Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Nirsevimab, Season 2

Overview

A Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) review of the evidence for benefits and harms for the long-acting monoclonal antibody nirsevimab, (Beyfortus, Sanofi and AstraZeneca) for prevention of respiratory syncytial virus (RSV))-associated lower respiratory tract infection (LRTI) in children <24 months who are at increased risk of severe disease entering their second 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 children aged 8–19 months* who are at increased risk of severe RSV disease and entering their second RSV season^† (200 mg) ?" The benefits chosen by 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). The quality of evidence from one Phase 2/3 randomized controlled trial (RCT) with standard of care as the comparator (palivizumab) was assessed using the GRADE approach234.

Benefit outcomes for GRADE were assessed up to 150 days after injection. No direct efficacy data was available. Thus, pharmacokinetic extrapolation was used and based on comparable pharmacokinetic levels from efficacy in infants <12 months of age for prevention of the first medically attended RSV-associated LRTI to pharmacokinetic levels in children ≤24 months with chronic lung disease (CLD) or congenital heart disease (CHD) entering their second RSV season (evidence certainty: low). No data was available for other benefits.

The evidence indicated that SAEs^§ might not be more common in the intervention group than placebo group (RR 8.4; 95% CI: 0.52, 135.5; evidence certainty: very low).

Introduction

On July 17, 2023, the U.S. Food and Drug Administration (FDA) approved nirsevimab (Beyfortus, commercialized by Sanofi, manufactured by AstraZeneca), a long-acting monoclonal antibody, for the prevention of respiratory syncytial virus (RSV)-associated lower respiratory tract infection (LRTI) in infants and young children5. 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 children who are at increased risk of severe RSV disease entering their second RSV season and 8–19 months of age at time of immunization?" (Table 1). For information on GRADE related to the first RSV season indication, please see: https://www.cdc.gov/acip/grade/nirsevimab-season1-rsv-infants-children.html

Methods

We conducted a systematic review of evidence on the efficacy, pharmacokinetic data, and safety of nirsevimab received by children 8–19 months entering their second RSV season. 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, pharmacokinetics, 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. 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 could be assessed as certainty of high, moderate, low, or very low certainty.

Relative risk (RR) for harm outcomes were calculated using event counts and total persons at risk available from one Phase 2/3 RCT.

Results

The results of the GRADE assessment were presented to ACIP on February 23, 2023. Data were reviewed from one published Phase 2/3 RCT, plus additional data provided by the sponsor and FDA2347.

The Phase 2/3 RCT was not designed or powered to evaluate efficacy. There were no cases of medically attended RSV-associated LRTI in the second RSV season through 150 days post dose, which was conducted in 2020 during the COVID-19 pandemic. In the absence of direct efficacy data for high-risk children entering their second RSV season, two pharmacokinetic data endpoints were used to extrapolate efficacy from the Phase 2b and Phase 3 trials among infants that did not qualify for palivizumab:89the day 150 nirsevimab serum concentration and an area under the curve nirsevimab concentration. The day 150 post-dose serum concentration of nirsevimab among high-risk children in their second RSV season of the Phase 2/3 trial was higher than the concentrations reported in the Phase 3 trial among late preterm and term infants. More than 90% of the high-risk children in the Phase 2/3 trial had nirsevimab area under the curve concentrations that exceeded the target (Table 3a). FDA considered extrapolation of efficacy data from other trials to be appropriate because the pathophysiology of RSV infection, mechanism of action of nirsevimab, and response to nirsevimab is expected to be sufficiently similar between the populations of the efficacy trials and the pharmacokinetic trial7.

For evaluation of potential harms, SAEs were not significantly different in the intervention group than the placebo group (RR: 8.4 [95% CI: 0.52, 135.5])^¶ (Table 3b). FDA noted in the 150-days post-dose follow-up period for RSV season 2, there were no adverse reactions (adverse events judged as drug-related); the most commonly reported adverse event was pyrexia, which was reported in 13.2% of subjects who received nirsevimab and 11.9% of subjects who received palivizumab7.

GRADE Summary

The initial GRADE evidence level was type 1 (high) for each outcome because the body of evidence consisted of randomized controlled trials1. In terms of critical benefits, pharmacokinetic extrapolation from efficacy in infants <12 months of age for prevention of the first medically attended RSV-associated LRTI to pharmacokinetic levels in children ≤24 months with CLD or CHD entering their second RSV season met pre-determined thresholds. This outcome was downgraded twice for very serious concern for indirectness, due to surrogate outcome, surrogate outcomes was established among infants born during or entering their 1st RSV season while trial data is from children entering their 2nd RSV season, and trial population that does not match proposed indication. This resulted in low certainty in the outcome. For the important harm outcome of SAEs, the available data showed that SAEs might not be more common in intervention group than placebo group with very low certainty. Certainty for the outcome of SAEs was downgraded once for serious concern for indirectness as the comparison group is palivizumab rather than placebo and very serious concern for imprecision due to the width of the confidence interval containing estimates for which different policy decisions might be considered (Table 4). The overall certainty in the evidence was very low.

Footnotes

* Infants aged ≥8 months of age have likely experienced an RSV season and are at decreased risk of severe RSV-associated disease compared with younger infants without prior RSV exposure. Children at increased risk of severe disease aged ≥20 months of age have likely experienced two RSV seasons.

^† Those at increased risk include children with chronic lung disease of prematurity who required medical support (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) any time during the 6-month period before the start of the second RSV season; children with profound immunocompromise (e.g., children who received a hematopoietic stem cell transplant, with severe combined immunodeficiency); children with cystic fibrosis who either have manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest imaging that persist when stable) or weight-for-length <10th percentile; and American Indian and Alaska Native children.

^§ Serious adverse events were defined as death, events that were life-threatening or required inpatient hospitalization, events that prolonged hospitalization, events that were persistent or that were associated with clinically significant disability or incapacity, or events that were considered to be of medical significance.

^¶ No serious adverse events were recorded in the group that received palivizumab in the first and second RSV season, therefore, the relative risk was calculated using the standard offset of 0.5.

Tables

Table 1: 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}

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

^{Abbreviations: RCT= randomized control trial; RSV= respiratory syncytial virus; LRTI= lower respiratory tract infection; CLD= chronic lung disease; CHD= congenital heart disease}

^{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 Pharmacokinetic extrapolation was used and based on comparable pharmacokinetic levels from efficacy in infants <12 months of age for prevention of the first medically attended RSV LRTI to pharmacokinetic levels in children ≤24 months with chronic lung disease (CLD) or congenital heart disease (CHD) entering their second RSV season. Based on pharmacokinetic and efficacy data from the Phase 2b and Phase 3 (MELODY) trials, a target area under the curve nirsevimab concentration of >12.8 mg*day/ml was established. For the CLD cohort, 129/132 (98%) participants met the target nirsevimab concentration, and for the CHD cohort, 58/58 (92%) participants met the target. Additionally, the concentration of nirsevimab 150 days after injection was higher compared with the 150-day concentration in the Phase 3 trial nirsevimab arm population.}

Table 3b: 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 as death, events that were life-threatening or required inpatient hospitalization, events that prolonged hospitalization, events that were persistent or that were associated with clinically significant disability or incapacity, or events that were considered to be of medical significance.}

^{b Season 1: single injection of 50 mg of nirsevimab if the infant weighed <5 kg or 100 mg if they weighed ≥5 kg; season 2: single injection of 200-mg of nirsevimab.}

^{c Season 1 and 2: injection of 15 mg per kilogram of body weight of palivizumab.}

^{d No serious adverse events were recorded in the group that received palivizumab in the first and second RSV season, therefore, the relative risk was calculated using the standard offset of 0.5}

Table 4: GRADE Evidence Profile Tables

^{Abbreviations: CI= confidence interval; RR= risk ratio}

^{a Very serious concern for indirectness, due to use of a surrogate outcome, the surrogate was established in infants born during or entering their 1st season while trial data is from children entering their 2nd season, and population that does not match proposed indication.}

^{b Pharmacokinetic extrapolation was used and based on comparable pharmacokinetic levels from efficacy in infants <12 months of age for prevention of the first medically attended RSV-associated LRTI to pharmacokinetic levels in children ≤24 months with chronic lung disease (CLD) or congenital heart disease (CHD) entering their second RSV season. Based on pharmacokinetic and efficacy data from the Phase 2b and Phase 3 (MELODY) trials, a target area under the curve nirsevimab concentration of > 12.8 mg*day/ml was established. For the CLD cohort, 129/132 (98%) participants met the target nirsevimab concentration, and for the CHD cohort, 58/58 (92%) participants met the target. Additionally, the concentration of nirsevimab 150 days after injection was higher compared with the 150-day concentration in the Phase 3 trial nirsevimab arm population.}

^{c Serious concern for indirectness as the comparison group is palivizumab rather than placebo.}

^{d Very serious concern for imprecision due to the width of the confidence interval containing estimates for which different policy decisions might be considered.}

^{e 180 trial participants received nirsevimab in both the first and second season. 40 received palivizumab in the first season and nirsevimab in the second season}

^{f No serious adverse events were recorded in the group that received palivizumab in the first and second RSV season, therefore, the relative risk and 95% confidence interval was calculated using the standard offset of 0.5}

^{g No serious adverse events were recorded in the group that received palivizumab in the first and second RSV season, therefore, the absolute risk and 95% confidence interval was calculated using the standard offset of 0.5}

Appendix 1. Studies Included in the Review of Evidence

^{Abbreviations: RCT= randomized controlled trial; RSV= respiratory syncytial virus; LRTI= lower respiratory tract infection}

^{a Additional data provided by sponsor.}

^{b 310 children were randomized 2:1 to received palivizumab in the first RSV season of the trial. At the start of the second RSV season, 262 children were randomized 1:1 to receive palivizumab or nirsevimab.}

^{c 180 trial participants received nirsevimab in both the first and second season. 40 received palivizumab in the first season and nirsevimab in the second season}

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

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