Prevention of respiratory syncytial virus lower respiratory tract infection with nirsevimab

Abstract

The present disclosure provides methods of preventing, reducing the risk of, or ameliorating RSV lower respiratory tract infection by administering nirsevimab.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 364,554, filed May 11, 2022, U.S. Provisional Application No. 63 / 363,633, filed April 26, 2022, U.S. Provisional Application No. 63 / 266,594, filed January 10, 2022, and U.S. Provisional Application No. 63 / 261,117, filed September 13, 2021, which are incorporated by reference herein.

[0002] This application relates to the prevention of infection or other diseases associated with respiratory syncytial virus (RSV). [Background technology]

[0003] Respiratory syncytial virus (RSV) is a common cold virus that belongs to the Paramyxoviridae family. RSV is highly pathogenic and easily transmitted. RSV is the most common cause of lower respiratory tract infection (LRTI) in infants and young children, with annual epidemics occurring worldwide. All children are at risk for severe RSV LRTI. 90% of children are infected with RSV within the first 2 years of life, and up to 40% of them will first become symptomatic with LRTI. RSV LRTI, characterized primarily by bronchiolitis or pneumonia, is a severe disease that has both acute and long-term effects on the developing lungs of these young children (Blanken et al., N Engl J Med. (2013) 368 (19): 1791-9).

[0004] Severe LRTI episodes often result in hospitalization. The main risk factors for hospitalization due to RSV are preterm birth, chronic lung disease (CLD), congenital heart disease, immunocompromised, and otherwise healthy infants under 6 weeks of age. However, the majority of the healthcare burden due to RSV infection occurs outside of hospitals as outpatient and emergency department visits, especially in healthy infants.

[0005] Prevention of RSV disease in all infants is a major public health priority. However, despite more than 50 years of vaccine development attempts, there is no licensed vaccine. The only currently approved RSV prophylactic is palivizumab (Synagis®), a humanized monoclonal antibody that targets the fusion (F) protein of RSV. Palivizumab is indicated for use only in high-risk children: preterm infants with a gestational age (GA) of 35 weeks or less, children with premature CLD, and children with hemodynamically significant congenital heart disease (CHD). In addition, further restrictions are imposed by local or national recommendation agencies on the use of palivizumab. For example, in the United States, palivizumab is not recommended for healthy preterm infants with a GA of 29 weeks or more according to guidelines from the American Academy of Pediatrics (AAP). Summary of the Invention [Problem to be solved by the invention]

[0006] There is a significant unmet medical need to protect healthy preterm and term infants from RSV. Phase 3 data are available from a study evaluating maternal immunization with RSV fusion (F) protein nanoparticles. However, the study did not meet its primary endpoint with sufficient precision, and efficacy against medically significant RSV LRTI was reported to be 39.4% (97.52% CI, -1.0 to 63.7). (Madhi et al., N Engl J Med. (2020) 383: 426-39). With no RSV prophylactic approved for the broader population of healthy infants and no RSV treatment, current management of these patients when they develop severe RSV disease is symptomatic. Therefore, there remains an urgent need to passively immunize all infants to prevent or reduce RSV infection. Another consideration in preventing or reducing RSV infection in infants is the duration of the RSV season. For example, RSV seasons may last for 5 months or more (e.g., 6, 7, 8, 9, or 10 months). Palivizumab must be administered monthly throughout the entire RSV season, which may limit its usefulness. See IMpact-RSV Study Group. "Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants." Pediatrics 102.3 (1998):531-537. Thus, there remains an urgent need for passive immunization that is effective in preventing or reducing RSV infection in infants with a single dose. Similarly, there is a need for effective passive immunization with a single dose that can be administered outside of RSV seasons. [Means for solving the problem]

[0007] The present disclosure provides, inter alia, a method for preventing RSV lower respiratory tract infection in an infant or pediatric subject in need thereof. In some embodiments, the method includes administering a single dose of nirsevimab to a subject prior to the start of a RSV season, the single dose being effective in preventing RSV LRTI for more than 5 months. In some embodiments, the method includes administering a single dose of nirsevimab to a subject after the end of a previous RSV season, the single dose being effective in preventing RSV LRTI throughout the next RSV season.

[0008] In some embodiments, the method includes administering a single dose of nirsevimab to the subject, where the administration occurs no more than once per RSV season. In some embodiments, the method includes administering a single dose of nirsevimab to the subject, where the administration occurs no more than once per year. In some embodiments, the method includes administering a single dose of nirsevimab to an infant or pediatric subject at a time other than a RSV season, where the administration occurs no more than once per year. In some embodiments, the single dose of nirsevimab is administered intramuscularly.

[0009] In some embodiments, the method includes administering a single dose of nirsevimab to the infant or pediatric subject every RSV season, the administration being prior to the start of the season (e.g., 1 month, 2 months, 3 months or more). In some embodiments, the method includes administering a single dose of nirsevimab to the infant or pediatric subject every RSV season that is effective to provide protection for more than 5 months (e.g., at least 6, 7, 8, 9 or 10 months). In some embodiments, the single dose of nirsevimab is effective to provide protection for at least 11 or 12 months.

[0010] In some embodiments, the method comprises administering a single dose of nirsevimab to an infant or pediatric subject per RSV season at the beginning or during the RSV season, the RSV season being greater than about 5 months, optionally the RSV season being about 6, about 7, about 8, about 9 or about 10 months. In some embodiments, the single dose of nirsevimab provides protection against RSV infection and / or RSV disease for greater than 5 months (preferably at least 6, 7, 8, 9, 10, 11 or 12 months). In some embodiments, the single dose of nirsevimab is administered intramuscularly.

[0011] In some embodiments, the method includes preventing very severe RSV infection in an infant or pediatric subject in need thereof. In some embodiments, the method includes administering to the subject a single dose of nirsevimab, the single dose being effective in preventing very severe RSV infection for greater than 5 months.

[0012] In some embodiments, the method comprises preventing lower respiratory tract infection (LRTI) of any cause or hospitalization due to LRTI of any cause in an infant or pediatric subject in need thereof. In some embodiments, the method comprises administering to the subject a single dose of nirsevimab, the single dose being effective in preventing LRTI of any cause or hospitalization due to any cause for greater than 5 months.

[0013] In some embodiments, the method includes preventing RSV LRTI in a subject at high risk of developing a RSV infection (e.g., at high risk of developing a RSV LRTI). In some embodiments, the method includes administering a first dose of nirsevimab to the subject before or during the subject's first RSV season, and a second dose of nirsevimab to the subject before or during the subject's second RSV season. In some embodiments, the amount of nirsevimab in the first dose is 50 mg if the subject weighs less than 5 kg at the time of administration, and 100 mg if the subject weighs 5 kg or more at the time of administration. In some embodiments, the amount of nirsevimab in the second dose is 200 mg.

[0014] In some embodiments, the method includes preventing RSV LRTI in a subject undergoing cardiac surgery. In some embodiments, the method includes administering a first dose of nirsevimab to the subject prior to the subject's first RSV season, where the amount of nirsevimab in the first dose is 50 mg if the subject weighs less than 5 kg at the time of administration of the first dose, or the amount of nirsevimab in the first dose is 100 mg if the subject weighs 5 kg or more at the time of administration of the first dose; and administering a second dose of nirsevimab to the subject after cardiac surgery, where the amount of nirsevimab in the second dose is 100 mg if the subject weighs 5 kg or more at the time of administration of the first dose. is 50 mg if the subject weighs less than 5 kg at the time of administration of the second dose and the second dose is administered within 90 days of administration of the first dose, or the amount of nirsevimab in the second dose is 100 mg if the subject weighs 5 kg or more at the time of administration of the second dose and the second dose is administered within 90 days of administration of the first dose, or the amount of nirsevimab in the second dose is 50 mg if the subject weighs 5 kg or more at the time of administration of the second dose and the second dose is administered within 90 days of administration of the first dose. In some embodiments, the second dose is administered as soon as the subject is stabilized after surgery. In some embodiments, the cardiac surgery is cardiac surgery with cardiopulmonary bypass.

[0015] In some embodiments, the method includes preventing RSV LRTI in a subject undergoing cardiac surgery. In some embodiments, the method includes administering a first dose of nirsevimab to the subject before the subject's second RSV season, where the amount of nirsevimab in the first dose is 200 mg; and administering a second dose of nirsevimab to the subject after cardiac surgery, where the amount of nirsevimab in the second dose is 200 mg if the second dose is administered within 90 days of administration of the first dose, or the amount of nirsevimab in the second dose is 100 mg if the second dose is administered more than 90 days after administration of the first dose. In some embodiments, the second dose is administered as soon as the subject is stabilized after surgery. In some embodiments, the cardiac surgery is cardiac surgery with cardiopulmonary bypass.

[0016] In some embodiments, the dose of nirsevimab is administered at birth.

[0017] Other features, objects and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that this detailed description, while illustrating embodiments and aspects of the present invention, is given by way of illustration only, not by way of limitation. Various changes and modifications within the scope of the present invention will become apparent to those skilled in the art from this detailed description.

[0018] The contents of the references incorporated herein in their entirety are incorporated to the extent they do not conflict with this disclosure. In case of conflict, the present disclosure will control. [Brief description of the drawings]

[0019] [Figure 1]Figure 2 shows the design of the study described in Example 2. Blood samples for pharmacokinetic analysis were collected from participants hospitalized with respiratory infection at screening or pre-dose on days 1, 31, 151 and 361 and up to day 361. Safety evaluations were performed up to day 361. a: Dose levels were stratified by body weight at time of administration. In the nirsevimab group, participants received nirsevimab 50 mg (0.5 mL) if <5 kg and nirsevimab 100 mg (1.0 mL) if ≥5 kg. Participants in the placebo group received the corresponding amount of saline, i.e., 0.5 mL if <5 kg and 1.0 mL if ≥5 kg. b: In Japan, the day 15 visit was replaced by a day 8 visit for blood sample collection (laboratory parameters). In Japan, blood samples were also collected at visits on days 31 and 151. In Europe, blood collection was limited by excluding day 31 evaluation for RSV serology. Blood samples for pharmacokinetic analysis were collected on day 15 instead of day 31. IM, intramuscular; LRTI, lower respiratory tract infection. [Diagram 2] Graph showing time to first RSV-related LRTI requiring medical consultation in the intent-to-treat (ITT) population. Kaplan-Meier curves from time-to-event analysis show estimates of the proportion of participants who were free of RSV-related LRTI requiring medical consultation. Hazard ratios and corresponding 95% CIs were obtained from stratified proportional hazards models. Checkmarks indicate censored data. [Diagram 3] Figure 1. Time to first RSV-related LRTI requiring medical consultation in an ITT population from South Africa. Kaplan-Meier curves from time-to-event analysis show estimates of the proportion of participants who did not have an RSV-related LRTI requiring medical consultation. Hazard ratios and corresponding 95% CIs were obtained from stratified proportional hazards models. Check marks indicate censored data. [Figure 4]Table showing subgroup analysis of incidence of RSV-related LRTI requiring consultation up to 150 days post-dose for the ITT population. a: Relative risk reduction and its 95% CI (mi-P adjusted) were estimated based on the exact conditional method using PROC GENMOD without stratification. RRR: Relative risk reduction. [Diagram 5] FIG. 1 is a panel of graphs showing individual nirsevimab serum concentrations over time, including nirsevimab serum concentrations in participants who developed LRTI requiring medical care in the first 150 days. The dark line represents participants with a breakthrough case of RSV LRTI requiring medical care before day 151. Day 151 is indicated by the gray dashed vertical line. [Figure 6] Further pooled efficacy data are presented demonstrating the efficacy of nirsevimab against lower respiratory tract infections of various severity requiring medical consultation and hospitalization due to respiratory disease of any cause.†=Estimates based on Poisson regression with robust variance (including test as a covariate); not corrected for multiplicity;‡=Includes imputation of missing data;#=Defined as cases requiring supplemental oxygen or intravenous fluids (exploratory endpoints);CI=confidence interval. [Figure 7] Further pooled efficacy data are presented demonstrating the efficacy of nirsevimab for LRTIs requiring consultation across subgroups. CI = confidence interval; RRR = relative risk reduction. [Figure 8] Further pooled efficacy data demonstrating efficacy of nirsevimab against physician-required lower respiratory tract infections (LRTIs) over 150 days are presented. CI = confidence interval. [Figure 9] Pooled efficacy data on hospitalized resource utilization for subjects receiving nirsevimab compared with placebo are shown. CPAP = continuous positive airway pressure; HFNC = high-flow nasal cannula; ICU = intensive care unit. [Figure 10]Pooled efficacy data on outpatient visits and antibiotic use for subjects receiving nirsevimab compared with placebo are shown. †= estimates based on Poisson regression with log follow-up time as offset; ‡= calculated as 100 × total number of events / total follow-up time (5 months): CI= confidence interval; RRR= relative risk reduction. [Figure 11A] RSV neutralizing antibody levels and fold increase from baseline following immunization with nirsevimab or placebo in Phase IIb are shown. CI = confidence interval; LLOQ = lower limit of quantification; RSV = respiratory syncytial virus; RSV+ = confirmed positive for RSV infection; RSV- = not confirmed or not tested for RSV infection. [Figure 11B] Shown are RSV neutralizing antibody levels and fold increase from baseline following immunization with nirsevimab or placebo in Phase 3 (MELODY). CI = confidence interval; LLOQ = lower limit of quantification; RSV = respiratory syncytial virus; RSV+ = confirmed positive for RSV infection; RSV- = not confirmed or not tested for RSV infection. [Figure 12A] Figure 1 shows the geometric mean fold increase (GMFR) in RSV neutralizing antibody levels from baseline through day 361 after immunization with nirsevimab or placebo in Phase IIb. CI = confidence interval; RSV yes = confirmed RSV infection; RSV no = no confirmed RSV infection. [Figure 12B] Figure 1 shows the geometric mean fold increase (GMFR) in RSV neutralizing antibody levels from baseline through day 361 after immunization with nirsevimab or placebo in Phase 3 (MELODY). CI = confidence interval; RSV = respiratory syncytial virus; RSV yes = confirmed RSV infection; RSV no = no confirmed RSV infection. [Figure 13A] 1 shows baseline RSV neutralizing antibody levels in patients in the Phase IIb and Phase III (MELODY) trials. CI = confidence interval; GMC = geometric mean concentration; NH = Northern Hemisphere; SH = Southern Hemisphere; LLOQ = lower limit of quantification. [Figure 13B]Compare baseline RSV neutralizing antibody levels across age groups in the Phase IIb and Phase III (MELODY) studies. CI = confidence interval; GMC = geometric mean concentration; LLOQ = lower limit of quantification. [Figure 14] Pooled analysis of efficacy of nirsevimab in reducing RSV LRTI across Phase IIb studies (Study 3) and the Phase III MELODY trial. CI = confidence interval; LRTI = lower respiratory tract infection; MA = medical consultation required; RRR = relative risk reduction; RSV = respiratory syncytial virus; wkGA = gestational age in weeks. [Figure 15A] Kaplan-Meier estimates of time to first consultative RSV VRTI by study by exposure quartile bin are shown. MA RSV LRTI = consultative RSV lower respiratory tract infection; Q = quartile. [Figure 15B] Shown is a forest plot of predictors in the pooled final exposure-response model by exposure quartile bins through day 151. AUC = area under the concentration-time curve; CI = confidence interval; HR = hazard ratio. [Figure 16]

[0033] Figure 1 shows the incidence of RSV LRTI requiring medical attention of various severities over 150 days post-dose (ITT population) for all subjects in the MELODY trial. ITT population = all infants undergoing randomization; MA RSV LRTI = RSV lower respiratory tract infection requiring medical attention; CI = confidence interval. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present disclosure provides prevention of RSV infection using nirsevimab using a single dose per season, which can be administered outside of RSV seasons. In some embodiments, the prevention method prevents RSV-related LRTI. In some embodiments, the prevention method herein prevents RSV-related hospitalization. This method can be used to provide passive immunization of all infants undergoing their first RSV season and children undergoing their first or second RSV season who are at high risk of developing RSV infection (e.g., children with CLR or CHD). This method can provide a cost-effective opportunity to protect all infants from RSV disease with a single administration per or before RSV season, effectively reducing or preventing RSV infection for 5 months or more (e.g., 6, 7, 8, 9, 10 months).

[0021] The present disclosure reveals an unexpectedly long duration of the preventive effect of treatment with nirsevimab, which may last beyond the length of the RSV season (typically 5 months in certain geographic regions, but potentially longer in other locations (e.g., more tropical locations)). Unexpectedly, it is shown herein that the preventive protective effect of nirsevimab, when administered according to the methods herein, lasts for more than 150 days (e.g., up to at least 8 months) after administration compared to placebo. Due to this surprising advantage, the inventors have discovered that a single dose of nirsevimab can be used to provide protection (e.g., protection against LRTIs or protection against RSV-related hospitalizations) beyond a 5-month RSV season (the typical length of an RSV season in temperate climates), and that a single dose of nirsevimab can provide protection throughout even longer seasons (e.g., at least 8 months or even 12 months) as observed in some tropical climates. Based on this unexpected period of protection, the inventors have determined that nirsevimab may be administered prior to the onset of the RSV season (e.g., several weeks to several months) to more effectively cover more eligible patients and / or provide protection throughout the entire RSV season in regions with longer seasons (e.g., tropical or subtropical climates). Thus, a single dose treatment of nirsevimab may be administered prior to the onset of the RSV season (i.e., at least 2, 3, or more weeks) regardless of the length of the RSV season in the region. In some embodiments, a single dose treatment of nirsevimab may be administered 1, 2, 3, or more months prior to the onset of the RSV season. In some embodiments, a single dose treatment of nirsevimab may be administered at any time of the year, whether during or outside of the RSV season.

[0022] The beginning and end of the RSV season may be determined by health care providers and epidemiologists for each geographic region, for example, by evaluating historical trends known to skilled practitioners or reports on the percentage of patients testing positive for RSV, among other surveillance methods. A typical RSV season in temperate climates lasts up to about 5 months (e.g., 3, 4, or 5 months). In some situations, RSV seasons may be longer (e.g., about 6, 7, or 8 months or more in length) due to local climate or local immunological trends. In some situations, RSV seasons may vary in duration due to interruptions caused by various factors (e.g., changes in hygiene and social behavior due to hand disinfection, mask wearing, and social distancing, as occurs during the COVID-19 pandemic). In both the northern and southern hemispheres, the RSV season typically begins in the fall (autumn) and ends in the spring. In the United States, the Centers for Disease Control and Prevention analyzes data on RSC activity at the national, regional, and state levels collected by a surveillance system called the National Respiratory and Enteric Virus Surveillance System (NREVSS). In Europe, the European Center for Disease Prevention and Control (ECDC) analyzes virological data through the European Surveillance System (TESSy). Generally, the RSV season in the United States ranges from mid-September to mid-November, with the season peaking in late December to mid-February, and ending in mid-April to mid-May in all 10 US Department of Health and Human Services (HHS) territories except Florida, where the RSV season begins earlier and lasts longer than most of the rest of the country. In most of the Southern Hemisphere, the RSV season typically occurs from May to September. In tropical or subtropical climates, the RSV season is often associated with the rainy season.

[0023] The ability of RSV prophylactic regimens to protect the maximum number of subjects from disease depends in part on the timing of prophylactic delivery relative to the onset of the RSV season.The onset of the RSV season may depend on multiple factors, such as geography and climate.Thus, the onset of the RSV season is often determined by the positive rate of RSV testing at a local, state, regional or national level.As used herein, "positive RSV testing" indicates that a subject is suffering from RSV infection.

[0024] RSV infection (e.g., a positive RSV test) may be determined by diagnostic methods known in the art. See, e.g., Midgley et.al., Determining the Seasonality of Respiratory Syncytial Virus in the United States: The Impact of Increased Molecular Testing. J Infect Dis. 2017 Aug 1. In some embodiments, RSV testing may be performed on an upper respiratory tract sample. In some embodiments, RSV testing may be performed on a lower respiratory tract sample. In some embodiments, RSV infection is determined by a polymerase chain reaction (PCR)-based method. In some embodiments, RSV infection is determined by an antigen-based method. In some embodiments, RSV infection is determined by virus isolation by culture. In some embodiments, RSV infection is determined by serology testing.

[0025] In some embodiments, the start of an RSV season is defined by the first two consecutive weeks in which the RSV test positivity rate exceeds a threshold during that two-week period, which in some embodiments is between 3% and 13%, e.g., 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or 13%.

[0026] In some embodiments, the start of an RSV season is defined by the first two consecutive weeks in which the PCR test positivity rate for RSV exceeds a threshold during that two-week period. In some embodiments, the threshold for a positive PCR test is between 3% and 13%, e.g., 3%, 5%, 7%, 10%, or 13%. In some embodiments, the threshold for a positive PCR test is 3%. In some embodiments, the threshold for a positive PCR test is 5%. In some embodiments, the threshold for a positive PCR test is 7%. In some embodiments, the threshold for a positive PCR test is 10%. In some embodiments, the threshold for a positive PCR test is 13%.

[0027] In some embodiments, the start of an RSV season is defined by the first two consecutive weeks in which the antigen test positivity rate for RSV exceeds a threshold during that two-week period. In some embodiments, the antigen test positivity threshold is between 3% and 13%, e.g., 3%, 5%, 7%, 10%, or 13%. In some embodiments, the antigen test positivity threshold is 3%. In some embodiments, the antigen test positivity threshold is 5%. In some embodiments, the antigen test positivity threshold is 7%. In some embodiments, the antigen test positivity threshold is 10%. In some embodiments, the antigen test positivity threshold is 13%.

[0028] Additional normalization processes for determining threshold positivity rates are known in the art (e.g., moving epidemic model (MEM), retrospective slope 10 (RS10), 10x baseline (10FB)). In some embodiments, a moving average of weekly test positivity is used. In some embodiments, a 5-week moving average of weekly test positivity is used. In some embodiments, the moving average is normalized to an epidemic peak of 1000 RSV test positives. In some embodiments, the start of an RSV epidemic is the second of two consecutive weeks when the normalized 5-week moving average for the subsequent weeks increases by at least 10 normalized RSV test positives per week, provided that the previous week also met this threshold. In some embodiments, the 4-week moving average is defined as the average number of test positives over the past two weeks, the current week, and the next week. In some embodiments, the start of an RSV epidemic is defined by the 4-week moving average compared to a pre-epidemic baseline. In some embodiments, the pre-epidemic baseline is defined as the 4-week moving average at week 29. In some embodiments, the start of an RSV season is defined as the first of two consecutive weeks in which the 4-week moving average of positive RSV tests is about 8-fold to about 13-fold greater than the 4-week moving average at the pre-season baseline.

[0029] In some embodiments, the subject is administered a single dose of nirsevimab prior to the start of the RSV season, where the start of the RSV season is defined by the first two consecutive weeks in which the average RSV test positivity over a two week period exceeds a threshold ranging from 3% to 13%. In some embodiments, the subject is administered a single dose of nirsevimab prior to the start of the RSV season, where the start of the RSV season is defined by the first two consecutive weeks in which the average RSV test positivity over a two week period exceeds 3%. In some embodiments, the subject is administered a single dose of nirsevimab prior to the start of the RSV season, where the start of the RSV season is defined by the first two consecutive weeks in which the average RSV test positivity over a two week period exceeds 5%. In some embodiments, the subject is administered a single dose of nirsevimab prior to the start of the RSV season, where the start of the RSV season is defined by the first two consecutive weeks in which the average RSV test positivity over a two week period exceeds 7%. In some embodiments, the subject is administered a single dose of nirsevimab before the start of the RSV season, the start of the RSV season being defined by the first two consecutive weeks in which the average RSV test positivity rate over a two-week period exceeds 10%. In some embodiments, the subject is administered a single dose of nirsevimab before the start of the RSV season, the start of the RSV season being defined by the first two consecutive weeks in which the average RSV test positivity rate over a two-week period exceeds 13%. In any of the embodiments of this paragraph, the RSV test positivity rate can be determined by PCR testing. In any of the embodiments of this paragraph, the RSV test positivity rate can be determined by antigen testing. In some embodiments, the antigen test includes direct immunofluorescence. In some embodiments, the antigen test is a rapid antigen detection test, such as ID NOW™ RSV, Directigen™ RSV, Directigen™ EZ RSV, BinaxNOW™ RSV, BD Veritor™ RSV, Sofia® RSV.

[0030] In some embodiments, the subject is administered a single dose of nirsevimab prior to the start of the RSV season, where the start of the RSV season is defined by the first two consecutive weeks in which the average positive rate of a PCR test over a two-week period exceeds a threshold, such as 3%. In some embodiments, the subject is administered a single dose of nirsevimab prior to the start of the RSV season, where the start of the RSV season is defined by the first two consecutive weeks in which the average positive rate of an antigen test over a two-week period exceeds 10%. In any of the embodiments of this paragraph, the positive rate of the RSV test can be determined by antigen testing.

[0031] As used herein, administering nirsevimab to a subject "before" the onset of the RSV season means administering nirsevimab to the subject at least 2 weeks before the onset of the RSV season, for example, as determined according to methods described herein or known in the art. In some embodiments, a subject who is administered a single dose of nirsevimab before the onset of the RSV season is administered nirsevimab about 2 weeks before the onset of the RSV season. In some embodiments, a subject who is administered a single dose of nirsevimab before the onset of the RSV season is administered nirsevimab about 3 weeks before the onset of the RSV season. In some embodiments, a subject who is administered a single dose of nirsevimab before the onset of the RSV season is administered nirsevimab about 4 weeks before the onset of the RSV season. In some embodiments, a subject who is administered a single dose of nirsevimab before the onset of the RSV season is administered nirsevimab about 1 month before the onset of the RSV season. In some embodiments, subjects who receive a single dose of nirsevimab before the start of the RSV season are administered nirsevimab about 2 months before the start of the RSV season. In some embodiments, subjects who receive a single dose of nirsevimab before the start of the RSV season are administered nirsevimab about 3 months before the start of the RSV season. In some embodiments, subjects who receive a single dose of nirsevimab before the start of the RSV season are administered nirsevimab about 4 months before the start of the RSV season. Thus, subjects who receive a single dose of nirsevimab before the start of the RSV season may be administered nirsevimab about 4 months to 2 weeks before the start of the RSV season.

[0032] In some embodiments, the start of the RSV season is predicted according to a period after the end of the previous RSV season (e.g., about 16-28 weeks before the end of the previous RSV season), e.g., as determined by a positivity rate (e.g., measured by PCR) below 3-10%, e.g., 3%). In some embodiments, the next RSV season is predicted to begin about 16 weeks after the end of the previous RSV season.

[0033] In some embodiments, the subject is administered a single dose of nirsevimab at a time predicted to occur after the end of the immediately preceding RSV season and before the beginning of the next RSV season (e.g., about 16-28 weeks after the end of the immediately preceding RSV season). In some embodiments, the subject who is administered a single dose of nirsevimab after the end of the immediately preceding RSV season is administered nirsevimab about 16 weeks after the end of the immediately preceding RSV season. In some embodiments, the subject who is administered a single dose of nirsevimab after the end of the immediately preceding RSV season is administered nirsevimab about 17 weeks after the end of the immediately preceding RSV season. In some embodiments, the subject who is administered a single dose of nirsevimab after the end of the immediately preceding RSV season is administered nirsevimab about 18 weeks after the end of the immediately preceding RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 19 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 20 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 21 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 22 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 23 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 24 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 25 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 26 weeks after the end of the most recent RSV season.In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 27 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 28 weeks after the end of the most recent RSV season.

[0034] In some embodiments, the end of the RSV season is defined by the first week in which the average RSV test positivity over a one-week period falls below a threshold. In some embodiments, the threshold is between 3% and 13%, such as 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or 13%. In some embodiments, the weekly RSV test positivity threshold is 3%. In some embodiments, the weekly RSV test positivity threshold is 5%. In some embodiments, the weekly RSV test positivity threshold is 7%. In some embodiments, the weekly RSV test positivity threshold is 10%. In some embodiments, the weekly RSV test positivity threshold is 13%.

[0035] In some embodiments, the end of the RSV season is defined by the first week in which the average PCR test positivity for RSV over a one week period falls below a threshold. In some embodiments, this threshold is between 3% and 13%. In some embodiments, the threshold for a positive PCR test is 3%. In some embodiments, the threshold for a positive PCR test is 5%. In some embodiments, the threshold for a positive PCR test is 7%. In some embodiments, the threshold for a positive PCR test is 10%. In some embodiments, the threshold for a positive PCR test is 13%.

[0036] In some embodiments, the end of the RSV season is defined by the first week in which the average antigen test positivity for RSV over a one-week period falls below a threshold. In some embodiments, the antigen test positivity threshold is 3%. In some embodiments, the antigen test positivity threshold is 5%. In some embodiments, the antigen test positivity threshold is 7%. In some embodiments, the antigen test positivity threshold is 10%. In some embodiments, the antigen test positivity threshold is 13%.

[0037] Additional methods for determining the end of the RSV season are known in the art (Retrospective Slope 10 (RS10), 10x Baseline (10FB)). In some embodiments, a moving average of weekly test positivity is used. In some embodiments, a 5-week moving average of weekly test positivity is used. In some embodiments, the moving average is normalized to the season peak of 1000 RSV test positivity. In some embodiments, the end of the RSV season is the week immediately prior to the normalized 5-week moving average exceeding an increase of 10 normalized RSV test positivity per week. In some embodiments, the 4-week moving average is defined as the average number of test positivity over the past 2 weeks, the current week, and the next week. In some embodiments, the end of the RSV season is defined by the 4-week moving average compared to the pre-season baseline. In some embodiments, the pre-season baseline is defined as the 4-week moving average at week 29. In some embodiments, the end of the RSV season is defined as the week immediately preceding when the 4-week moving average of RSV test positivity is about 8-fold to about 13-fold greater than the 4-week moving average at the pre-season baseline.

[0038] In some embodiments, the subject is administered a single dose of nirsevimab at a time predicted to occur after the end of the previous RSV season and before the start of the next RSV season. In some embodiments, the subject is administered a single dose of nirsevimab before the start of the next RSV season, the next RSV season being defined by a period of time after the end of the previous RSV season, the end of the previous RSV season being defined by the first week in which the average positive rate of RSV testing over a one-week period falls below a threshold. In some embodiments, the threshold is between 3% and 13%, for example, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12% or 13%. In some embodiments, the subject is administered a single dose of nirsevimab before the start of the next RSV season, the start of the next RSV season being defined by the end of the previous RSV season, the end of the previous RSV season being defined by the first week in which the average positive rate of PCR testing over a one-week period falls below 3%. In some embodiments, the subject is administered a single dose of nirsevimab before the start of the next RSV season, the start of the next RSV season being defined by the end of the previous RSV season, the end of the previous RSV season being defined by the first week in which the average antigen test positivity rate over a one-week period falls below 10%. In some embodiments, the subject is administered a single dose of nirsevimab about one week after the end of the previous RSV season. In some embodiments, the subject is administered a single dose of nirsevimab about two weeks after the end of the previous RSV season. In some embodiments, the subject is administered a single dose of nirsevimab about three weeks after the end of the previous RSV season. In some embodiments, the subject is administered a single dose of nirsevimab about four weeks after the end of the previous RSV season. In some embodiments, the subject is administered a single dose of nirsevimab about one month after the end of the previous RSV season. In some embodiments, the subject is administered a single dose of nirsevimab about 2 months after the end of the most recent RSV season. In some embodiments, the subject is administered a single dose of nirsevimab about 3 months after the end of the most recent RSV season. In some embodiments, the subject is administered a single dose of nirsevimab about 4 months after the end of the most recent RSV season.In some embodiments, the subject is administered a single dose of nirsevimab about 5 months after the end of the most recent RSV season. In some embodiments, the subject is administered a single dose of nirsevimab about 6 months after the end of the most recent RSV season. In some embodiments, the subject is administered a single dose of nirsevimab about 7 months after the end of the most recent RSV season.

[0039] In some embodiments, the start of the RSV season is determined by meteorological season. Meteorological season depends on the temperature cycle of the region. For example, in the Northern Hemisphere, meteorological fall includes September, October, and November, and meteorological spring includes March, April, and May. In the Southern Hemisphere, meteorological fall includes March, April, and May, and meteorological spring includes September, October, and November. In some embodiments, the start of the RSV season is autumn. In some embodiments, the end of the RSV season is defined by meteorological season. In some embodiments, the end of the RSV season is spring. In some embodiments, the subject is administered nirsevimab after the end of an RSV season determined by meteorological season or before the start of the next RSV season. In some embodiments, the subject is administered nirsevimab in the spring. In some embodiments, the subject is administered nirsevimab in late spring. In some embodiments, nirsevimab is administered to a subject in the summer or fall (fall).

[0040] In some embodiments, the subject is administered a single dose of nirsevimab prior to the start of the RSV season, where the start of the RSV season is predicted by a local, state, regional or national health department (e.g., ECDC, CDC). In some embodiments, the subject is administered a single dose of nirsevimab after the end of the immediately preceding RSV season, where the end of the RSV season is declared by a local, state, regional or national health department.

[0041] In some embodiments, the subject is administered a single dose of nirsevimab before the start of the RSV season, the start of the RSV season being predicted by the NREVSS. In some embodiments, the subject is administered a single dose of nirsevimab after the end of the previous RSV season, the end of the RSV season being declared by the NREVSS.

[0042] In some embodiments, the subject is administered a single dose of nirsevimab before the start of the RSV season, and the start of the RSV season is predicted by TESSy. In some embodiments, the subject is administered a single dose of nirsevimab after the end of the previous RSV season, and the end of the RSV season is declared by TESSy.

[0043] As used herein, "positive rate" refers to the positive rate of RSV tests over a defined period of time. As used herein, "RSV status" or "event status" refers to a subject's test result from an RSV test. As used herein, "RSV test positive" means that a subject is infected with RSV.

[0044] As used herein, "severe RSV disease" or "severe RSV infection" includes lower respiratory tract infection (RSV LRTI) caused by RSV infection or RSV-related hospitalization. In some embodiments, RSV LRTI is characterized by bronchiolitis or pneumonia. As used herein, "severe RSV" is synonymous with "severe RSV" and "very severe RSV" is synonymous with "very severe RSV."

[0045] In some embodiments, a "severe RSV infection" is characterized by at least one of the following: increased respiratory rate (≥60 breaths / min for <2 months of age; ≥50 breaths / min for 2-6 months of age; ≥40 breaths / min for 6-24 months of age); hypoxemia on room air (O2 <95% below 1800 m; O2 <92% above 1800 m); initial apnea; retractions; grunting; nasal flaring; acute hypoxia or ventilatory failure; dehydration due to respiratory distress requiring intravenous hydration; intercostal, subcostal or supraventricular retractions. In some embodiments, a severe RSV infection is characterized by hospitalization due to RSV LRTI requiring medical attention.

[0046] As used herein, a "very severe RSV infection" is characterized by hospitalization due to RSV LRTI requiring medical attention and the need for supplemental oxygen and / or intravenous fluids. In some embodiments, a "very severe RSV infection" is characterized by an oxygen saturation (SaO2) of less than 90%.

[0047] As used herein, "prevention," "protection," and "providing protection" are used interchangeably. In some embodiments, protection from RSV refers to inhibition or reduction of RSV disease. As used herein, "inhibition" includes both partial and complete inhibition, including, for example, reduction of one or more symptoms of RSV disease and / or reduction of the risk of RSV disease. In some embodiments, protection from RSV refers to reduction in the severity of symptoms caused by RSV infection. In some embodiments, providing protection refers to inhibition or reduction of lower respiratory tract infections caused by RSV infection (RSV-associated LRTI, particularly RSV-associated LRTI requiring medical attention). In some embodiments, providing protection refers to inhibition or reduction of RSV-associated hospitalizations. In some embodiments, providing protection refers to inhibition or reduction of the development of RSV disease (e.g., RSV LRTI). In some embodiments, protection refers to inhibition or reduction of severe RSV infection (e.g., severe RSV LRTI, particularly severe RSV LRTI requiring medical attention). In some embodiments, protection refers to inhibiting or reducing very severe RSV infection (e.g., very severe RSV LRTI, particularly very severe RSV LRTI requiring medical attention). In some embodiments, protection refers to reducing the risk of RSV disease. In some embodiments, protection refers to reducing the risk of lower respiratory tract infection caused by RSV infection (RSV-associated LRTI, particularly RSV-associated LRTI requiring medical attention). In some embodiments, protection refers to reducing the risk of RSV-associated hospitalization. In some embodiments, protection refers to reducing the risk of developing RSV. In some embodiments, protection refers to reducing the risk of severe RSV (e.g., severe RSV LRTI, particularly severe RSV LRTI requiring medical attention). In some embodiments, protection refers to reducing the risk of very severe RSV (e.g., very severe RSV LRTI, particularly very severe RSV LRTI requiring medical attention).

[0048] In some embodiments, protection refers to reducing the risk of LRTI of any cause, particularly LRTI of any cause requiring medical attention. In some embodiments, protection refers to reducing the risk of hospitalization due to LRTI of any cause.

[0049] Protection may be understood as a comparison to a subject not administered nirsevimab. In some embodiments, protection from RSV refers to inhibition or reduction of RSV disease compared to a subject not administered nirsevimab. In some embodiments, protection from RSV refers to inhibition or reduction of lower respiratory tract infections caused by RSV infection (RSV-associated LRTIs, particularly RSV-associated LRTIs requiring medical attention) compared to a subject not administered nirsevimab. In some embodiments, protection from RSV refers to inhibition or reduction of RSV-associated hospitalizations compared to a subject not administered nirsevimab. In some embodiments, protection from RSV refers to inhibition or reduction of RSV onset compared to a subject not administered nirsevimab. In some embodiments, protection from RSV refers to inhibition or reduction of severe RSV (e.g., severe RSV LRTIs, particularly severe RSV LRTIs requiring medical attention) compared to a subject not administered nirsevimab. In some embodiments, protection from RSV means inhibition or reduction of very severe RSV infection (e.g., very severe RSV LRTI, particularly very severe RSV LRTI requiring medical attention) compared to subjects who are not administered nirsevimab.

[0050] In some embodiments, protection from RSV refers to a reduced risk of RSV disease compared to subjects who were not administered nirsevimab. In some embodiments, protection from RSV refers to a reduced risk of lower respiratory tract infection caused by RSV infection (RSV-related LRTI, particularly RSV-related LRTI requiring medical care) compared to subjects who were not administered nirsevimab. In some embodiments, protection from RSV refers to a reduced risk of RSV-related hospitalization compared to subjects who were not administered nirsevimab. In some embodiments, protection from RSV refers to a reduced risk of RSV development compared to subjects who were not administered nirsevimab. In some embodiments, protection from RSV refers to a reduced risk of severe RSV (e.g., severe RSV LRTI, particularly severe RSV LRTI requiring medical care) compared to subjects who were not administered nirsevimab. In some embodiments, protection from RSV refers to a reduced risk of very severe RSV infection (e.g., very severe RSV LRTI, particularly very severe RSV LRTI requiring medical care) compared to subjects who were not administered nirsevimab.

[0051] As used herein, the terms "immunized" or "immunization" with respect to administration of nirsevimab includes passive immunization.

[0052] As used herein, "RSV-associated LRTI," "RSV-confirmed LRTI," and "RSV LRTI" are used interchangeably. In some embodiments, the RSV LRTI is a medically required RSV LRTI (MA RSV LRTI or RSV MALRTI).

[0053] As used herein, RSV lower respiratory tract disease (RSV LRTD) is synonymous with RSV LRTI. Similarly, RSV LRTD requiring medical attention is synonymous with RSV LRTI requiring medical attention. LRTD and LRTI are not necessarily synonymous outside the context of RSV infection.

[0054] As used herein, "LRTI of any cause" and "LRTI of any cause requiring medical attention" refer to all cases of LRTI or LRTI requiring medical attention, respectively, including, but not limited to, RSV LRTI (for LRTI of any cause) or MA RSV LRTI (for MA LRTI of any cause). As used herein, "respiratory disease of any cause" includes any case of respiratory disease, including, but not limited to, respiratory disease caused by RSV infection. As used herein, "hospitalization due to LRTI of any cause" includes hospitalization due to any LRTI, including, but not limited to, hospitalization due to RSV LRTI.

[0055] As used herein, a time point "outside the RSV season" refers to a time point that is not within the RSV season and includes the first two weeks (i.e., two consecutive weeks) in which the positivity rate exceeds a threshold established to determine the beginning of the season. In some embodiments, a period outside the RSV season is a period of more than about 2, 3, or 4 weeks or more than about 1, 2, 3, 4, 5, 6, or 7 months prior to the beginning of the RSV season. As used herein, "beginning" with respect to the RSV season means the "start" or "beginning" of the season, and these terms are used interchangeably herein. In some embodiments, the beginning of the RSV season is defined by a two-week period (e.g., a two-week period in which the positivity rate exceeds a threshold). In some embodiments, the beginning of the RSV season is defined by a start date. As used herein, "RSV season" can refer to RSV-A, RSV-B, or both seasons.

[0056] As used herein, "subtropical" and "semitropical" are used interchangeably.

[0057] As used herein, an "infant" subject is a human subject aged 1 year (12 months) or less. As used herein, a "pediatric" subject is a human child subject over 1 year of age. In some embodiments, a pediatric subject is a human subject over 1 year of age (12 months) and up to 24 months of age.

[0058] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0059] The term "and / or," as used herein, means "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Thus, as a non-limiting example, "A and / or B," when used in combination with open-ended language such as "comprising," can, for example, in some embodiments refer to only A (optionally including elements other than B); in other embodiments, it can refer to only B (optionally including elements other than A); in yet other embodiments, it can refer to both A and B (optionally including other elements).

[0060] As used herein, "at least one" means one or more of a plurality of elements in a list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to the specifically identified elements, to be optionally present. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B" may, for example, in one embodiment, refer to at least one (optionally multiple) A where B is not present (optionally including elements other than B); in another embodiment, refer to at least one (optionally multiple) B where A is not present (optionally including elements other than A); in yet another embodiment, refer to at least one (optionally multiple) A and at least one (optionally multiple) B (optionally including other elements).

[0061] When a numerical value is listed alone or as part of a numerical range, it should be understood that the numerical value may vary above and below the stated value with appropriate variance for the stated value as would be recognized by one of ordinary skill in the art. As used herein, the term "approximately" or "about" when applied to one or more values ​​of interest refers to a value similar to the stated reference value. In certain embodiments, the term refers to a range of values ​​that falls within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction of the stated reference value (greater or less), unless otherwise stated or clear from the context. As used herein, the term "approximately" or "about" applied to the number of weeks means ±3 days. As used herein, the term "approximately" or "about" applied to the number of months means ±2 weeks.

[0062] Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular. Throughout this specification and the embodiments, the terms "having" and "including" or variations such as "having", "having", "including" or "including" are understood to mean the inclusion of a recited integer or group of integers, but not the exclusion of any other integer or group of integers. Although a number of documents are cited herein, this citation is not an admission that any of these documents form part of the general knowledge in the art. All publications and other references mentioned herein are incorporated by reference in their entirety.

[0063] I. Nirsevimab and Pharmaceutical Compositions Thereof In various embodiments, the antibody administered according to the methods and uses disclosed herein is nirsevimab. Nirsevimab (also known as MEDI8897) is a recombinant human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) against the pre-fusion conformation of the RSV F protein. See, for example, U.S. Patent No. 10,689,437, which is incorporated herein by reference in its entirety. This antibody binds to both the F1 and F2 subunits of the F protein at a highly conserved epitope and locks RSV F in the pre-fusion conformation to block fusion and viral entry into the host cell. The heavy chain of nirsevimab has the following sequence, which surrounds the complementarity determining regions (CDRs) and variable domains (Vs), and is represented by the sequence: H ) are shown in italics. [ka] In some embodiments, nirsevimab has a heavy chain sequence of SEQ ID NO: 1. In some embodiments, nirsevimab has a heavy chain sequence of SEQ ID NO: 1 that lacks the C-terminal lysine (K456) (SEQ ID NO: 11). In some embodiments, nirsevimab comprises a mixture of antibodies comprising the heavy chain sequence SEQ ID NO: 1 and antibodies comprising the heavy chain sequence SEQ ID NO: 11. In the above sequences, V HThe amino acid sequence of is represented in SEQ ID NO:2, and the amino acid sequences of the heavy chain CDRs (HCDRs) are represented in SEQ ID NOs:3-5, respectively. The heavy chain contains a triple amino acid substitution (YTE) shown above by underlining and bolding. This YTE triple mutation (M252Y / S254T / T256E; EU numbering) was made to wild-type human IgG1 in the fragment crystallizable (Fc) region. The heavy chain of nirsevimab contains a triple amino acid substitution ("YTE") that has been shown to extend the antibody half-life by several weeks, although an extension of efficacy beyond five months was not predicted.

[0064] The light chain of nirsevimab has the following sequence, which surrounds the CDRs and contains a variable domain (V L ) are shown in italics. [ka] In the above sequence, V L The amino acid sequence of this is shown in SEQ ID NO: 7, and the amino acid sequences of the light chain CDR (LCDR) are shown in SEQ ID NOs: 8 to 10, respectively.

[0065] Nirsevimab neutralizes RSV by binding to the prefusion conformation of the RSV F protein at a site distinct from that bound by palivizumab. In preclinical studies, nirsevimab was more than 150-fold more potent than palivizumab in vitro and approximately 9-fold more potent than palivizumab in vivo in a cotton rat model (Zhu et al., Sci Transl Med. (2017) 9:eaaj.1928).

[0066] The antibody is provided to a subject in need thereof as a pharmaceutical composition. The pharmaceutical composition may include a pharma- ceutically acceptable carrier, diluent, and / or excipient and is formulated for intramuscular injection. In some embodiments, the composition is a sterile, preservative-free liquid solution that includes a buffer (e.g., histidine), an amino acid (e.g., arginine or methionine), a polyol (e.g., sucrose), and a surfactant (e.g., polysorbate 80 or polysorbate 20). In further embodiments, the composition includes 100 mg / mL nirsevimab, 30 mM histidine / histidine-HCl, 80 mM arginine-HCl, 120 mM sucrose, and 0.02%-0.04% (w / v) polysorbate 80 (pH 6.0). Further embodiments of compositions comprising nirsevimab are described in International Application No. PCT / US2018 / 020264, the entirety of which is incorporated herein by reference.

[0067] In some embodiments of the pharmaceutical composition, nirsevimab is present at a concentration of about 25 mg / ml or more (e.g., about 25 mg / ml to about 250 mg / ml). In some embodiments of the pharmaceutical composition, nirsevimab is present at a concentration of about 50 mg / ml or more (e.g., about 50 mg / ml to about 250 mg / ml). In some embodiments of the pharmaceutical composition, nirsevimab is present at a concentration of about 50 mg / ml to about 200 mg / ml. In some embodiments, nirsevimab is present at a concentration of about 75 mg / ml or more (e.g., about 75 mg / ml to about 250 mg / ml). In some embodiments, nirsevimab is present at a concentration of about 100 mg / ml or more. In some embodiments, nirsevimab is present at a concentration of about 100 mg / ml to about 165 mg / ml. In some embodiments, nirsevimab is present at a concentration of about 100 mg / ml.

[0068] In some embodiments, the pharmaceutical composition has a pH in the range of about pH 5.5 to about pH 6.5. In some embodiments, the pH is in the range of about pH 5.7 to about pH 6.3. In some embodiments, the pH is in the range of about pH 5.7 to about pH 6.1. In some embodiments, the pH is about pH 5.8. In some embodiments, the pH is about pH 6.0.

[0069] In some embodiments of the pharmaceutical composition, the salt is present at a concentration of about 75 mM to about 100 mM. In some embodiments, the salt is present at a concentration of about 75 mM to about 80 mM. In some embodiments, the salt is arginine hydrochloride, for example, at a concentration of about 75 mM to about 100 mM (optionally at a concentration of about 80 mM). In some embodiments of the pharmaceutical composition, the sugar (e.g., sucrose) is present at a concentration of about 100 mM to about 140 mM (optionally at a concentration of about 120 mM).

[0070] In some embodiments of the pharmaceutical composition, the composition comprises one or more buffering agents. In some embodiments, the buffering agent comprises histidine hydrochloride. In some embodiments, the concentration of the buffering agent is about 10 mM to about 50 mM, optionally about 30 mM.

[0071] In some embodiments of the pharmaceutical composition, the composition includes a surfactant. In some embodiments, the surfactant is a polysorbate, such as, for example, polysorbate-80. In some embodiments, the surfactant is present at a concentration of about 0.02% to 0.04% (w / v). In one embodiment, the surfactant is present at a concentration of about 0.02%. In another embodiment, the surfactant is present at a concentration of about 0.04%.

[0072] In some embodiments, the pharmaceutical composition is provided in a single-unit vial or a multi-unit vial. Each unit may contain 50, 100 or 200 mg of nirsevimab. In some embodiments, in a single-unit container (e.g., a vial or a prefilled injector or syringe), the container contains a nominal fill volume of 0.5 mL of the 100 mg / mL pharmaceutical composition described above. In other embodiments, in a single-unit container (e.g., a vial or a prefilled injector or syringe), the container contains a nominal fill volume of 1 mL of the 100 mg / mL pharmaceutical composition described above. In a multi-unit container, the container may contain multiple nominal fill volumes of 0.5 mL of the 100 mg / mL pharmaceutical composition described above. In other embodiments, a multi-unit container may contain multiple nominal fill volumes of 0.5 mL and / or 1 mL of the 100 mg / mL pharmaceutical composition described above.

[0073] In some embodiments, an article of manufacture (e.g., a kit) is provided that includes a single-unit or multi-unit container that contains a pharmaceutical composition of nirsevimab (e.g., a 100 mg / mL composition as described above). In some embodiments, the article of manufacture may further include instructions for use.

[0074] In some embodiments, a pharmaceutical composition comprising nirsevimab is for use in any of the methods described herein. In some embodiments, nirsevimab is used in the manufacture of a medicament for use in any of the methods used herein. In some embodiments, a product comprising nirsevimab is used in any of the methods described herein.

[0075] Subjects may be intramuscularly or subcutaneously injected with one or more units of the composition depending on their body weight. Intramuscular or subcutaneous administration may be inseparable or difficult to distinguish in the case of certain small subjects (e.g., infants), and intramuscular and / or subcutaneous administration may be acceptable for such subjects. For example, infants weighing less than 5 kg may be intramuscularly or subcutaneously injected with one unit (50 mg per unit) of nirsevimab provided in such pharmaceutical compositions, and infants weighing 5 kg or more may be intramuscularly or subcutaneously injected with 100 mg of nirsevimab provided in such pharmaceutical compositions (e.g., two 50 mg units, one 100 mg unit). Pediatric subjects over 1 year old and / or entering their second RSV season may be intramuscularly or subcutaneously injected with 200 mg of nirsevimab (e.g., four 50 mg units, two 100 mg units, or one 200 mg unit). In some embodiments, pediatric subjects receiving 200 mg of nirsevimab intramuscularly or subcutaneously are at high risk of developing a RSV infection, such as a RSV LRTI.

[0076] II.How to use Nirsevimab may be injected into a human subject (e.g., subcutaneously or preferably intramuscularly) to prevent RSV infection (particularly RSV LRTI). In some embodiments, Nirsevimab may be injected into an infant or pediatric subject (e.g., subcutaneously or preferably intramuscularly) to prevent RSV infection (particularly RSV LRTI). In some embodiments, Nirsevimab may be injected into an infant or pediatric subject, for example in a prophylactic regimen, to reduce the risk of LRTI (e.g., bronchitis or pneumonia) in the subject. In some embodiments, Nirsevimab may be injected into an infant or pediatric subject to reduce the risk of LRTI requiring medical attention. In some embodiments, Nirsevimab may be injected into an infant or pediatric subject to reduce the risk of severe RSV infection (particularly severe RSV LRTI). In some embodiments, Nirsevimab may be injected into an infant or pediatric subject to reduce the risk of very severe RSV infection (particularly very severe RSV LRTI). In some embodiments, for example in a prophylactic regimen, nirsevimab may be injected into an infant or pediatric subject to reduce the risk of hospitalization. In some embodiments, nirsevimab may be injected into an infant or pediatric subject to reduce the incidence of LRTI. In some embodiments, nirsevimab may be injected into an infant or pediatric subject to reduce the incidence of LRTI requiring medical attention. In some embodiments, nirsevimab may be injected into an infant or pediatric subject to reduce the incidence of severe RSV infection (particularly severe RSV LRTI). In some embodiments, nirsevimab may be injected into an infant or pediatric subject to reduce the incidence of very severe RSV infection (particularly very severe RSV LRTI). In some embodiments, nirsevimab may be injected into an infant or pediatric subject to reduce the incidence of hospitalization.

[0077] In some embodiments, nirsevimab may be injected into an infant or pediatric subject in a method to obtain protection from respiratory syncytial virus (RSV) infection and / or RSV disease for more than 5 months. In some embodiments, nirsevimab may be injected into an infant or pediatric subject in a method to obtain protection from respiratory syncytial virus (RSV) infection and / or RSV disease for at least 8 months (optionally about 12 months). In some embodiments, nirsevimab may be injected into an infant or pediatric subject in a method to obtain protection from respiratory syncytial virus (RSV) infection and / or RSV disease for at least one RSV season. In some embodiments, the RSV infection and / or RSV disease comprises a RSV LRTI. In some embodiments, the RSV infection and / or RSV disease comprises a RSV LRTI requiring medical attention. In some embodiments, the RSV infection and / or RSV disease comprises hospitalization due to a RSV LRTI.

[0078] In various embodiments, a subject may be injected with a single dose of nirsevimab (e.g., 50, 100, or 200 mg) prior to the RSV season. In some embodiments, the RSV injection may be administered at any time of the year. In some embodiments, the injection may be administered at birth or shortly after birth. In some embodiments, the injection may be administered prior to the start of the RSV season. In some embodiments, a subject who is administered a single dose of nirsevimab prior to the start of the RSV season is administered nirsevimab about 2 weeks prior to the start of the RSV season. In some embodiments, a subject who is administered a single dose of nirsevimab prior to the start of the RSV season is administered nirsevimab about 3 weeks prior to the start of the RSV season. In some embodiments, a subject who is administered a single dose of nirsevimab prior to the start of the RSV season is administered nirsevimab about 4 weeks prior to the start of the RSV season. In some embodiments, subjects who receive a single dose of nirsevimab before the start of the RSV season are administered nirsevimab about 1 month before the start of the RSV season. In some embodiments, subjects who receive a single dose of nirsevimab before the start of the RSV season are administered nirsevimab about 2 months before the start of the RSV season. In some embodiments, subjects who receive a single dose of nirsevimab before the start of the RSV season are administered nirsevimab about 3 months before the start of the RSV season. In some embodiments, subjects who receive a single dose of nirsevimab before the start of the RSV season are administered nirsevimab about 4 months before the start of the RSV season. Therefore, subjects who receive a single dose of nirsevimab before the start of the RSV season are administered nirsevimab about 4 months to about 2 weeks before the start of the RSV season.

[0079] In some embodiments, the subject is administered a single dose of nirsevimab at a time predicted to occur after the end of the immediately preceding RSV season and before the beginning of the next RSV season (e.g., about 16-28 weeks after the end of the immediately preceding RSV season). In some embodiments, the subject who is administered a single dose of nirsevimab after the end of the immediately preceding RSV season is administered nirsevimab about 16 weeks after the end of the immediately preceding RSV season. In some embodiments, the subject who is administered a single dose of nirsevimab after the end of the immediately preceding RSV season is administered nirsevimab about 17 weeks after the end of the immediately preceding RSV season. In some embodiments, the subject who is administered a single dose of nirsevimab after the end of the immediately preceding RSV season is administered nirsevimab about 18 weeks after the end of the immediately preceding RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 19 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 20 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 21 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 22 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 23 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 24 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 25 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 26 weeks after the end of the most recent RSV season.In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 27 weeks after the end of the most recent RSV season. In some embodiments, subjects who receive a single dose of nirsevimab after the end of the most recent RSV season are administered nirsevimab about 28 weeks after the end of the most recent RSV season.

[0080] In another embodiment, when the RSV season is long (e.g., more than 5 months, e.g., 6, 7, 8, 9 or 10 months), the injection may be administered at the beginning or during the RSV season. In a further embodiment, when the RSV season is long (e.g., more than 5 months, e.g., 6, 7, 8, 9 or 10 months), the injection does not need to be limited to the beginning or during the RSV season. In some embodiments, even when the RSV season is longer than 5 months (e.g., 6, 7, 8, 9 or 10 months), a single dose of nirsevimab administered outside or within the RSV season (e.g., during or at the beginning of the RSV season) provides protection against RSV infection in a subject for at least the entire RSV season. In certain embodiments, a single dose of nirsevimab administered before or within an RSV season (e.g., during or at the beginning of an RSV season) provides protection against RSV in a subject over multiple RSV seasons (e.g., two RSV seasons) or at least one RSV season extended by an interruption. In some embodiments, the protection comprises preventing RSV infection. In some embodiments, the protection comprises reducing the risk of RSV infection. In some embodiments, the protection comprises preventing RSV-associated LRTI. In some embodiments, the protection comprises reducing the risk of RSV-associated LRTI. In some embodiments, the protection comprises preventing RSV-associated hospitalization. In some embodiments, the protection comprises reducing the risk of RSV-associated hospitalization.

[0081] In some embodiments, nirsevimab may be administered to an infant or pediatric subject prior to the subject's first RSV season. In some embodiments, nirsevimab may be administered to a subject for the first time prior to the subject's second or subsequent RSV season. In some embodiments, nirsevimab may be administered to a subject prior to the subject's second or subsequent RSV season. In such embodiments, nirsevimab may be administered for the first time. In some embodiments, nirsevimab may be administered again to a subject prior to the subject's second or subsequent RSV season.

[0082] In some embodiments, the subject is administered a first dose of 50 mg or 100 mg of nirsevimab before or during the subject's first RSV season. In some embodiments, if the subject weighs less than 5 kg at the time of administration, the subject is administered a 50 mg dose, and if the subject weighs 5 kg or more at the time of administration, the subject is administered a 100 mg dose. In some embodiments, the subject is administered a second dose of 200 mg of nirsevimab before or during the subject's second RSV season.

[0083] In some embodiments, a subject at high risk of developing a RSV infection (e.g., RSV LRTI) ("high-risk subject" or "subject susceptible to severe RSV disease") is administered a first dose of 50 mg or 100 mg of nirsevimab before or during their first RSV season. In some embodiments, a high-risk subject is administered a 50 mg dose before or during their first RSV season if the subject weighs less than 5 kg at the time of administration, and a 100 mg dose if the subject weighs 5 kg or more at the time of administration. In some embodiments, a high-risk subject is administered a second dose of 200 mg of nirsevimab before or during their second RSV season. In some embodiments, the high-risk subject has premature birth, chronic lung disease (CLD), congenital heart disease (CHD), a suppressed or depressed immune system, an immunodeficiency, a neuromuscular disorder, Down's syndrome, congenital airway abnormalities, and / or cystic fibrosis.

[0084] In some embodiments, a single dose of nirsevimab may be administered to an infant or pediatric subject only once per RSV season. In such embodiments, a single dose of nirsevimab may be administered at the beginning of an RSV season or during an RSV season. In some embodiments, a single dose of nirsevimab may be administered to an infant or pediatric subject only once a year. In such embodiments, a single dose of nirsevimab may be administered at the beginning of an RSV season or during an RSV season. Thus, in some embodiments, nirsevimab may be administered to a subject born outside of an RSV season. In another embodiment, nirsevimab may be administered to a subject experiencing an interrupted RSV season. For example, an RSV season may be interrupted by changes in hygiene or social behavior due to, for example, more frequent hand disinfection, mask wearing, and social distancing, as occurs during the COVID-19 pandemic. In such embodiments, the interrupted RSV season resumes, for example, when hygiene or social behavior ends. In some embodiments, nirsevimab may be administered to a subject prior to the subject's first RSV season, which occurs after the subject enters the second year of life (i.e., at least 1 year of age). For example, the subject's first RSV season may not occur until the subject enters the second year of life, for example, due to a global pandemic, an interruption in the RSV season, or the subject's relocation to another climate. In such embodiments, the first RSV season may occur during the subject's first year of life, or may be delayed beyond the first year of life. In further embodiments, nirsevimab may be administered to a subject who has experienced a RSV season of more than 5 months (e.g., 6, 7, 8, 9, or 10 months). In such embodiments, a single dose of nirsevimab (e.g., 50, 100, or 200 mg) is sufficient to provide protection against RSV infection (e.g., RSV-related LRTI, hospitalization) in an immunized individual for at least one RSV season or at least one RSV season that is extended by an interruption.

[0085] In some embodiments, nirsevimab is administered in a serum AUC greater than 10 day mg / mL, 11 day mg / mL, 12 day mg / mL, 13 day mg / mL, or 14 day mg / mL. 0-∞ In some embodiments, nirsevimab is administered to a subject in an amount effective to produce a serum AUC of greater than 12.8 day mg / mL. 0-∞ The compound is administered to a subject in an amount effective to produce the desired effect.

[0086] In some embodiments, the subject has a serum AUC greater than 10 day·mg / mL, 11 day·mg / mL, 12 day·mg / mL, 13 day·mg / mL, or 14 day·mg / mL. 0-∞ In some embodiments, the subject has a serum AUC of greater than 12.8 day·mg / mL. 0-∞ Shows.

[0087] In some embodiments, a single dose of nirsevimab is administered to a subject, and the amount of nirsevimab in the single dose is effective to provide an increase in RSV neutralizing antibody (Nab) levels in the subject after administration compared to the subject's RSV Nab level at the time of administration. In some embodiments, the nirsevimab in the single dose is present in an amount effective to provide an increase in RSV Nab levels in the subject 21, 31, 41, 51, 61, 71, 81, 91, 101, 111, 121, 131, 141, 151, 161, 171, 181, 191, 201, 211, 221, 231, 241, 251, 261, 271, 281, 291, 301, 311, 321, 331, 341, 351, or 361 days after administration compared to the subject's RSV Nab level at the time of administration. In some embodiments, the nirsevimab in the single dose is present in an amount effective to provide an increase in the RSV Nab level in the subject 31, 91, 151 or 361 days after administration compared to the subject's RSV Nab level at the time of administration. In some embodiments, the nirsevimab in the single dose is present in an amount effective to provide an increase in the RSV Nab level in the subject about 5, about 6, about 7, about 8, about 9, about 10, about 11 or about 12 months after administration compared to the subject's RSV Nab level at the time of administration. In some embodiments, nirsevimab is present in a single dose in an amount effective to provide a RSV Nab level in the subject at about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months after administration that is greater than 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 times higher than the subject's RSV Nab level at the time of administration. In some embodiments, nirsevimab is present in a single dose in an amount effective to provide a RSV Nab level in the subject at about 12 months after administration that is greater than 5 times higher than the subject's RSV Nab level at the time of administration. In some embodiments, nirsevimab is present in a single dose in an amount effective to provide a RSV Nab level in the subject at about 12 months after administration that is greater than 7 times higher than the subject's RSV Nab level at the time of administration.

[0088] In some embodiments, nirsevimab is present in a single dose in an amount effective to provide an increase in RSV Nab levels in the subject at about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months after administration, compared to RSV Nab levels in subjects with confirmed RSV infection and not receiving nirsevimab. In some embodiments, nirsevimab is present in a single dose in an amount effective to provide an RSV Nab level in the subject at about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months after administration that is greater than 1, 2, 3, 4, or 5 times greater than RSV Nab levels in subjects with confirmed RSV infection and not receiving nirsevimab. In some embodiments, nirsevimab is present in a single dose in an amount effective to provide an RSV Nab level in the subject at about 12 months after administration that is greater than 3 times greater than RSV Nab levels in subjects with confirmed RSV infection and not receiving nirsevimab.

[0089] In some embodiments, the subject is administered a single dose of nirsevimab containing 50 mg, 100 mg, or 200 mg of nirsevimab. In some embodiments, the subject exhibits an increase in RSV Nab levels after administration of a single dose of nirsevimab compared to the subject's RSV Nab levels at the time of administration. In some embodiments, the subject exhibits an increase in RSV Nab levels 21, 31, 41, 51, 61, 71, 81, 91, 101, 111, 121, 131, 141, 151, 161, 171, 181, 191, 201, 211, 221, 231, 241, 251, 261, 271, 281, 291, 301, 311, 321, 331, 341, 351, or 361 days after administration of a single dose of nirsevimab compared to the subject's RSV Nab levels at the time of administration. In some embodiments, the subject exhibits an elevated RSV Nab level 31, 91, 151 or 361 days after administration of a single dose of nirsevimab compared to the subject's RSV Nab level at the time of administration. In some embodiments, the subject exhibits an elevated RSV Nab level about 5, about 6, about 7, about 8, about 9, about 10, about 11 or about 12 months after administration of a single dose of nirsevimab compared to the subject's RSV Nab level at the time of administration. In some embodiments, the subject's RSV Nab level about 5, about 6, about 7, about 8, about 9, about 10, about 11 or about 12 months after administration of a single dose of nirsevimab is greater than 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 times higher than the subject's RSV Nab level at the time of administration. In some embodiments, the subject's RSV Nab level at about 12 months after administration of a single dose of nirsevimab is more than 5-fold higher than the subject's RSV Nab level at the time of administration. In some embodiments, the subject exhibits an increase in RSV Nab level at about 12 months after administration of a single dose of nirsevimab that is more than 7-fold higher than the subject's RSV Nab level at the time of administration. In some embodiments, the subject exhibits an increase in RSV Nab level at about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months after administration of a single dose of nirsevimab compared to the RSV Nab level in a subject with confirmed RSV infection and who did not receive nirsevimab.In some embodiments, the subject exhibits elevated RSV Nab levels at about 5, 6, 7, 8, 9, 10, 11, or 12 months after administration of a single dose of nirsevimab that are greater than 1, 2, 3, 4, or 5 times higher than subjects with confirmed RSV infection who did not receive nirsevimab. In some embodiments, the subject exhibits elevated RSV Nab levels at about 12 months after administration of a single dose of nirsevimab that are greater than 3 times higher than subjects with confirmed RSV infection who did not receive nirsevimab.

[0090] The subject in need of nirsevimab treatment may be any subject susceptible to RSV infection. In some embodiments, the subject is an infant, such as an infant aged 3 months or less, more than 3 months and less than 6 months, or more than 6 months (e.g., more than 6 months and less than 12 months). In some embodiments, the infant is a late preterm infant or a full-term infant ("term" infant) (e.g., born at a gestational age of 35 weeks or more), and optionally, the infant is healthy. In some embodiments, the infant is a preterm infant born at a gestational age of 29 weeks or more, and optionally, the infant is healthy. In some embodiments, the infant is born at a gestational age of less than 29 weeks.

[0091] In some embodiments, the subject is a premature infant in the first or second year of life, or a child who remains at risk for RSV infection beyond the second year of life. In some embodiments, the subject weighs less than 5 kg. In some embodiments, the subject weighs 5 kg or more.

[0092] In some embodiments, the subject is at high risk of developing RSV infection (e.g., RSV-associated LRTI). The level of risk can be determined by a medical professional. For example, see the guidelines provided by the American Academy of Pediatrics. For example, children suffering from any of the following underlying conditions are considered to be at high risk: - Children under 2 years of age with chronic lung disease (CLD) or congenital heart disease (CHD); - Children with a suppressed immune system; and - Children suffering from neuromuscular disorders, for example those who have difficulty swallowing or clearing mucus secretions and who have a gestational age of 35 weeks or less.

[0093] Premature infants are at high risk for CLD due to immaturity of the lungs at birth and lung damage caused by treatments such as the use of ventilators and / or high oxygen concentrations. Infants with CLD are at particular risk of illness due to RSV infection. In some embodiments, the subject to be immunized may be suffering from CLD. In some embodiments, the subject to be immunized may be a child (e.g., an infant or a pediatric subject) suffering from CLD.

[0094] Children suffering from CHD include those suffering from hemodynamically significant CHD, which may adversely affect pulmonary blood flow. Children suffering from hemodynamically significant CHD have a higher rate of RSV-related hospitalization. In some embodiments, the subject to be immunized may suffer from CHD. In some embodiments, the subject to be immunized may be a child suffering from CHD (e.g., an infant or pediatric subject).

[0095] In some subjects, the subject to be immunized may have Down's syndrome. It has been reported that children with Down's syndrome are at significantly higher risk of severe RSV infection than children without Down's syndrome (Beckhaus et al., Pediatrics (2018) 142 (3): e20180225). In some embodiments, the subject to be immunized may be a child (e.g., an infant or a pediatric subject) with Down's syndrome.

[0096] In some embodiments, the subject to be immunized may have cystic fibrosis. In some embodiments, the subject to be immunized may be a child (e.g., an infant or pediatric subject) with cystic fibrosis.

[0097] In some embodiments, the subject to be immunized may be immunocompromised. In some embodiments, the subject to be immunized may be an immunocompromised child (e.g., an infant or pediatric subject). In some embodiments, the subject to be immunized may be immunocompromised (e.g., combined etiology, antibody etiology, or other etiology of immunodeficiency). In some embodiments, the subject to be immunized may be an immunocompromised child (e.g., an infant or pediatric subject). In some embodiments, the subject to be immunized may suffer from a primary immunodeficiency. In some embodiments, the subject to be immunized may be a child (e.g., an infant or pediatric subject) suffering from a primary immunodeficiency. In some embodiments, the subject to be immunized may suffer from a human immunodeficiency virus infection. In some embodiments, the subject to be immunized may be a child (e.g., an infant or pediatric subject) suffering from a human immunodeficiency virus infection. In some embodiments, the subject to be immunized may have a history of organ transplant or bone marrow transplant. In some embodiments, the subject to be immunized may be a child (e.g., an infant or pediatric subject) with a history of organ transplant or bone marrow transplant. In some embodiments, the subject to be immunized is receiving immunosuppressive chemotherapy. In some embodiments, the subject to be immunized may be a child (e.g., an infant or pediatric subject) receiving immunosuppressive chemotherapy. In some embodiments, the subject to be immunized is receiving systemic high dose corticosteroid therapy. In some embodiments, the subject to be immunized may be a child (e.g., an infant or pediatric subject) receiving systemic high dose corticosteroid therapy. In some embodiments, the subject to be immunized is receiving other immunosuppressive therapies. In some embodiments, the subject to be immunized may be a child (e.g., an infant or pediatric subject) receiving other immunosuppressive therapies. In some embodiments, the subject to be immunized may be a congenital airway abnormality. In some embodiments, the subject to be immunized may be a child (e.g., an infant or pediatric subject) receiving congenital airway abnormalities.

[0098] In some embodiments, the subject is a subject who has undergone cardiac surgery after receiving a first dose of nirsevimab before or during the first RSV epidemic and is receiving a second dose of nirsevimab after the surgery. In some embodiments, the cardiac surgery is cardiac surgery involving cardiopulmonary bypass. In some embodiments, the subject is administered a second dose of nirsevimab within 90 days of receiving a first dose of nirsevimab, the second dose of nirsevimab being 50 mg if the subject weighs less than 5 kg at the time of administration of the second dose, and 100 mg if the subject weighs 5 kg or more at the time of administration of the second dose. In some embodiments, the subject is administered a second dose of nirsevimab more than 90 days after receiving a first dose of nirsevimab, the second dose of nirsevimab being 50 mg (regardless of the subject's weight). In some embodiments, the subject is administered a second dose of nirsevimab as soon as the subject is stabilized after surgery.

[0099] In some embodiments, the subject is a subject who has undergone cardiac surgery after administering a first dose of nirsevimab before or during the second RSV season, and the subject is administered a second dose of nirsevimab after the surgery. In some embodiments, the cardiac surgery is cardiac surgery involving cardiopulmonary bypass. In some embodiments, the subject is administered a second dose of nirsevimab within 90 days of administering a first dose of nirsevimab, and the second dose of nirsevimab is 200 mg. In some embodiments, the subject is administered a second dose of nirsevimab more than 90 days after administering a first dose of nirsevimab, and the second dose of nirsevimab is 100 mg. In some embodiments, the subject is administered a second dose of nirsevimab as soon as the subject is stabilized after surgery.

[0100] RSV infection can be diagnosed and monitored by a variety of known tests that can be performed on upper and lower respiratory tract specimens, including, for example, real-time reverse transcriptase polymerase chain reaction (rRT-PCR), antigen tests, viral culture, and serology. Some tests can distinguish between RSV subtypes (A and B).

[0101] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have the meanings commonly understood by those skilled in the art. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein may also be used in the practice or testing of this disclosure. In case of conflict, the present specification, including definitions, will control. In general, the nomenclature used in connection with neurology, medicine, medicinal chemistry and cell biology and the techniques described herein are those known and commonly used in the art. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications as commonly performed in the art or as described herein.

[0102] In order that the present invention may be better understood, the following representative embodiments and examples are given, which are for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way.

[0103] Representative embodiments of the present disclosure 1. A method for preventing respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject in need thereof, comprising administering a single dose of nirsevimab to the subject at a time other than an RSV season, wherein the administration is no more than once a year.

[0104] 2. The method of embodiment 1, 91 or 94, wherein the subject is administered nirsevimab intramuscularly.

[0105] 3. The method of embodiment 1, 91 or 94, wherein the subject is administered nirsevimab subcutaneously.

[0106] 4. The method of any one of embodiments 1 to 3 or 91, wherein the subject is an infant born outside of the RSV season and the time of administration of nirsevimab is a time from birth to before the start of the infant's first RSV season.

[0107] 5. The method of any one of embodiments 1-4 or 91, wherein the RSV season is about 5 months.

[0108] 6. The method of any one of embodiments 1-4 or 91, wherein the RSV season is greater than about 5 months.

[0109] 7. The method of any one of embodiments 1-6 or 91, wherein the subject is administered a single dose of nirsevimab about 2 weeks before the start of the RSV season.

[0110] 8. The method of any one of embodiments 1-6 or 91, wherein the subject is administered a single dose of nirsevimab about 3 weeks before the start of the RSV season.

[0111] 9. The method of any one of embodiments 1-6 or 91, wherein the subject is administered a single dose of nirsevimab about 4 weeks before the start of the RSV season.

[0112] 10. The method of any one of embodiments 1-6 or 91, wherein the subject is administered a single dose of nirsevimab about one month before the start of the RSV season.

[0113] 11. The method of any one of embodiments 1-6 or 91, wherein the subject is administered a single dose of nirsevimab approximately 2 months prior to the start of the RSV season.

[0114] 12. The method of any one of embodiments 1-6 or 91, wherein the subject is administered a single dose of nirsevimab about 3 months prior to the start of the RSV season.

[0115] 13. The method of any one of embodiments 1-6 or 94, wherein the subject is administered a single dose of nirsevimab about 1 week after the end of the most recent RSV season, and the most recent RSV season is more than about 9 months.

[0116] 14. The method of any one of embodiments 1-6 or 94, wherein the subject is administered a single dose of nirsevimab approximately 2 weeks after the end of the most recent RSV season, and the most recent RSV season is more than about 9 months.

[0117] 15. The method of any one of embodiments 1-6 or 94, wherein the subject is administered a single dose of nirsevimab approximately 3 weeks after the end of the most recent RSV season, and the most recent RSV season is more than about 9 months.

[0118] 16. The method of any one of embodiments 1-6 or 94, wherein the subject is administered a single dose of nirsevimab about 4 weeks after the end of the most recent RSV season, and the most recent RSV season is more than about 8 months.

[0119] 17. The method of any one of embodiments 1-6 or 94, wherein the subject is administered a single dose of nirsevimab approximately 1 month after the end of the most recent RSV season, and the most recent RSV season is greater than about 8 months.

[0120] 18. The method of any one of embodiments 1-6 or 94, wherein the subject is administered a single dose of nirsevimab approximately 2 months after the end of the most recent RSV season, and the most recent RSV season is more than about 7 months.

[0121] 19. The method of any one of embodiments 1-6 or 94, wherein the subject is administered a single dose of nirsevimab approximately 3 months after the end of the most recent RSV season, and the most recent RSV season is more than about 6 months.

[0122] 20. The method of any one of embodiments 1-6 or 94, wherein the subject is administered a single dose of nirsevimab approximately 4 months after the end of the most recent RSV season, and the most recent RSV season is more than about 5 months.

[0123] 21. The method of any one of embodiments 1-6 or 94, wherein the subject is administered a single dose of nirsevimab approximately 5 months after the end of the most recent RSV season, and the most recent RSV season is more than about 4 months.

[0124] 22. The method of any one of embodiments 1-6 or 94, wherein the subject is administered a single dose of nirsevimab approximately 6 months after the end of the most recent RSV season, and the most recent RSV season is more than about 3 months.

[0125] 23. The method of any one of embodiments 1-6 or 94, wherein the subject is administered a single dose of nirsevimab approximately 7 months after the end of the most recent RSV season, and the most recent RSV season is more than about 2 months.

[0126] 24. The method of any one of embodiments 1-12 or 91, wherein the beginning of the RSV season is defined by the first two consecutive weeks in which the average positive rate of RSV tests over a two-week period exceeds a threshold, the threshold being between 3% and 13%.

[0127] 25. The method of embodiment 24, wherein the threshold is 3%.

[0128] 26. The method of embodiment 24, wherein the threshold is 5%.

[0129] 27. The method of embodiment 24, wherein the threshold is 7%.

[0130] 28. The method of embodiment 24, wherein the threshold is 10%.

[0131] 29. The method of embodiment 24, wherein the threshold is 13%.

[0132] 30. The method of any one of embodiments 13-23 or 94, wherein the end of the immediately preceding RSV season is defined by the first week in which the average positive rate of RSV tests over a one-week period falls below a threshold throughout the entire one-week period, the threshold being between 3% and 13%.

[0133] 31. The method of embodiment 30, wherein the threshold is 3%.

[0134] 32. The method of embodiment 30, wherein the threshold is 5%.

[0135] 33. The method of embodiment 30, wherein the threshold is 7%.

[0136] 34. The method of embodiment 30, wherein the threshold is 10%.

[0137] 35. The method of embodiment 30, wherein the threshold is 13%.

[0138] 36. The method of any one of embodiments 24 to 35, wherein the test is a PCR test.

[0139] 37. The method of any one of embodiments 24 to 35, wherein the test is an antigen test.

[0140] 38. The method of any one of embodiments 1-12 or 91, wherein the beginning of the RSV season is defined by the first two consecutive weeks in which the average PCR RSV test positivity rate is greater than 3% throughout the entire two-week period.

[0141] 39. The method of any one of embodiments 1-12 or 91, wherein the beginning of the RSV season is defined by the first two consecutive weeks in which the average antigen test positivity rate exceeds 10% throughout the entire two-week period.

[0142] 40. The method of any one of embodiments 13-23 or 94, wherein the end of the previous RSV season is defined by the first week in which the average PCR test positivity rate is less than 3% throughout the entire week period.

[0143] 41. The method of any one of embodiments 13-23 or 94, wherein the end of the previous RSV season is defined by the first week in which the average antigen test positivity rate is less than 10% throughout the entire week period.

[0144] 42. The method of any one of embodiments 1 to 12 or 91, wherein the start of the RSV season is defined by a meteorological season, and the meteorological season is fall (autumn).

[0145] 43. The method of any one of embodiments 1 to 12 or 91, wherein the start of the RSV season is predicted by a local, state, regional or national health department.

[0146] 44. The method of any one of embodiments 13-23 or 94, wherein the end of the RSV season is declared by a local, state, regional or national health department.

[0147] 45. A method for preventing respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject in need thereof, comprising intramuscularly administering a single dose of nirsevimab to the subject before the onset of the RSV season, at the onset of the RSV season, or every RSV season during the RSV season, wherein the RSV season is greater than about 5 months, and optionally the RSV season is about 6, about 7, about 8, about 9, or about 10 months.

[0148] 46. ​​A method for preventing respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject in need thereof, comprising intramuscularly administering a single dose of nirsevimab to the subject, wherein the single dose provides protection against RSV infection and / or RSV disease for more than 5 months, preferably at least 6, 7, 8, 9, 10, 11 or 12 months.

[0149] 47. The method of any one of embodiments 1-46, 91, or 94, wherein the subject is a healthy late preterm or term infant born at a gestational age (GA) of 35 weeks 0 days or greater and is 1 year old or younger.

[0150] 48. The method of embodiment 47, wherein the subject weighs less than 5 kg and is administered a 50 mg dose of nirsevimab.

[0151] 49. The method of embodiment 47, wherein the subject is 5 kg or greater and is administered a 100 mg dose of nirsevimab.

[0152] 50. The method of any one of embodiments 1 to 46, 91, or 94, wherein the subject is a healthy premature infant born at a gestational age of 29 weeks 0 days to 34 weeks 6 days and is 1 year old or younger.

[0153] 51. The method of embodiment 50, wherein the subject weighs less than 5 kg and is administered a 50 mg dose of nirsevimab.

[0154] 52. The method of embodiment 50, wherein the subject weighs 5 kg or more and is administered a dose of 100 mg of nirsevimab.

[0155] 53. The method of any one of embodiments 1-46, 91, or 94, wherein the subject is at high risk of developing RSV LRTI.

[0156] 54. The method of any one of embodiments 1-46, 91, or 94, wherein the subject is at high risk of developing a RSV infection.

[0157] 55. The method of embodiment 53 or 54, wherein the subject is a pediatric subject.

[0158] 56. The method of any one of embodiments 53-55, wherein the subject was born with a gestational age of less than 29 weeks; and / or has chronic lung disease (CLD), congenital heart disease (CHD), a suppressed immune system, a weakened immune system, an immunodeficiency, a neuromuscular disorder, Down's syndrome, a congenital airway abnormality, and / or cystic fibrosis.

[0159] 57. The method of embodiment 56, wherein the subject is less than 5 kg, the subject is 1 year old or younger, and a 50 mg dose of nirsevimab is administered.

[0160] 58. The method of embodiment 56, wherein the subject is 5 kg or more, the subject is 1 year old or younger, and a 100 mg dose of nirsevimab is administered.

[0161] 59. The method of embodiment 56, wherein the subject is 5 kg or more, the subject is in the second year of life or later, and a 200 mg dose of nirsevimab is administered.

[0162] 60. The method of embodiment 56, wherein the subject is a pediatric patient born at a gestational age of less than 29 weeks; and / or suffers from chronic lung disease or congenital heart disease.

[0163] 61. The method of embodiment 60, wherein the subject is 5 kg or more, the subject is in the second year of life or later, and a 200 mg dose of nirsevimab is administered.

[0164] 62. The method of any one of embodiments 53-61, wherein the subject is a pediatric patient undergoing a first or second RSV epidemic.

[0165] 63. The method of any one of embodiments 1-62, 91, or 94, wherein administration occurs prior to the subject's first RSV season.

[0166] 64. A method for preventing respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject, comprising administering a single dose of nirsevimab intramuscularly to the subject, the administration being no more than once a year.

[0167] 65. A method for preventing respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject in need thereof, comprising administering a single dose of nirsevimab intramuscularly to the subject, the administration being performed only once per season.

[0168] 66. The method of embodiment 64 or 65, wherein administration occurs outside of an RSV epidemic season.

[0169] 67. The method according to embodiment 64 or 65, wherein administration is performed during an RSV epidemic.

[0170] 68. A method of obtaining protection from respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) and / or RSV disease in an infant or pediatric subject, comprising administering a single dose of nirsevimab intramuscularly to the subject, wherein the single dose provides protection for greater than 5 months to at least 8 months, optionally about 12 months.

[0171] 69. A method for obtaining protection from respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) and / or RSV disease in an infant or pediatric subject, comprising administering a single dose of nirsevimab intramuscularly to the subject, wherein the single dose provides protection for at least one RSV season.

[0172] 70. The method of any one of embodiments 1-69, 91 or 94, wherein the single dose comprises 50-200 mg of nirsevimab.

[0173] 71. The amount of nirsevimab in a single dose is 50 mg if the subject is an infant weighing less than 5 kg at the time of administration, or 100 mg if the subject is an infant weighing 5 kg or more at the time of administration, or The method of any one of embodiments 1-70, 91, or 94, wherein the dose is 200 mg if the subject is a pediatric subject entering its second RSV season.

[0174] 72. The method of embodiment 71, wherein pediatric patients undergoing a second RSV season are at high risk for RSV infection.

[0175] 73. The method of any one of embodiments 1-72, 91 or 94, wherein preventing RSV LRTI includes preventing RSV LRTI requiring medical attention, optionally bronchiolitis or pneumonia.

[0176] 74. The method of any one of embodiments 1-73, 91 or 94, wherein preventing RSV LRTI comprises preventing RSV-related hospitalization.

[0177] 75. The method of any one of embodiments 1-73, 91 or 94, wherein preventing RSV LRTI includes preventing severe RSV LRTI.

[0178] 76. The method of any one of embodiments 1-73, 91 or 94, wherein preventing RSV LRTI includes preventing very severe RSV LRTI.

[0179] 77. The method of any one of embodiments 1 to 73, 91 or 94, wherein preventing RSV LRTI includes preventing LRTI of any cause.

[0180] 78. The method of any one of embodiments 1-77, 91 or 94, wherein preventing RSV LRTI includes preventing hospitalization due to LRTI of any cause.

[0181] 79. A method for preventing very severe respiratory syncytial virus (RSV) infection in an infant or pediatric subject, comprising administering a single dose of nirsevimab to the subject, wherein the single dose is effective in preventing very severe RSV infection for greater than 5 months.

[0182] 80. A method for preventing lower respiratory tract infection (LRTI) of any cause or hospitalization due to LRTI of any cause in an infant or pediatric subject, comprising administering to the subject a single dose of nirsevimab, wherein the single dose is effective in preventing LRTI of any cause or hospitalization of any cause for greater than 5 months.

[0183] 81. A method for preventing very severe RSV LRTI in an infant or pediatric subject in need thereof, comprising administering a single dose of nirsevimab to the subject at a time other than the RSV season, wherein the administration is performed no more than once a year.

[0184] 82. A single dose of nirsevimab is Nirsevimab at 100 mg / mL; 30mM Histidine / Histidine-HCl 80 mM Arginine-HCl, 120 mM sucrose, and 0.02% to 0.04% (w / v) polysorbate 80 (pH 6.0) The method of any one of embodiments 1 to 81, 91 or 94, provided in a pharmaceutical composition comprising:

[0185] 83. The amount of nirsevimab in a single dose was determined to be greater than 12.8 day·mg / mL in subjects with a serum AUC 0-∞ The method of any one of embodiments 1 to 82, 91 or 94, wherein the method is effective to produce

[0186] 84. The method of any one of embodiments 1 to 83, 91 or 94, wherein the amount of nirsevimab in a single dose is effective to result in an increase in RSV neutralizing antibody (Nab) levels in the subject (e.g., more than 5-fold higher, more than 7-fold higher) at about 12 months after administration compared to the subject's RSV Nab level at the time of administration.

[0187] 85. The method of any one of embodiments 1 to 84, 91 or 94, wherein the amount of nirsevimab in a single dose is effective to result in an increase in RSV Nab levels (e.g., more than three-fold higher) in the subject at about 12 months after administration compared to the RSV Nab levels of a subject with confirmed RSV infection and who has not been administered nirsevimab.

[0188] 86. The method of any one of embodiments 1 to 85, 91 or 94, wherein the amount of nirsevimab in the single dose is effective to reduce antibiotic usage in the subject compared to antibiotic usage in a subject who has not been administered nirsevimab.

[0189] 87. The method of any one of claims 1 to 86, 91 or 94, wherein a single dose of nirsevimab is administered intramuscularly or subcutaneously.

[0190] 88. A method for preventing RSV LRTI in a subject at high risk of developing a RSV infection, comprising administering to the subject a first dose of nirsevimab prior to the subject's first RSV season and a second dose of nirsevimab prior to the subject's second RSV season, wherein the amount of nirsevimab in the first dose is 50 mg if the subject weighs less than 5 kg at the time of administration; and 100 mg if the subject weighs 5 kg or more at the time of administration; The method, wherein the amount of nirsevimab in the second dose is 200 mg.

[0191] 89. A method for preventing RSV LRTI in a subject undergoing cardiac surgery, comprising: a) administering to the subject a first dose of nirsevimab prior to the subject's first RSV season; i) the amount of nirsevimab in the first dose is 50 mg if the subject weighs less than 5 kg at the time of administration of the first dose; or ii) the amount of nirsevimab in the first dose is 100 mg if the subject weighs 5 kg or more at the time of administration of the first dose; and b) administering a second dose of nirsevimab to the subject following cardiac surgery; i) the amount of nirsevimab in the second dose is 50 mg if the subject weighs less than 5 kg at the time of administration of the second dose and the second dose is administered within 90 days of administration of the first dose; or ii) the amount of nirsevimab in the second dose is 100 mg if the subject weighs 5 kg or more at the time of administration of the second dose and the second dose is administered within 90 days of administration of the first dose; or iii) the amount of nirsevimab in the second dose is 50 mg if the second dose is administered more than 90 days after administration of the first dose. wherein optionally the second dose is administered as soon as the subject is stabilized after surgery, and optionally the cardiac surgery is cardiac surgery involving cardiopulmonary bypass.

[0192] 90. The method of any one of embodiments 1-89, 91 or 94, wherein the dose of nirsevimab is administered at birth.

[0193] 91. A method for preventing respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject, comprising administering a single dose of nirsevimab to the subject prior to the onset of the RSV season, wherein the single dose is effective in preventing RSV LRTI for greater than 5 months.

[0194] 92. The method of embodiment 91, wherein the subject is administered a single dose of nirsevimab about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, or about 3 months before the start of the RSV season.

[0195] 93. The method of embodiment 91 or 92, wherein the beginning of the RSV season is defined by the first two consecutive weeks in which the average positivity rate of RSV testing over a two-week period exceeds a threshold, the threshold being between 3% and 13%, optionally, (i) the RSV testing is a PCR test and the threshold is 3%, or (ii) the RSV testing is an antigen test and the threshold is 10%.

[0196] 94. A method for preventing respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject, comprising administering a single dose of nirsevimab to the subject after the end of a previous RSV season, wherein the single dose is effective to prevent RSV LRTI throughout the next RSV season.

[0197] 95. The method of embodiment 94, wherein the subject is administered a single dose of nirsevimab about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or about 7 months after the end of the most recent RSV season.

[0198] 96. The method of embodiment 94 or 95, wherein the end of the previous RSV season is defined by the first week in which the average positivity rate of RSV tests over a one-week period falls below a threshold, the threshold being between 3% and 13%, optionally, (i) the RSV test is a PCR test and the threshold is 3%, or (ii) the RSV test is an antigen test and the threshold is 10%.

[0199] 97. A pharmaceutical composition comprising nirsevimab for use in the method according to any one of embodiments 1 to 96.

[0200] 98. Use of nirsevimab in the manufacture of a medicament for use in the method according to any one of embodiments 1 to 96.

[0201] 99. A product comprising nirsevimab for use in the method according to any one of embodiments 1 to 96.

[0202] 100. The product of embodiment 99, comprising a single-unit container or a multi-unit container, each unit containing about 50, 100 or 200 mg of nirsevimab.

[0203] 101. The product of embodiment 99 or 100, wherein the container is a vial or a prefilled syringe or injector.

[0204] 102. A pharmaceutical composition comprising a single dose of nirsevimab for use in preventing respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject, wherein the pharmaceutical composition is administered to the subject before the onset of the RSV season and is effective in preventing RSV LRTI for more than 5 months.

[0205] 103. The pharmaceutical composition of embodiment 102, wherein the pharmaceutical composition is administered to the subject about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, or about 3 months before the start of the RSV season.

[0206] 104. The pharmaceutical composition of embodiment 102 or 103, wherein the beginning of the RSV season is defined by the first two consecutive weeks in which the average positive rate of RSV testing over a two-week period exceeds a threshold, the threshold being between 3% and 13%, and optionally, (i) the RSV testing is a PCR test and the threshold is 3%, or (ii) the RSV testing is an antigen test and the threshold is 10%.

[0207] 105. A pharmaceutical composition comprising a single dose of nirsevimab for use in preventing respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject, wherein the pharmaceutical composition is administered to the subject after the end of the immediately preceding RSV season and is effective to prevent RSV LRTI throughout the next RSV season.

[0208] 106. The pharmaceutical composition of embodiment 105, wherein the pharmaceutical composition is administered to the subject about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or about 7 months after the end of the most recent RSV season.

[0209] 107. The pharmaceutical composition of embodiment 105 or 106, wherein the end of the previous RSV season is defined by the first week in which the average positivity rate of RSV tests over a one-week period falls below a threshold, the threshold being between 3% and 13%, optionally, (i) the RSV test is a PCR test and the threshold is 3%, or (ii) the RSV test is an antigen test and the threshold is 10%.

[0210] 108. The pharmaceutical composition of any one of embodiments 102 to 107, wherein the subject is at high risk of developing a RSV infection.

[0211] 109. The pharmaceutical composition of embodiment 108, wherein the subject was born with a gestational age of less than 29 weeks; and / or has chronic lung disease (CLD), congenital heart disease (CHD), a suppressed immune system, a weakened immune system, an immunodeficiency, a neuromuscular disorder, Down's syndrome, a congenital airway abnormality, and / or cystic fibrosis.

[0212] 110. A pharmaceutical composition comprising a single dose of nirsevimab for use in preventing very severe respiratory syncytial virus (RSV) infection in an infant or pediatric subject, the pharmaceutical composition being effective in preventing very severe RSV infection for more than 5 months.

[0213] 111. A pharmaceutical composition comprising a single dose of nirsevimab for use in preventing lower respiratory tract infections (LRTI) of any cause or hospitalization due to LRTI of any cause in an infant or pediatric subject, wherein the pharmaceutical composition is effective in preventing LRTI of any cause or hospitalization due to any cause for more than 5 months.

[0214] 112. Use of nirsevimab in the manufacture of a medicament for the prevention of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject, wherein the medicament is administered to the subject in a single dose before the start of the RSV season and is effective in preventing RSV LRTI for more than 5 months.

[0215] 113. The use of embodiment 112, wherein the medicament is administered to the subject about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, or about 3 months before the start of the RSV season.

[0216] 114. The use of embodiment 112 or 113, wherein the beginning of the RSV season is defined by the first two consecutive weeks in which the average positivity rate of RSV tests over a two-week period exceeds a threshold, the threshold being between 3% and 13%, optionally, (i) the RSV test is a PCR test and the threshold is 3%, or (ii) the RSV test is an antigen test and the threshold is 10%.

[0217] 115. Use of nirsevimab in the manufacture of a medicament for the prevention of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject, wherein the medicament is administered to the subject in a single dose after the end of the immediately preceding RSV season and is effective to prevent RSV LRTI throughout the next RSV season.

[0218] 116. The use of embodiment 115, wherein the pharmaceutical agent is administered to the subject about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or about 7 months after the end of the most recent RSV season.

[0219] 117. The use of embodiment 115 or 116, wherein the end of the immediately preceding RSV season is defined by the first week in which the average positivity rate of RSV tests over a one-week period falls below a threshold, the threshold being between 3% and 13%, optionally, (i) the RSV test is a PCR test and the threshold is 3%, or (ii) the RSV test is an antigen test and the threshold is 10%.

[0220] 118. The use of any one of embodiments 112 to 117, wherein the subject is at high risk of developing a RSV infection.

[0221] 119. The pharmaceutical composition of embodiment 118, wherein the subject was born with a gestational age of less than 29 weeks; and / or has chronic lung disease (CLD), congenital heart disease (CHD), a suppressed immune system, a weakened immune system, an immunodeficiency, a neuromuscular disorder, Down's syndrome, a congenital airway abnormality, and / or cystic fibrosis.

[0222] 120. Use of nirsevimab in the manufacture of a medicament for preventing very severe respiratory syncytial virus (RSV) infection in an infant or pediatric subject, wherein the medicament is administered to the subject in a single dose and is effective in preventing very severe RSV infection for more than 5 months.

[0223] 121. Use of nirsevimab in the manufacture of a medicine for the prevention of lower respiratory tract infections (LRTI) of any cause or hospitalization due to LRTI of any cause in an infant or pediatric subject, wherein the medicine is administered to the subject in a single dose and is effective in preventing LRTI of any cause or hospitalization due to any cause for more than 5 months.

[0224] 122. A product comprising a single dose of nirsevimab for use in the prevention of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject, wherein the single dose is administered to the subject prior to the onset of the RSV season and is effective in preventing RSV LRTI for greater than 5 months.

[0225] 123. The product of embodiment 122, wherein the single dose is administered to the subject about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, or about 3 months before the start of the RSV season.

[0226] 124. The product of embodiment 122 or 123, wherein the beginning of the RSV season is defined by the first two consecutive weeks in which the average positivity rate of RSV tests over a two-week period exceeds a threshold, the threshold being between 3% and 13%, optionally, (i) the RSV test is a PCR test and the threshold is 3%, or (ii) the RSV test is an antigen test and the threshold is 10%.

[0227] 125. A product comprising a single dose of nirsevimab for use in the prevention of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in an infant or pediatric subject, wherein the single dose is administered to the subject after the end of the immediately preceding RSV season and is effective to prevent RSV LRTI throughout the next RSV season.

[0228] 126. The product of embodiment 125, wherein the single dose is administered to the subject about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or about 7 months after the end of the most recent RSV season.

[0229] 127. The product of embodiment 125 or 126, wherein the end of the previous RSV season is defined by the first week in which the average positivity rate of RSV tests over a one-week period falls below a threshold, the threshold being between 3% and 13%, optionally, (i) the RSV test is a PCR test and the threshold is 3%, or (ii) the RSV test is an antigen test and the threshold is 10%.

[0230] 128. The product of any one of embodiments 122 to 127, wherein the subject is at high risk of developing a RSV infection.

[0231] 129. The product of embodiment 128, wherein the subject was born with a gestational age of less than 29 weeks; and / or has chronic lung disease (CLD), congenital heart disease (CHD), a suppressed immune system, a weakened immune system, an immunodeficiency, a neuromuscular disorder, Down's syndrome, a congenital airway abnormality, and / or cystic fibrosis.

[0232] 130. A product comprising a single dose of nirsevimab for use in preventing very severe respiratory syncytial virus (RSV) infection in infants or pediatric subjects, wherein the single dose is effective in preventing very severe RSV infection for more than 5 months.

[0233] 131. A product containing a single dose of nirsevimab for use in the prevention of lower respiratory tract infections (LRTI) of any cause or hospitalization due to LRTI of any cause in infant or pediatric subjects, wherein the single dose is effective in preventing LRTI of any cause or hospitalization due to any cause for more than 5 months. EXAMPLES

[0234] Example 1: Safety and efficacy of nirsevimab against respiratory syncytial virus in healthy late preterm and term infants This example describes the clinical trial protocol for a Phase 3 randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of nirsevimab against RSV in healthy late preterm and term infants. This is a single-dose study to determine whether nirsevimab prevents RSV-confirmed LRTI requiring medical attention in healthy infants undergoing their first RSV season (Figure 1).

[0235] Primary Objectives and Related Endpoints The primary objective is to evaluate the efficacy of nirsevimab in reducing LRTI requiring medical attention due to RSV confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) compared to placebo up to 150 days post-dose when administered as a single fixed intramuscular (IM) dose to infants aged 35 weeks 0 days or older and undergoing their first RSV epidemic. The primary efficacy outcome is the incidence of LRTI requiring medical attention (inpatient and outpatient) due to RSV confirmed by RT-PCR over 150 days post-dose (i.e., 5-month RSV epidemic). After RSV detection by RT-PCR, RSV A and RSV B subtypes are determined by genotypic analysis of sequence variations in the mature F protein from all RSV positive isolates / samples compared to contemporary RSV A and RSV B reference strains. The case definition of RSV LRTI requiring medical attention for the primary outcome is shown in Table 1 below (one item from each row is required to meet the case definition of RSV LRTI). Subgroup analyses of the primary endpoint were prespecified according to hemisphere, age at randomization, sex, race, weight, and gestational age.

[0236] [Table 1]

[0237] Secondary Objectives and Endpoints Effectiveness A secondary objective is to evaluate the efficacy of nirsevimab in reducing hospitalizations due to RSV confirmed by RT-PCR compared to placebo. Secondary efficacy outcomes include the incidence of hospitalizations due to this condition during the same period. All cases were confirmed by central RSV testing using real-time RT-PCR.

[0238] safety Another secondary objective is to evaluate the safety and tolerability of nirsevimab when administered as a single fixed IM dose compared to placebo. Relevant endpoints are safety and tolerability of nirsevimab as assessed by the occurrence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), adverse events of special interest (AESIs) and new-onset chronic diseases (NOCDs).

[0239] Pharmacokinetics (PK) Another secondary objective is to evaluate single-dose serum concentrations of nirsevimab. Relevant endpoints are serum concentrations and estimated PK parameters of nirsevimab (apparent clearance and AUC 0-∞ ) The pharmacokinetics of nirsevimab were determined as previously described (Domachowske et al., Pediatr Infect Dis J. (2018) 37:886-92).

[0240] Anti-drug antibodies Another secondary objective was to evaluate anti-drug antibody (ADA) responses to nirsevimab in serum. The relevant outcome was the incidence of ADA to nirsevimab in serum. Positive anti-nirsevimab antibody responses were defined as a titer of 50 or greater, as previously described (Griffin et al., N Engl J Med. (2020) 383: 415-25; Domachowske, see above).

[0241] Exploratory objectives and endpoints Medical resource utilization and caregiver burden Exploratory objectives are to assess healthcare resource utilization and caregiver burden for nirsevimab recipients compared with placebo recipients. Relevant outcomes are: - Scale of health resource utilization: e.g., number and duration of hospital and intensive care admissions; number and duration of subjects requiring respiratory support and supplemental oxygen; number and type of outpatient visits (e.g., emergency room, urgent care, outpatient care); and number and duration of prescription and over-the-counter medications; and - Caregiver burden for subjects with LRTI caused by RT-PCR-confirmed RSV requiring medical attention: number of days of caregiver absence from work; and subjects absent from day care.

[0242] RSV neutralizing antibody power Another exploratory objective is to determine serum anti-RSV neutralizing antibody levels achieved by a single dose of nirsevimab compared to maternal RSV neutralizing antibody levels and RSV neutralizing antibody levels induced after infection in the placebo group. The relevant endpoint is serum anti-RSV neutralizing antibody levels (IU / mL) for nirsevimab recipients compared to placebo recipients.

[0243] RSV serology Another exploratory objective is to assess exposure to RSV by measuring serological responses to various RSV proteins. Relevant endpoints are: - Antibody levels against RSV pre-F, post-F, Ga, Gb and N at various time points. - Changes in antibody levels (serology) that indicate exposure to RSV.

[0244] Monitoring RSV resistance Another exploratory objective is to characterize resistance to nirsevimab by genotyping and phenotyping. Relevant endpoints are genotyping and susceptibility of RSV variants to neutralization by nirsevimab.

[0245] RSV LRTI after 151 days Another exploratory objective is to evaluate the incidence of RT-PCR-confirmed RSV-attributable LRTI requiring medical attention compared with placebo after day 151. Relevant outcomes are the incidence of RT-PCR-confirmed RSV-attributable LRTI requiring medical attention (inpatient and outpatient) from days 152 to 361.

[0246] Study design This study is to determine whether nirsevimab prevents RSV-confirmed LRTI requiring medical attention in healthy infants undergoing their first RSV epidemic. The enrolled population will be healthy late preterm and term infants aged ≥35 weeks 0 days GA undergoing their first RSV epidemic who have not received RSV prophylaxis based on American Academy of Pediatrics (AAP) or other local or national guidelines. Briefly, a total of approximately 3,000 infants will be enrolled. Subjects will be randomly assigned in a 2:1 ratio to receive a single IM dose of nirsevimab (N=2,000) or placebo (N=1,000). Nirsevimab dose levels will be stratified by weight at time of administration: nirsevimab 50 mg for infants weighing <5 kg or nirsevimab 100 mg for infants weighing ≥5 kg. Subjects in the placebo group will receive the corresponding volume of saline, i.e., 0.5 mL if they weigh less than 5 kg or 1.0 mL if they weigh 5 kg or more. Randomization will be stratified by hemisphere (Northern Hemisphere (NH), Southern Hemisphere (NH)) and subject age at randomization (≤3 months, >3 months <6 months, >6 months). Enrollment of infants >6 months of age will be limited to approximately 500 cases.

[0247] The study includes two cohorts: a primary cohort (N = ≈1,500) and a supplementary safety cohort (hereafter referred to as the safety cohort; N = ≈1,500) for a total of ≈3,000 unrelated subjects. The primary cohort included participants enrolled from 150 sites (20 countries) in NH in 2019 and 10 sites (1 country) in SH in 2020. The safety cohort includes subjects enrolled after the NH 2020 enrollment season. Given the significant reduction in RSV circulation due to coronavirus disease 2019 (COVID-19) pandemic-related measures, the efficacy analysis performed in the primary analysis of the primary cohort will serve the purpose of evaluating the efficacy of nirsevimab.

[0248] All subjects will be followed for approximately 510 days after dosing. Subjects will be monitored throughout the study period for LRTI. All subjects seeking treatment for respiratory illness (either in an inpatient facility or outpatient care) will be evaluated for the development of LRTI. Respiratory samples should be taken and a Respiratory Assessment Form completed from all subjects found to have LRTI and all subjects requiring hospitalization for respiratory infection even if not diagnosed with LRTI. Samples should be taken for all of these events (even those that do not meet the protocol definition of LRTI). Subjects who are hospitalized with a primarily respiratory infection (i.e., upper or lower respiratory tract) or respiratory deterioration during hospitalization or who are seeking outpatient care (including ER visits) for lower respiratory tract illness will be evaluated clinically for the presence of LRTI and for RSV by central laboratory diagnostic testing of respiratory secretions.

[0249] In addition to clinical assessment of LRTI, there are protocol definitions that use objective criteria for adjudication of medically involved, protocol-defined LRTI (Table 1 ).

[0250] Testing for RSV is performed centrally using a US Food and Drug Administration-licensed and European Conformity marked in vitro diagnostic real-time RT-PCR assay (Lyra RSV+human metapneumovirus [hMPV] assay; Quidel Corporation, San Diego, CA). Diagnosis of RSV LRTI requires having an RSV-positive respiratory sample by RT-PCR in a central laboratory.

[0251] This study will be performed across five respiratory virus seasons (three in the Northern Hemisphere (NH) and two in the Southern Hemisphere (SH)) to better characterize RSV cases across multiple seasons.

[0252] Blood samples for pharmacokinetics (PK) and anti-drug antibodies (ADA) will be collected at screening or pre-dose on days 1, 31, 151, and 361, and from subjects hospitalized with respiratory infections through day 361. In Japan, the day 15 visit will be replaced by a day 8 visit for blood sample collection (laboratory parameters). In Japan, blood samples will also be collected at the day 31 and day 151 visits. In Europe, blood volume will be limited, excluding the day 31 evaluation for RSV serology. Safety evaluations will be performed through day 361. Dose levels will be stratified by body weight at time of dosing.

[0253] Inclusion criteria Subjects must meet all of the following criteria: - Healthy infants in the first year of life (infants with underlying conditions such as cystic fibrosis or Down syndrome and no other risk factors) born at a GA of 35 weeks 0 days or more; - Infants in their first RSV season at the time of screening; and - Subjects are able to complete a follow-up period of 17 months after receiving study medication.

[0254] Exclusion criteria Subjects will be excluded from participating in this study if they meet any of the following criteria: - Meets national or other regional criteria for receiving commercially available palivizumab; - Any fever (≥100.4°F (≥38°C), regardless of route) or acute illness within 7 days prior to randomization; - Any history of LRTI or active LRTI before or at the time of randomization; - Known history of RSV infection or active RSV infection prior to or at the time of randomization; - Any medications (chronic or otherwise) anticipated to be administered within 7 days prior to randomization or during the study, except for the following: a) multivitamins and iron; and b) infrequent use of over-the-counter (OTC) medications (e.g., painkillers) for the systemic treatment of common childhood conditions, as may be permitted per the investigator's discretion; - Current or future administration of immunosuppressive drugs such as steroids (except for topical steroids at the discretion of the investigator); - History of or planned administration during the study of blood, blood products, or immunoglobulin products; - Administration of any investigational medicinal product; - Known renal impairment; - Known liver dysfunction, including known or suspected active or chronic hepatitis infection; - History of CLD / bronchopulmonary dysplasia; - Clinically significant congenital anomalies of the respiratory tract; - Chronic attacks or ongoing or unstable neurological disorders; - CHD, except for children with uncomplicated CHD (e.g. patent ductus arteriosus, small septal defect); - Previous history of suspected or actual life-threatening acute events; - known immune deficiency, e.g. human immunodeficiency virus (HIV); - Mothers with HIV infection (unless the child is proven to be uninfected); - Any known allergies (e.g. to immunoglobulin preparations) or history of allergic reactions; - Administration of palivizumab or other RSV mAb or any RSV vaccine (including maternal RSV vaccination); - Administration of any monoclonal or polyclonal antibodies (e.g., Hepatitis B immune globulin, IV immune globulin); - Any condition that, in the opinion of the investigator, would interfere with the evaluation of the investigational product or the safety of the subject or the interpretation of the study results; or - Concurrent enrollment in another interventional trial.

[0255] statistical methods General requirements. There are two study cohorts: Primary cohort and Safety cohort. The Primary cohort includes subjects from the NH2019, SH2020, and NH2020 enrollment seasons (enrollment was halted after one subject from NH2020 was enrolled due to the impact of the COVID-19 pandemic). The Safety cohort includes subjects enrolled after the NH2020 enrollment season. The Intent-to-treat (ITT) population is defined as all subjects who are randomized. Subjects are included in the treatment arm corresponding to the treatment to which they were randomized. All analyses, except safety, will be performed on the ITT population unless otherwise specified. Subjects in the ITT population and primary cohort will be ITT Population 1 (ITT1). Subjects in the ITT population and safety cohort will be ITT Population 2 (ITT2).

[0256] The as-treated population includes all subjects who were randomized and received any amount of investigational drug. Subjects will be in the treatment group that corresponds to the treatment actually administered. All safety analyses will be performed on the as-treated population. The subjects in the as-treated population and the primary cohort will be the as-treated population 1 (AT1). The subjects in the as-treated population and the safety cohort will be the as-treated population 2 (AT2).

[0257] statistical analysis Three analyses are planned for this study: primary analysis, safety analysis, and final analysis. Efficacy analysis will be performed on the intent-to-treat population (all randomized participants), and safety analysis will be based on the as-treated population (participants who received any of the study drugs). A sample size of 3000 participants was selected taking into account the safety database and provided greater than 99% power for the primary efficacy endpoint. A sample size of approximately 1500 participants for the primary efficacy analysis will have greater than 99% power to detect a 70% relative risk reduction at a two-sided significance level of 0.05, assuming an 8% event rate in the placebo group.

[0258] The primary analysis will be performed after all randomized subjects from the primary cohort (except for one subject enrolled in the NH2020 season) have been followed up to Day 361 and will be the primary analysis of this study designed to evaluate efficacy. For the primary analysis, all efficacy, pharmacokinetic (PK), ADA, and safety data collected for the primary cohort through at least Day 361 will be analyzed. The safety analysis will be performed after all subjects in the safety cohort have been followed up to Day 151. For the safety analysis, in addition to the analyses performed during the primary analysis based on the primary cohort, all available efficacy, PK, ADA, RSV neutralizing antibody, RSV serology, and safety data collected for the safety cohort will be analyzed (only a descriptive summary is provided for efficacy data collected for the safety cohort). The final analysis will be performed when all subjects have completed the final study visit (i.e., Day 511). Given the significant reduction in RSV circulation due to COVID-19 pandemic-related measures, the efficacy analysis performed in the primary cohort will serve the purpose of evaluating the efficacy of nirsevimab in the study population.

[0259] Efficacy data will also be collected on the safety cohort, but only a descriptive summary will be provided and there is no intention to pool the efficacy data of the safety cohort with that of the primary cohort. Both the primary and safety cohorts will serve the purpose of evaluating the safety of nirsevimab, both alone and in combination.

[0260] For participants who did not develop an RSV LRTI and were not followed up through day 150 post-treatment, their event status was considered missing and entered at the event rate observed in the placebo group, and imputation was repeated.

[0261] Primary efficacy analysis Incidence of RSV LRTI (inpatient and outpatient) during the 5-month RSV season will be presented based on RSV test results (centrally performed by RT-PCR) and objective clinical LRTI criteria and by treatment group. For subjects with RSV LRTI events requiring multiple visits, only the first event will be used in the primary analysis.

[0262] The primary efficacy analysis of the primary endpoint is performed on ITT1. RSV LRTI occurring 150 days after dosing contributes to the primary efficacy analysis. For subjects who do not have RSV LRTI requiring medical care and are not followed up for 150 days after dosing, the event status of the subject is imputed assuming the placebo RSV LRTI rate observed conditional on the stratification factors using multiple imputation techniques and accounted for in SAP. A Poisson regression model with robust variance is used as the primary efficacy analysis model to compare the incidence of RSV LRTI requiring medical care between nirsevimab and placebo, including treatment group, age at randomization (i.e., 3 months or less, 3 months to 6 months, and more than 6 months), and temperature hemisphere (NH and SH) dichotomy as covariates. In addition, the model provides a two-sided p-value for the relative risk and the corresponding two-sided 95% confidence interval (CI). RRR is defined as (1-Pn / Ps), where Pn is the incidence of RSV LRTI in the nirsevimab group over 150 days after dosing, and Ps is the incidence of RSV LRTI in the placebo group over 150 days after dosing generated by the model. Statistical significance is achieved when the two-sided p-value is 0.05 or less.

[0263] During blinded data review prior to database lock for the primary analysis, a decision was made to remove the stratification factor hemisphere from the full model, given that there were no RSV LRTI events requiring a visit through 150 days post-dose for SH in the primary cohort that would have caused known convergence or estimation issues. Similar considerations were applied to other analyses of the primary efficacy endpoints, with hemisphere being excluded from the corresponding models.

[0264] Further analysis of the primary endpoint The incidence of RSV LRTI over 150 days post-dose between treatment groups will be compared as a secondary analysis of the primary endpoint using a Cochran-Mantel-Haenszel approach stratified by age group at randomization (i.e., ≤3 months, >3 months to ≤6 months, >6 months). This further analysis will be performed in ITT1. In addition, a time-to-event analysis evaluating time to first RSV LRTI may be performed as a supplemental analysis. Analyses may also include all RSV positive LRTI endpoints using either central or local laboratory results. Various approaches to handling missing data (i.e., early discontinuation or no RSV LRTI before discontinuation) may be considered for supplemental analyses. Further analyses may be performed to adjust for the duration of efficacy follow-up and to evaluate efficacy in subgroups. These analyses will be described in the SAP. A summary of the incidence of RSV LRTI requiring a visit over 150 days post-dose will also be summarized by treatment group in ITT2.

[0265] Secondary endpoint analysis For efficacy analyses, the incidence of hospitalization due to RSV LRTI over 150 days post-dose will be presented by treatment group. Efficacy against hospitalization due to RSV LRTI will be assessed in ITT1 using methods similar to those described above for the primary efficacy endpoint. Incidence of hospitalization due to RSV LRTI over 150 days post-dose will also be summarized by treatment group in ITT2.

[0266] As explained above, the analysis of the primary endpoint is performed using a Poisson regression model with robust variance. A hierarchical approach is used to control the overall type I error. Secondary endpoints are tested only if statistical significance for the primary endpoint is demonstrated. That is, secondary hypotheses are tested at the 0.05 significance level only if a treatment effect on the primary efficacy endpoint is demonstrated at the two-sided 0.05 significance level. Thus, the overall type I error is controlled at 0.05. Therefore, no further multiplicity adjustment is necessary.

[0267] Regarding safety analysis, this analysis will be performed for the entire as-treated population, AT1, and AT2. The safety of nirsevimab will be evaluated primarily by the occurrence of TEAEs and TESAEs. Adverse events will be graded according to the latest version of the National Cancer Institute Common Terminology Criteria for Adverse Events, as applicable to pediatric evaluations. Adverse events will be coded according to the International Medical Dictionary, and a summary of type, incidence, severity, and relationship to study drug will be provided by treatment group. Other safety assessments will include: (1) the occurrence of AESIs, including targeted AEs of hypersensitivity (including anaphylaxis), thrombocytopenia, and immune complex diseases (e.g., vasculitis, endocarditis, neuritis, glomerulonephritis) following study drug administration; and (2) the occurrence of NOCD following study drug administration.

[0268] For PK analysis, individual nirsevimab serum concentration data following a single dose of nirsevimab will be tabulated by treatment group along with descriptive statistics. PK parameters (e.g., C max , AUC, apparent clearance and terminal half-life) will be estimated using non-compartmental analysis, if data permit.

[0269] For ADA analyses, the incidence of ADA to nirsevimab will be assessed and the number and percentage of ADA-positive subjects will be summarized by treatment group. ADA titers will be listed by subject at various time points. The impact of ADA on PK, efficacy, and association with TEAEs and TESAEs will be evaluated. These summaries will be performed for the entire as-treated population, AT1, and AT2 unless otherwise specified.

[0270] Exploratory endpoint analyses For analyses of healthcare resource utilization (HRU) and caregiver burden, HRU magnitude (e.g., number and duration of hospital and ICU admissions; number and duration of subjects requiring respiratory support and supplemental oxygen; number and type of outpatient visits, e.g., ER, urgent care, outpatient care; and number and duration of prescription and over-the-counter medications) will be summarized overall by treatment group and for the following subgroups: subjects with at least one LRTI requiring medical attention caused by RSV confirmed by RT-PCR, subjects with LRTI requiring medical attention not caused by RSV, and subjects with non-protocol-defined LRTI that can be further classified by RSV status. These summaries will be performed for ITT1 and ITT2 (if data permits).

[0271] A summary of caregiver burden (e.g., caregiver days missed from work; subjects absent from day care) for subjects with RT-PCR-confirmed RSV-induced LRTI requiring medical attention will be summarized by treatment group for ITT1 and ITT2 (when data permit).

[0272] RSV neutralizing antibody and RSV serology tests Regarding the analysis of RSV neutralizing antibody levels induced by nirsevimab, nirsevimab will be compared with maternal RSV neutralizing antibody levels and RSV neutralizing antibody levels induced after infection in the placebo group. RSV serological responses will be evaluated as an indicator of RSV exposure in the placebo and nirsevimab groups.

[0273] Monitoring RSV resistance to nirsevimab Genotyping of the full-length mature F protein is performed on all centrally confirmed RSV positive isolates using the Lyra RSV+hMPV real-time RT-PCR assay from Quidel Corporation. RSV genotyping reports amino acid changes in the mature F protein sequence compared to contemporary RSV A and RSV B reference strains. Phenotyping reports changes in susceptibility of engineered recombinant RSV variants to nirsevimab and palivizumab neutralization compared to laboratory-derived reference viruses.

[0274] RSV LRTI occurring between days 152 and 361 Incidence of RSV LRTI (inpatients and outpatients) requiring a medical visit from days 152 to 361 will be based on RSV test results (centrally performed by RT-PCR) and objective clinical LRTI criteria, and will be summarized by treatment group for ITT1 and ITT2.

[0275] Example 2: Nirsevimab protects healthy late preterm and term infants from respiratory syncytial virus This example describes the results of a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a single dose of nirsevimab for RSV-confirmed LRTI requiring medical attention in healthy late preterm and term infants undergoing their first RSV season.

[0276] In this study, infants (gestational age ≥ 35 weeks) were randomized 2:1 to receive a single intramuscular injection of nirsevimab or placebo at the beginning of the RSV season. The primary efficacy outcome was the incidence of RSV LRTI requiring medical attention over 150 days, and the secondary outcome was the incidence of RSV-related hospitalization over 150 days. The results of this study show that a single dose of nirsevimab administered before the RSV season protected healthy late preterm and term infants from RSV LRTI requiring medical attention. Importantly, the results surprisingly show that the protective effect of a single dose of nirsevimab was sustained for more than 5 months (up to 12 months). Thus, a single dose of nirsevimab is sufficient to provide protection from RSV infection for at least one 5-month RSV season (e.g., two RSV seasons), whether during or outside the RSV season. Thus, the extended period of protection afforded by a single dose of nirsevimab may protect subjects born outside of the RSV season, subjects experiencing an interruption in the RSV season, and / or subjects experiencing an RSV season of more than 5 months (e.g., 6, 7, 8, 9 or 10 months).

[0277] method This clinical trial was carried out according to the protocol described above in Example 1. Further details are as follows.

[0278] participants Healthy infants born late preterm or at term (gestational age ≥35 weeks 0 days at birth), aged ≤1 year, and entering their first RSV season were eligible to participate. Potential participants were excluded if they met national or other local criteria for receiving commercially available palivizumab, had any fever or acute illness within 7 days prior to randomization, or had RSV infection before or at the time of randomization.

[0279] Study design Participants were randomized 2:1 to receive a single intramuscular injection of nirsevimab or saline placebo 50 mg or 100 mg (if body weight <5 kg or ≥5 kg at dosing, respectively). Randomization was stratified by hemisphere (North or South) and age (≤3 months, >3 months to ≤6 months, or >6 months). Respiratory illness requiring medical consultation was recorded throughout the study. The primary cohort included participants enrolled from 150 sites (20 countries) in 2019 in the Northern Hemisphere and 10 sites (1 country) in 2020 in the Southern Hemisphere. See also Figure 1.

[0280] Evaluation items The primary efficacy outcome was the incidence of RSV LRTI requiring medical consultation over 150 days after administration of nirsevimab or placebo; the secondary efficacy outcome was the incidence of hospitalization due to this condition during the same period. All cases were confirmed by central laboratory RSV testing using real-time reverse transcriptase polymerase chain reaction (RT-PCR). The case definition of RSV LRTI requiring medical consultation for the primary outcome is shown in Table 1 (see above).

[0281] Subgroup analyses of the primary outcome were prespecified according to hemisphere, age at randomization, sex, race, weight, and gestational age. Adverse events were graded by severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events and coded by the International Medical Dictionary. Hypersensitivity (including anaphylaxis), immune complex disease, and thrombocytopenia were designated as adverse events of special interest.

[0282] The pharmacokinetics (PK) of nirsevimab was determined as described in Domachowske et al., Pediatr Infect Dis J. (2018) 37:886-92. Serum samples were collected pre-dose, 15 days post-dose (occasionally replacing day 8), days 31, 151 and 361, and when participants were hospitalized for respiratory illness. Anti-drug antibodies were assessed; a positive anti-nirsevimab antibody response was defined as a titer of 50 or greater, as described in Griffin et al., N Engl J Med. (2020) 383:415-25 and Domachowske, supra.

[0283] statistical analysis All analyses were based on the primary cohort. Efficacy analyses were performed on the intent-to-treat population (all randomized participants); safety analyses were based on the as-treated population (participants who received any study drug). A sample size of 3000 participants was selected taking into account the safety database and provided greater than 99% power for the primary efficacy endpoint. A sample size of approximately 1500 participants for the primary efficacy analysis had greater than 99% power to detect a 70% relative risk reduction at a two-sided significance level of 0.05 under the assumption of an 8% event rate in the placebo group.

[0284] Analysis of the primary endpoint was performed using a Poisson regression model with robust variance. A hierarchical approach was used to control for overall type I error; secondary endpoints were examined only if statistical significance for the primary endpoint was demonstrated.

[0285] For participants who did not develop an RSV LRTI and were not followed up until 150 days post-dose, their event status was considered missing and entered with the event rate observed in the placebo group, and imputation was repeated.

[0286] Further analysis of the primary and secondary efficacy endpoints Follow-up after nirsevimab or placebo was conducted by telephone (every 2 weeks for 150 days after dosing, monthly for 150-360 days after dosing, and every 2 weeks for 361-510 days after dosing) and in person at study site visits (days 8, 15, 31, 91, 151, and 361).

[0287] For lower respiratory tract events requiring medical attention, RSV status was determined by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in a central laboratory. After RSV detection by RT-PCR, RSV A and RSV B subtypes were determined by genotypic analysis of mature F protein sequence variations from all RSV-positive isolates / samples compared to contemporary RSV A and RSV B reference strains.

[0288] A pooled analysis of RSV LRTI hospitalization endpoints was prespecified under a multiplicity protection hierarchical testing strategy. The rationale for the pooled analysis of all intent-to-treat (ITT) participants in the Phase 2b study D5290C00003 and ITT participants in the primary cohort of this study was to evaluate the overall efficacy of RSV hospitalization in the target population (preterm and term infants). A pooled analysis of 860 ITT participants weighing <5 kg in the Phase 2b study and ITT participants in the primary cohort of this study was performed to evaluate efficacy in all participants with clinically effective exposures suggested by pharmacokinetic analysis. Combining these participants for analysis was justified based on similar study designs and disease similarity between infant and pediatric populations. Statistical testing of the null hypothesis that the incidence of RSV LRTI hospitalizations was identical between nirsevimab and placebo groups was performed only if a P value ≤ 0.05 was achieved for the primary efficacy analysis.

[0289] More specifically, after the significance of the primary efficacy endpoint was proven, the secondary efficacy endpoint was first validated by pooling all ITT participants in Phase 2b study D5290C00003 and ITT participants in the primary cohort of this study. If significance was proven (two-sided at 0.05), the secondary efficacy endpoint was further validated by pooling 860 participants weighing less than 5 kg on Day 1 of Phase 2b study (i.e., 290 participants randomized to placebo and 570 participants randomized to nirsevimab) and ITT participants in the primary cohort of this study. If significance was again proven (two-sided at 0.05), the secondary efficacy endpoint was validated using only ITT participants in the primary cohort of this study.

[0290] The Cochran-Mantel-Haenszel test based on observational data was used as a secondary analysis model for the primary and secondary efficacy endpoints. Kaplan-Meier curves were constructed for time to first RSV LRTI requiring consultation, and hazard ratios and corresponding 95% CIs were obtained from stratified proportional hazards models using the stratification factor (age at randomization) as a stratum. For subgroup analyses on the primary endpoint, relative risk reductions and their 95% CIs (mid-P adjusted) were estimated within each level of subgroups based on the exact conditional method using PROC GENMOD without stratification.

[0291] For each of the impact endpoints (i.e. LRTI requiring all consultations due to RSV with any laboratory result, LRTI requiring all consultations due to RSV with central laboratory result, LRTI requiring all consultations of any cause, any respiratory illness due to RSV with any laboratory result, any respiratory illness due to RSV with central laboratory result, and any respiratory illness of any cause), efficacy (relative risk reduction for nirsevimab vs placebo) and 95% CI were estimated based on Poisson regression with robust variance by treatment period. Estimates of the number of cases averted during the RSV season (and associated 95% CI) were calculated from the epidemic phase difference in estimated case numbers between nirsevimab and placebo and expressed per 1000 infants immunized using bootstrap. In this analysis, only participants from the Northern Hemisphere were included. Pooled analysis of efficacy against RSV hospitalization from trials in preterm infants was prespecified with a multiplicity protection hierarchical testing strategy.

[0292] result Of 1490 randomized participants, 1478 (99.2%) received nirsevimab (n=987) or placebo (n=491). The incidence of RSV LRTIs requiring medical consultation was 1.2% (n=12) in the nirsevimab group and 5.0% (n=25) in the placebo group, corresponding to an efficacy of 74.5% (95% CI 49.6, 87.1; p<0.0001). The incidence of RSV-related hospitalization was lower in the nirsevimab group compared with the placebo group (0.6% (n=6) vs. 1.6% (n=8), efficacy 62.1% (95% CI -8.6, 86.8)). The incidence of very severe RSV LRTI requiring medical consultation was lower in the nirsevimab group compared to the placebo group (0.5% (n=5) vs. 1.4% (n=7); efficacy 64.2% (95% CI -12.1, 88.6)). Very severe RSV LRTI was an exploratory endpoint defined as cases of hospitalization due to RSV LRTI requiring medical consultation requiring supplemental oxygen or intravenous fluids. For all 1,000 immunized infants, the estimated number of cases of LRTI averted from any cause was 93.6 (95% CI 63.0, 124.0), and the estimated number of averted hospitalizations due to respiratory illness from any cause was 17.7 (95% CI 2.0, 33.0). Adverse events were similar between study arms. Further details of the clinical trial results are described below.

[0293] Group Healthy infants born late preterm or at term (gestational age ≥35 weeks 0 days at birth), aged 1 year or younger, and undergoing their first RSV season were eligible to participate. Potential participants were excluded if they met national or other local criteria for receiving commercially available palivizumab, had any fever or acute illness within 7 days prior to randomization, or had RSV infection prior to or at the time of randomization. Between July 23, 2019 and November 30, 2019, 1027 participants were enrolled in NH and followed through the 2019 / 20 RSV season. Between January 8, 2020 and March 15, 2020, 462 participants were enrolled in South Africa and followed through the expected 2020 season. One participant was enrolled in Japan before enrollment was halted due to the COVID-19 pandemic. In total, 1,490 participants were randomized in the primary cohort, and 1,478 (99.2%) received an injection (nirsevimab: n=987; placebo: n=491). Overall, 1,465 and 1,367 participants completed the 150-day and 360-day follow-up periods, respectively.

[0294] The study population was primarily full-term infants (86%). Median age was 2.60 months (range 0.03-11.10 months). Baseline characteristics were similar between treatment groups, as shown in the table below.

[0295] [Table 2]

[0296] Effectiveness RSV LRTIs requiring medical consultation occurred in 1.2% (n=12 / 994) of participants randomized to receive nirsevimab and 5.0% (n=25 / 496) of participants receiving placebo, corresponding to a nirsevimab-related efficacy of 74.5% (95% CI 49.6, 87.1; p<0.0001 by both Poisson regression and Cochran-Mantel-Haenszel tests; Table 3), thus meeting the primary endpoint.

[0297] [Table 3]

[0298] Time-to-event analysis confirmed that infants who received nirsevimab had a lower risk of RSV LRTI requiring medical attention compared with infants who received placebo (hazard ratio, 0.23; 95% CI 0.12, 0.47) (Figure 2). Of the RSV LRTIs that occurred, all 12 cases in the nirsevimab group were RSV A, whereas in the placebo group, 21 were RSV A and 4 were RSV B. There was no contribution from South Africa to the primary efficacy estimate due to the decline in RSV in South Africa during the COVID-19 pandemic (Tempia et al., Eurosurveillance (2021) (in press)). However, off-season RSV transmission began after day 151, with 12 cases occurring by day 361 (nirsevimab: 6 / 308 (1.9%) participants vs. placebo 6 / 154 (3.9%) participants). A Kaplan-Meier plot of these data is shown in Figure 3. One case occurred in the NH after day 151 and on day 165 in the nirsevimab group. The data in Figure 3 show that the protective effect of a single dose of nirsevimab 50 mg persisted beyond the length of a typical RSV season (approximately 5 months or 150 days). Protective effect, as indicated by a reduction in RSV-associated LRTIs requiring medical consultation, was evident for more than 240 days (approximately 8 months) by the end of the 360-day (approximately 12 months) study period (Figure 3).

[0299] During the 150-day period, hospitalization due to RSV LRTI occurred in 6 / 994 (0.6%) participants in the nirsevimab group and 8 / 496 (1.6%) in the placebo group, corresponding to an efficacy estimate of 62.1% (95% CI -8.6, 86.8; P = 0.0708, Poisson regression) (Table 3). Healthcare utilization associated with these cases is shown in Table 4.

[0300] [Table 4]

[0301] Subgroup analyses according to hemisphere, age at randomization, sex, race, weight, and gestational age showed consistent efficacy in favor of nirsevimab, although trends toward less efficacy were observed with younger age (≤3.0 months vs. >3.0 months) and lower weight (<5 kg vs. ≥5 kg; Figure 4).

[0302] The impact was evaluated in NHs where a typical RAV epidemic occurred before the establishment of the COVID-19 pandemic. A clear impact was seen on LRTIs of any cause and hospitalizations due to any respiratory disease: for every 1,000 immunized infants, the number of averted cases of LRTIs of any cause was estimated to be 93.6 (95% CI 63.0, 124.0) and the number of averted hospitalizations due to any respiratory disease was estimated to be 17.7 (95% CI 2.0, 33.0). An overview of the impact of nirsevimab in the ITT population from the Northern Hemisphere (NH) is summarized in the table below.

[0303] [Table 5]

[0304] Pharmacokinetics Nirsevimab serum concentrations declined proportionally after day 31 without any signs of nonlinearity (Figure 5). The mean (SD) half-life of nirsevimab was 66.9 (10.9) days and was similar in both weight subgroups. At day 151, the mean (SD) nirsevimab serum concentrations were 19.6 (7.7) and 31.1 (13.7) μg / mL in the <5 kg and ≥5 kg subgroups, respectively. Four participants in the nirsevimab group were unable to have quantified serum concentrations at any time point; dosing errors were not reported but may have occurred.

[0305] Anti-drug antibodies Post-baseline anti-drug antibodies were detected in 58 of 951 (6.1%) and 5 of 473 (1.1%) participants who received nirsevimab or placebo, respectively, with results available through 361 days. Two of 12 nirsevimab recipients who developed RSV LRTI requiring medical attention during the 150-day period after dose administration had anti-drug antibodies at titers of 400 detected by laboratory testing on days 151 and 361. Nirsevimab recipients who tested positive for anti-drug antibodies after baseline had a safety profile similar to nirsevimab recipients without anti-drug antibodies.

[0306] Safety and Adverse Event Profile The type and frequency of adverse events occurring during the study were similar in both groups. A summary of treatment-emergent adverse events (TEAEs) at 360 days post-dose that occurred in the as-treated population is summarized in Table 6.

[0307] Most adverse events that occurred during treatment were grade 1 or 2 in severity. Adverse events of grade 3 or greater severity were reported in 3.6% (36 / 987) of those receiving nirsevimab and 4.3% (21 / 491) of those receiving placebo. The incidence of adverse events within 1 day of dose administration in the nirsevimab group was low (1.8% of participants in the nirsevimab group and 0.6% of participants in the placebo group). These adverse events were all grade 1 in severity and were managed by the parents at home with over-the-counter treatment medications. The incidence of adverse events within 7 days of dose administration was similar in both groups (13.4% of participants in the nirsevimab group and 12.8% of participants in the placebo group; Table 6). During this period, the incidence of adverse events in the system organ class of systemic disorders and administration site conditions was low, occurring in 0.4% (2 / 491) of participants in the placebo group and 0.6% (6 / 987) of participants in the nirsevimab group. These were fever (3 participants), malaise (2 participants), and local injection site pain or swelling (3 participants).

[0308] [Table 6]

[0309] Severe adverse events were reported in 6.8% (67 / 987) of participants receiving nirsevimab and 7.3% (36 / 491) of participants receiving placebo. None were considered by the investigator to be related to the study drug. Only one adverse event of special interest was reported in one patient in the nirsevimab group who presented with a generalized macular rash without systemic features 6 days after dosing, and this event was related to treatment. No anaphylaxis or other serious hypersensitivity reactions were reported.

[0310] By day 361, three deaths had occurred (all in the nirsevimab group). One death of unknown cause occurred on day 140 in a participant with failure to thrive. An underlying chronic condition that had not been diagnosed prior to death was suspected based on reports of adverse events of recurrent vomiting, hypoglycemia, and anemia. Two deaths (days 143 and 338) were due to gastroenteritis in participants who did not seek medical care for this illness. None of the deaths were known to be attributable to RSV, and none were considered by the investigators to be related to nirsevimab. The above studies demonstrate that a single dose of nirsevimab, a monoclonal antibody, provides substantial protection against RSV LRTIs requiring medical attention when administered to healthy late preterm and term infants prior to the RSV season. Efficacy against all LRTIs requiring medical attention of any cause has been observed. Furthermore, nirsevimab was well tolerated. Only 1% of participants reported treatment-related adverse events, with local reactogenicity and fever occurring infrequently.

[0311] The 90% effective concentration of nirsevimab determined preclinically was 6.8 μg / mL (Zhu et al., supra). The PK data herein support protective antibody levels extending to 150 days post-dose across age / weight subgroups. Data from South Africa support the duration of protection beyond 5 months, the typical length of an RSV season.

[0312] In conclusion, this study demonstrated that nirsevimab, a monoclonal antibody against RSV with an extended half-life, is effective in preventing clinically required RSV LRTI in healthy late preterm and term infants. Use of nirsevimab could reduce the substantial burden of disease and potentially prevent long-term consequences associated with RSV disease in the general infant population.

[0313] Further analysis of pooled data Table 7 below shows the demographics and baseline characteristics of subjects in the Phase IIb and Phase III (MELODY) studies, with 786 subjects in the placebo group and 1564 subjects in the nirsevimab treatment group. These studies evaluated ethnically diverse populations, the median age of subjects was 2 months (range 1 day to 11 months), and the demographics and baseline characteristics were balanced between treatment groups.

[0314] [Table 7]

[0315] [Table 8]

[0316] Nirsevimab demonstrated consistent efficacy across all RSV lower respiratory tract infections of varying severity requiring consultation (Figure 6 and Table 8) and across subgroups (Figure 7). Additionally, nirsevimab demonstrated efficacy against lower respiratory tract infections requiring consultation of any cause and respiratory disease of any cause involving hospitalization. See Figure 6. Demonstrative efficacy against LRTI of any cause does not exclude "displacement" of RSV by another pathogen, but provides reassurance that the overall treatment efficacy of nirsevimab outweighs the possibility of "displacement."

[0317] As shown in Figure 8, the efficacy of nirsevimab against lower respiratory tract infections requiring medical attention was consistent over 150 days (5 months).

[0318] Subject inpatient healthcare resource utilization tended to be lower with nirsevimab compared to placebo. Measures of inpatient healthcare utilization included hospitalization, intensive care unit (ICU) admission, continuous positive airway pressure (CPAP) / high-flow nasal cannula (HFNC), mechanical ventilation, and supplemental oxygen use. See Figure 9. Nirsevimab treatment was also associated with fewer outpatient visits and fewer antibiotic use compared to placebo administration. See Figure 10.

[0319] These results are consistent with those described above, in which nirsevimab is a long-acting antibody that provides protection against RSV for at least one flu season with a single dose, is effective across a range of severities of RSV lower respiratory tract infection, is effective against lower respiratory tract infections requiring medical attention regardless of cause, and is effective against hospitalization due to lower respiratory tract infections regardless of cause. Nirsevimab also has the associated benefits of reducing hospitalization, outpatient visits, and antibiotic use.

[0320] Example 3: Nirsevimab for prophylaxis of RSV: Neutralizing antibody levels after a single dose Two international placebo-controlled trials found that nirsevimab reduced RSV LRTIs requiring medical consultation compared with placebo during RSV seasons (Phase III: MELODY, healthy term and late preterm infants, 74.5%; Phase IIb: healthy preterm infants, 70.1% (95% CI, 52.3 to 81.2 p<0.001)). RSV neutralizing antibodies (RSV Nabs) were measured up to day 361 from the studies.

[0321] Infants were randomized 2:1 to receive a single intramuscular injection of nirsevimab or placebo before their first RSV season as described above. Serum samples collected before and after dosing were tested with a validated RSV neutralization assay; RSV Nab levels are reported in international units (IU) / mL.

[0322] RSV Nab levels were quantified by interpolation from a serially diluted pooled serum reference standard curve calibrated to the first international standard of antiserum against RSV-NIBSC 16 / 284 (also referred to as the WHO RSV A reference standard).

[0323] Overall, 1402 infants in MELODY and 741 infants in Phase IIb had available data. Baseline geometric mean RSV Nab levels were similar in both studies (MELODY, 134 IU / mL; Phase IIb, 87 IU / mL). At day 151, nirsevimab recipients had approximately 50-fold higher RSV Nab levels compared to baseline (MELODY, 6901 IU / mL; Phase IIb, 4799 IU / mL), with the highest levels sampled at day 31 in MELODY (19711 IU / mL) and day 91 in Phase IIb (8479 IU / mL); levels remained more than 5-fold higher through day 361 (MELODY, 978 IU / mL; Phase IIb, 739 IU / mL). At day 361, placebo recipients without confirmed RSV infection during the study had RSV Nab levels of 38-48 IU / mL; nirsevimab recipients had RSV Nab levels of 757-982 IU / mL, more than 19-fold higher than placebo recipients without confirmed RSV infection. See Figures 11A-11B.

[0324] In conclusion, after immunization with nirsevimab, RSV Nab levels were approximately 50-fold higher on day 151 compared to baseline levels. RSV Nab levels remained elevated through day 361, suggesting protection beyond day 151.

[0325] Further analysis of Nab data An updated analysis of data from 1,402 infants in MELODY and 741 infants in Phase IIb was performed. At day 151, nirsevimab recipients had RSV Nab levels approximately 50-fold higher compared to baseline (MELODY, 6901 IU / mL; Phase IIb, 4799 IU / mL), with the highest levels sampled on day 31 in MELODY (19737 U / mL) and day 91 in Phase IIb (8479 IU / mL). RSV Nab levels remained more than 7-fold higher compared to baseline through day 361 (MELODY, 978 IU / mL; Phase IIb, 739 IU / mL). At day 361, placebo recipients without confirmed RSV infection during the study had lower RSV Nab levels of 38-48 IU / mL compared to 151-162 IU / mL in recipients with confirmed RSV infection; nirsevimab recipients had RSV Nab levels of 757-979 IU / mL, more than 19-fold higher than placebo recipients without confirmed RSV infection and more than 3-fold higher than placebo recipients with confirmed RSV infection. See Figures 12A-12B.

[0326] Within each study, similar levels of RSV Nab were observed at baseline regardless of hemisphere, sex, or treatment group. Comparing the two studies, lower RSV Nab levels were observed in preterm infants in the Phase IIb study compared to late preterm and term infants in MELODY. Infants over 6 months of age at baseline had the lowest RSV Nab levels. See Figures 13A-13B.

[0327] Example 4: Pooled Efficacy of Nirsevimab Against RSV LRTI in Preterm and Term Infants Nirsevimab reduced the incidence of medically-accepted (MA) respiratory syncytial virus (RSV) lower respiratory tract infections (LRTI) in two double-blind, placebo-controlled trials (Phase IIb [NCT02878330]: extremely preterm and moderately preterm infants ≥29 to <35 weeks gestational age [wkGA], efficacy 70.1%; Phase III: MELODY [NCT03979313], healthy term infants and late preterm infants ≥35 wkGA, efficacy 74.5%). This example reports a pooled efficacy analysis of nirsevimab in term and preterm infants ≥29 wkGA through day 151.

[0328] Infants were randomized 2:1 to receive an intramuscular injection of nirsevimab (<5 kg, 50 mg; ≥5 kg, 100 mg) or placebo before their first RSV season. Data were pooled from Phase IIb and MELODY studies for infants under optimized dosing regimens (i.e., infants <5 kg at time of dosing who received the 50 mg dose from Phase IIb and all infants in MELODY) to assess efficacy (relative risk reduction compared to placebo) against various severities of MA RSV LRTI, including hospitalization due to RSV LRTI.

[0329] Only infants <5 kg were included from Phase IIb because in this study, infants were given 50 mg regardless of age and weight. MA RSV LRTI was defined as: positive RSV PCR by central laboratory testing, at least one sign of LRT involvement of crackles, rales, wet rales, or wheezing, and at least one sign of severity including increased respiratory rate (≥60 breaths / min, <2 months; ≥50 breaths / min, 2-6 months; ≥40 breaths / min, >6 months), hypoxemia on room air (O2 saturation <95% at ≤1800 m, O2 saturation <92% at >1800 m) or clinical signs of respiratory distress (initial apnea, retractions, grunting, nasal flaring, acute hypoxia or ventilatory failure, dehydration due to respiratory distress).

[0330] Overall, 860 infants (median age at randomization: 1.60 [range 0.1-6.4] months; female: 47.6%) from Phase IIb and 1490 infants (median age at randomization: 2.60 [0.03-11.10] months; female: 48.4%) from MELODY were included. Demographics were comparable across studies, except for gestational age (GA) and age at randomization. Through day 151, efficacy of nirsevimab was 79.5% against MA RSV LRTI, 77.3% against hospitalization due to RSV LRTI, and 86.0% against very severe RSV LRTI (Figure 14). Consistent efficacy was observed across the following subgroups: age, sex, ancestry, weight, and region at randomization, as well as across various disease severity endpoints.

[0331] In conclusion, in a pooled analysis of two randomized, placebo-controlled trials, nirsevimab prophylaxis demonstrated consistent efficacy across RSV LRTI severity up to day 151.

[0332] Example 5: Population Pharmacokinetics and Exposure-Response of Nirsevimab Against Respiratory Syncytial Virus in Infants, Including Infants at Higher Risk for Severe Disease In two global, pivotal, placebo-controlled trials, nirsevimab reduced RSV-confirmed lower respiratory tract infections (LRTIs) requiring medical attention compared with placebo across RSV seasons (Phase III NCT03979313: MELODY, healthy term or late preterm infants, 74.5%; Phase IIb NCT02878330: healthy preterm infants, 70.1%). A third randomized, pivotal, palivizumab-controlled trial (Phase II / III NCT03959488: MEDLEY) evaluated nirsevimab in infants at higher risk for severe RSV disease, including very preterm infants (gestational age <29 weeks), preterm infants with chronic lung disease (CLD) and / or congenital heart disease (CHD). Infants in MEDLEY received one dose of nirsevimab (infants weighing less than 5 kg, 50 mg; ≥5 kg, 100 mg) followed by four monthly placebo doses or five monthly palivizumab doses (15 mg / kg).

[0333] Efficacy in the MEDLEY trial was established based on pharmacokinetic extrapolation. The extrapolation relies on the assumption of similar exposure-response across pediatric populations, which is justified based on nirsevimab's mechanism of action (binding to RSV to prevent viral entry), the lack of endogenous targets, and comparable viral pathogenesis. Analyses described below were performed to support the extrapolation of efficacy from Phase IIb and MELODY to the MEDLEY trial.

[0334] Nirsevimab was administered as a single IM injection. Weight-banded dosing (<5 kg, 50 mg; ≥5 kg, 100 mg) was applied in the MELODY and MEDLEY studies; in Phase IIb, all infants received 50 mg. Pharmacokinetic data pooled across studies were analyzed using a population pharmacokinetic approach. Efficacy exposure targets were defined based on exposure-response analysis of the primary endpoint (RSV MALRTI over 150 days post-dose) pooled from Phase IIb and MELODY studies. Individual exposures in MEDLEY subjects were compared to exposure targets, with a goal of >80% of infants exceeding the target for extrapolation to be concluded as successful.

[0335] A nirsevimab pharmacokinetic model, including the effects of body weight and postmenstrual age, adequately described the data. No differences in pharmacokinetics were observed in infants with CLD or CHD. The efficacy exposure goal was determined to be an area under the curve (AUC) >12.8 day·mg / mL.

[0336] In the total MEDLEY cohort, 94.3% (558 / 592) of infants had exposures above the target, with corresponding numbers in subgroups of particular interest: 94.1% (128 / 136) of infants with preterm CLD, 80.3% (53 / 66) of infants with CDH, and 93.6% (44 / 47) of very preterm infants with a GA <29 weeks who had neither CLD nor CHD.

[0337] In conclusion, nirsevimab provides protection against RSV disease in infants who are at higher risk for severe RSV disease.

[0338] How to determine exposure goals for efficacy Exposure response to RSV LTRI, requiring a 150-day post-dose visit, was assessed based on pooled data from Phase 2b studies and MELODY (nirsevimab or placebo-treated populations) to define efficacy exposure targets. Time to first event was assessed using Cox proportional hazards models stratified by study and age group at dose (<3.0 months, ≥3.0 to 6.0 months, and >6.0 months) with area under the concentration-time curve (AUC; derived from individual estimates of baseline clearance from population PK models) as the exposure metric. AUC was categorized into four bins based on exposure quartiles defined from Phase 2b studies.

[0339] Kaplan-Meier curves for time to first RSV LRTI requiring medical visit by day 151 with test and exposure bins or placebo are shown in Figure 15A. Exposure-response analysis showed that AUC above the first quartile (>12.8 mg·day / mL) provided significant protection from RSV LRTI requiring medical visit compared to placebo (p<0.001) with a hazard ratio of <0.3 (Figures 15A and 15B). The hazard ratio for exposure below the first quartile was lower (0.48), supporting the AUC of >12.8 mg·day / mL as the exposure target (Figure 15B).

[0340] Example 6: Prevalence over time and lack of geographic distribution of nirsevimab escape variants in RSV strains worldwide since 1956 The nirsevimab binding site has been historically well conserved, but the paucity of recent promising genomic data limits investigation of the temporal evolution and transmission patterns of potential escape variants. This example reports the temporal prevalence, geographic diversity, and resistance profiles of global RSV isolates containing nirsevimab binding site substitutions through 2021.

[0341] As part of the ongoing INFORM-RSV (global) and OUTSMART-RSV (US) molecular epidemiology studies (2015-2021), RSV-positive samples, primarily from infants, were collected and sequenced. Additional RSV F protein sequences were obtained from NCBI GenBank (1956-2016). Identified RSV F protein substitutions in the nirsevimab binding site (AA 62-69 and AA 196-212) compared to the 2013 NLD reference strain were evaluated with a recombinant RSV neutralization susceptibility assay.

[0342] Overall, 2,385 published RSV F sequences from 37 countries (RSV A: N = 1,525; RSV B: N = 860) and 5,675 prospective RSV F sequences from 17 countries (RSV A: N = 2,875; RSV B: N = 2,800) were collected and analyzed. During the nirsevimab clinical development period from 2016 to 2021, more than 98% of the amino acids in the nirsevimab binding site remained highly conserved at all 25 positions in RSV A and at 23 of 25 positions in RSV B. In 2015, the nirsevimab binding site polymorphism I206M:Q209R (which maintains susceptibility to nirsevimab neutralization) emerged among circulating RSV strains. RSV BF variants with reduced susceptibility to nirsevimab neutralization have been regularly detected in several different countries at low frequencies (<1.0%), such as L203I (United States, 1993; 3005x), K65Q:K68N (Kenya, 2012; 1239x), K68Q:S211N (Netherlands and Taiwan, 2005-2007; 35.7x), N201S (South Africa, 2017; 126.7x), K68Q:I206M:Q209R (Japan, 2018; 46.4x), N201T:I206M:Q209R (United States, 2018; <417.8x) and K68N (Canada, 2019; 29.9x). Nirsevimab neutralized all other RSV A and BF protein variants containing binding site substitutions identified in both the Northern and Southern Hemispheres.

[0343] In conclusion, the nirsevimab binding site has remained highly conserved among circulating RSV strains since 1956. Nirsevimab escape variants are rare and have not increased in geographic frequency.

[0344] Example 7. Pooled analysis of nirsevimab resistance over 150 days post-dose in preterm and term infants In two global placebo-controlled trials, nirsevimab, a monoclonal antibody against the RSV prefusion (F) protein with extended half-life, reduced medically required (MA) RSV LRTIs compared to placebo throughout the RSV season (Phase III: MELODY, healthy term and late preterm infants, 74.5%; Phase IIb: Study 3, healthy preterm infants, 70.1%). This example summarizes the resistance analysis of RT-PCR-confirmed RSV isolates from subjects over 150 days post-dose.

[0345] Infants were randomized 2:1 to receive a single intramuscular injection of nirsevimab or placebo before their first RSV season.RT-PCR-confirmed RSV isolates were reversed for genotyping of RSV F and phenotyping of substitutions identified in a recombinant RSV neutralization susceptibility assay.

[0346] In a pooled proposed dose analysis of Phase 2b (Study 3; nirsevimab 50 mg if <5 kg at time of administration) and MELODY (nirsevimab 50 or 100 mg if <5 kg or ≥5 kg at time of administration, respectively), no subjects with MA RSV LRTI in either treatment group had RSV isolates containing substitutions associated with nirsevimab resistance (nirsevimab, RSV A: 0 / 14 and RSV B: 0 / 5; placebo, RSV A: 0 / 35 and RSV B: 0 / 16). In Study 3 (nirsevimab 50m if ≥ 5 kg at time of administration), 2 / 18 subjects in the nirsevimab group and 0 / 20 subjects in the placebo group with MA RSV LRTI had RSV isolates with nirsevimab binding site substitutions I64T+K68E+I206M+Q209R (> 447-fold) or N208S (> 387-fold) that reduce susceptibility to nirsevimab neutralization (nirsevimab, RSV A: 0 / 9 and RSV B: 2 / 9; placebo, RSV A: 0 / 10 and RSV B: 0 / 10). Subjects with RSV isolates with F protein sequence mutations that maintain susceptibility to nirsevimab neutralization were balanced between treatment groups regardless of RSV disease severity. Subjects with MA RSV LRTI (protocol undefined) or hospitalized due to RSV disease did not have RSV isolates conferring nirsevimab resistance.

[0347] In conclusion, the lack of nirsevimab resistance following immunization at the recommended dose supports the efficacy and neutralizing activity of nirsevimab against both RSV A and B strains throughout the RSV pandemic.

[0348] Example 8. Safety of Nirsevimab for Respiratory Syncytial Virus Prophylaxis in Immunocompromised Children: Phase 2 MUSIC Study This example reports the interim safety analysis of the MUSIC study (NCT04484935), a 12-month Phase 2, open-label, uncontrolled, single-dose study to evaluate the safety and tolerability of nirsevimab along with pharmacokinetics and anti-drug antibody development in immunocompromised children aged 24 months and younger.

[0349] Children aged <12 months and undergoing their first RSV season received a single nirsevimab intramuscular (IM) injection of 50 mg if they weighed <5 kg or 100 mg if they weighed ≥5 kg, and children aged >12 months to <24 months and undergoing their second RSV season received a single nirsevimab IM injection of 200 mg. Subcategories of immunocompromised subjects at the time of informed consent included: A) primary immunodeficiency; B) human immunodeficiency virus infection; C) history of solid organ or bone marrow transplant; D) receiving immunosuppressive chemotherapy; E) receiving systemic high-dose corticosteroid therapy; or F) receiving other immunosuppressive therapy. Adverse events (AEs), serious adverse events (SAEs), AEs of special interest (AESIs; immediate hypersensitivity including anaphylaxis, immune complex disease, or thrombocytopenia), and new onset chronic diseases (NOCDs) were assessed during the 12-month follow-up period. Adverse events were graded by severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events.

[0350] A total of 100 immunocompromised children aged 24 months or younger were enrolled by February 28, 2022 in Japan (n=26), Ukraine (n=21), the United States (n=19), South Africa (n=14), Spain (n=10), Belgium (n=6), Poland (n=3), and the United Kingdom (n=1). Of these, a planned interim analysis was performed on 60 children who were enrolled by December 31, 2021 and had follow-up data for ≥151 days after dosing (cut-off date May 16, 2022) or who discontinued early. All children had severe and complex underlying conditions at baseline. Twenty-eight children belonged to the immunocompromised subcategory A, one to subcategory B, 12 to subcategory C, 9 to subcategory D, 17 to subcategory E, and 9 to subcategory F. One child belonged to more than one immunocompromised subcategory.

[0351] All investigator-assessed AEs related to treatment were grade 1 or 2 in severity. No SAEs or NOCDs were attributed to nirsevimab by the investigator. No anaphylaxis was reported. No serious hypersensitivity reactions were reported. One death (cause unknown) occurred 124 days post-dose; this was determined by the investigator to be unrelated to treatment.

[0352] This interim analysis shows that a single IM dose of nirsevimab was well tolerated and had a favorable safety profile in immunocompromised children aged 24 months and younger. Nirsevimab administered once per RSV season has the potential to address an important unmet medical need to prevent RSV infection in high-risk, immunocompromised children.

[0353] Example 9. Nirsevimab for prevention of RSV disease in healthy late preterm and term infants: Follow-up across a second RSV season Nirsevimab, a highly neutralizing monoclonal antibody with a long half-life of approximately 70 days, has been shown to protect term and late preterm infants against medically-accepted (MA) respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) throughout their first RSV season in the Phase 3 MELODY trial (≥35 weeks gestational age, efficacy 74.5%; NCT03979313).

[0354] Antibody-dependent enhancement (ADE) may theoretically occur when non-neutralizing or subneutralizing antibodies bind to viral antigens without blocking or eliminating infection. To address this concern, infants were followed up to the second RSV season (510 days after dosing) without rechallenge to assess the theoretical risk of ADE in the setting of low nirsevimab concentrations. This example reports the incidence and disease severity of MA RSV LRTI during the second RSV season.

[0355] Infants were randomized 2:1 to receive a single intramuscular injection of nirsevimab (50 mg for infants <5 kg at time of dosing; 100 mg for infants ≥5 kg at time of dosing) or placebo before their first RSV season. Infants were followed for a period of 17 months after dosing for detection of cases of MA RSV LRTI. Cases of MA RSV LRTI met predefined clinical criteria for disease severity and were confirmed by real-time reverse transcriptase polymerase chain reaction. "Any cause" refers to any LRTI or respiratory illness requiring medical attention, including cases of MA RSV LRTI.

[0356] Overall, 1490 infants were randomized into the intent-to-treat population (994 nirsevimab and 496 placebo), of which 1446 (964 nirsevimab and 482 placebo) were followed through the second epidemic. During the first epidemic, the incidence of MA RSV LRTI was 1.2% in nirsevimab recipients and 5.0% in placebo recipients. During the second epidemic, the incidence was lower, occurring in 0.7% and 0.4% for nirsevimab and placebo recipients, respectively (Table 9). There were no cases of MA RSV LRTI requiring hospitalization during the second epidemic. Similarly, during the second epidemic, the incidence of MA LRTI of any cause and the incidence of hospitalization due to respiratory illness of any cause were balanced between treatment groups.

[0357] In conclusion, the incidence of MA RSV LRTIs during the second RSV season was low and balanced across treatment groups, with no evidence of ADE in nirsevimab recipients.

[0358] [Table 9]

[0359] Example 10. Safety and Efficacy of Nirsevimab for RSV Lower Respiratory Tract Infection Requiring Medical Attendance in All Infants Enrolled in the Phase 3 MELODY Trial The phase 3 MELODY trial (n=1490) evaluated nirsevimab, a single-dose extended half-life monoclonal antibody, and demonstrated efficacy of 74.5% (95% CI 49.6, 87.1; NCT03979313) against medically-accepted (MA) respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI; primary endpoint) in late preterm and term infants. This Example summarizes safety and efficacy data for all 3012 infants enrolled in MELODY.

[0360] Infants were randomized 2:1 to receive a single intramuscular injection of nirsevimab (50 mg if <5 kg at dose; 100 mg if ≥5 kg at dose) or placebo before their first RSV season. Enrollment began on July 23, 2019 and ended on October 22, 2021, after a pause due to the COVID-19 pandemic. All treated infants were monitored for adverse events (AEs) for 360 days post-dose. All randomized infants were monitored for the incidence of MA RSV LRTI for 150 days post-dose. Cases met predefined clinical criteria for disease severity and were laboratory confirmed. RSV G genes were sequenced and subtyped compared to RSV A or B reference strains.

[0361] Overall, 2994 infants were dosed (1998 nirsevimab, 996 placebo). Most infants (nirsevimab 93.9%; placebo 93.5%) completed 150 days of follow-up after dosing, and almost half of these (nirsevimab 48.0%; placebo 48.1%) had completed 360 days at the time of this analysis.

[0362] The incidence of AEs was similar between treatment groups (Table 10). In nirsevimab recipients, 4 deaths had occurred at the time of this analysis and were assessed as unrelated to treatment; no deaths occurred in placebo recipients.

[0363] [Table 10]

[0364] Nirsevimab demonstrated 76.4% (95% CI: 62.3, 85.2) efficacy against MA RSV LRTI, 76.8% (95% CI: 49.4, 89.4) efficacy against MA RSV LRTI with hospitalization, and 78.6% (95% CI: 48.8, 91.0) efficacy against very severe MA RSV LRTI compared to placebo (Figure 16). A trend for a reduction in the incidence of RSV subtypes A and B was observed (Table 11).

[0365] [Table 11]

[0366] Thus, in the entire MELODY study population, a single dose of nirsevimab protected late preterm and term infants against MA RSV LRTI, associated hospitalization, and severe disease across the RSV season.

[0367] Example 11. Antiviral resistance This example describes nirsevimab escape variants measured in vitro and in vivo.

[0368] In cell culture After three passages in cell culture of RSV A2 and B9320 strains in the presence of nirsevimab, escape variants were selected. Recombinant RSV A variants that showed reduced susceptibility to nirsevimab included those with the identified substitutions N67I:N208Y (103-fold compared to the reference). Recombinant RSV B variants that showed reduced susceptibility to nirsevimab included those with the identified substitutions N208D (>90,000-fold), N208S (>24,000-fold), K68N:N201S (>13,000-fold) or K68N:N208S (>90,000-fold). All resistance-associated substitutions identified among neutralization escape variants were located in the nirsevimab binding site (amino acids 62-69 and 196-212) and were found to reduce binding affinity to the RSV F protein.

[0369] In surveillance testing In prospective, observational, global molecular epidemiology studies (OUTSMART-RSV and INFORM-RSV), genetic diversity of the RSV F protein sequence remains low (most amino acids in RSV A and RSV B are >99% conserved), and the prevalence of variants with substitutions associated with nirsevimab resistance is rare (<1%). Since 2015, most amino acid residues in the nirsevimab binding site have remained highly conserved (>99%) at all positions in RSV A and at 22 of 25 positions in RSV B. The concomitant mutation I206M:Q209R in the binding site, which has been prevalent in RSV B since 2017, retains complete susceptibility to nirsevimab (I206M:Q209R, 0.23-fold change). The S211N substitution, which is increasing in prevalence, also conferred sensitivity to nirsevimab both alone (1.2-fold change) and with co-occurring substitutions (I206M:Q209R:S211N, 0.5-fold change).

[0370] In clinical trials In subjects receiving the recommended dose of nirsevimab 50 mg if weighing less than 5 kg in MELODY, MEDLEY, MUSIC, and D5290C00003, subjects with medically required RSV lower respiratory tract infection (MA RSV LRTI) or any RSV case definition did not have RSV isolates containing substitutions associated with consensus nirsevimab resistance in any treatment group.

[0371] In D5290C00003 (subjects who received a single dose of nirsevimab 50 mg), two of 40 subjects with RSV infections corresponding to any case definition had variants containing substitutions associated with nirsevimab resistance. RSV B variants occurred in two subjects with concomitant I64T:K68E:I206M:Q209R or N208S substitutions who were receiving less than the recommended nirsevimab dose and showed reduced susceptibility to nirsevimab (IC50>ULOQ). Resistance-associated substitutions were not identified as the predominant variant at any sampling time point in the MELODY, MEDLEY, or MUSIC studies, including after day 361 when nirsevimab titers were reduced.

[0372] Minimal data are available indicating that variants resistant to nirsevimab may be cross-resistant to other monoclonal antibodies targeting the RSV F protein; palivizumab retained full neutralization capacity against the resistance-associated substitutions identified in D5290C00003. Nirsevimab retained activity against recombinant RSV carrying palivizumab resistance-associated substitutions identified in molecular epidemiology studies and palivizumab neutralization escape variants.

[0373] Example 12. Immunogenicity This Example summarizes the measurement of anti-drug antibodies in the Phase 2b trials, MELODY and MEDLEY.

[0374] In Phase 2b and MELODY (primary cohort), anti-nirsevimab antibodies were detected in 84 / 1498 (5.6%) infants who received a single dose of nirsevimab in the recommended dosing regimen during the 361-day post-treatment period, and 68 / 1423 (4.8%) tested positive for anti-drug antibodies (ADA) to the YTE domain. In MELODY, 14 / 896 (1.6%) subjects tested positive for nirsevimab neutralizing antibodies. In subjects who received a single dose of nirsevimab during the first RSV epidemic in MEDLEY, anti-nirsevimab antibodies were detected in 32 / 587 (5.5%) infants during the 361-day post-treatment period. Nirsevimab neutralizing antibodies were detected in 2 / 564 (0.4%) infants, and 31 / 564 (5.5%) infants tested positive for ADA against the YTE domain. Eight subjects (4.4%) of 180 subjects who received a second dose of nirsevimab during the second RSV season were ADA positive 360 ​​days after the first RSV dose, and none had detectable ADA 150 days after the second RSV dose. None of the 10 ADA positive subjects during the second RSV season were positive during the first RSV season. Eight subjects had anti-YTE ADA during the second RSV season, and one of these subjects also had neutralizing antibodies. For subjects who received nirsevimab during the first or second RSV season in MUSIC, 0 / 60 (0.0%) children had detectable anti-nirsevimab antibodies during the 151-day post-dose period. Nirsevimab neutralizing antibodies were detected in 0 / 60 (0.0%) children, and 2 / 60 (3.3%) children tested positive for ADA against the YTE domain.

[0375] The occurrence of ADAs to nirsevimab is not expected to have a clinically relevant impact on its clearance (up to 5 months), efficacy, or safety.

[0376] [Table 12]

[0377]

Table 13

Claims

1. A pharmaceutical composition for preventing respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in a subject from birth, comprising a single dose of nirsevimab, wherein the single dose is effective in preventing RSV LRTD in the subject for more than five months.

2. The pharmaceutical composition described in claim 1, wherein a single dose of nirsevimab is administered to the subject 2 weeks ± 3 days, 3 weeks ± 3 days, 4 weeks ± 3 days, 1 month ± 2 weeks, 2 months ± 2 weeks, or 3 months ± 2 weeks before the start of the RSV season.

3. 3. The pharmaceutical composition of claim 2, wherein the beginning of the RSV season is defined by the first two consecutive weeks in which the average rate of positive RSV tests over a two-week period exceeds a threshold, said threshold being between 3% and 13%.

4. A pharmaceutical composition for preventing respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in a subject, comprising a single dose of nirsevimab, wherein the single dose is administered to the subject after the end of a previous RSV season and is effective in preventing RSV LRTD in the subject throughout the next RSV season.

5. The pharmaceutical composition of claim 4, wherein the single dose of nirsevimab is administered to the subject 1 week ± 3 days, 2 weeks ± 3 days, 3 weeks ± 3 days, 4 weeks ± 3 days, 1 month ± 2 weeks, 2 months ± 2 weeks, 3 months ± 2 weeks, 4 months ± 2 weeks, 5 months ± 2 weeks, 6 months ± 2 weeks or 7 months ± 2 weeks after the end of the most recent RSV season.

6. 6. The pharmaceutical composition of claim 5, wherein the end of the immediately preceding RSV season is defined by the first week in which the average positive rate of RSV tests over a one-week period falls below a threshold, the threshold being between 3% and 13%.

7. The pharmaceutical composition of claim 4, wherein a single dose of nirsevimab is effective in preventing RSV LRTD in the subject for more than 5 months.

8. The pharmaceutical composition of claim 1 or 4, wherein a single dose of nirsevimab is effective in preventing RSV LRTD in the subject for at least 5 to 6 months, at least 6 months, at least 8 months, as long as 12 months, or at least 12 months.

9. The pharmaceutical composition of claim 1 or 4, wherein the subject is at high risk of developing an RSV infection.

10. The subject is a) born at a gestational age of less than 29 weeks; and / or b) have chronic lung disease (CLD), congenital heart disease (CHD), a suppressed immune system, a weakened immune system, an immunodeficiency, a neuromuscular disorder, Down's syndrome, a congenital airway abnormality and / or cystic fibrosis; The pharmaceutical composition of claim 9.

11. The amount of nirsevimab in the single dose has a serum AUC of greater than 12.8 day mg / mL in the subject. ０－∞ 10. The pharmaceutical composition of claim 1 or 4, which is effective to produce

12. a) the amount of nirsevimab in said single dose is effective to result in an increase in RSV neutralizing antibody (Nab) levels in said subject at 12 months ± 2 weeks after administration compared to said subject's RSV Nab level at the time of administration; and / or b) The pharmaceutical composition of claim 1 or 4, wherein the amount of nirsevimab in the single dose is effective to result in an increase in RSV Nab levels in the subject 12 months ± 2 weeks after administration compared to the RSV Nab levels of an individual with confirmed RSV infection who has not been administered nirsevimab.

13. The amount of nirsevimab in the single dose is 50 mg if the subject weighs less than 5 kg at the time of administration; and 100 mg if the subject weighs 5 kg or more at the time of administration; The pharmaceutical composition according to any one of claims 1 to 3.

14. The amount of nirsevimab in the single dose is 50 mg if the subject is an infant weighing less than 5 kg at the time of administration; 100 mg if the subject is an infant weighing 5 kg or more at the time of administration; and 200 mg if the subject is a pediatric subject undergoing its second RSV season. The pharmaceutical composition according to any one of claims 4 to 7.

15. Preventing RSV LRTD involves: a) RSV LRTD requiring medical attention; b) RSV-related hospitalization; c) severe RSV infection; and / or d) Very severe RSV infection The pharmaceutical composition according to claim 1 or 4, which is used to prevent:

16. A pharmaceutical composition for preventing extremely severe respiratory syncytial virus (RSV) infection in a subject from birth, comprising a single dose of nirsevimab, wherein the single dose is effective in preventing extremely severe RSV infection in the subject for more than five months.

17. The pharmaceutical composition of claim 16, wherein a single dose of nirsevimab is effective in preventing hospitalization of the subject due to RSV LRTD requiring medical attention, with the subject receiving (i) supplemental oxygen, (ii) intravenous fluids, or (iii) supplemental oxygen and intravenous fluids.

18. The pharmaceutical composition described in claim 17, wherein a single dose of nirsevimab is effective in preventing a decrease in oxygen saturation to below 90% in the subject.

19. The pharmaceutical composition of claim 16, wherein a single dose of nirsevimab is effective in preventing extremely severe RSV infection in the subject for at least 5 to 6 months, at least 6 months, at least 8 months, as long as 12 months, or at least 12 months.

20. A pharmaceutical composition for preventing lower respiratory tract infections (LRTIs) of any cause or hospitalization due to LRTIs of any cause in a subject from birth, comprising a single dose of nirsevimab, said single dose being effective in preventing LRTIs of any cause in said subject or hospitalization due to LRTIs of any cause in said subject for more than five months.

21. The pharmaceutical composition of claim 20, wherein a single dose of nirsevimab is effective in preventing LRTI of any cause in the subject or hospitalization due to LRTI of any cause in the subject for at least 5 to 6 months, at least 6 months, at least 8 months, as long as 12 months, or at least 12 months.

22. The amount of nirsevimab in the single dose 50 mg if the subject weighs less than 5 kg at the time of administration; and 100 mg if the subject weighs 5 kg or more at the time of administration; The pharmaceutical composition according to any one of claims 16 to 21.

23. A pharmaceutical composition described in any one of claims 1, 4, 16, and 20, wherein a single dose of nirsevimab is administered to a subject at or shortly after birth.

24. The pharmaceutical composition of any one of claims 1, 4, 16, and 20, wherein the amount of nirsevimab in the single dose is effective to reduce antibiotic use in the subject compared to antibiotic use in an individual who is not administered nirsevimab.

25. 21. The pharmaceutical composition of any one of claims 1, 4, 16, and 20, wherein the pharmaceutical composition is administered intramuscularly or subcutaneously.

26. A pharmaceutical composition for preventing respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in a subject at high risk of developing RSV infection, wherein the pharmaceutical composition is administered to the subject at a first dose of nirsevimab prior to the subject's first RSV season, and at a second dose of nirsevimab prior to the subject's second RSV season; The amount of nirsevimab in the first dose is 50 mg if the subject weighs less than 5 kg at the time of administration; and 100 mg if the subject weighs 5 kg or more at the time of administration; and the amount of nirsevimab in the second dose is 200 mg; wherein the first dose of nirsevimab is effective in preventing RSV LRTD in the subject for more than 5 months. Pharmaceutical compositions.

27. ​​The pharmaceutical composition of claim 26, wherein the first dose of nirsevimab is effective in preventing RSV LRTD in the subject for at least 5 to 6 months, at least 6 months, at least 8 months, as long as 12 months, or at least 12 months.

28. 1. A pharmaceutical composition for preventing respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in a subject undergoing cardiac surgery, wherein the subject is administered a first dose and a second dose of nirsevimab, wherein: a) the first dose of nirsevimab is administered before the subject's first RSV season, wherein: i) the amount of nirsevimab in the first dose is 50 mg if the subject weighs less than 5 kg at the time of administration of the first dose; or ii) the amount of nirsevimab in the first dose is 100 mg if the subject weighs 5 kg or more at the time of administration of the first dose; and b) the second dose of nirsevimab is administered after the cardiac surgery; i) the amount of nirsevimab in the second dose is 50 mg if the subject weighs less than 5 kg at the time of administration of the second dose and the second dose is administered within 90 days of administration of the first dose; or ii) the amount of nirsevimab in the second dose is 100 mg if the subject weighs 5 kg or more at the time of administration of the second dose and the second dose is administered within 90 days of administration of the first dose; or iii) the amount of nirsevimab in the second dose is 50 mg if the second dose is administered more than 90 days after administration of the first dose; Pharmaceutical compositions.

29. Use of a single dose of nirsevimab in the manufacture of a pharmaceutical for preventing respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in a subject from birth, wherein the single dose is effective in preventing RSV LRTD in the subject for more than 5 months.

30. Use of a single dose of nirsevimab in the manufacture of a pharmaceutical for preventing respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in a subject from birth, wherein the single dose is administered to the subject after the end of the previous RSV season and is effective in preventing RSV LRTD in the subject throughout the next RSV season.

31. The use of claim 29 or 30, wherein a single dose of nirsevimab is effective in preventing RSV LRTD in the subject for at least 5 to 6 months, at least 6 months, at least 8 months, as long as 12 months, or at least 12 months.

32. Use of a single dose of nirsevimab in the manufacture of a medicament for preventing very severe respiratory syncytial virus (RSV) infection in a subject from birth, wherein the single dose is effective in preventing very severe RSV infection in the subject for more than 5 months, at least 5 to 6 months, at least 6 months, at least 8 months, as long as 12 months, or at least 12 months.

33. Use of a single dose of nirsevimab in the manufacture of a medicament for preventing lower respiratory tract infections (LRTIs) of any cause or hospitalization due to LRTIs of any cause in a subject from birth, wherein the single dose is effective in preventing LRTIs of any cause in the subject or hospitalization due to LRTIs of any cause in the subject for more than 5 months, at least 5 to 6 months, at least 6 months, at least 8 months, as long as 12 months, or at least 12 months.

34. Use of nirsevimab in the manufacture of a pharmaceutical for a method of preventing respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in a subject at high risk of developing RSV infection, said method comprising administering to said subject a first dose of nirsevimab prior to said subject's first RSV season and a second dose of nirsevimab prior to said subject's second RSV season; wherein the amount of nirsevimab in the first dose is 50 mg if the subject weighs less than 5 kg at the time of administration; and 100 mg if the subject weighs 5 kg or more at the time of administration; the amount of nirsevimab in said second dose is 200 mg; The use, wherein the first dose of nirsevimab is effective in preventing RSV LRTD in the subject for more than 5 months, at least 5 to 6 months, at least 6 months, at least 8 months, as long as 12 months, or at least 12 months.

35. Use of nirsevimab in the manufacture of a medicament for a method of preventing respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in a subject undergoing cardiac surgery, said method comprising: a) administering to said subject a first dose of nirsevimab prior to said subject's first RSV season; i) the amount of nirsevimab in the first dose is 50 mg if the subject weighs less than 5 kg at the time of administration of the first dose; and ii) the amount of nirsevimab in the first dose is 100 mg if the subject weighs 5 kg or more at the time of administration of the first dose; and b) administering to said subject a second dose of nirsevimab after said cardiac surgery, wherein i) the amount of nirsevimab in the second dose is 50 mg if the subject weighs less than 5 kg at the time of administration of the second dose and the second dose is administered within 90 days of administration of the first dose; ii) the amount of nirsevimab in the second dose is 100 mg if the subject weighs 5 kg or more at the time of administration of the second dose and the second dose is administered within 90 days of administration of the first dose; and iii) the amount of nirsevimab in the second dose is 50 mg if the second dose is administered more than 90 days after administration of the first dose; Including, use.

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