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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Nirsevimab, Season 1						Print
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			OverviewIntroductionMethodsResultsGRADE Summary
		
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 certainty [*1*].
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 approach [*2-5*].
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 children [*4*]. 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 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 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: https://www.cdc.gov/vaccines/acip/recs/grade/nirsevimab-season2-rsv-infants-children.html.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 injection [*5*]. 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 FDA [*3-5,8*].
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 investigator [8]. FDA noted that overall, the incidence of SAEs was low, and types of SAEs reported are consistent with childhood illnesses [*9*].GRADE Summary
The initial GRADE evidence level was type 1 (high) for each outcome because the body of evidence consisted of randomized controlled trials [2]. 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
References
Ahmed F. U.S. Advisory Committee on Immunization Practices (ACIP)  https://www.cdc.gov/vaccines/acip/recs/grade/downloads/handbook.pdf
Hammitt LL, Dagan R, Yuan Y, Baca Cots M, Bosheva M, Madhi SA, et al. Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants. *New England Journal of Medicine.* 386(9): 837-846. https://doi.org/10.1056/NEJMoa2110275
Muller WJ, Madhi SA, Seoane Nunez B, et al. Nirsevimab for Prevention of RSV in Term and Late-Preterm Infants. N Engl J Med. Apr 20 2023;388(16):1533-1534. https://doi.org/10.1056/NEJMc2214773
Griffin MP, Yuan Y, Takas T, Domachowske JB, Madhi SA, Manzoni P, et al. Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants. *New England Journal of Medicine*. 2020. 383(5): 415-425. https://doi.org/10.1056/NEJMoa1913556
Sanofi/AstraZeneca, 2023 personal communication, August 2022 – February 2023.
CDC ACIP charter https://www.cdc.gov/vaccines/acip/committee/charter.html
FDA. Nirsevimab approval press release. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-prevent-rsv-babies-and-toddlers
Sanofi/AstraZeneca. October 19, 2022. ACIP slides https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-10-19-20/02-RSV-Mat-Ped-Felter-508.pdf
FDA Briefing Document, Nirsevimab https://www.fda.gov/media/169226/downloadTable 1: Policy Questions and PICO
Table 1: Policy Questions and PICO
Policy question
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?**Population**
Infants <8 months of age, born during or entering their first RSV seasonIntervention
Nirsevimab (1 injection prior to start of RSV season or at birth if born during season, 50 mg if <5 kg or 100 mg if ≥5 kg)Comparison
No nirsevimab prophylaxisOutcomes
Medically attended RSV-associated LRTI
RSV-associated LRTI with hospitalization
RSV-associated LRTI with ICU admission
RSV-associated death
All-cause medically attended LRTI
All-cause LRTI-associated hospitalization
Serious adverse eventsAbbreviations: RSV= respiratory syncytial virus; IM= intramuscular; LRTI= lower respiratory tract infection; ICU= intensive care unitTable 2: Outcomes and Rankings
Table 2: Outcomes and Rankings
Outcome
Importance
Included in evidence profileMedically attended RSV-associated LRTI
Critical
YesRSV-associated LRTI with hospitalization
Critical
YesRSV-associated LRTI with ICU admission
Critical
YesRSV-associated death
Critical
NoaAll-cause medically attended LRTI
Important
YesAll-cause LRTI-associated hospitalization
Important
YesSerious adverse events
Important
Yes**Abbreviations:** RSV= respiratory syncytial virus; LRTI= lower respiratory tract infection; ICU= intensive care unita 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 LRTIa
Table 3a: Summary of studies reporting medically attended RSV-associated LRTI
Authors last name, pub year
Age or other characteristic of importance
n/N interventionb
n/N comparison
Comparator
Efficacyc (95% CI)
Study limitations (Risk of Bias)Muller, 2023 and Hammitt, 2022 Phase 3 RCTd
Infants born ≥35 weeks gestational age
24/2009
54/1003
Placebo
76.4% (62.3%, 85.2%)
NoneGriffin, 2020 Phase 2b RCTd
Infants born 29–34 weeks gestation weighing <5 kg;
7/570
26/290
Placebo
86.2% (68.08%, 94.0%)
None
**Abbreviations:**CI= confidence interval; SD= standard deviation; RCT= randomized control triala 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 RCTc 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 sponsorTable 3b: Summary of studies reporting RSV-associated LRTI with hospitalizationa
Table 3b: Summary of studies reporting RSV-associated LRTI with hospitalization
Authors last name, pub year
Age or other characteristic of importance
n/N interventionb
n/N comparison
Comparator
Efficacyc (95% CI)
Study limitations (Risk of Bias)Muller, 2023 and Hammitt, 2022 Phase 3 RCTd
Infants born ≥35 weeks gestational age
9/2009
20/1003
Placebo
76.8% (49.4%, 89.4%)
NoneGriffin, 2020 Phase 2b RCTd
Infants born 29–34 weeks gestation weighing <5 kg
3/570
13/290
Placebo
86.5% (53.5%, 96.1%)
None
**Abbreviations:** LRTI= Lower Respiratory Tract Illness; CI = confidence interval; RCT= randomized control triala 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 imputation
was 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 admissiona
Table 3b: Summary of studies reporting RSV-associated LRTI with hospitalization
Authors last name, pub year
Age or other characteristic of importance
n/N interventionb
n/N comparison
Comparator
Efficacy (95% CI)
Study limitations (Risk of Bias)Muller, 2023 and Hammitt, 2022 Phase 3 RCTc
Infants born ≥35 weeks gestational age
1/2009
1/1003
Placebo
48.3% (-725.6%, 96.8%)d
NoneGriffin, 2020 Phase 2b RCTc
Infants born 29–34 weeks gestation weighing <5 kg
0/570
5/290
Placebo
100.0 (44.5, NE)e
None
**Abbreviations:** CI= confidence interval; IRR= Incidence rate ratio; RCT= randomized control trial; NE= not estimablea 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 RCTc Additional data provided by sponsor.d Efficacy was estimated from Poisson regression with robust variance after multiple imputation
was 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 dataTable 3d: Summary of studies reporting all-cause medically attended LRTIa
Table 3d: Summary of studies reporting all-cause medically attended LRTI
Authors last name, pub year
Age or other characteristic of importance
**n/N (%) interventionb**
n/N (%) comparison
Comparator
**Efficacyc**(95% CI)
Study limitations (Risk of Bias)Muller, 2023 and Hammitt, 2022 Phase 3 RCTd
Infants born ≥35 weeks gestational age
171/2009
139/1003
Placebo
38.2% (23.7%, 50.0%)
NoneGriffin, 2020 Phase 2b RCTd
Infants born 29–34 weeks gestation weighing <5 kg
99/570
72/290
Placebo
26.9% (4.9%, 43.8)
None
**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 hospitalizationa
Table 3e: Summary of studies reporting all-cause LRTI-associated hospitalization
Authors last name, pub year
Age or other characteristic of importance
**n/N interventionb**
n/N comparison
Comparator
**Efficacyc**(95% CI)
Study limitations (Risk of Bias)Muller, 2023 and Hammitt, 2022 Phase 3 RCTd
Infants born ≥35 weeks gestational age
45/2009
37/1003
Placebo
38.9% (6.3%, 60.2%)
NoneGriffin, 2020 Phase 2b RCTd
Infants born 29–34 weeks gestation weighing <5 kg
33/570
35/290
Placebo
50.0% (21.4%, 68.1%)
None
**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 eventsa
Table 3e: Summary of studies reporting all-cause LRTI-associated hospitalization
Authors last name, pub year
Age or other characteristic of importance
**n/N (%) interventionb**
n/N **(%)**comparison
Comparator
RR (95% CI)
Study limitations (Risk of Bias)Muller, 2023 and Hammitt, 2022 Phase 3 RCTc
Infants born ≥35 weeks gestational age
125/1998 (6.3)
74/996 (7.4)
Placebo
0.84 (0.64, 1.11)
NoneGriffin, 2020 Phase 2b RCTc
Infants born 29–34 weeks gestation weighing <5 kg
70/572 (12.2)
61/288 (21.2)
Placebo
0.58 (0.43, 0.80)
None
**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
Grade Summary of Findings Table
Certainty assessment
No of patients
Effect
Certainty
ImportanceNo of studies
Study design
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations
Nirsevimab (1 injection prior to start of RSV season or after birth if born during season, 50 mg if <5 kg or 100 mg if ≥5 kg)
no intervention
Relative
(95% CI)
Absolute
(95% CI)Medically attended RSV-associated LRTI2
randomized trials
not serious
not serious
not serious
not serious
none
31/2579 (1.2%)
5.4%a
**HR 0.210**
(0.139 to 0.315)
**42 fewer per 1,000**
(from 46 fewer to 37 fewer)
⨁⨁⨁⨁
High
CRITICAL23.1%b
**177 fewer per 1,000**
(from 195 fewer to 152 fewer)11.0%c
**86 fewer per 1,000**
(from 94 fewer to 74 fewer)RSV-associated LRTI with hospitalization2
randomized trials
not serious
not serious
not serious
not serious
none
12/2579 (0.5%)
2.0%a
**HR 0.194**
(0.099 to 0.377)
**16 fewer per 1,000**
(from 18 fewer to 12 fewer)
⨁⨁⨁⨁
High
CRITICAL1.3%d
**10 fewer per 1,000**
(from 12 fewer to 8 fewer)RSV-associated LRTI with ICU admission2
randomized trials
not serious
not serious
not serious
seriouse
none
1/2579 (0.0%)
0.1%a
**HR 0.100**
(0.012 to 0.836)
**90 fewer per 100,000**
(from 99 fewer to 16 fewer)
⨁⨁⨁◯
Moderate
CRITICAL0.35%f
**315 fewer per 100,000**
(from 346 fewer to 57 fewer)All-cause medically attended LRTI2
randomized trials
not serious
not serious
not serious
not serious
none
270/2579 (10.5%)
13.9%a
**HR 0.652**
(0.553 to 0.770)
**46 fewer per 1,000**
(from 60 fewer to 30 fewer)
⨁⨁⨁⨁
High
IMPORTANTAll-cause LRTI-associated hospitalization2
randomized trials
not serious
not serious
not serious
not serious
none
78/2579 (3.0%)
3.7%a
**HR 0.551**
(0.404 to 0.751)
**16 fewer per 1,000**
(from 22 fewer to 9 fewer)
⨁⨁⨁⨁
High
IMPORTANTSerious adverse events2
randomized trials
not serious
not serious
not serious
seriousg
none
195/2570 (7.6%)
135/1284 (10.5%)
**RR 0.73**
(0.59 to 0.89)
**28 fewer per 1,000**
(from 43 fewer to 12 fewer)
⨁⨁⨁◯
Moderate
IMPORTANT
**Abbreviations:** CI= confidence interval; HR= hazard ratio; RR= risk ratioa 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
Appendix 1. Studies Included in the Review of Evidence
Last name first author, Publication year
Study design
Country (or more detail, if needed)
Population
Age
Total population
N Intervention
N comparison
Outcomes
Funding sourcePhase 3 RCTa Muller, 2023 and Hammitt, 2022
Phase 3 RCT
Austria, Belgium, Bulgaria, Canada, Czechia, Estonia, Finland, France, Germany, Israel, Japan, South Korea, Latvia, Lithuania, Poland, Russia, Spain, Sweden, United Kingdom, United States, South Africa
Age at randomization, n (%)
≤3 months: 1179/3012 (59.0%)
>3.0 to ≤6.0 months: 959/3012 (31.8%)
>6.0 months: 275/3012 (9.1%)
3,012
2,009
1,003
Medically attended RSV-associated LRTI; RSV-associated LRTI with hospitalization; RSV-associated LRTI with ICU admission; RSV-associated death; All-cause medically attended LRTI; All-cause LRTI-associated hospitalization; Serious adverse events
Muller: AstraZeneca and Sanofi Hammitt: MedImmune/AstraZeneca and SanofiPhase 2b RCTa Griffin, 2020
Phase 2b RCT
Bulgaria, Canada, Czechia, France, Hungary, Italy, Poland, Russian Federation, Spain, United Kingdom, United States, Argentina, Australia, Brazil, Chile, New Zealand, and South Africa.
Mean age: 3.29 months (SD: 2.22)
860
570 (593 infants were excluded from the analysis due to under dosing)
290
Medically attended RSV-associated LRTI; RSV-associated LRTI with hospitalization; RSV-associated LRTI with ICU admission; RSV-associated death; All-cause medically attended LRTI; All-cause LRTI-associated hospitalization; Serious adverse events
AstraZeneca and Sanofi Pasteur
**Abbreviations:** RCT = randomized controlled trial; SD = standard deviation; RSV= respiratory syncytial virus; LRTI= lower respiratory tract infection; ICU= intensive care unita Additional data provided by sponsor.Appendix 2. Databases and strategies used for systematic reviewa
Appendix 2. Databases and strategies used for systematic reviewa
Database
Strategy**Medline****(OVID)****1946-**
Nirsevimab OR MEDI8897 OR ((Antibodies, Monoclonal, Humanized/ OR Antibodies, Monoclonal/) AND (respiratory syncytial virus infections/ OR respiratory syncytial virus, human/)) OR (VRN8S9CW5V OR nirsevimab OR 1989556-22-0).rn OR Nirsevimab.nm
Limit 2015 –**Embase****(OVID)****1974-**
Nirsevimab OR MEDI8897 OR (Monoclonal antibody/ AND human respiratory syncytial virus/) OR (VRN8S9CW5V OR nirsevimab OR 1989556-22-0).rn OR (VRN8S9CW5V OR nirsevimab OR 1989556-22-0).dy
Limit 2015 –**Cochrane Library**
(Nirsevimab OR MEDI8897 OR VRN8S9CW5V OR 1989556-22-0)
Limit 2015 –**CINAHL****(****EbscoHost****)**
(Nirsevimab OR MEDI8897 OR VRN8S9CW5V OR 1989556-22-0)
Limit 2015 –**Scopus**
TITLE-ABS-KEY(Nirsevimab OR MEDI8897 OR VRN8S9CW5V OR 1989556-22-0)**Clinicaltrials.gov**
(Nirsevimab OR MEDI8897 OR VRN8S9CW5V OR 1989556-22-0)
a Most recent search conducted May 11, 2022.Top of Page
							
					
							Last Reviewed:  August 24, 2023						Source: 	National Center for Immunization and Respiratory Diseases
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