Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Nirsevimab, Season 1

Overview

A Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) review of the evidence for benefits and harms of the long-acting monoclonal antibody nirsevimab, (Beyfortus, Sanofi and AstraZeneca) 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 February 23, 2023. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from high certainty to very low certainty1.

The policy question was, "Should one dose of nirsevimab be recommended for infants aged <8 months born during or entering their first RSV season (50 mg for infants <5 kg and 100 mg for infants ≥5 kg)?" 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); RSV-associated death (critical); all-cause medically attended LRTI (important); and all-cause LRTI-associated 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 3 randomized controlled trial (RCT) and one Phase 2b RCT were assessed using the GRADE approach2345.

For benefit and harm outcomes, available data was pooled from the Phase 3 and Phase 2b RCTs. Benefits were assessed up to 150 days after injection. A lower risk of medically attended RSV-associated LRTI* was observed with nirsevimab use compared to placebo (risk ratio [RR] 0.21, 95% confidence interval [CI]: 0.14, 0.31, evidence certainty: high), efficacy of 79.0% (95% CI: 68.5%, 86.1%). A lower risk of RSV-associated LRTI with hospitalization was observed (RR 0.19; 95% CI: 0.10, 0.38; evidence certainty: high), efficacy 80.6% (95% CI: 62.3%, 90.1%). A lower risk of RSV-associated LRTI with ICU admission was observed (RR 0.10; 95% CI: 0.01, 0.84; evidence certainty: moderate), efficacy 90% (95% CI: 16.4%, 98.8%). All-cause medically attended LRTI^† was observed (RR 0.65; 95% CI 0.55, 0.77; evidence certainty: high), efficacy 34.8% (95% CI: 23.0%, 44.7%). Finally, all-cause LRTI-associated hospitalization was observed (RR 0.55; 95% CI 0.40, 0.75; evidence certainty: high), efficacy 44.9% (95% CI: 24.9%, 59.6%). No deaths due to RSV were observed in the Phase 3 or Phase 2b trials.

The evidence indicated that SAEs^§ were not more common in the group that received nirsevimab compared to those in the placebo group (RR 0.73; 95% CI: 0.59, 0.89; evidence certainty: moderate).

Introduction

On July 17, 2023, the U.S. Food and Drug Administration (FDA) approved nirsevimab (Beyfortus, Sanofi, and AstraZeneca), a long-acting monoclonal antibody, for the prevention of respiratory syncytial virus (RSV)-associated lower respiratory tract infection (LRTI) in infants and young children4. As part of the process employed by ACIP, a systematic review and GRADE evaluation of the evidence for nirsevimab 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 products6. Evidence of benefits and harms were reviewed based on the GRADE approach1. 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 nirsevimab be recommended for infants born during or entering their first RSV season and <8 months of age at time of immunization?" (Table 1). For information on GRADE related to the second RSV season indication, please see: Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Nirsevimab, Season 2 | Advisory Committee on Immunization Practices (ACIP) | CDC.

Methods

We conducted a systematic review of evidence on the efficacy and safety of nirsevimab. We assessed outcomes and evaluated the quality of evidence using the GRADE approach from August 2022–February 2023.

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, RSV-associated LRTI with ICU admission, and RSV-associated death. Important benefits of interest are 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 nirsevimab. Records of relevant observational studies as well as randomized controlled trials were included if they 1) provided data on infants injected with nirsevimab; 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. No relevant observational studies were identified through the systematic review. The systematic review was conducted through May, 2022. 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 pooled one Phase 3 RCT and one Phase 2b RCT and estimated using Poisson regression with robust variance after multiple imputation was applied for subjects that did not experience the outcome and discontinued before day 151 after injection5. Efficacy was estimated using 1-relative risk. Relative risk for the harm outcome was calculated using pooled event counts and total persons at risk available from one Phase 3 RCT and one Phase 2b RCT.

Results

The results of the GRADE assessment were presented to ACIP on February 23, 2023. Data were reviewed from one published Phase 3 RCT, one published Phase 2b RCT, plus additional data provided by the sponsor and FDA3457.

For benefit and harm outcomes, available data was pooled from the Phase 3^¶ and Phase 2b** RCTs. A lower risk of medically attended RSV-associated LRTI was observed with nirsevimab use compared to placebo (efficacy: 79.0% [95% CI: 68.5%, 86.1%]) (Table 3a). Nirsevimab lowered the risk of RSV-associated LRTI with hospitalization (efficacy 80.6% [95% CI: 62.3%, 90.1%]) (Table 3b). A lower risk of RSV-associated LRTI with ICU admission was observed with nirsevimab use (efficacy 90.0% [95% CI: 16.4%, 98.8%]) (Table 3c). A lower risk of all-cause medically attended LRTI was observed with use of nirsevimab (efficacy 34.8% [95% CI: 23.0%, 44.7%]) (Table 3d). Finally, all-cause LRTI-associated hospitalization was observed with nirsevimab use (efficacy 44.9% [95% CI: 24.9%, 59.6%]) (Table 3e). No deaths due to RSV were observed in the trials.

For evaluation of potential harms, SAEs were not more common in the group that received nirsevimab compared with the placebo group (RR: 0.73 [95% CI: 0.59, 0.89]) (Table 3f). No SAEs or deaths were considered related to nirsevimab by the investigator7. FDA noted that overall, the incidence of SAEs was low, and types of SAEs reported are consistent with childhood illnesses8.

GRADE Summary

The initial GRADE evidence level was type 1 (high) for each outcome because the body of evidence consisted of randomized controlled trials2. In terms of critical benefits, the available data indicated that the nirsevimab was effective at preventing medically attended RSV LRTI and RSV LRTI with hospitalization, with no concerns in the certainty assessment. The available data indicated that nirsevimab was likely effective at preventing medically attended RSV LRTI with ICU admission with moderate certainty; certainty was downgraded once for serious concern for imprecision due the small number of events observed in the trial, leading to fragility in the estimate. The data available for the important benefits of all-cause medically attended LRTI and all-cause LRTI-associated hospitalization, showed that nirsevimab was effective at preventing both outcomes 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 nirsevimab 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

* Medically attended RSV-associated LRTI was defined as ≥1 documented physical examination findings localizing to the lower respiratory tract (rhonchi, rales, crackles, or wheeze), ≥1 clinical sign of severity (increased respiratory rate [age <2 months, ≥60 breaths/min; age 2–6 months, ≥50 breaths/min; age >6 months to 2 years, ≥40 breaths/min]; hypoxemia in room air-oxygen saturation <95% at altitudes ≤1,800 meters or <92% at altitudes >1,800 meters; acute hypoxic or ventilatory failure; new onset apnea; nasal flaring; retractions [intercostal, subcostal, or supraventricular retractions]; grunting; dehydration due to respiratory distress), an inpatient or outpatient encounter, and a positive RSV PCR test.

^† All-cause medically attended LRTI was defined as all lower respiratory tract infections with ≥1 clinical sign of severity: increased respiratory rate (age <2 months, ≥60 breaths/min; age 2–6 months, ≥50 breaths/min; age >6 months to 2 years, ≥40 breaths/min); hypoxemia in room air-oxygen saturation <95% at altitudes ≤1,800 meters or <92% at altitudes >1,800 meters; acute hypoxic or ventilatory failure; new onset apnea; nasal flaring; retractions (intercostal, subcostal, or supraventricular retractions); grunting; dehydration due to respiratory distress with an inpatient or outpatient encounter, regardless of whether they tested positive for RSV.

^§ 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 listed.

^¶ Due to the COVID-19 pandemic, the Phase 3 trial stopped enrollment after randomization of 1,490 participants and initial results were published. Enrollment resumed for a total of 3,012 participants. Pooled estimates include all Phase 3 participants.

** Infants ≥5 kg from the Phase 2b study were excluded from the pooled estimates because the Phase 2b study found infants ≥5 kg required a higher dose for sufficient efficacy and subsequent trials used a higher dose for infants ≥5 kg. For infants <5 kg, 50 mg of nirsevimab is recommended. For infants ≥5 kg, 100 mg of nirsevimab is recommended. In the phase 2b study, all infants received 50 mg of nirsevimab. All infants who received nirsevimab were categorized into four bins based on pharmacokinetic measure of nirsevimab exposure, the area under the curve (AUC) nirsevimab concentration. In this study, the majority of infants ≥5 kg had an AUC nirsevimab concentration in the lowest quartile (i.e., < 12.8 mg*days/mL). Compared with placebo, the hazard ratio (HR) for medically attended RSV-associated LRTI through 150 days was higher (HR: 0.48) in those with an AUC nirsevimab concentration < 12.8 mg*days/mL than with infants with an AUC nirsevimab concentration in the top three quartiles (top quartile HR: 0.19, second quartile HR: 0.16, third quartile HR: 0.27) (reference: Simões EAF, Madhi SA, Muller WJ, Atanasova V, Bosheva M, Cabañas F, et al. Efficacy of nirsevimab against respiratory syncytial virus lower respiratory tract infections in preterm and term infants, and pharmacokinetic extrapolation to infants with congenital heart disease and chronic lung disease: a pooled analysis of randomised controlled trials. The Lancet Child & Adolescent Health. 2023;7(3): 180–189. Doi:10.1016/S2352-4642(22)00321-2.). The dose used in the phase 3 trial and included by FDA in the product label is based on these results. Therefore, infants ≥5 kg in the phase 2b study were assumed to be underdosed and excluded from pooled analyses for efficacy.

^†† Additional details can be found on pages 38–39 of the June 8, 2023 Antimicrobial Drugs Advisory Committee Meeting Briefing Document, https://www.fda.gov/media/169226/download

Tables and Appendices

Table 1: Policy Questions and 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
^a No events occurred in the studies with this outcome included in the review of evidence.}

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

_{Abbreviations: CI= confidence interval; SD= standard deviation; RCT= randomized control trial
^a Medically attended RSV-associated LRTI was defined as ≥1 documented physical examination findings localizing to the lower respiratory tract: rhonchi; rales; crackles; or wheeze and ≥1 clinical sign of severity: increased respiratory rate (age <2 months, ≥60 breaths/min; age 2–6 months, ≥50 breaths/min; age >6 months to 2 years, ≥40 breaths/min); hypoxemia in room air-oxygen saturation <95% at altitudes ≤1,800 meters or <92% at altitudes >1,800 meters; acute hypoxic or ventilatory failure; new onset apnea; nasal flaring; retractions (intercostal, subcostal, or supraventricular retractions); grunting; dehydration due to respiratory distress with an inpatient or outpatient encounter and RSV PCR positive test.
^b Intervention was a single injection of 50 mg of nirsevimab if the infant weighed <5 kg or 100 mg if they weighed ≥5 kg for the Phase 3 RCT or 50mg nirsevimab for Phase 2b RCT
^c Efficacy was estimated from Poisson regression with robust variance after multiple imputation was applied for subjects that did not have a medically attended-RSV-associated LRTI event and discontinued before day 151 after injection.
^d Additional data provided by sponsor}

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

_{Abbreviations: LRTI= Lower Respiratory Tract Illness; CI = confidence interval; RCT= randomized control trial
^a RSV-associated LRTI with hospitalization was defined as ≥1 documented physical examination findings localizing to the lower respiratory tract: rhonchi; rales; crackles; or wheeze and ≥1 clinical sign of severity: increased respiratory rate (age <2 months, ≥60 breaths/min; age 2–6 months, ≥50 breaths/min; age >6 months to 2 years, ≥40 breaths/min); hypoxemia in room air-oxygen saturation <95% at altitudes ≤1,800 meters or <92% at altitudes >1,800 meters; acute hypoxic or ventilatory failure; new onset apnea; nasal flaring; retractions (intercostal, subcostal, or supraventricular retractions); grunting; dehydration due to respiratory distress with an inpatient encounter and RSV PCR positive test.
^b Intervention was a single injection of 50 mg of nirsevimab if the infant weighed <5 kg or 100 mg if they weighed ≥5 kg for the Phase 3 RCT or 50mg nirsevimab for Phase 2b RCT.
^c Efficacy was estimated from Poisson regression with robust variance after multiple imputationwas applied for subjects that did not have MA-RSV LRTI event and discontinued before day 151 after injection.
^d Additional data provided by sponsor.}

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

_{Abbreviations: CI= confidence interval; IRR= Incidence rate ratio; RCT= randomized control trial; NE= not estimable
^a RSV-associated LRTI with ICU admission was defined as ≥1 documented physical examination findings localizing to the lower respiratory tract: rhonchi; rales; crackles; or wheeze and ≥1 clinical sign of severity: increased respiratory rate (age <2 months, ≥60 breaths/min; age 2–6 months, ≥50 breaths/min; age >6 months to 2 years, ≥40 breaths/min); hypoxemia in room air-oxygen saturation <95% at altitudes ≤1,800 meters or <92% at altitudes >1,800 meters; acute hypoxic or ventilatory failure; new onset apnea; nasal flaring; retractions (intercostal, subcostal, or supraventricular retractions); grunting; dehydration due to respiratory distress with an inpatient encounter with ICU admission and RSV PCR positive test.
^b Intervention was a single injection of 50 mg of nirsevimab if the infant weighed <5 kg or 100 mg if they weighed ≥5 kg for the Phase 3 RCT or 50mg nirsevimab for Phase 2b RCT
^c Additional data provided by sponsor.
^d Efficacy was estimated from Poisson regression with robust variance after multiple imputationwas applied for subjects that did not have MA-RSV LRTI event and discontinued before day 151 after injection.
^e Efficacy was estimated from exact conditional Poisson regression based on observed data}

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

_{Abbreviations: RR= relative risk; CI= confidence interval; RCT= randomized controlled trial.
^a All-cause medically attended LRTI was defined as all lower respiratory tract infections with ≥1 clinical sign of severity: increased respiratory rate (age <2 months, ≥60 breaths/min; age 2–6 months, ≥50 breaths/min; age >6 months to 2 years, ≥40 breaths/min); hypoxemia in room air-oxygen saturation <95% at altitudes ≤1,800 meters or <92% at altitudes >1,800 meters; acute hypoxic or ventilatory failure; new onset apnea; nasal flaring; retractions (intercostal, subcostal, or supraventricular retractions); grunting; dehydration due to respiratory distress with an inpatient or outpatient encounter, regardless of whether they tested positive for RSV.
^b Intervention was a single injection of 50 mg of nirsevimab if the infant weighed <5 kg or 100 mg if they weighed ≥5 kg for the Phase 3 RCT or 50mg nirsevimab for Phase 2b RCT.
^c Multiple imputation was applied for subjects that did not have any MA LRTI event and discontinued before Day 151 after injection.
^d Additional data provided by sponsor.}

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

_{Abbreviations: RR= relative risk; CI= confidence interval; RCT= randomized controlled trial.
^a All-cause LRTI-associated hospitalization was defined as ≥1 documented physical examination findings localizing to lower respiratory tract: rhonchi; rales; crackles; or wheeze + inpatient hospitalization.
^b Intervention was a single injection of 50 mg of nirsevimab if the infant weighed <5 kg or 100 mg if they weighed ≥5 kg for the Phase 3 RCT or 50mg nirsevimab for Phase 2b RCT.
^c Multiple imputation was applied for subjects that did not have any hospitalization for respiratory illness and discontinued before Day 151 after injection.
^d Additional data provided by sponsor.}

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 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 listed.
^b Intervention was a single injection of 50 mg of nirsevimab if the infant weighed <5 kg or 100 mg if they weighed ≥5 kg for the Phase 3 RCT or 50mg nirsevimab for Phase 2b RCT.
^c Additional data provided by sponsor.}

Table 4: GRADE Evidence Profile Tables

_{Abbreviations: CI= confidence interval; HR= hazard ratio; RR= risk ratio
^a Rate observed in the placebo group of the Phase 3 RCT.
^b 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.
^c 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.
^d Acute respiratory infections, New Vaccine Surveillance Network data 2016-2020 (unpublished).
^e Only seven events recorded in both trials.
^f Acute respiratory infections, New Vaccine Surveillance Network data 2016-2020 (unpublished). Proportion of hospitalizations admitted to ICU. Arriola CS, Kim L, Langley G, Anderson EJ, Openo K, Martin AM, et al. Estimated Burden of Community-Onset Respiratory Syncytial Virus–Associated Hospitalizations Among Children Aged <2 Years in the United States, 2014–15, Journal of the Pediatric Infectious Diseases Society. 2020; 9(5): 587–595. Doi: 10.1093/jpids/piz087.
^g Trials were underpowered to detect rare events (e.g., anaphylaxis).}

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 Additional data provided by sponsor.}

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

_{^a Most recent search conducted May 11, 2022.}