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 trial^2,3 (RCT) and one phase 1 RCT^3,4 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 LRTD  or 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 LRTD  or 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.^5,6 Previously, 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.^2–4 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 https://www.cdc.gov/vaccines/acip/recs/grade/protein-subunit-rsv-vaccines-older-adults.html

^† 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.

References

1. U.S. Advisory Committee on Immunization Practices (ACIP) Handbook for Developing Evidence-based Recommendations: Formulating questions, conducting the systematic review, and assessing the certainty of the evidence using GRADE. https://www.cdc.gov/vaccines/acip/recs/grade/downloads/ACIP-GRADE-Handbook_4-22-24.pdf
2. Wilson E, Goswami J, Baqui AH, et al. Efficacy and Safety of an mRNA-Based RSV PreF Vaccine in Older Adults. N Engl J Med. 2023 Dec 14;389(24):2233-2244. doi: 10.1056/NEJMoa2307079.
3. Moderna data on file, personal communication August 2023-June 2024. Data provided to ACIP Work Group for RSV in Adults. Cambridge, MA; June 2024.
4. Shaw CA, Essink B, Harper C, et al. Safety and Immunogenicity of an mRNA-Based RSV Vaccine Including a 12-Month Booster in a Phase I Clinical Trial in Healthy Older Adults. J Infect Dis. 2024 Feb 22:jiae081. doi: 10.1093/infdis/jiae081.
5. Food and Drug Administration (FDA). Summary Basis for Regulatory Action: mRESVIA. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; May 31, 2024 https://www.fda.gov/media/179634/download?attachment
6. Food and Drug Administration (FDA). Approval letter: mRESVIA. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; June 14, 2024. https://www.fda.gov/media/179015/download?attachment
7. Food and Drug Administration (FDA). Package insert: mRESVIA. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; May, 2024 https://www.fda.gov/media/179005/download?attachment

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

Table 2: Outcomes and Rankings

Table 3 Summary of Studies Reporting Outcomes

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 4: Grade Summary of Findings Table

Table 5: Summary of Evidence for Outcomes of Interest

Appendix 1. Studies Included in the Review of Evidence

Appendix 2. Databases and strategies used for systematic review

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