m. For calculation of absolute effect, the baseline number of events was not taken from the placebo arm of the trial given concerns that the baseline captured in the trial underestimated the true population-based incidence. Instead the calculation uses the control rate described in footnote m.

o. Serious concern for inconsistency because the point estimates between the studies differed substantially, although the confidence intervals overlapped.

p. 39,322 person-years of observation

q. This represents a control rate of 290 cases of severe RSV illness requiring supplemental oxygen or other respiratory support per 100,000 adults aged ≥60 years per RSV season (196 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).

r. For calculation of absolute effect, the baseline number of events was not taken from the placebo arm of the trial given concerns that the baseline captured in the trial underestimated the true population-based incidence. Instead the calculation uses the control rate described in footnote q.

s. 34,167 person-years of observation.

t. 43,696 person-years of observation.

u. Measures of relative and absolute effect could not be estimated due to zero events.

v. Pooled relative risk estimates were independently calculated using counts of events and participants in the pivotal phase 3 trials, as well as from earlier the phase 1/2 trials.

w. For calculation of absolute effect, the baseline number of events was taken from the rates observed in the placebo arm.

x. Very serious concern for imprecision due to fragility of the estimate, adjustment of relative risk for zero events observed, and confidence interval containing estimates for which different policy decisions might be considered.

y. Absolute risk was unable to be calculated due to zero events in the placebo arm and no reliable data to estimate the true baseline rate of this outcome in the general population.

z. Differences in the risk of grade ≥3 reactogenicity between GSK and Pfizer vaccines are not unexpected given that one of the products is adjuvanted and one is not; therefore inconsistency was felt to be not serious, as we would expect that the risk of grade ≥3 reactogenicity is different between the vaccine products.

Appendix 1. Studies Included in the Review of Evidence

References in this appendix:2345678

Appendix 2. Databases and strategies used for systematic review