Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Clesrovimab

Overview

A Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) review of the evidence for benefits and harms of the long-acting monoclonal antibody clesrovimab, (Enflonsia, Merck) for prevention of respiratory syncytial virus (RSV)-associated lower respiratory tract infection (LRTI) in infants born during or entering their first RSV season was presented to the Advisory Committee on Immunization Practices (ACIP) on April 15, 2025. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from high certainty to very low certainty [1].

The policy question was, "Should one dose of clesrovimab be recommended for infants aged <8 months born during or entering their first RSV season?" The benefits chosen by the ACIP Maternal/Pediatric RSV Work Group (Work Group) as critical or important to policy decisions were prevention of medically attended RSV-associated LRTI (critical); RSV-associated LRTI with hospitalization (critical); RSV-associated LRTI with intensive care unit (ICU) admission (critical); all-cause medically attended LRTI (important); and all-cause LRTI with hospitalization (important). The harm chosen by the Work Group as important to policy decisions was serious adverse events (SAEs) (important). Following a systematic review, the quality of evidence from one Phase 2b/3 randomized controlled trial (RCT) was assessed using the GRADE approach [2-4].

Outcomes (benefits) were assessed up to 150 days after injection. A lower risk of medically attended RSV-associated LRTI* was observed with clesrovimab use compared to placebo, (efficacy: 60.4% [95% CI: 44.1%, 71.9%]; evidence certainty: high). A lower risk of RSV-associated LRTI with hospitalization^† was observed (efficacy: 90.9% [95% CI: 76.2%, 96.5%]; evidence certainty: high). A lower risk of RSV-associated LRTI with ICU admission^§ was observed (efficacy: 100.0% [95% CI: 24.0%, 100.0%]; evidence certainty: moderate). A significantly lower risk of all-cause medically attended LRTI^¶ was not observed (efficacy: 13.1% [95% CI: -0.6%, 24.8%]; evidence certainty: high). Finally, a lower risk of all-cause LRTI-associated hospitalization** was observed (efficacy: 49.0% [95% CI: 26.7%, 64.5%]; evidence certainty: high).

The evidence indicated that SAEs^†† were not more common in the group that received clesrovimab compared to those in the placebo group (risk ratio: 0.93; 95% CI: 0.77, 1.12; evidence certainty: moderate).

Introduction

On June 19, 2025, the U.S. Food and Drug Administration (FDA) approved clesrovimab (Enflonsia, Merck), a long-acting monoclonal antibody, for the prevention of RSV-associated LRTI in infants and young children [4]. As part of the process employed by ACIP, a systematic review and GRADE evaluation of the evidence for clesrovimab was conducted and presented to ACIP. ACIP adopted a modified GRADE approach in 2010 as the framework for evaluating the scientific evidence that informs recommendations for the use of vaccines, immune globulin preparations, and specific antibody products [6]. Evidence of benefits and harms were reviewed based on the GRADE approach [1]. No conflicts of interest were reported by CDC and Work Group members involved in the GRADE analysis.

The policy question was, "Should one dose of clesrovimab be recommended for infants aged <8 months born during or entering their first RSV season?" (Table 1).

Methods

We conducted a systematic review of evidence on the efficacy and safety of clesrovimab. We assessed outcomes and evaluated the quality of evidence using the GRADE approach from September 2024-February 2025.

Work Group members were asked to pre-specify and rate the importance of relevant patient-important outcomes before the GRADE assessment. Outcomes of interest included individual benefits and harms (Table 2). The critical benefits of interest for infants selected by the Work Group were medically attended RSV-associated LRTI, RSV-associated LRTI with hospitalization, and RSV-associated LRTI with ICU admission. Important benefits of interest were all-cause medically attended LRTI and all-cause LRTI-associated hospitalization. The harm outcome rated by the workgroup as important was SAEs.

A systematic literature search was completed to review all available evidence on the efficacy and safety of clesrovimab. Records of relevant observational studies as well as randomized controlled trials were included if they 1) provided data on infants injected with clesrovimab; 2) involved human subjects; 3) reported primary data; and 4) included data relevant to the efficacy and safety outcomes being measured. We identified potentially relevant studies through Medline, Embase, Cochrane Library, CINAHL, Scopus, and clinicaltrials.gov from the start of each database to December 2, 2024. Two reviewers independently screened all titles and abstracts and removed irrelevant references. Disagreements were resolved by consensus. No relevant observational studies were identified through the systematic review. In addition, unpublished relevant data were obtained through direct communication with the manufacturer. Publications of updated analyses of clinical trial data were also included. 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 could be assessed as high, moderate, low, or very low.

Relative risks for benefit outcomes were from one Phase 2b/3 RCT [2-4]. Efficacy was defined as 1-relative risk, and the relative risk was estimated using a modified Poisson regression approach with robust variance.

Results

The results of the GRADE assessment were presented to ACIP on April 15, 2025. Data were reviewed from one published Phase 2b/3 RCT, plus additional data provided by the sponsor [2-4].

For benefit and harm outcomes, available data were pooled from the Phase 2b/3 RCT. A lower risk of medically attended RSV-associated LRTI was observed with clesrovimab use compared to placebo (efficacy: 60.4% [95% CI: 44.1%, 71.9%]) (Table 3a). Clesrovimab lowered the risk of RSV-associated LRTI with hospitalization (efficacy: 90.9% [95% CI: 76.2%, 96.5%]) (Table 3b). A lower risk of RSV-associated LRTI with ICU admission was observed with clesrovimab use (efficacy: 100% [95% CI: 24.0%, 100.0%]) (Table 3c). No difference in all-cause medically attended LRTI was observed with use of clesrovimab (efficacy 13.1% [95% CI: -0.6%, 24.8%]) (Table 3d). Finally, lower risk of all-cause LRTI-associated hospitalization was observed with clesrovimab use (efficacy: 49.0% [95% CI: 26.7%, 64.5%]) (Table 3e).

For evaluation of potential harms, SAEs were not more common in the group that received clesrovimab compared with the placebo group (RR: 0.93 [95% CI: 0.77, 1.12]) (Table 3f). In the clesrovimab arm, 1 (0.0%) of infants experienced an SAE judged to be related to the investigational drug in the clesrovimab arm, compared with 1 (0.1%) of infants in the placebo arm. No deaths were considered related to the investigational drug by the investigator [2].

GRADE Summary

The initial GRADE evidence level was high for each outcome because the body of evidence consisted of a randomized controlled trial [2-4]. In terms of critical benefits, the available data indicated that clesrovimab was effective at preventing medically attended RSV-associated LRTI and RSV-associated LRTI with hospitalization, with no concerns in the certainty assessment. The available data indicated that clesrovimab was likely effective at preventing RSV-associated LRTI with ICU admission with moderate certainty; certainty was downgraded once for serious concern for imprecision because the number of study participants did not meet the optimal information size. The data available for the important benefit of all-cause medically attended LRTI showed that clesrovimab was likely ineffective with moderate certainty; certainty was downgraded once for serious concern for imprecision as the confidence interval contained estimates for which different policy decisions might be considered. For all-cause LRTI with hospitalization, the available data indicated that clesrovimab was effective at preventing the outcome with no concerns in the certainty assessment. For the important harm outcome of SAEs, the available data showed that SAEs were likely not more common in the group that received clesrovimab compared with those in the placebo group with moderate certainty; certainty was downgraded once for serious concern for imprecision because efficacy trials were not powered to detect rare events (e.g., anaphylaxis). (Table 4)

Footnotes

* RSV-associated medically attended LRTI was defined by the presence of the following while seen in an outpatient or inpatient clinical setting: cough or difficulty breathing; ≥ 1 indicator of LRTI or severity (wheezing, chest wall in-drawing/retractions, rales/crackles, hypoxemia, tachypnea, dehydration due to respiratory symptoms); a nasopharyngeal sample that was RSV-positive by reverse transcriptase-polymerase chain reaction (RT-PCR).

^† RSV-associated LRTI hospitalization was defined by cough or difficulty breathing; ≥ 1 of the following: wheezing, chest wall in-drawing/retractions, rales/crackles, hypoxemia, tachypnea, dehydration due to respiratory symptoms; hospital admission for respiratory illness; and a nasopharyngeal sample that was RSV positive by RT-PCR.

^§ RSV-associated LRTI with intensive care unit (ICU) admission was defined as hospital admission for respiratory illness; a nasopharyngeal sample that was RSV positive by RT-PCR; and evidence of admission to ICU in the associated serious adverse event narrative by looking for ≥ 1 of the following key terms: ICU, pediatric intensive care unit, neonatal intensive care unit, mechanical ventilation, ventilator, intubation, intubated, intensive care, intensive care unit, intensive treatment unit, critical care unit.

^¶ All-cause medically attended LRTI was defined by the presence of cough or difficulty breathing while seen in an outpatient or inpatient clinical setting and ≥ 1 of the following: wheezing, chest wall in-drawing/retractions, rales/crackles, hypoxemia, tachypnea, dehydration due to respiratory symptoms.

^** All-cause LRTI-associated hospitalization was defined by the presence of the following: cough or difficulty breathing; ≥ 1 of the following: wheezing, chest wall in-drawing/retractions, rales/crackles, hypoxemia, tachypnea, dehydration due to respiratory symptoms; and hospital admission for respiratory illness.

^†† Serious adverse events were defined in the protocol as any adverse event that: results in death; is immediately life-threatening; requires inpatient hospitalization or prolongs an existing hospitalization; results in persistent or significant disability/incapacity; or is an important medical event that may jeopardize the subject or may require medical intervention to prevent one of the outcomes above.

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

Abbreviations: RSV= respiratory syncytial virus; IM= intramuscular; LRTI= lower respiratory tract infection; ICU= intensive care unit

Table 2: Outcomes and Rankings

Abbreviations: RSV= respiratory syncytial virus; LRTI= lower respiratory tract infection; ICU= intensive care unit

Table 3a: Summary of studies reporting prevention of medically attended RSV-associated LRTI^a

Abbreviations: CI= confidence interval; SD= standard deviation; RCT= randomized control trial

^a RSV-associated medically attended LRTI was defined by the presence of the following while seen in an outpatient or inpatient clinical setting: cough or difficulty breathing; ≥ 1 indicator of LRTI or severity (wheezing, chest wall in-drawing/retractions, rales/crackles, hypoxemia, tachypnea, dehydration due to respiratory symptoms); and a nasopharyngeal sample that was RSV positive by reverse transcriptase-polymerase chain reaction (RT-PCR).

^b Efficacy was defined as 1-relative risk, and the relative risk was estimated using a modified Poisson regression approach.

^c Patients were randomized 2:1 to the clesrovimab and placebo arms.

Table 3b: Summary of studies reporting prevention of RSV-associated LRTI with hospitalization^a

Abbreviations: LRTI= lower respiratory tract illness; CI= confidence interval; RCT= randomized control trial

^a RSV-associated LRTI hospitalization was defined as the presence of the following while seen in an inpatient clinical setting: cough or difficulty breathing and ≥ 1 or more indicator of LRTI (wheezing, rhonchi, rales/crackles) and ≥ 1 indicator of severity (chest wall in-drawing/retractions, hypoxemia, tachypnea, dehydration due to respiratory symptoms); and a nasopharyngeal sample that was RSV positive by RT-PCR testing.

^b Efficacy was defined as 1-relative risk, and the relative risk was estimated using a modified Poisson regression approach.

^c Patients were randomized 2:1 to the clesrovimab and placebo arms.

Table 3c: Summary of studies reporting prevention of RSV-associated LRTI with ICU admission^a

Abbreviations: CI= confidence interval; RCT= randomized control trial

^a RSV-associated LRTI with ICU admission was defined as hospital admission for respiratory illness; a nasopharyngeal sample that was RSV positive by RT-PCR; and evidence of admission in ICU in the associated serious adverse event narrative by looking for ≥ 1 of the following key terms: ICU, PICU, NICU, mechanical ventilation, ventilator, intubation, intubated, intensive care, intensive care unit, intensive treatment unit, critical care unit.

^b Efficacy and 95% CI were estimated by an exact method.

^c Patients were randomized 2:1 to the clesrovimab and placebo arms.

Table 3d: Summary of studies reporting prevention of all-cause medically attended LRTI^a

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

^a All-cause medically attended LRTI was defined by the presence of cough or difficulty breathing while seen in an outpatient or inpatient clinical setting and ≥ 1 of the following: wheezing, chest wall in-drawing/retractions, rales/crackles, hypoxemia, tachypnea, dehydration due to respiratory symptoms.

^b Efficacy was defined as 1-relative risk, and the relative risk was estimated using a modified Poisson regression approach.

^c Patients were randomized 2:1 to the clesrovimab and placebo arms.

Table 3e: Summary of studies reporting prevention of all-cause LRTI-associated hospitalization^a

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

^a All-cause LRTI-associated hospitalization was defined by the presence of the following: cough or difficulty breathing; ≥ 1 of the following: wheezing, chest wall in-drawing/retractions, rales/crackles, hypoxemia, tachypnea, dehydration due to respiratory symptoms; and hospital admission for respiratory illness.

^b Efficacy was defined as 1-relative risk, and the relative risk was estimated using a modified Poisson regression approach.

^c Patients were randomized 2:1 to the clesrovimab and placebo arms.

Table 3f: Summary of studies reporting serious adverse events^a

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

^a Serious adverse events are adverse events resulting in death, hospitalization, significant disability, or requiring medical intervention care, or admission to an intensive care unit, intensive treatment unit, or critical care unit. Serious adverse events may be related or unrelated to the study intervention.

^b Patients were randomized 2:1 to the clesrovimab and placebo arms.

Table 4. Grade Summary of Findings Table

Abbreviations: CI= confidence interval; RR= risk ratio

a. Concern for indirectness was noted as the trial excluded infants who were palivizumab-eligible and took place during a season with disrupted seasonality due to COVID-19. This was deemed not serious.

b. Rate observed in the placebo group of the Phase 2b/3 RCT.

c. New Vaccine Surveillance Network rate of acute respiratory infection (not restricted to LRTI). Lively JY, Curns AT, Weinberg GA, Edwards KM, Staat MA, Prill MM, et al. Respiratory Syncytial Virus-Associated Outpatient Visits Among Children Younger Than 24 Months, Journal of the Pediatric Infectious Diseases Society. 2019; 8(3):284-286. doi: 10.1093/jpids/piz011.

d. Assumes 47.5% of acute respiratory infections from Lively et al 2019 are LRTI. Rainisch G, Adhikari B, Meltzer MI, Langley G. Estimating the impact of multiple immunization products on medically-attended respiratory syncytial virus (RSV) infections in infants. Vaccine. 2020;38(2):251-257. doi: 10.1016/j.vaccine.2019.10.023.

e. New Vaccine Surveillance Network data 2016-2020 (unpublished), included if with acute respiratory infection.

f. Concern for risk of bias was noted as this outcome was not a trial endpoint and was assessed post-hoc. This concern was deemed not serious.

g. Serious concern for imprecision was noted as the number of study participants did not meet optimal information size.

h. Serious concern for imprecision: the confidence interval containing estimates for which different policy decisions might be considered.

Appendix 1. Studies Included in the Review of Evidence

Abbreviations: RCT= randomized controlled trial; SD= standard deviation; RSV= respiratory syncytial virus; LRTI= lower respiratory tract infection; ICU= intensive care unit

^a N= Number of randomized participants, dosed with clesrovimab or placebo.

Appendix 2. Databases and search strategies used for systematic review^a

^a Most recent search conducted December 2, 2024.