Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Moderna mRNA RSV Vaccine (mResvia) in older adults

Overview

A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence of benefits and harms from Moderna messenger ribonucleic acid (mRNA) Respiratory Syncytial Virus (RSV) vaccination (mResvia) 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 the GRADE assessment was separated by vaccine type (protein subunit vaccines, mRNA vaccine). On this webpage GRADE for the mRNA vaccine product (Moderna mResvia) is reviewed.*

The ACIP Work Group for RSV prevention in adults (Work Group) chose the following benefit 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 Moderna mResvia among persons aged 60 years and older was conducted. The quality of evidence from one phase 2/3 randomized controlled trial23 (RCT) and one phase 1 RCT34 were assessed using the GRADE approach. Efficacy findings were based on analyses of data collected during November 2021 to March 2024.

In adults aged ≥75 years, there were insufficient cases in the phase 3 clinical trial to detect a lower rate^† of RSV LRTD^§ after vaccination compared with placebo (incidence rate ratio [IRR]: 0.56 [95% confidence interval (CI): 0.22, 1.35]; evidence certainty: moderate) corresponding to a vaccine efficacy of 44.0% (95% CI: -34.6%, 78.2%). Using data from all participants aged ≥60 years, the trial also had insufficient cases to detect a lower rate of medically attended^¶ RSV LRTDor hospitalization for RSV respiratory illness following vaccination compared with placebo (IRR: 0.61 [95% CI: 0.22, 1.59]; evidence certainty: low and IRR: 0.20 [95% CI: 0.00, 4.64]; evidence certainty: very low). Vaccine efficacy against medically attended RSV LRTDor hospitalization for RSV respiratory illness were 39.0% (95% CI: -58.8%, 78.1%) and 80.1% (95% CI: -363.7%, 100%), respectively. There were no data to inform the outcome of severe RSV respiratory illness requiring supplemental oxygen/respiratory support and no deaths due to RSV respiratory illness were observed in the clinical trial, so these outcomes were not included in the evidence profile.

For adults aged 60–74 years at increased risk of severe RSV disease** a lower rate of RSV LRTD was observed following vaccination compared with placebo (IRR: 0.33 [95% CI: 0.18, 0.58]; evidence certainty: high); vaccine efficacy against RSV LRTD was 66.8% (95% CI: 41.5%, 82.1%). The additional benefit outcomes of medically attended RSV LRTD and hospitalization for RSV respiratory illness included all adults aged ≥60 years (rather than those 60-74 at increased risk of severe disease only), so the effect estimates and certainty assessments are the same as for the policy question in adults aged ≥75 years.

In terms of harms, data were included from all trial participants aged ≥60 years from the phase 2/3 and phase 1 RCTs, 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 data indicated that serious adverse events (SAEs)^†† may be balanced between participants in the vaccine and placebo arms (risk ratio [RR]: 1.00 [95% CI: 0.95, 1.05]; evidence certainty: low). Reactogenicity^§§ grade ≥3^¶¶ following vaccination was likely higher following vaccination (RR: 1.54 [95% CI: 1.40, 1.68]; evidence certainty: moderate). No inflammatory neurologic events*** were observed within 42 days after injection in either trial, so this outcome was not included in the evidence profile.

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.

Introduction

On May 31, 2024, the U.S. Food and Drug Administration (FDA) approved the Biologics License Application (BLA) for use of Moderna RSV vaccine mResvia for use in adults aged ≥60 years.56Previously, 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). This recommendation was for any FDA-approved RSV vaccine product in this age group, so Moderna's mResvia vaccine was included in this recommendation, after it received FDA approval. Following a year of the 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 RSV vaccination 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 Moderna mResvia. 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 O2/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 Moderna mResvia. 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 Moderna mResvia; 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 manufacturer. 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 event counts and total person-time available from the phase 2/3 clinical trial. Vaccine efficacy estimates were defined as (1-IRR) x 100%. To assess safety, risk ratios were calculated using pooled counts of events and total participants available in the body of evidence, including both the phase 2/3 RCT and the phase 1 RCT. Estimates were pooled 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 one phase 2/3 RCT and one phase 1 RCT, including additional unpublished data provided by the manufacturer.234 Characteristics of the included studies are shown in Appendix 1.

In evaluation of benefits, mean follow-up time from the phase 2/3 RCT was 18 months post-vaccination per participant (median 19 months).

For the policy question in adults aged ≥75 years, the phase 3 clinical trial was not powered to detect a lower rate of RSV LRTD after vaccination compared to placebo (vaccine efficacy: 44.0% [95% CI: -34.6%, 78.2%]) (Table 3a). Including data from all participants aged ≥60 years, the trial was also not powered to detect a lower rate of medically attended RSV LRTD or hospitalization for RSV respiratory illness following vaccination compared with placebo (vaccine efficacy: 39.0% [95% CI: -58.8%, 78.1%] and 80.1% [-363.7%, 100%], respectively) (Table 3c and 3d). There were no data to inform the outcome of severe RSV respiratory illness requiring supplemental oxygen/respiratory support and no deaths due to RSV respiratory illness were observed in the clinical trial.

For the policy question in adults aged 60–74 years at increased risk of severe RSV disease, a lower rate of RSV LRTD was observed following vaccination compared with placebo (vaccine efficacy: 66.8% [95% CI: 41.5%, 82.1%]) (Table 3b). The additional outcomes included all adults aged ≥60 years (rather than among those with increased risk of severe RSV disease), so the effect estimates are the same as in the above paragraph.

Harms data were available from the phase 2/3 RCT as well as an earlier phase 1 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 placebo groups (pooled RR: 1.00 [95% CI: 0.95, 1.05]) (Table 3e). One participant in the mResvia group had an SAE of facial paralysis with onset four days after vaccination assessed as related to mResvia.7 Within 28 days and 42 days post vaccination, there was no imbalance in reports of facial paralysis (including Bell's palsy) between the vaccine and placebo groups.7 Grade ≥3 local or systemic reactions following vaccination, were reported by 6.1% of vaccine recipients and 4.0% of placebo recipients (pooled RR: 1.54; 95% CI: 1.40, 1.68) (Table 3f). There were no events of inflammatory neurological events within 42 days of vaccination or placebo receipt in either trial.

GRADE Summary

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

Regarding critical benefits outcomes, for both adults aged ≥75 and 60-74 years at increased risk of severe RSV disease, the available data indicated that the vaccine may be effective at preventing medically attended LRTD and hospitalization for RSV respiratory illness with low and very low certainty, respectively. Certainty for medically attended RSV LRTD was downgraded once due to serious concern for indirectness (inclusion of all adults aged ≥60 years) and once more due to serious concern for imprecision (the width of the confidence interval contained estimates for which different policy decisions may be considered). Certainty for RSV hospitalization was downgraded once due to serious concern for indirectness (inclusion of all adults aged ≥60 years) and twice more due to very serious concern for imprecision (the width of the confidence interval contained estimates for which different policy decisions may be considered and fragility in the estimate).

For important benefits in adults aged ≥75 years, the available data indicated that the vaccine is likely effective in preventing LRTD with moderate certainty. The certainty in this estimate was downgraded once due to serious concern for imprecision (the 95% confidence interval contains estimates for which different policy decisions might be considered). There were no data to inform the outcomes of severe RSV respiratory illness requiring supplemental oxygen/respiratory support and no deaths due to RSV respiratory illness were observed in the trial.

In terms of important benefits in adults aged 60–74 years at increased risk of severe RSV, the available data indicated that the vaccine is effective in preventing LRTD with high certainty. There were no data to inform the outcomes of severe RSV respiratory illness requiring supplemental oxygen/respiratory support and no deaths due to RSV respiratory illness were observed in the trial.

For harms in both adults aged ≥75 years and 60–74 years at increased risk of severe RSV disease, all effect estimates and downgrades were the same as data from adults ≥60 years were considered. The critical outcome of serious adverse events may be balanced between vaccine and placebo groups with low certainty. Certainty for serious adverse events following vaccination with mResvia was downgraded once due to serious concern for indirectness (inclusion of all adults aged ≥60 years) and once due to serious concern for inconsistency (though the confidence intervals overlapped, the effect measures from the phase 1 trial and phase 2/3 trial were substantially different). For the important outcome of reactogenicity (grade ≥3) the available evidence indicated that vaccination with mResvia likely increases severe reactogenicity with moderate certainty. The certainty was downgraded once due to serious concern for indirectness (estimate includes all adults aged ≥60 years). There were no events of inflammatory neurologic events observed in the trial within 42 days after receipt of vaccine or placebo.

Footnotes

* For details on the GRADE assessment for protein subunit RSV vaccines (GSK AREXVY and Pfizer ABRSVO) please see Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Protein subunit RSV vaccines (GSK Arexvy and Pfizer Abrysvo) in older adults | CDC.

^† 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 2/3 trial (Efficacy= 1 – incidence rate ratio x 100%).

^§ The phase 2/3 trial had 2 co-primary end points: ≥2 or ≥3 signs/symptoms LRTD. The end point of 3 sign/symptom LRTD was used for the GRADE assessment. Lower respiratory signs/symptoms: Tachypnea, hypoxemia, shortness of breath, fever and/or cough, sputum production, pleuritic chest pain, wheezing and/or rales and/or rhonchi.

^¶ Medically attended events based on Emergency Department/Urgent Care visits only.

** Population in these analyses were adults aged ≥60 years with chronic obstructive pulmonary disease [COPD], asthma, chronic respiratory disease, heart failure, diabetes mellitus, advanced liver disease, and/or advanced renal disease.

†† Serious adverse events were defined as death, life-threatening event, hospitalization, incapacity to perform normal life functions, medically important event, or congenital anomaly/birth defect through end of available follow-up period.

^§§ Severe local or systemic reactions solicited through 7 days post-injection.

^¶¶ Severe reactogenicity events were defined as grade 3 or 4 solicited local reactions (injection site pain, injection site erythema [redness], injection site swelling/induration [hardness], axillary [underarm] swelling or tenderness ipsilateral to the side of injection) or systemic reactions (headache, fatigue, myalgia, arthralgia, nausea/vomiting, chills, or fever. See Appendix 3 for table of grade 3 or 4 reaction definitions.

*** 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 Question 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 data were available to inform outcome.

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

Table 3 Summary of Studies Reporting Outcomes

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

References in this table:23

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

^a Lower respiratory signs/symptoms: Tachypnea, hypoxemia, shortness of breath, fever and/or cough, sputum production, pleuritic chest pain, wheezing and/or rales and/or rhonchi.

^b Efficacy estimates were independently calculated by CDC using counts of events ≥14 days after injection and total person-time available from the Moderna phase 2/3 trial (Efficacy=1 – incidence rate ratio x 100%). CDC method of efficacy estimation differed from manufacturer (manufacturer used 1 – Hazard Ratio). The manufacturer estimated efficacy of a single dose against RSV LRTD with ≥3 signs/symptoms among adults aged ≥75 years to be 43.8% (95% CI: -27.1, 75.2).

Table 3b: Summary of Studies Reporting LRTD in Adults Aged 60–74 Years at Increased Risk of Severe RSV Disease

References in this table:23

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

^a Lower respiratory signs/symptoms: Tachypnea, hypoxemia, shortness of breath, fever and/or cough, sputum production, pleuritic chest pain, wheezing and/or rales and/or rhonchi.

^b Chronic obstructive pulmonary disease [COPD], asthma, chronic respiratory disease, heart failure, diabetes mellitus, advanced liver disease, advanced renal disease.

^c Efficacy estimates were independently calculated by CDC using counts of events ≥14 days after injection and total person-time available from the Moderna phase 2/3 trial (Efficacy=1 – incidence rate ratio x 100%). CDC method of efficacy estimation differed from manufacturer (manufacturer used 1 – Hazard Ratio). The manufacturer estimated efficacy of a single dose against RSV LRTD with ≥3 signs/symptoms among adults aged ≥60 years with ≥1 comorbidity to be 66.8% (95% CI: 42.5, 80.9).

The following tables use data from all trial participants aged ≥60 years and apply to both policy questions, pertaining to adults aged ≥75 years and adults aged 60–74 years who are at increased risk of severe RSV disease.

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

References in this table:23

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

^a Lower respiratory signs/symptoms: Tachypnea, hypoxemia, shortness of breath, fever and/or cough, sputum production, pleuritic chest pain, wheezing and/or rales and/or rhonchi.

^b Efficacy estimates were independently calculated by CDC using counts of events ≥14 days after injection and total person-time available from the Moderna phase 2/3 trial (Efficacy=1 – incidence rate ratio x 100%). CDC method of efficacy estimation differed from manufacturer (manufacturer used 1 – Hazard Ratio). The manufacturer estimated efficacy of a single dose against medically attended RSV LRTD among adults aged ≥60 years to be 38.7% (95% CI: -47.9, 74.6).

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

References in this table:23

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

^a Efficacy estimates were independently calculated by CDC using counts of events ≥14 days after injection and total person-time available from the Moderna phase 2/3 trial using a 0.5 correction factor to account for zero events in the vaccine arm (Efficacy=1 – incidence rate ratio x 100%). The manufacturer did not estimate efficacy.

Table 3e: Summary of Studies Reporting Serious Adverse Events^a

References in this table:234

Abbreviations: RR = relative risk; CI = confidence interval; RCT = randomized controlled trial

^a Death, life-threatening event, hospitalization, incapacity to perform normal life functions, medically important event, or congenital anomaly/birth defect, through data cut-off.

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

Table 3f: Summary of Studies Reporting Reactogenicity^a

References in this table:234

^a Grade 3 or 4 solicited local or systemic reactions through 7 days post injection. See Appendix 3 reaction definitions.

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

Table 4: Grade Summary of Findings Table

Table 4a: GRADE Summary of Findings Table in Adults Aged ≥75 Years

CI: confidence interval; RR: risk ratio

Explanations

a. Serious concern for imprecision due to the confidence intervals containing estimates for which different policy decisions might be considered.

b. 4,899 person-years of observation.

c. 4,877 person-years of observation.

d. Rate ratio and the corresponding 95% CIs were calculated as 1- vaccine efficacy observed in the manufacturer’s phase 3 clinical trial 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.

e. 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 LRTI/LRTD available in the literature.

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

g. 27,617 person-years of observation.

h. 27,383 person-years of observation.

i. 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 aged 75 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).

j. 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 i.

k. Very serious concern for imprecision due to the confidence intervals containing absolute risk reduction estimates for which different policy decisions might be considered and fragility of the estimate.

l. 13,137 person-years of observation.

m. 23,071 person-years of observation.

n. This represents a control rate of 314 cases of RSV-associated hospitalization per 100,000 adults aged 75 and older over one RSV season. 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.

o. 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 n.

p. 27,746 person-years of observation.

q. 27,578 person-years of observation.

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

s. Serious concern for inconsistency as the risk ratios observed in the phase 1 and phase 2/3 trials had substantially different point estimates.

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

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

Table 4b GRADE Summary of Findings Table in Adults Aged 60–74 Years at Increased Risk of Severe RSV Disease

Explanations

a. 8,203 person-years of observation.

b. 8,009 person-years of observation.

c. Rate ratio and the corresponding 95% CIs were calculated as 1- vaccine efficacy observed in the manufacturer’s phase 3 clinical trial 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 LRTI/LRTD available in the literature.

e. Serious concern for indirectness due to inclusion of adults without comorbidities.

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

g. 27,617 person-years of observation.

h. 27,383 person-years of observation.

i.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 LRTD 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).

j. 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 i.

k. Very serious concern for imprecision due to the confidence intervals containing absolute risk reduction estimates for which different policy decisions might be considered and fragility of the estimate.

l. 13,137 person-years of observation.

m. 13,071 person-years of observation.

n. 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.

o. 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 n.

p. 27,746 person-years of observation.

q. 27,578 person-years of observation.

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

s. Serious concern for inconsistency as the risk ratios observed in the phase 1 and phase 2/3 trials had substantially different point estimates.

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

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

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

Appendix 1. Studies Included in the Review of Evidence

References in this appendix:234

Appendix 2. Databases and strategies used for systematic review

Appendix 3. Definitions of Grade 3 and 4 Solicited Local and Systemic Adverse Reactions