Video Abstract

Video Abstract

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BACKGROUND:

Data describing respiratory syncytial virus (RSV) neutralizing antibody (nAb) levels for nirsevimab, a recently approved, extended half-life, anti-RSV fusion protein (F protein) monoclonal antibody, relative to the previous standard of care, palivizumab, have not been reported.

METHODS:

MEDLEY was a randomized, palivizumab-controlled, phase 2/3 study of nirsevimab during 2 RSV seasons (season 1 and 2) in infants born preterm (≤35 weeks’ gestational age; dosed season 1 only) or with congenital heart disease or chronic lung disease of prematurity (dosed seasons 1 and 2). Participants were randomly assigned to receive a single dose of nirsevimab followed by 4 monthly placebo doses, or 5 once-monthly doses of palivizumab. Anti-RSV F protein serology (ie, levels of prefusion [pre-F]/postfusion [post-F] conformation antibodies), nirsevimab and palivizumab concentrations, and RSV nAbs were measured in participant serum collected at baseline (pre-dose) and days 31, 151, and 361.

RESULTS:

Serologic data were similar in seasons 1 and 2. Nirsevimab predominately conferred pre-F antibodies, whereas palivizumab conferred pre-F and post-F antibodies. Nirsevimab and palivizumab serum concentrations highly correlated with nAb levels in both seasons. In season 1, nAb levels in nirsevimab recipients were highest in day 31 samples and gradually declined but remained 17-fold above baseline at day 361. nAb levels in palivizumab recipients increased incrementally with monthly doses to day 151. nAb levels followed similar patterns in season 2. nAb levels were ∼10-fold higher with nirsevimab compared with palivizumab across both seasons.

CONCLUSIONS:

Nirsevimab prophylaxis confers ∼10-fold higher and more sustained RSV nAb levels relative to palivizumab.

Subjects:
Infectious Diseases, RSV
Topics:
neutralizing antibodies, nirsevimab, palivizumab, monoclonal antibodies, serologic tests
What’s Known on This Subject:

Monoclonal antibody prophylaxis has a history of preventing severe RSV-associated lower respiratory tract disease in infants through the direct provision of anti-RSV fusion protein nAbs. Previous placebo-controlled clinical studies have revealed that nirsevimab confers high and sustained levels of nAbs.

What This Study Adds:

These data illustrate that a single dose of nirsevimab confers ∼10-fold higher levels of RSV nAbs compared with palivizumab, which were sustained through 1 year post-administration, suggesting nirsevimab may offer protection for a period beyond a typical 5-month RSV season.

Respiratory syncytial virus (RSV) is the global leading cause of lower respiratory tract infection (LRTI) among infants and young children aged ≤24 months.1–4 The prophylactic administration of RSV neutralizing antibodies (nAbs) to infants at higher risk of severe RSV lower respiratory tract disease was demonstrated as an effective disease prevention strategy in the early 1990s with the use of RSV intravenous immune globulin.5 Because it possesses essential roles in host cell entry, the RSV fusion protein (F protein) has since become a prominent target for the development of prophylactic monoclonal antibodies (mAbs).6–8 

Palivizumab is a humanized mAb that targets an antigenic site II epitope present in the prefusion and postfusion conformations of the RSV F protein (pre-F/post-F).6,9 Palivizumab has been an effective prophylaxis for multiple pediatric populations at higher risk of severe RSV disease throughout its >25-year history of use (eg, infants born preterm [gestational age (GA) ≤35 weeks] and/or with congenital heart disease or chronic lung disease of prematurity [CHD/CLD]).10 However, a considerable RSV disease burden among all infants,11 combined with a requirement for monthly palivizumab dosing9 and local United States policy decisions restricting palivizumab use among preterm infants to those born extremely preterm (GA ≤29 weeks),12 spurred the development of nirsevimab, a highly potent, human, extended half-life (∼71 days)13 anti-RSV F protein mAb, designed to confer protection for an entire 5-month RSV season after a single intramuscular dose.13,14 Nirsevimab targets a highly conserved epitope in the pre-F-exclusive antigenic site Ø to prevent RSV host cell entry.13–16 Nirsevimab has demonstrated consistently high efficacy against medically attended RSV LRTI during randomized placebo-controlled trials in healthy term and preterm infants,17–19 with efficacy rates of 79.5% (95% confidence interval [CI]: 65.9–87.7) against medically attended RSV LRTI and 77.3% (95% CI: 50.3–89.7) against RSV LRTI hospitalization observed ≥150 days post-dose in a pooled analysis of infants enrolled in the pivotal phase 2b (GA ≥29 to <35 weeks; NCT02878330) and phase 3 MELODY (GA ≥35 weeks; NCT03979313) trials.20 Nirsevimab subsequently demonstrated an efficacy of 83.2% (95% CI: 67.8–92.0) against RSV LRTI hospitalization in these populations during the phase 3b HARMONIE trial (NCT05437510).21 

The safety and pharmacokinetics (PK) of nirsevimab were evaluated in infants at higher risk of severe RSV disease in the phase 2/3, randomized, palivizumab-controlled MEDLEY trial (NCT03959488), wherein nirsevimab demonstrated a comparable safety profile to palivizumab22,23 that was consistent with placebo-controlled nirsevimab trials.13,24 PK data from MEDLEY and the phase 2b and MELODY trials enabled the extrapolation of efficacy to infants born extremely preterm and/or with CHD/CLD20,22 and supported the approval of nirsevimab for the prevention of RSV lower respiratory tract disease in neonates and infants born during or entering their first RSV season, as well as in children ≤24 months of age who remain vulnerable to severe RSV disease through their second RSV season in the United States in July 2023.25,26 Although nirsevimab and other anti-site Ø antibodies have displayed comparatively higher neutralizing potencies than palivizumab in preclinical studies,14,27–29 clinical data revealing nAb levels conferred by nirsevimab relative to palivizumab have not been reported. This prespecified exploratory analysis from MEDLEY describes the potency and longevity of RSV nAbs associated with nirsevimab and palivizumab.

The methodology of the MEDLEY trial has been previously described.23 The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonization Good Clinical Practice guidelines. Each site had approval from an institutional ethics review board or ethics committee, and appropriate written informed consent was obtained for each infant before enrollment.

Participants were recruited between May 21, 2019 and April 28, 2021.30 Infants eligible to receive palivizumab under local or national policy guidelines born during or before their first RSV season were enrolled into the trial in the following 2 cohorts: infants born preterm (GA ≤35 weeks) and infants with CHD/CLD, irrespective of GA at birth. The trial was assessed as 2 RSV seasons (seasons 1 and 2), with participation in season 2 restricted to the CHD/CLD cohort in accordance with guidelines for palivizumab use. The baseline characteristics of season 123 and season 222 participants have been previously published.

Before season 1, participants were randomly assigned 2:1 to receive either 1 intramuscular dose of nirsevimab (weight-banded dosing: 50 mg if infant weight <5 kg, 100 mg if ≥5 kg) followed by 4 once-monthly doses of placebo or 5 once-monthly intramuscular doses of palivizumab (15 mg/kg weight per dose). Participants who received nirsevimab in season 1 received 200 mg of nirsevimab followed by 4 once-monthly placebo doses in season 2 (nirsevimab/nirsevimab group). Participants who received palivizumab in season 1 were randomly reassigned 1:1 to switch to the season 2 nirsevimab and placebo regimen (palivizumab/nirsevimab group) or continue with 5 palivizumab once-monthly doses (palivizumab/palivizumab group). Study interventions were administered on days 1 (baseline), 31, 61, 91, and 121, and participants were followed to day 361 (ie, 360 days post-first dose study intervention) in their respective seasons.23 

Serum samples were obtained from participants at baseline/pre-dose and on days 31 (non-European Union participants only), 151, and 361 in their respective seasons. Samples were archived at −80 ± 10° C until analysis.

Pre-F and post-F antibody levels were assessed by using a validated multiplex RSV serology assay, as previously described.31,32 Participant serum samples, quality-control serum samples, and the serum reference calibration curve were incubated on a 96-well Multiplex Custom RSV Serology SECTOR plate coated with RSV pre-F and post-F antigens to allow immune complexes to form. A monoclonal SULFO-TAG-labeled anti-human immunoglobulin antibody (Meso Scale Discovery, Rockville, MD; lot no. W0019421-20191211-WTK) was used to bind antibodies before measuring electrochemiluminescence in relative light units using a Meso Scale Discovery SECTOR S600 plate reader. Test sample antibody concentrations were determined by interpolating their electrochemiluminescence response from a standard curve generated from a serially diluted pooled serum reference standard. Antibody levels were reported in arbitrary units per milliliter (AU/mL). The lower limit of quantification (LLOQ) was 62 AU/mL for pre-F antibodies and 41 AU/mL for post-F antibodies. All pre/post-F antibodies measured at season 1 baseline (pre-dose) were presumed to be maternal antibodies.

Serum concentrations of nirsevimab were determined using a validated colorimetric enzyme-linked immunosorbent assay (AstraZeneca, Gaithersburg, MD). Serum concentrations of palivizumab were measured using a validated electrochemiluminescent assay (AstraZeneca, Gaithersburg, MD). The LLOQ was 0.5 µg/mL for nirsevimab33 and 10 µg/mL for palivizumab.34 

RSV nAb levels were assessed using a fluorescent focus-based microneutralization assay. Per previous analyses,32,35 heat-inactivated serum samples were pre-incubated with a known quantity of a recombinant RSV A expressing green fluorescent protein (Aragen BioSciences, Hyderbda, India; lot no. PC-071-014) and incubated with Vero cells for 22 to 24 hours. Viral infection was determined by counting the number of green fluorescent protein-positive cells (fluorescent foci units) using a cell imaging reader. nAb concentrations were determined by interpolating the fluorescent foci unit response with a serum reference standard curve calibrated to the World Health Organization’s first International Standard for Antiserum to RSV, National Institute for Biological Standards and Control, code 16/284, and reported in IU/mL.36 The LLOQ was 50 IU/mL.

A palivizumab population PK model37 was used in conjunction with MEDLEY participant weights, postmenstrual ages (ie, the sum of gestational and postnatal ages), and dosing information to predict a full nAb time course through day 361 after 5 once-monthly doses. The conversion factor was 7046 IU/mL = 1 mg/mL.

For serology, PK and nAb measurements reported less than the LLOQ, and half of the respective assay LLOQ was assigned in all calculations in this analysis. The geometric mean concentrations (GMCs), geometric mean fold rises (GMFR), and corresponding 95% CIs were summarized by treatment group at each prespecified time point for all measurements of anti-RSV pre-F, post-F, and nAbs. The CIs for GMC and GMFRs were calculated assuming log-normal distribution for participants’ antibody titers or fold rises. Pearson correlations for anti-RSV F protein mAb and nAb correlations were calculated based on log-transformed nirsevimab or palivizumab concentrations and log-transformed RSV nAb levels. Anti-RSV mAb less than the LLOQ were excluded from Pearson correlation calculations.

A total of 925 infants were randomly assigned to receive nirsevimab (n = 616) or palivizumab (n = 309) in season 1, with 88.4% (543/614) of nirsevimab recipients and 86.5% (263/304) of palivizumab recipients completing season 1 day 361 (Fig 1A [overall participants], Fig 1B [preterm cohort], and Fig 1C [CHD/CLD cohort]). Of these, 84.5% (262/310) of participants in the CHD/CLD cohort continued to season 2, with 180 participants in the nirsevimab/nirsevimab group, 40 participants in the palivizumab/nirsevimab group, and 42 participants in the palivizumab/palivizumab group. Sixteen participants receiving nirsevimab (13 nirsevimab/nirsevimab; 3 palivizumab/nirsevimab) had serum concentration time profiles not consistent with nirsevimab dosing per protocol. As such, season 2 serology, PK, and nAb data from these participants were removed from this analysis. At least 95% of participants across the 3 groups completed season 2 day 361.

FIGURE 1
CONSORT flow diagram for the (A) overall MEDLEY season 1 population and the (B) preterm and (C) CHD/CLD cohorts. Database lock date: February 22, 2023.
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CONSORT flow diagram for the (A) overall MEDLEY season 1 population and the (B) preterm and (C) CHD/CLD cohorts. Database lock date: February 22, 2023.

FIGURE 1
CONSORT flow diagram for the (A) overall MEDLEY season 1 population and the (B) preterm and (C) CHD/CLD cohorts. Database lock date: February 22, 2023.
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CONSORT flow diagram for the (A) overall MEDLEY season 1 population and the (B) preterm and (C) CHD/CLD cohorts. Database lock date: February 22, 2023.

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Trends in anti-RSV F protein serology were examined to explore how the specific site Ø binding of nirsevimab and site II binding of palivizumab translated to levels of pre-F and post-F antibodies post-dosing and to assess whether these changed in participants who switched from palivizumab to nirsevimab in season 2. Pre-F antibody levels in nirsevimab recipients were highest in samples obtained at the first post-dose measurement, day 31, and declined through season 1 but remained 7-fold above baseline at day 361 (GMFR [95% CI]: 7 [6–9]; Fig 2A, Table 1, Supplemental Table 3). Pre-F antibody levels were lower in palivizumab recipients at day 31 but accumulated with repeated doses to exceed those observed in nirsevimab recipients by day 151 before declining to levels below nirsevimab recipients at day 361. As expected, post-F antibody levels were lower in nirsevimab recipients compared with palivizumab recipients at all season 1 post-baseline time points (Fig 2A, Supplemental Table 3). Post-baseline serologic data were similar between season 1 cohorts in both trial arms (Supplemental Table 3).

FIGURE 2
Summary of anti-RSV F protein pre-F and post-F antibodies in MEDLEY trial participants (as-treated population). Data displayed are GMCs with error bars depicting 95% CI. “n” represents the number of participants with anti-RSV F protein pre-F and post-F antibody data available at each time point. a Participants with suspected dosing errors in season 2 are excluded from this analysis. BL, baseline; DX, day X.
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Summary of anti-RSV F protein pre-F and post-F antibodies in MEDLEY trial participants (as-treated population). Data displayed are GMCs with error bars depicting 95% CI. “n” represents the number of participants with anti-RSV F protein pre-F and post-F antibody data available at each time point. a Participants with suspected dosing errors in season 2 are excluded from this analysis. BL, baseline; DX, day X.

FIGURE 2
Summary of anti-RSV F protein pre-F and post-F antibodies in MEDLEY trial participants (as-treated population). Data displayed are GMCs with error bars depicting 95% CI. “n” represents the number of participants with anti-RSV F protein pre-F and post-F antibody data available at each time point. a Participants with suspected dosing errors in season 2 are excluded from this analysis. BL, baseline; DX, day X.
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Summary of anti-RSV F protein pre-F and post-F antibodies in MEDLEY trial participants (as-treated population). Data displayed are GMCs with error bars depicting 95% CI. “n” represents the number of participants with anti-RSV F protein pre-F and post-F antibody data available at each time point. a Participants with suspected dosing errors in season 2 are excluded from this analysis. BL, baseline; DX, day X.

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TABLE 1

Summary of Anti-RSV Pre-F and Post-F Antibody GMFRs in MEDLEY Study Participants (As-Treated Population)

VisitSummary StatisticsSeason 1 (Preterm and CHD/CLD Cohorts)Season 2 (CHD/CLD Cohort Only)
PalivizumabNirsevimabPalivizumab/
palivizumab		Palivizumab/
nirsevimab		Nirsevimab/
nirsevimab
Preterm (n = 206)CHD/CLD (n = 98)Overall (n = 304)Preterm (n = 406)CHD/CLD (n = 208)Overall (n = 614)CHD/CLD (n = 42)CHD/CLD (n = 40)CHD/CLD (n = 180)
Pre-F antibodies 
Day 31a n 63 45 108 147 98 245 15 17 77 
GMFR (95% CI) 38 (24–60) 92 (47–180) 55 (37–81) 131 (97–177) 605 (386–946) 242 (185–316) 133 (43–412) 502 (139–1814) 726 (441–1197) 
GMFR ratio (95% CI) — 3 (2–6) 7 (3–15) 4 (3–7) — 4 (1–20) 5 (2–18) 
Day 151 n 167 82 249 344 180 524 34 35 146 
GMFR (95% CI) 75 (55–100) 182 (114–292) 100 (77–129) 36 (30–45) 111 (81–153) 53 (45–64) 124 (53–287) 139 (61–313) 177 (127–246) 
GMFR ratio (95% CI) — 0 (0–1) 1 (0–1) 1 (0–1) — 1 (0–4) 1 (1–3) 
Day 361 n 159 85 244 328 181 509 35 35 140 
GMFR (95% CI) 2 (1–2) 4 (2–7) 2 (2–3) 5 (4–6) 15 (11–22) 7 (6–9) 5 (2–12) 17 (7–43) 23 (16–33) 
GMFR ratio (95% CI) — 3 (2–4) 4 (2–8) 3 (2–5) — 4 (1–14) 5 (2–12) 
Post-F antibodies 
Day 31a n 63 45 108 146 94 240 15 16 72 
GMFR (95% CI) 31 (19–52) 93 (48–182) 49 (33–74) 1 (1–1) 2 (2–4) 1 (1–2) 152 (59–391) 3 (0–27) 2 (1–4) 
GMFR ratio (95% CI) — 0 (0–0) 0 (0–0) 0 (0–0) — 0 (0–0) 0 (0–0) 
Day 151 n 167 82 249 331 172 503 34 34 141 
GMFR (95% CI) 68 (50–92) 170 (108–268) 92 (71–119) 0 (0–0) 0 (0–1) 0 (0–0) 103 (43–249) 1 (0–3) 1 (0–1) 
GMFR ratio (95% CI) — 0 (0–0) 0 (0–0) 0 (0–0) — 0 (0–0) 0 (0–0) 
Day 361 n 159 85 244 325 178 503 35 35 138 
GMFR (95% CI) 2 (1–2) 4 (2–7) 2 (2–3) 0 (0–0) 0 (0–0) 0 (0–0) 5 (2–14) 1 (0–3) 0 (0–1) 
GMFR ratio (95% CI) — 0 (0–0) 0 (0–0) 0 (0–0) — 0 (0–1) 0 (0–0) 
VisitSummary StatisticsSeason 1 (Preterm and CHD/CLD Cohorts)Season 2 (CHD/CLD Cohort Only)
PalivizumabNirsevimabPalivizumab/
palivizumab		Palivizumab/
nirsevimab		Nirsevimab/
nirsevimab
Preterm (n = 206)CHD/CLD (n = 98)Overall (n = 304)Preterm (n = 406)CHD/CLD (n = 208)Overall (n = 614)CHD/CLD (n = 42)CHD/CLD (n = 40)CHD/CLD (n = 180)
Pre-F antibodies 
Day 31a n 63 45 108 147 98 245 15 17 77 
GMFR (95% CI) 38 (24–60) 92 (47–180) 55 (37–81) 131 (97–177) 605 (386–946) 242 (185–316) 133 (43–412) 502 (139–1814) 726 (441–1197) 
GMFR ratio (95% CI) — 3 (2–6) 7 (3–15) 4 (3–7) — 4 (1–20) 5 (2–18) 
Day 151 n 167 82 249 344 180 524 34 35 146 
GMFR (95% CI) 75 (55–100) 182 (114–292) 100 (77–129) 36 (30–45) 111 (81–153) 53 (45–64) 124 (53–287) 139 (61–313) 177 (127–246) 
GMFR ratio (95% CI) — 0 (0–1) 1 (0–1) 1 (0–1) — 1 (0–4) 1 (1–3) 
Day 361 n 159 85 244 328 181 509 35 35 140 
GMFR (95% CI) 2 (1–2) 4 (2–7) 2 (2–3) 5 (4–6) 15 (11–22) 7 (6–9) 5 (2–12) 17 (7–43) 23 (16–33) 
GMFR ratio (95% CI) — 3 (2–4) 4 (2–8) 3 (2–5) — 4 (1–14) 5 (2–12) 
Post-F antibodies 
Day 31a n 63 45 108 146 94 240 15 16 72 
GMFR (95% CI) 31 (19–52) 93 (48–182) 49 (33–74) 1 (1–1) 2 (2–4) 1 (1–2) 152 (59–391) 3 (0–27) 2 (1–4) 
GMFR ratio (95% CI) — 0 (0–0) 0 (0–0) 0 (0–0) — 0 (0–0) 0 (0–0) 
Day 151 n 167 82 249 331 172 503 34 34 141 
GMFR (95% CI) 68 (50–92) 170 (108–268) 92 (71–119) 0 (0–0) 0 (0–1) 0 (0–0) 103 (43–249) 1 (0–3) 1 (0–1) 
GMFR ratio (95% CI) — 0 (0–0) 0 (0–0) 0 (0–0) — 0 (0–0) 0 (0–0) 
Day 361 n 159 85 244 325 178 503 35 35 138 
GMFR (95% CI) 2 (1–2) 4 (2–7) 2 (2–3) 0 (0–0) 0 (0–0) 0 (0–0) 5 (2–14) 1 (0–3) 0 (0–1) 
GMFR ratio (95% CI) — 0 (0–0) 0 (0–0) 0 (0–0) — 0 (0–1) 0 (0–0) 

Only participants who have both season 1 baseline and season 2 post-baseline results are included in the GMFR summary. Fold rises at season 2 post-baseline visits were calculated relative to season 1 baseline. The 95% CIs for GMFR were calculated assuming log normal distribution for participants’ fold rises. GMFRs ratios are calculated for nirsevimab versus palivizumab in respective preterm, CHD/CLD, and overall cohorts in season 1, and for palivizumab/nirsevimab and nirsevimab/nirsevimab groups versus palivizumab/palivizumab in season 2. Data from participants with suspected dosing errors in season 2 are excluded from this analysis.

a

Non-European Union participants only.

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Overall trends in serologic data were similar between study seasons. Pre-F antibody levels in the nirsevimab/nirsevimab and palivizumab/nirsevimab groups were similar at all season 2 post-baseline time points, whereas levels in the palivizumab/palivizumab group displayed a similar overall trajectory to season 1 (Fig 2B, Supplemental Table 3). Post-F antibody levels were higher in the palivizumab/palivizumab group compared with both nirsevimab regimens at all season 2 post-baseline time points (Fig 2B, Table 1, Supplemental Table 3).

Correlations between the serum concentrations of nirsevimab or palivizumab and RSV nAb levels were evaluated in both seasons. The serum concentrations of nirsevimab (Pearson correlation coefficient = 0.98; Fig 3A) and palivizumab strongly correlated (Pearson correlation coefficient = 0.82; Fig 3B) with RSV nAb levels during season 1. mAb serum concentrations were below the LLOQ in 8.2% (42/514) of nirsevimab recipients and 99.2% (253/255) of palivizumab recipients with PK and nAb data available at season 1 day 361 (Supplemental Table 4). Notably, 81.0% (34/42) of nirsevimab and 21.7% (55/253) of palivizumab recipients with mAb serum concentrations below the LLOQ had detectable RSV nAbs at day 361, likely reflecting natural immune responses following RSV exposure during the study.

FIGURE 3
Anti-RSV F protein mAb serum concentrations versus anti-RSV nAb levels according to MEDLEY study prophylaxis regimen. n numbers correspond to the number of participants who received nirsevimab or palivizumab at the beginning of season 1 and season 2. Data were not available for all participants at each time point. a Participants with suspected dosing errors in season 2 are excluded from this analysis. For serum concentration measurements of anti-RSV mAbs reported less than the LLOQ (0.5 µg/mL for nirsevimab32 and 10 µg/mL for palivizumab), half of the LLOQ was assigned. Anti-RSV mAb concentrations less than the LLOQ are excluded from the calculation of Pearson correlations.
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Anti-RSV F protein mAb serum concentrations versus anti-RSV nAb levels according to MEDLEY study prophylaxis regimen. n numbers correspond to the number of participants who received nirsevimab or palivizumab at the beginning of season 1 and season 2. Data were not available for all participants at each time point. a Participants with suspected dosing errors in season 2 are excluded from this analysis. For serum concentration measurements of anti-RSV mAbs reported less than the LLOQ (0.5 µg/mL for nirsevimab32 and 10 µg/mL for palivizumab), half of the LLOQ was assigned. Anti-RSV mAb concentrations less than the LLOQ are excluded from the calculation of Pearson correlations.

FIGURE 3
Anti-RSV F protein mAb serum concentrations versus anti-RSV nAb levels according to MEDLEY study prophylaxis regimen. n numbers correspond to the number of participants who received nirsevimab or palivizumab at the beginning of season 1 and season 2. Data were not available for all participants at each time point. a Participants with suspected dosing errors in season 2 are excluded from this analysis. For serum concentration measurements of anti-RSV mAbs reported less than the LLOQ (0.5 µg/mL for nirsevimab32 and 10 µg/mL for palivizumab), half of the LLOQ was assigned. Anti-RSV mAb concentrations less than the LLOQ are excluded from the calculation of Pearson correlations.
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Anti-RSV F protein mAb serum concentrations versus anti-RSV nAb levels according to MEDLEY study prophylaxis regimen. n numbers correspond to the number of participants who received nirsevimab or palivizumab at the beginning of season 1 and season 2. Data were not available for all participants at each time point. a Participants with suspected dosing errors in season 2 are excluded from this analysis. For serum concentration measurements of anti-RSV mAbs reported less than the LLOQ (0.5 µg/mL for nirsevimab32 and 10 µg/mL for palivizumab), half of the LLOQ was assigned. Anti-RSV mAb concentrations less than the LLOQ are excluded from the calculation of Pearson correlations.

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Similar correlations were observed in season 2. Nirsevimab serum concentrations highly correlated with nAb levels in the nirsevimab/nirsevimab (Pearson correlation coefficient = 0.95; Fig 3C) and palivizumab/nirsevimab (Pearson correlation coefficient = 0.97; Fig 3D) groups. A strong correlation was also observed in the palivizumab/palivizumab group, despite a lower number of participants (Pearson correlation coefficient = 0.86; Fig 3E). The mAb serum concentrations were below the LLOQ in 6.2% (9/145), 8.8% (3/34), and 95.0% (19/20) of participants with PK and nAb data available at season 2 day 361 in the nirsevimab/nirsevimab, palivizumab/nirsevimab, and palivizumab/palivizumab groups, with 77.8% (7/9), 66.7% (2/3), and 52.6% (10/19) of participants in these respective groups showing evidence of natural RSV nAb responses (Supplemental Table 4).

The dynamics of RSV nAb levels during the trial are depicted in Fig 4. nAb levels were similar between season 1 cohorts in both trial arms (Supplemental Table 5). nAb levels in nirsevimab recipients resembled trends in pre-F antibody levels during season 1. nAb levels were highest in day 31 samples and gradually declined during season 1 but remained 17-fold above baseline at day 361 (day 361 GMFR [95% CI]: 17 [15–19]; Fig 4A, Table 2). nAb levels in palivizumab recipients accumulated with repeated dosing and were higher at day 151 compared with day 31. GMFR ratios indicated that measured nAb levels were 11-fold higher with nirsevimab compared with palivizumab at day 151 (day 151 GMFR ratio [95% CI]: 11 [9–13]; Table 2). Measured nAb levels in palivizumab recipients were consistent with those predicted using the PK model, suggesting that nAb levels in nirsevimab recipients were ∼10-fold higher compared with palivizumab throughout season 1.

FIGURE 4
Summary of anti-RSV nAb levels in MEDLEY study participants (as-treated population). Data displayed are GMCs with error bars depicting 95% CIs. “n” numbers represent the number of participants with nAb data available at each time point. a Participants with suspected dosing errors in season 2 are excluded from this analysis. b The full time course of RSV nAb following palivizumab dosing was predicted from a popPK model36 and participant weights and postmenstrual ages (ie, the sum of gestational and postnatal ages) and was converted to nAb with conversion factor 7046 IU/mL = 1 mg/mL. c LLOQ for anti-RSV fluorescent focus microneutralization assay = 50 IU/mL. BL, baseline; DX, day X; popPK, population pharmacokinetics.
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Summary of anti-RSV nAb levels in MEDLEY study participants (as-treated population). Data displayed are GMCs with error bars depicting 95% CIs. “n” numbers represent the number of participants with nAb data available at each time point. a Participants with suspected dosing errors in season 2 are excluded from this analysis. b The full time course of RSV nAb following palivizumab dosing was predicted from a popPK model36 and participant weights and postmenstrual ages (ie, the sum of gestational and postnatal ages) and was converted to nAb with conversion factor 7046 IU/mL = 1 mg/mL. c LLOQ for anti-RSV fluorescent focus microneutralization assay = 50 IU/mL. BL, baseline; DX, day X; popPK, population pharmacokinetics.

FIGURE 4
Summary of anti-RSV nAb levels in MEDLEY study participants (as-treated population). Data displayed are GMCs with error bars depicting 95% CIs. “n” numbers represent the number of participants with nAb data available at each time point. a Participants with suspected dosing errors in season 2 are excluded from this analysis. b The full time course of RSV nAb following palivizumab dosing was predicted from a popPK model36 and participant weights and postmenstrual ages (ie, the sum of gestational and postnatal ages) and was converted to nAb with conversion factor 7046 IU/mL = 1 mg/mL. c LLOQ for anti-RSV fluorescent focus microneutralization assay = 50 IU/mL. BL, baseline; DX, day X; popPK, population pharmacokinetics.
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Summary of anti-RSV nAb levels in MEDLEY study participants (as-treated population). Data displayed are GMCs with error bars depicting 95% CIs. “n” numbers represent the number of participants with nAb data available at each time point. a Participants with suspected dosing errors in season 2 are excluded from this analysis. b The full time course of RSV nAb following palivizumab dosing was predicted from a popPK model36 and participant weights and postmenstrual ages (ie, the sum of gestational and postnatal ages) and was converted to nAb with conversion factor 7046 IU/mL = 1 mg/mL. c LLOQ for anti-RSV fluorescent focus microneutralization assay = 50 IU/mL. BL, baseline; DX, day X; popPK, population pharmacokinetics.

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TABLE 2

Summary of Anti-RSV nAb GMFRs in MEDLEY Study Participants (As-Treated Population)

VisitSummary StatisticsSeason 1 (Preterm and CHD/CLD Cohorts)Season 2 (CHD/CLD Cohort Only)
PalivizumabNirsevimabPalivizumab/
palivizumab		Palivizumab/
nirsevimab		Nirsevimab/
nirsevimab
PretermCHD/CLDOverallPretermCHD/CLDOverallCHD/CLDCHD/CLDCHD/CLD
(n = 206)(n = 98)(n = 304)(n = 406)(n = 208)(n = 614)(n = 42)(n = 40)(n = 180)
Day 31a n 64 45 109 142 97 239 15 9 35 
GMFR(95% CI) 6(4−9) 8(6−11) 7(5−9) 263(207−334) 474(384−585) 334(282−395) 14(7−26) 303(120−767) 611(366−1021) 
GMFR ratio(95% CI) — 41(27−63) 60(41−89) 48(35−65) — 22(8−63) 45(19−108) 
Day 151 n 168 82 250 345 181 526 34 35 143 
GMFR(95% CI) 9(7−12) 14(11−19) 11(9−13) 98(84−114) 158(131−190) 116(103−130) 13(7−24) 180(123−265) 245(201−300) 
GMFR ratio(95% CI) — 11(8−14) 11(8−15) 11(9−13) — 14(7−29) 19(12−32) 
Day 361 n 160 84 244 322 176 498 35 33 140 
GMFR(95% CI) 1(0−1) 1(1−1) 1(1−1) 15(13−18) 21(17−26) 17(15−19) 2(1−3) 25(15−39) 38(31−48) 
GMFR ratio(95% CI) — 27(20−37) 23(15−34) 26(20−33) — 15(6−35) 23(13−41) 
VisitSummary StatisticsSeason 1 (Preterm and CHD/CLD Cohorts)Season 2 (CHD/CLD Cohort Only)
PalivizumabNirsevimabPalivizumab/
palivizumab		Palivizumab/
nirsevimab		Nirsevimab/
nirsevimab
PretermCHD/CLDOverallPretermCHD/CLDOverallCHD/CLDCHD/CLDCHD/CLD
(n = 206)(n = 98)(n = 304)(n = 406)(n = 208)(n = 614)(n = 42)(n = 40)(n = 180)
Day 31a n 64 45 109 142 97 239 15 9 35 
GMFR(95% CI) 6(4−9) 8(6−11) 7(5−9) 263(207−334) 474(384−585) 334(282−395) 14(7−26) 303(120−767) 611(366−1021) 
GMFR ratio(95% CI) — 41(27−63) 60(41−89) 48(35−65) — 22(8−63) 45(19−108) 
Day 151 n 168 82 250 345 181 526 34 35 143 
GMFR(95% CI) 9(7−12) 14(11−19) 11(9−13) 98(84−114) 158(131−190) 116(103−130) 13(7−24) 180(123−265) 245(201−300) 
GMFR ratio(95% CI) — 11(8−14) 11(8−15) 11(9−13) — 14(7−29) 19(12−32) 
Day 361 n 160 84 244 322 176 498 35 33 140 
GMFR(95% CI) 1(0−1) 1(1−1) 1(1−1) 15(13−18) 21(17−26) 17(15−19) 2(1−3) 25(15−39) 38(31−48) 
GMFR ratio(95% CI) — 27(20−37) 23(15−34) 26(20−33) — 15(6−35) 23(13−41) 

Only participants who have both season 1 baseline and season 2 post-baseline results are included in the GMFR summary. Fold rises at season 2 post-baseline visits were calculated relative to season 1 baseline. The 95% CIs for GMFR were calculated assuming log normal distribution for participants’ fold rises. GMFRs ratios are calculated for nirsevimab versus palivizumab in respective preterm, CHD/CLD, and overall cohorts in season 1 and for palivizumab/nirsevimab and nirsevimab/nirsevimab groups versus palivizumab/palivizumab in season 2. Data for participants with suspected dosing errors in season 2 are excluded from this analysis.

a

Non-European Union participants only.

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Season 1 day 361 (baseline season 2) nAb levels were higher among nirsevimab recipients, whereas levels in palivizumab recipients declined toward the LLOQ (Fig 4B; Supplemental Table 5). nAb levels in the nirsevimab/nirsevimab and palivizumab/nirsevimab groups were similar at all season 2 post-baseline time points. Participants in both nirsevimab groups had ∼10-fold higher nAb levels compared with the palivizumab/palivizumab group over the PK model-predicted time course to season 2 day 151. This trend was maintained for the remainder of season 2, with higher nAb levels observed in both nirsevimab groups compared with the palivizumab/palivizumab group at day 361.

Serum RSV nAb levels have been observed to protect against severe RSV LRTI in studies of maternally transferred antibodies38–41 and mAb immunoprophylaxis14,17–20,32,42–44 and thus are frequently used to compare RSV interventions in the absence of a well-established correlate of protection.45,46 This prespecified exploratory analysis from the MEDLEY trial illustrates that nirsevimab confers ∼10-fold higher and more sustained levels of nAbs through 1 year post-dose compared with the previous standard of care, palivizumab.

Trends in serologic data were consistent between MEDLEY study seasons and reflected the respective binding site locations, half-lives, and dosing schedules of both mAbs (nirsevimab: site Ø, pre-F exclusive, ∼71-day half-life; palivizumab: site II, present in both pre-F and post-F, ∼20-day half-life).6,9,13 A single dose of nirsevimab predominately conferred high and sustained levels of pre-F antibodies, which were highest at the first post-dosing measurement and remained above baseline levels at day 361. Successive monthly doses of palivizumab conferred incremental increases in both pre-F and post-F antibodies through day 151, with levels of both antibodies remaining above baseline levels at day 361.

Serum concentrations of nirsevimab and palivizumab strongly correlated with RSV nAb levels for each of the season 1 and 2 participant groups, with higher Pearson correlations observed among nirsevimab recipients in both seasons. Approximately 90% of nirsevimab recipients had measurable nirsevimab serum concentrations at day 361 in both seasons, whereas palivizumab serum concentrations were below the LLOQ in >95% of participants at the same time points. Participants with mAb serum concentrations below the LLOQ at day 361 displayed signs of natural immune responses (nirsevimab: 81% season 1, 66.7% to 77.8% season 2; palivizumab: 21.0% season 1, 52.6% season 2), consistent with previous analyses of pivotal nirsevimab trials32 and real-world studies of palivizumab use.47 These data illustrate that nirsevimab and palivizumab prophylaxis still allow infants to elicit natural immune responses and suggest additional cases of asymptomatic or mild RSV infection beyond the 25 cases of medically attended RSV-associated LRTI observed during the trial.

Overall trends in nAb levels among nirsevimab recipients resembled those observed with pre-F antibodies. Although pre-F antibody levels were comparable between nirsevimab and palivizumab recipients at day 151, nAb levels were ∼10-fold higher among nirsevimab recipients throughout both seasons. Serologic analyses have revealed that anti-site Ø and anti-site II antibodies respectively account for ∼35% and <10% of overall anti-RSV neutralization activity,48 suggesting that this observed ∼10-fold difference in nAb levels in nirsevimab recipients is due to the greater neutralization potency of anti-site Ø antibodies. nAb levels after nirsevimab dosing remained 17-fold higher than baseline at season 1 day 361, with similar longevity in season 2, reflecting the extended half-life conferred by the M252Y/S254T/T256E(YTE)-modification.14 The authors of previous analyses have suggested a palivizumab serum concentration of ∼100 µg/mL (705 IU/mL RSV nAbs) as a protective threshold against ICU admission for infants at higher risk of RSV disease.43 In this context, day 361 nAb GMCs from nirsevimab recipients in MEDLEY (1009 IU/mL [season 1]; 1373–1776 IU/mL [season 2]) and the phase 2b and MELODY trials32 suggest that a single dose of nirsevimab may offer protection for a period beyond a typical 5-month RSV season.

These prespecified exploratory analyses were not sufficiently powered for statistical significance testing. Other limitations included the relatively small size of the palivizumab/nirsevimab and palivizumab/palivizumab groups that precluded the ability to perform subgroup analyses, restrictions in sample volumes available from infants or children resulting in limited sample availability at all time points, and the limited number of serum sample collection time points, requiring the use of a population PK model to predict a full nAb time course after palivizumab dosing. However, predicted palivizumab nAb levels were consistent with measured levels in both seasons, suggesting that this is a justified surrogate for this analysis.

The potential differences in natural immune responses between nirsevimab and palivizumab recipients cannot be explored in further detail because of assay limitations. For example, the multiplex RSV serology assay determines pre-F and post-F antibody levels by quantifying all antibodies specifically bound to purified pre-F and post-F proteins using an anti-human detection antibody.31,32 Similarly, the RSV microneutralization assay measures all RSV nAb responses within participants’ serum samples.35 Consequently, neither assay is capable of distinguishing between anti-RSV antibodies provided by nirsevimab or palivizumab prophylaxis, maternal antibody transfer, or natural immune responses. The authors of vaccine studies for other viral infections routinely use serologic responses to nonvaccine antigens (eg, anti-nucleocapsid antibodies) to infer the presence of natural infection following immunization.49 However, developing similar serologic definitions for RSV infection has been complicated by interest in the attachment protein as a prospective vaccine antigen, and cross-reactivity between anti-nucleocapsid protein antibodies for RSV and human metapneumovirus,50 another virus of the Pneumoviridae family that is also prevalent in infants and young children.51 Although the mAb PK and RSV nAb correlation data suggest that nirsevimab and palivizumab allow for the development of natural immune responses, robust comparisons between study interventions are not feasible because nAb levels remained above the LLOQ in ≥91% of nirsevimab recipients at day 361 in both seasons. Although the ∼20-day half-life of palivizumab illustrates that natural RSV nAb responses are present in palivizumab recipients, the authors of previous analyses have suggested that residual nirsevimab activity may persist through day 361,32,52 indicating that additional experimental approaches are required to accurately evaluate natural immune responses after nirsevimab prophylaxis and to assess their potential impacts on RSV disease severity. However, the differences in day 361 RSV nAb levels between nirsevimab and palivizumab recipients in both seasons reveal that nirsevimab offers more protection than natural immunity alone.

These limitations are balanced by several important observations. The low level of RSV pre-F, post-F, and nAbs at baseline suggest that maternally transferred antibodies represent a relatively small proportion of overall RSV antibodies among participants after nirsevimab and palivizumab dosing. Similarly, previous analyses of the phase 2b and MELODY studies have revealed that RSV nAb levels are similar among nirsevimab recipients with and without confirmed RSV LRTIs.32 These observations, combined with the atypical prevalence of RSV during the study due to coronavirus disease 2019 pandemic public health initiatives,53,54 low numbers of confirmed RSV cases, and the large increases in RSV F protein and nAb levels after nirsevimab and palivizumab dosing, suggest that the presence of maternally transferred antibodies and/or natural immune responses does not significantly affect the interpretation of data described in this analysis. Despite these limitations, these data represent the first comparison of RSV nAb levels after nirsevimab and palivizumab dosing in a clinical setting and will provide health authorities and public health advisory bodies with valuable insights to inform nirsevimab use in future RSV seasons.

These findings reveal that a single dose of nirsevimab is associated with ∼10-fold higher and more sustained levels of nAbs through 1 year post-dose compared with the previous standard of care, palivizumab, and further support nirsevimab use for the prevention of RSV-associated lower respiratory tract disease in all infants.

We thank the MEDLEY trial participants and their families, members of the investigator teams, and the full clinical team at AstraZeneca. We would like to thank PPD Vaccines, Richmond, Virginia, for their assistance in developing the RSV multiplex serology assay and measuring anti-RSV nAbs, as reported in this article. The authors acknowledge Rebecca A. Bachmann, PhD, of AstraZeneca, for facilitating author discussion and providing strategic advice and critical review of this manuscript. Medical writing support was provided by Craig O’Hare, PhD, of Ashfield MedComms, an Inizio company, which was in accordance with Good Publication Practice 2022 guidelines (https://www.ismpp.org/gpp-2022; Ann Intern Med. 2022 doi:10.7326/M22-1460) and funded by AstraZeneca.

Ms Wilkins conceptualized the analysis, developed the methodology for the serologic analysis of RSV F protein antibodies and RSV neutralizing antibodies, and analyzed and interpreted these data; Dr Wählby Hamrén conceptualized the analysis, developed the methodology for the pharmacokinetic analysis of serum palivizumab concentrations, and analyzed and interpreted these data; Dr Chang made substantial contributions to the analysis, validation and visualization of data; Dr Clegg made substantial contributions to the interpretation, review, and visualization of pharmacokinetic data; Prof Domachowske collected and supported the interpretation and validation of MEDLEY participant data; Profs Englund and Muller collected and supported the interpretation of MEDLEY participant data; Dr Kelly supported the conceptualization of the analysis, the interpretation and validation of all data described within the manuscript, and provided supervision throughout the analysis; Dr Leach supported the conceptualization of the analysis and the interpretation of all data described within the manuscript; Dr Villafana supported the design of the MEDLEY study and conceptualization of this analysis, the interpretation of data described in this manuscript, and the acquisition of study funding; the first draft of the manuscript was written in collaboration with a professional medical writer under the direction of all authors; and all authors critically reviewed and edited the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

This trial has been registered at https://www.clinicaltrials.gov (identifier NCT03959488).

Data sharing statement: Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. The AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.

AU/mL

arbitrary units per milliliter

CHD

congenital heart disease

CI

confidence interval

CLD

chronic lung disease of prematurity

F protein

fusion protein

GA

gestational age

GMC

geometric mean concentration

GMFR

geometric mean fold rise

LLOQ

lower limit of quantification

LRTI

lower respiratory tract infection

mAb

monoclonal antibody

nAb

neutralizing antibody

PK

pharmacokinetics

Pre-F

prefusion conformation of the respiratory syncytial virus fusion protein

Post-F

postfusion conformation of the respiratory syncytial virus fusion protein

RSV

respiratory syncytial virus

1
Hall
 
CB
,
Weinberg
 
GA
,
Iwane
 
MK
, et al.
The burden of respiratory syncytial virus infection in young children
.
N Engl J Med
.
2009
;
360
(
6
):
588
–
598
Google Scholar
Crossref
Search ADS
PubMed
 
2
Stein
 
RT
,
Bont
 
LJ
,
Zar
 
H
, et al.
Respiratory syncytial virus hospitalization and mortality: systematic review and meta-analysis
.
Pediatr Pulmonol
.
2017
;
52
(
4
):
556
–
569
Google Scholar
Crossref
Search ADS
PubMed
 
3
Langley
 
JM
,
Bianco
 
V
,
Domachowske
 
JB
, et al.
Incidence of respiratory syncytial virus lower respiratory tract infections during the first 2 years of life: a prospective study across diverse global settings
.
J Infect Dis
.
2022
;
226
(
3
):
374
–
385
Google Scholar
Crossref
Search ADS
PubMed
 
4
Tsitsiklis
 
A
,
Osborne
 
CM
,
Kamm
 
J
, et al.
Lower respiratory tract infections in children requiring mechanical ventilation: a multicentre prospective surveillance study incorporating airway metagenomics
.
Lancet Microbe
.
2022
;
3
(
4
):
e284
–
e293
Google Scholar
Crossref
Search ADS
PubMed
 
5
Groothuis
 
JR
,
Simoes
 
EA
,
Levin
 
MJ
, et al.
Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. The Respiratory Syncytial Virus Immune Globulin Study Group
.
N Engl J Med
.
1993
;
329
(
21
):
1524
–
1530
Google Scholar
Crossref
Search ADS
PubMed
 
6
Battles
 
MB
,
McLellan
 
JS
.
Respiratory syncytial virus entry and how to block it
.
Nat Rev Microbiol
.
2019
;
17
(
4
):
233
–
245
Google Scholar
Crossref
Search ADS
PubMed
 
7
Mazur
 
NI
,
Terstappen
 
J
,
Baral
 
R
, et al.
Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape
.
Lancet Infect Dis
.
2023
;
23
(
1
):
e2
–
e21
Google Scholar
Crossref
Search ADS
PubMed
 
8
Mazur
 
NI
,
Higgins
 
D
,
Nunes
 
MC
, et al.
Respiratory Syncytial Virus Network (ReSViNET) Foundation
.
The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates
.
Lancet Infect Dis
.
2018
;
18
(
10
):
e295
–
e311
Google Scholar
Crossref
Search ADS
PubMed
 
9
US Food and Drug Administration (FDA)
.
SYNAGIS® (palivizumab) prescribing information
. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/103770s5185lbl.pdf. Accessed July 12, 2024
10
Garegnani
 
L
,
Styrmisdottir
 
L
,
Roson Rodriguez
 
P
, et al.
Palivizumab for preventing severe respiratory syncytial virus (RSV) infection in children
.
Cochrane Database Syst Rev
.
2021
;
11
(
11
):
CD013757
Google Scholar
PubMed
 
11
Munro
 
APS
,
Martinón-Torres
 
F
,
Drysdale
 
SB
,
Faust
 
SN
.
The disease burden of respiratory syncytial virus in Infants
.
Curr Opin Infect Dis
.
2023
;
36
(
5
):
379
–
384
Google Scholar
Crossref
Search ADS
PubMed
 
12
American Academy of Pediatrics Committee on Infectious Diseases
;
American Academy of Pediatrics Bronchiolitis Guidelines Committee
.
Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection
.
Pediatrics
.
2014
;
134
(
2
):
415
–
420
Crossref
Search ADS
PubMed
 
13
US Food and Drug Administration (FDA)
.
BEYFORTUS™ (nirsevimab-alip) prescribing information
. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761328s000lbl.pdf. Accessed July 12, 2024
14
Zhu
 
Q
,
McLellan
 
JS
,
Kallewaard
 
NL
, et al.
A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants
.
Sci Transl Med
.
2017
;
9
(
388
):
eaaj1928
Google Scholar
Crossref
Search ADS
PubMed
 
15
McLellan
 
JS
,
Chen
 
M
,
Joyce
 
MG
, et al.
Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus
.
Science
.
2013
;
342
(
6158
):
592
–
598
Google Scholar
Crossref
Search ADS
PubMed
 
16
Wilkins
 
D
,
Langedijk
 
AC
,
Lebbink
 
RJ
, et al.
INFORM-RSV Study Group
.
Nirsevimab binding-site conservation in respiratory syncytial virus fusion glycoprotein worldwide between 1956 and 2021: an analysis of observational study sequencing data
.
Lancet Infect Dis
.
2023
;
23
(
7
):
856
–
866
Google Scholar
Crossref
Search ADS
PubMed
 
17
Griffin
 
MP
,
Yuan
 
Y
,
Takas
 
T
, et al.
Nirsevimab Study Group
.
Single-dose nirsevimab for prevention of RSV in preterm infants
.
N Engl J Med
.
2020
;
383
(
5
):
415
–
425
Google Scholar
Crossref
Search ADS
PubMed
 
18
Muller
 
WJ
,
Madhi
 
SA
,
Seoane
 
NB
, et al.
MELODY Study Group
.
Nirsevimab for prevention of RSV in term and late-preterm infants
.
N Engl J Med
.
2023
;
388
(
16
):
1533
–
1534
Google Scholar
Crossref
Search ADS
PubMed
 
19
Hammitt
 
LL
,
Dagan
 
R
,
Yuan
 
Y
, et al.
MELODY Study Group
.
Nirsevimab for prevention of RSV in healthy late-preterm and term infants
.
N Engl J Med
.
2022
;
386
(
9
):
837
–
846
Google Scholar
Crossref
Search ADS
PubMed
 
20
Simoes
 
EAF
,
Madhi
 
SA
,
Muller
 
WJ
, 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
.
Lancet Child Adolesc Health
.
2023
;
7
(
3
):
180
–
189
Google Scholar
Crossref
Search ADS
PubMed
 
21
Drysdale
 
SB
,
Cathie
 
K
,
Flamein
 
F
, et al.
HARMONIE Study Group
.
Nirsevimab for prevention of hospitalizations due to RSV in infants
.
N Engl J Med
.
2023
;
389
(
26
):
2425
–
2435
Google Scholar
Crossref
Search ADS
PubMed
 
22
Domachowske
 
JB
,
Chang
 
Y
,
Atanasova
 
V
, et al.
Safety of re-dosing nirsevimab prior to RSV season 2 in children with heart or lung disease
.
J Pediatric Infect Dis Soc
.
2023
;
12
(
8
):
477
–
480
Google Scholar
Crossref
Search ADS
PubMed
 
23
Domachowske
 
JB
,
Madhi
 
SA
,
Simoes
 
EAF
, et al.
MEDLEY Study Group
.
Safety of nirsevimab for RSV in infants with heart or lung disease or prematurity
.
N Engl J Med
.
2022
;
386
(
9
):
892
–
894
Google Scholar
Crossref
Search ADS
PubMed
 
24
Mankad
 
VS
,
Leach
 
A
,
Chang
 
Y
, et al.
Comprehensive summary of safety data on nirsevimab in infants and children from all pivotal randomized clinical trials
.
Pathogens
.
2024
;
13
(
6
):
503
Google Scholar
Crossref
Search ADS
PubMed
 
25
Sanofi
.
FDA approves Beyfortus™ (nirsevimab-alip) to protect infants against RSV disease. 2023
. Available at: https://www.sanofi.com/assets/dotcom/pressreleases/2023/2023-07-17-17-00-00-2705911-en.pdf. Accessed July 12, 2024
26
US Food and Drug Administration (FDA)
.
FDA approves new drug to prevent RSV in babies and toddlers
. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-prevent-rsv-babies-and-toddlers. Accessed August 27, 2024
27
Brady
 
T
,
Cayatte
 
C
,
Roe
 
TL
, et al.
Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection
.
Front Immunol
.
2023
;
14
:
1283120
Google Scholar
Crossref
Search ADS
PubMed
 
28
McLellan
 
JS
,
Chen
 
M
,
Leung
 
S
, et al.
Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody
.
Science
.
2013
;
340
(
6136
):
1113
–
1117
Google Scholar
Crossref
Search ADS
PubMed
 
29
Kwakkenbos
 
MJ
,
Diehl
 
SA
,
Yasuda
 
E
, et al.
Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming
.
Nat Med
.
2010
;
16
(
1
):
123
–
128
Google Scholar
Crossref
Search ADS
PubMed
 
30
National Institutes of Health (NIH)
.
NCT03959488: a study to evaluate the safety of MEDI8897 for the prevention of medically attended respiratory syncytial virus (RSV) lower respiratory track infection (LRTI) in high-risk children
. Available at: https://classic.clinicaltrials.gov/ct2/show/NCT03959488. Accessed July 12, 2024
31
Schepp
 
RM
,
de Haan
 
CAM
,
Wilkins
 
D
, et al.
Development and standardization of a high-throughput multiplex immunoassay for the simultaneous quantification of specific antibodies to five respiratory syncytial virus proteins
.
mSphere
.
2019
;
4
(
2
):
e00236-19
Google Scholar
Crossref
Search ADS
PubMed
 
32
Wilkins
 
D
,
Yuan
 
Y
,
Chang
 
Y
, et al.
Durability of neutralizing RSV antibodies following nirsevimab administration and elicitation of the natural immune response to RSV infection in infants
.
Nat Med
.
2023
;
29
(
5
):
1172
–
1179
Google Scholar
Crossref
Search ADS
PubMed
 
33
Domachowske
 
JB
,
Khan
 
AA
,
Esser
 
MT
, et al.
Safety, tolerability and pharmacokinetics of MEDI8897, an extended half-life single-dose respiratory syncytial virus prefusion F-targeting monoclonal antibody administered as a single dose to healthy preterm infants
.
Pediatr Infect Dis J
.
2018
;
37
(
9
):
886
–
892
Google Scholar
Crossref
Search ADS
PubMed
 
34
AstraZeneca
.
Data on file
.
2024
35
Shambaugh
 
C
,
Azshirvani
 
S
,
Yu
 
L
, et al.
Development of a high-throughput respiratory syncytial virus fluorescent focus-based microneutralization assay
.
Clin Vaccine Immunol
.
2017
;
24
(
12
):
e00225-17
Google Scholar
Crossref
Search ADS
PubMed
 
36
McDonald
 
JU
,
Rigsby
 
P
,
Dougall
 
T
,
Engelhardt
 
OG
;
Establishment of the first WHO International Standard for antiserum to respiratory syncytial virus: report of an international collaborative study
.
Vaccine
.
2018
;
36
(
50
):
7641
–
7649
Google Scholar
Crossref
Search ADS
PubMed
 
37
Robbie
 
GJ
,
Zhao
 
L
,
Mondick
 
J
,
Losonsky
 
G
,
Roskos
 
LK
.
Population pharmacokinetics of palivizumab, a humanized anti-respiratory syncytial virus monoclonal antibody, in adults and children
.
Antimicrob Agents Chemother
.
2012
;
56
(
9
):
4927
–
4936
Google Scholar
Crossref
Search ADS
PubMed
 
38
Stensballe
 
LG
,
Ravn
 
H
,
Kristensen
 
K
, et al.
Respiratory syncytial virus neutralizing antibodies in cord blood, respiratory syncytial virus hospitalization, and recurrent wheeze
.
J Allergy Clin Immunol
.
2009
;
123
(
2
):
398
–
403
Google Scholar
Crossref
Search ADS
PubMed
 
39
Capella
 
C
,
Chaiwatpongsakorn
 
S
,
Gorrell
 
E
, et al.
Prefusion F, postfusion F, G antibodies, and disease severity in infants and young children with acute respiratory syncytial virus infection
.
J Infect Dis
.
2017
;
216
(
11
):
1398
–
1406
Google Scholar
Crossref
Search ADS
PubMed
 
40
Walsh
 
EE
,
Wang
 
L
,
Falsey
 
AR
, et al.
Virus-specific antibody, viral load, and disease severity in respiratory syncytial virus infection
.
J Infect Dis
.
2018
;
218
(
2
):
208
–
217
Google Scholar
Crossref
Search ADS
PubMed
 
41
Kampmann
 
B
,
Madhi
 
SA
,
Munjal
 
I
, et al.
MATISSE Study Group
.
Bivalent prefusion F vaccine in pregnancy to prevent RSV illness in infants
.
N Engl J Med
.
2023
;
388
(
16
):
1451
–
1464
Google Scholar
Crossref
Search ADS
PubMed
 
42
The IMpact-RSV Study Group
.
Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants
.
Pediatrics
.
1998
;
102
(
3
):
531
–
537
Crossref
Search ADS
 
43
Forbes
 
ML
,
Kumar
 
VR
,
Yogev
 
R
, et al.
Serum palivizumab level is associated with decreased severity of respiratory syncytial virus disease in high-risk infants
.
Hum Vaccin Immunother
.
2014
;
10
(
10
):
2789
–
2794
Google Scholar
Crossref
Search ADS
PubMed
 
44
Maas
 
BM
,
Lommerse
 
J
,
Plock
 
N
, et al.
Forward and reverse translational approaches to predict efficacy of neutralizing respiratory syncytial virus (RSV) antibody prophylaxis
.
EBioMedicine
.
2021
;
73
:
103651
Google Scholar
Crossref
Search ADS
PubMed
 
45
Fong
 
Y
,
Huang
 
Y
,
Borate
 
B
, et al.
Antibody correlates of protection from severe respiratory syncytial virus disease in a vaccine efficacy trial
.
Open Forum Infect Dis
.
2023
;
10
(
1
):
ofac693
Google Scholar
Crossref
Search ADS
PubMed
 
46
Kulkarni
 
PS
,
Hurwitz
 
JL
,
Simões
 
EAF
,
Piedra
 
PA
.
Establishing correlates of protection for vaccine development: considerations for the respiratory syncytial virus vaccine field
.
Viral Immunol
.
2018
;
31
(
2
):
195
–
203
Google Scholar
Crossref
Search ADS
PubMed
 
47
Claydon
 
J
,
Sur
 
A
,
Callejas
 
A
, et al.
Respiratory syncytial virus-neutralizing serum antibody titers in infants following palivizumab prophylaxis with an abbreviated dosing regimen
.
PLoS One
.
2017
;
12
(
4
):
e0176152
Google Scholar
Crossref
Search ADS
PubMed
 
48
Ngwuta
 
JO
,
Chen
 
M
,
Modjarrad
 
K
, et al.
Prefusion F-specific antibodies determine the magnitude of RSV neutralizing activity in human sera
.
Sci Transl Med
.
2015
;
7
(
309
):
309ra162
Google Scholar
Crossref
Search ADS
PubMed
 
49
Falsey
 
AR
,
Sobieszczyk
 
ME
,
Hirsch
 
I
, et al.
AstraZeneca AZD1222 Clinical Study Group
.
Phase 3 safety and efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 vaccine
.
N Engl J Med
.
2021
;
385
(
25
):
2348
–
2360
Google Scholar
Crossref
Search ADS
PubMed
 
50
Zhang
 
Y
,
Pohl
 
J
,
Brooks
 
WA
,
Erdman
 
DD
.
Serologic cross-reactions between nucleocapsid proteins of human respiratory syncytial virus and human metapneumovirus
.
J Clin Microbiol
.
2015
;
53
(
5
):
1609
–
1615
Google Scholar
Crossref
Search ADS
PubMed
 
51
Wang
 
X
,
Li
 
Y
,
Deloria-Knoll
 
M
, et al;
Respiratory Virus Global Epidemiology Network
.
Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study
.
Lancet Glob Health
.
2021
;
9
(
1
):
e33
–
e43
Google Scholar
Crossref
Search ADS
PubMed
 
52
Clegg
 
L
,
Freshwater
 
E
,
Leach
 
A
, et al.
Population pharmacokinetics of nirsevimab in preterm and term infants
.
J Clin Pharmacol
.
2024
;
64
(
5
):
555
–
567
Google Scholar
Crossref
Search ADS
PubMed
 
53
Abu-Raya
 
B
,
Viñeta Paramo
 
M
,
Reicherz
 
F
,
Lavoie
 
PM
.
Why has the epidemiology of RSV changed during the COVID-19 pandemic?
EClinicalMedicine
.
2023
;
61
:
102089
Google Scholar
Crossref
Search ADS
PubMed
 
54
Bozzola
 
E
,
Barni
 
S
,
Villani
 
A
.
Respiratory syncytial virus pediatric hospitalization in the COVID-19 era
.
Int J Environ Res Public Health
.
2022
;
19
(
23
):
15455
Google Scholar
Crossref
Search ADS
PubMed
 

Competing Interests

CONFLICT OF INTEREST DISCLOSURES: Deidre Wilkins, Ulrika Wählby Hamrén, Yue Chang, Lindsay E. Clegg, and Tonya Villafana are current employees of AstraZeneca and may own AstraZeneca stock or stock options. Deidre Wilkins, Ulrika Wählby Hamrén, Amanda Leach, and Tonya Villafana are named inventors on patents planned, issued, or pending relating to nirsevimab. Amanda Leach and Elizabeth J. Kelly are former employees of AstraZeneca and may own AstraZeneca stock or stock options. Elizabeth J. Kelly is a current employee of Sanofi and may own Sanofi stock or stock options. Joseph Domachowske has received research grants from AstraZeneca, GSK, Merck, Moderna, Pfizer, and Sanofi, and honoraria from GSK, and has provided consultancy for AstraZeneca, GSK, and Sanofi. Janet A. Englund has received research grants from AstraZeneca, GSK, Merck, and Pfizer, and has provided consultancy for AbbVie, Ark Biopharma, AstraZeneca, Enanta Pharmaceuticals, GSK, Meissa Vaccines, Merck, Pfizer, Sanofi, and Shionogi. William J. Muller has received research grants from Ansun Biopharma, Astellas Pharma, AstraZeneca, Biotech Karius, Eli Lilly, Enanta Pharmaceuticals, F. Hoffmann-La Roche, Gilead Sciences, Janssen, Melinta Therapeutics, Merck, Moderna, Nabriva Therapeutics, Paratek Pharmaceuticals, Pfizer, and Tetraphase Pharmaceuticals. Dr Muller has also provided consultancy for AstraZeneca, DiaSorin Molecular LLC, Invivyd, and Sanofi, and expert testimony to Finley Law Firm, P.C.

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