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BACKGROUND: Nirsevimab is an extended half-life monoclonal antibody (mAb) licensed for the prevention of respiratory syncytial virus (RSV)-associated lower respiratory tract disease in neonates, infants and medically vulnerable children. We characterized RSV isolates recovered from participants enrolled in MEDLEY: a randomized, palivizumab-controlled phase 2/3 trial of nirsevimab in infants born preterm and/or with congenital heart disease or chronic lung disease of prematurity. METHODS: Participants were assessed in two RSV seasons (Season 1 and 2). Season 1 participants were randomized (2:1) to receive a single dose of nirsevimab (50 mg if weight <5 kg or 100 mg if weight ≥5 kg in Season 1; 200 mg in Season 2) followed by four monthly doses of placebo, or five once-monthly doses of palivizumab (15 mg/kg weight per dose). Season 2 participants continued nirsevimab and placebo (nirsevimab/nirsevimab) or were re-randomized (1:1) to switch to nirsevimab (palivizumab/nirsevimab) or continue palivizumab (palivizumab/palivizumab). Cases of RSV infection were identified by central testing of nasal swabs from participants seeking medical attention for respiratory illnesses. Nirsevimab and palivizumab binding site substitutions were assessed via microneutralization assay. RESULTS: Twenty-five cases of confirmed RSV infection were observed during the trial and sequenced: 12 in nirsevimab recipients and 10 in palivizumab recipients during Season 1, and 1 case in each Season 2 group. Molecular sequencing of RSV A (n = 14) isolates detected no nirsevimab binding site substitutions, and 3 palivizumab neutralization-resistant substitutions (Lys272Met, Lys272Thr, Ser275Leu). The nirsevimab binding site Ile206Met:Gln209Arg and Ile206Met:Gln209Arg:Ser211Asn substitutions were the only anti-RSV mAb binding site substitutions detected among RSV B isolates (n = 11). Nirsevimab neutralized all nirsevimab and palivizumab binding site substitutions in RSV A and B isolates recovered from MEDLEY participants. CONCLUSION: No binding site substitution detected during MEDLEY affected RSV susceptibility to nirsevimab neutralization.

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BACKGROUND AND OBJECTIVES: Immunocompromised children may have increased risk for severe respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI), potentially leading to prolonged hospitalization, intensive care, and death. The open-label phase II MUSIC trial evaluated the safety and pharmacokinetics of nirsevimab, an extended half-life monoclonal antibody against RSV, in immunocompromised children aged ≤24 months. METHODS: Participants received a single intramuscular injection of nirsevimab (first RSV season: 50 mg if <5 kg/100 mg if ≥5 kg; second season: 200 mg). Safety, antidrug antibodies, and pharmacokinetics were evaluated to day 361. RESULTS: Participants (n = 100) had ≥1 immunocompromising conditions: primary immunodeficiency (n = 33), previous transplantation (n = 16), HIV infection (n = 8) or treatment with high-dose systemic corticosteroids (n = 29), immunosuppressive chemotherapy (n = 20), or other immunosuppressive therapies (n = 15). Six children experienced eight treatment-related adverse events (none categorized as serious). Three deaths occurred, all were unrelated to treatment. Eleven children, developed antidrug antibodies, with minimal effects on pharmacokinetics and no apparent impact on safety. Nirsevimab serum concentrations at day 151 were similar to those effective in preventing medically attended RSV LRTI in healthy infants. Fourteen children had increased nirsevimab clearance. No protocol-defined medically attended RSV LRTIs occured through day 151. CONCLUSIONS: Among immunocompromised children aged ≤24 months, nirsevimab was well tolerated with no safety concerns and serum concentrations were supportive of efficacy. A subset of children with increased nirsevimab clearance, had conditions potentially associated with protein loss; however, the impact on efficacy is unknown.

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BACKGROUND: There is limited evidence regarding the proportion of wheeze in young children attributable to respiratory syncytial virus lower respiratory tract infections (RSV-LRTI) occurring early in life. This cohort study prospectively determined the population attributable risk (PAR) and risk percent (PAR%) of wheeze in 2-<6-year-old children previously surveilled in a primary study for RSV-LRTI from birth to their second birthday (RSV-LRTI<2Y). METHODS: From 2013 to 2021, 2-year-old children from 8 countries were enrolled in this extension study (NCT01995175) and were followed through quarterly surveillance contacts until their sixth birthday for the occurrence of parent-reported wheeze, medically-attended wheeze or recurrent wheeze episodes (≥4 episodes/year). PAR% was calculated as PAR divided by the cumulative incidence of wheeze in all participants. RESULTS: Of 1395 children included in the analyses, 126 had documented RSV-LRTI<2Y. Cumulative incidences were higher for reported (38.1% vs. 13.6%), medically-attended (30.2% vs. 11.8%) and recurrent wheeze outcomes (4.0% vs. 0.6%) in participants with RSV-LRTI<2Y than those without RSV-LRTI<2Y. The PARs for all episodes of reported, medically-attended and recurrent wheeze were 22.2, 16.6 and 3.1 per 1000 children, corresponding to PAR% of 14.1%, 12.3% and 35.9%. In univariate analyses, all 3 wheeze outcomes were strongly associated with RSV-LRTI<2Y (all global P < 0.01). Multivariable modeling for medically-attended wheeze showed a strong association with RSV-LRTI after adjustment for covariates (global P < 0.0001). CONCLUSIONS: A substantial amount of wheeze from the second to sixth birthday is potentially attributable to RSV-LRTI<2Y. Prevention of RSV-LRTI<2Y could potentially reduce wheezing episodes in 2-<6-year-old children.

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The United States (U.S.) Food and Drug Administration (FDA) oversees the safety and quality of drugs and vaccines that are used in the U.S. Administration of the FDA falls under the jurisdiction of the U.S. Department of Health and Human Services (HHS). The regulatory oversight of the FDA is complex and comprehensive, requiring the various roles and responsibilities to be divided across six main centers. The activities of two of these centers, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) are the primary focus of this review.

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BACKGROUND: Respiratory syncytial virus (RSV) is a substantial cause of infant morbidity and mortality due to seasonal peaks of bronchiolitis across the United States. Clinical and viral surveillance plays a pivotal role in helping hospital systems prepare for expected surges in RSV bronchiolitis. Existing surveillance efforts have shown a geographic pattern of RSV positivity across the United States, with cases typically starting in the southeast and spreading north and west. Public health measures implemented due to the COVID-19 pandemic disrupted viral transmission across the nation and altered the expected seasonality of RSV. The impact of these changes on the geographic progression of infant RSV bronchiolitis across the United States has not been described. METHODS: Here, we used clinical and viral surveillance data from four health care systems located in different regions of the United States to describe the geographic progression of infant RSV bronchiolitis across the country from 2015 to 2023. RESULTS: Prior to widespread circulation of SARS-CoV-2, infant RSV bronchiolitis followed an established geographic pattern associated with seasonal epidemics originating in Florida and spreading north (North Carolina and New York) and later westward (Nevada). Although public health and social measures implemented during the COVID-19 pandemic disrupted the seasonality of RSV disease, infant RSV bronchiolitis epidemics progressed across the nation in a pattern identical to the prepandemic era. CONCLUSIONS: Our findings highlight the importance of ongoing clinical and viral surveillance to optimally track the onset of RSV epidemics and allow health care systems to prepare for expected RSV bronchiolitis surges.

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BACKGROUND: Bronchiolitis due to respiratory syncytial virus (RSV) is the leading cause of hospitalization among American infants. The overall burden of RSV among infants has been historically under-estimated due to variable testing practices, particularly in the outpatient setting. Universal masking and social distancing implemented during the coronavirus disease 2019 (COVID-19) pandemic altered RSV seasonality, however potential consequences on RSV testing practices across different healthcare settings and sociodemographic groups have not been described. Variable testing practices could also affect accurate assessment of the effects of two recently approved RSV preventative agents targeting infants. METHODS: Utilizing real-time clinical and viral surveillance, we examined RSV testing practices among infants with bronchiolitis within four United States healthcare systems across different healthcare settings and sociodemographic groups pre- and post-COVID-19. RESULTS: RSV testing among infants with bronchiolitis increased since 2015 within each healthcare system across all healthcare settings and sociodemographic groups, with a more dramatic increase since the COVID-19 pandemic. Outpatient testing remained disproportionately low compared to hospital-based testing, although there were no major differences in testing frequency among sociodemographic groups in either setting. CONCLUSIONS: Although RSV testing increased among infants with bronchiolitis, relatively low outpatient testing rates remain a key barrier to accurate RSV surveillance.

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To date, safe and effective strategies to prevent medically attended respiratory syncytial virus (RSV) illness across the infant population have been limited to passive immunoprophylaxis for those at highest risk. While active vaccination strategies are finally available to protect adults 60 years and older from serious RSV infection, safe and effective vaccines for use in children have yet to emerge. In contrast, passive immunization strategies designed to protect all infants against RSV has finally met with success, with 2 new strategies approved by the US Food and Drug Administration during the second half of 2023. The first RSV passive immunization strategy to gain licensure for use in all infants is an extended half-life monoclonal antibody directed against an antigenic binding site on the RSV-F prefusion protein, a conformation not known to exist until 2013. The second novel passive immunization strategy approved during 2023 that has the potential to protect much of the infant population from RSV during young infancy centers on boosting preexisting RSV immunity during pregnancy using a prefusion RSV-F vaccine. The resulting boosted humoral immune response to RSV in the mother becomes part of the transplacental antibody endowment that is actively transported across the placenta to provide protection to those babies born at or near term. This review describes how and why these advances came to fruition seemingly "all at once" and provides insight into other passive immunization approaches that remain under development.

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BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis is the leading cause of hospitalizations among infants in the United States. Unpredictability in RSV seasonality has occurred following the onset of the coronavirus disease 2019 (COVID-19) pandemic. Local surveillance networks can enhance the ability to appropriately time prophylaxis when exposure risk is highest. METHODS: A retrospective, cohort study was conducted to describe the epidemiologic patterns of RSV disease among outpatient, emergency department and inpatient encounters in children <5 years in Central New York before and after the onset of the COVID-19 pandemic. Local data were collected from October 2015 to January 2023 and compared to state-level data. Linear regression models were used to identify clinical and sociodemographic differences before and after the pandemic. RESULTS: Local variation in RSV seasonality was noted prior to the COVID-19 pandemic, however highly atypical circulation patterns appeared in the post-COVID-19 era. Since March 2020, patterns for local and state-defined RSV seasons have remained atypical (local season onset in 2021: week 27 and 2022: week 27; state season onset in 2021: week 31 and 2022: week 38). After adjusting for increases in testing, RSV bronchiolitis cases were not significantly different during pre- and post-pandemic eras. In comparison to the 2021 bronchiolitis season, the 2022 season had a higher proportion of RSV cases despite decreased testing. CONCLUSIONS: Temporal patterns for RSV have shifted during the COVID-19 pandemic. Local surveillance networks may be advantageous in trending community-level RSV activity to optimize prophylaxis administration. Changes in RSV testing patterns occurred throughout the study period and should be accounted for when describing infant and childhood RSV disease.

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In children with congenital heart disease and/or chronic lung disease entering their second respiratory syncytial virus (RSV) season, 200 mg nirsevimab had a similar safety profile to that of palivizumab and resulted in nirsevimab serum exposures associated with efficacy in healthy infants, supporting efficacy in this population at risk of severe RSV disease.

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Nirsevimab is a monoclonal antibody that binds to the respiratory syncytial virus (RSV) fusion protein. During the Phase 2b (NCT02878330) and MELODY (NCT03979313) clinical trials, infants received one dose of nirsevimab or placebo before their first RSV season. In this pre-specified analysis, isolates from RSV infections were subtyped, sequenced and analyzed for nirsevimab binding site substitutions; subsequently, recombinant RSVs were engineered for microneutralization susceptibility testing. Here we show that the frequency of infections caused by subtypes A and B is similar across and within the two trials. In addition, RSV A had one and RSV B had 10 fusion protein substitutions occurring at >5% frequency. Notably, RSV B binding site substitutions were rare, except for the highly prevalent I206M:Q209R, which increases nirsevimab susceptibility; RSV B isolates from two participants had binding site substitutions that reduce nirsevimab susceptibility. Overall, >99% of isolates from the Phase 2b and MELODY trials retained susceptibility to nirsevimab.

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Healthcare provider vaccine knowledge and attitudes influence delivery of a strong vaccine recommendation. We aim to describe HPV vaccine knowledge, attitudes, and recommendation or discussion practices (KAP) among New York State medical providers, dentists, and pharmacists. A survey to assess providers' KAP was distributed electronically to NYS members of medical organizations. Descriptive and inferential statistical methods were used to characterize provider KAP. Responses from 1637 surveys were included, from 864 (53%) medical providers, 737 (45%) dentists, and 36 (2%) pharmacists. 59% (509/864) of medical providers responded that they recommend HPV vaccine to patients, with 390/509 (77%) strongly recommending vaccine at 11-12 years. Medical providers were more likely to report recommending HPV vaccine for children ages 11-12 years if they strongly agreed that HPV vaccine prevents cancer 326/391 (83%) vs 64/117 (55%) and responded that HPV vaccination does not increase the risk of unprotected sex (386/494 (78%) vs 4/15 (25%)) (p < .05). Less than 1/3 of dentists reported discussing HPV vaccine with 11-26-year-old females (230/737, 31%) and males (205/737, 28%) at least "sometimes." Dentists were more likely to answer that they routinely discuss HPV vaccine with children ages 11-12 years if they responded that HPV vaccination does not increase sexual activity (70/73 (96%) vs 528/662 (80%), p < .001). Few pharmacists reported discussing HPV vaccine with 11-26-year-old females (6/36 (17%)) and males (5/36 (14%)) at least "sometimes." Gaps in HPV vaccine knowledge among providers still exist and may influence vaccine attitudes and recommendation or discussion practices.

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BACKGROUND: Various case definitions of respiratory syncytial virus lower respiratory tract infection (RSV-LRTI) are currently proposed. We assessed the performance of 3 clinical case definitions against the World Health Organization definition recommended in 2015 (WHO 2015). METHODS: In this prospective cohort study conducted in 8 countries, 2401 children were followed up for 2 years from birth. Suspected LRTIs were detected via active and passive surveillance, followed by in-person clinical evaluation including single timepoint respiratory rate and oxygen saturation (by pulse oximetry) assessment, and nasopharyngeal sampling for RSV testing by polymerase chain reaction. Agreement between case definitions was evaluated using Cohen's κ statistics. RESULTS: Of 1652 suspected LRTIs, 227 met the WHO 2015 criteria for RSV-LRTI; 73 were classified as severe. All alternative definitions were highly concordant with the WHO 2015 definition for RSV-LRTI (κ: 0.95-1.00), but less concordant for severe RSV-LRTI (κ: 0.47-0.82). Tachypnea was present for 196/226 (86.7%) WHO 2015 RSV-LRTIs and 168/243 (69.1%) LRTI/bronchiolitis/pneumonia cases, clinically diagnosed by nonstudy physicians. Low oxygen saturation levels were observed in only 55/226 (24.3%) WHO 2015 RSV-LRTIs. CONCLUSIONS: Three case definitions for RSV-LRTI showed high concordance with the WHO 2015 definition, while agreement was lower for severe RSV-LRTI. In contrast to increased respiratory rate, low oxygen saturation was not a consistent finding in RSV-LRTIs and severe RSV-LRTIs. This study demonstrates that current definitions are highly concordant for RSV-LRTIs, but a standard definition is still needed for severe RSV-LRTI. CLINICAL TRIAL REGISTRATION: NCT01995175.

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X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.

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Community-wide vaccine uptake remains sub-optimal. Healthcare provider (HCP) vaccine recommendations influence patient vaccination; however, provider vaccine recommendation behavior is highly influenced by one's own vaccine attitudes and/or knowledge. We aim to describe vaccine knowledge, attitudes, and recommendation practices (KAP) among New York State HCPs. A survey to assess HCP KAP was developed and electronically distributed to NYS members of national medical organizations via their local chapter administrators. Descriptive statistical methods were used to define provider KAP. A total of 864 surveys were included, 500 (60%) and 336 (40%) primary and specialty care providers, respectively. Eighty-one percent (402/499) of primary care providers (PCPs) report encountering vaccine hesitant patients daily or weekly. Of the 500 PCPs who responded, only 204 (41%) stated strong agreement with confidence in their communications with vaccine hesitant patients. HCPs who correctly answered all four knowledge questions were more likely to self-report routine recommendations of standard vaccines to all patients when compared to those who correctly answered fewer questions (489/588 (83%) vs 135/241 (56%), p < .05). HCPs were more likely to routinely recommend standard vaccines to all patients if they also report initiating vaccine discussion (476/485 (98%) vs 148/344 (43%), p < .05) and reviewing and recommending vaccinations at each encounter (315/320 (98%) vs 308/508 (61%), p < .05). Vaccine hesitancy exists across healthcare specialties and provider roles. Focused interventions should include reaching all HCPs to promote vaccinations for disease prevention, tailoring messages to reduce HCP vaccine misperceptions, and increasing awareness of evidence-based office strategies known to facilitate immunizations.

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BACKGROUND: Safe and effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in young children. METHODS: We conducted a phase 1 dose-finding study and are conducting an ongoing phase 2-3 safety, immunogenicity, and efficacy trial of the BNT162b2 vaccine in healthy children 6 months to 11 years of age. We present results for children 6 months to less than 2 years of age and those 2 to 4 years of age through the data-cutoff dates (April 29, 2022, for safety and immunogenicity and June 17, 2022, for efficacy). In the phase 2-3 trial, participants were randomly assigned (in a 2:1 ratio) to receive two 3-µg doses of BNT162b2 or placebo. On the basis of preliminary immunogenicity results, a third 3-µg dose (≥8 weeks after dose 2) was administered starting in January 2022, which coincided with the emergence of the B.1.1.529 (omicron) variant. Immune responses at 1 month after doses 2 and 3 in children 6 months to less than 2 years of age and those 2 to 4 years of age were immunologically bridged to responses after dose 2 in persons 16 to 25 years of age who received 30 µg of BNT162b2 in the pivotal trial. RESULTS: During the phase 1 dose-finding study, two doses of BNT162b2 were administered 21 days apart to 16 children 6 months to less than 2 years of age (3-µg dose) and 48 children 2 to 4 years of age (3-µg or 10-µg dose). The 3-µg dose level was selected for the phase 2-3 trial; 1178 children 6 months to less than 2 years of age and 1835 children 2 to 4 years of age received BNT162b2, and 598 and 915, respectively, received placebo. Immunobridging success criteria for the geometric mean ratio and seroresponse at 1 month after dose 3 were met in both age groups. BNT162b2 reactogenicity events were mostly mild to moderate, with no grade 4 events. Low, similar incidences of fever were reported after receipt of BNT162b2 (7% among children 6 months to <2 years of age and 5% among those 2 to 4 years of age) and placebo (6 to 7% among children 6 months to <2 years of age and 4 to 5% among those 2 to 4 years of age). The observed overall vaccine efficacy against symptomatic Covid-19 in children 6 months to 4 years of age was 73.2% (95% confidence interval, 43.8 to 87.6) from 7 days after dose 3 (on the basis of 34 cases). CONCLUSIONS: A three-dose primary series of 3-µg BNT162b2 was safe, immunogenic, and efficacious in children 6 months to 4 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).

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BACKGROUND: In a phase 2b trial and the phase 3 MELODY trial, nirsevimab, an extended half-life, monoclonal antibody against respiratory syncytial virus (RSV), protected healthy infants born preterm or at full term against medically attended RSV lower respiratory tract infection (LRTI). In the MEDLEY phase 2-3 trial in infants at higher risk for severe RSV infection, nirsevimab showed a similar safety profile to that of palivizumab. The aim of the current analysis was to assess the efficacy of nirsevimab using a weight-banded dosing regimen in infants born between 29 weeks gestational age and full term. METHODS: Infants enrolled in the phase 2b and MELODY trials were randomised (2:1) to receive a single intramuscular injection of nirsevimab (infants weighing <5 kg received 50 mg; those weighing ≥5 kg received 100 mg) or placebo before the RSV season. Infants in MEDLEY were randomised (2:1) to receive one dose of nirsevimab (infants weighing <5 kg received 50 mg; those weighing ≥5 kg received 100 mg) followed by four monthly placebo doses, or five once-a-month intramuscular doses of palivizumab. We report a prespecified pooled efficacy analysis assessing the weight-banded dosing regimen proposed on the basis of the phase 2b and MELODY trials, in addition to extrapolated efficacy in infants with chronic lung disease, congenital heart disease, or extreme preterm birth (<29 weeks' gestational age) based on pharmacokinetic data from the phase 2-3 MEDLEY safety trial. For the pooled efficacy analysis, the primary endpoint was incidence of medically attended RSV LRTI through 150 days post-dose. The secondary efficacy endpoint was number of admissions to hospital for medically attended RSV LRTI. The incidence of very severe RSV LRTI was an exploratory endpoint, defined as cases of hospital admission for medically attended RSV LRTI that required supplemental oxygen or intravenous fluids. We also did a prespecified exploratory analysis of medically attended LRTI of any cause (in the investigator's judgement) and hospital admission for respiratory illness of any cause (defined as any upper respiratory tract infection or LRTI leading to hospital admission). Post hoc exploratory analyses of outpatient visits and antibiotic use were also done. Nirsevimab serum concentrations in MEDLEY were assessed using population pharmacokinetic methods and the pooled data from the phase 2b and MELODY trials. An exposure target was defined on the basis of an exposure-response analysis. To successfully demonstrate extrapolation, more than 80% of infants in MEDLEY had to achieve serum nirsevimab exposures at or above the predicted efficacious target. FINDINGS: Overall, 2350 infants (1564 in the nirsevimab group and 786 in the placebo group) in the phase 2b and MELODY trials were included in the pooled analysis. Nirsevimab showed efficacy versus placebo with respect to the primary endpoint of medically attended RSV LRTI (19 [1%] nirsevimab recipients vs 51 [6%] placebo recipients; relative risk reduction [RRR] 79·5% [95% CI 65·9-87·7]). Consistent efficacy was shown for additional endpoints of RSV LRTI hospital admission (nine [1%] nirsevimab recipients vs 21 [3%] placebo recipients; 77·3% [50·3-89·7]) and very severe RSV (five [<1%] vs 18 [2%]; 86·0% [62·5-94·8]). Nirsevimab recipients had fewer hospital admissions for any-cause respiratory illness (RRR 43·8% [18·8-61·1]), any-cause medically attended LRTI (35·4% [21·5-46·9]), LRTI outpatient visits (41·9% [25·7-54·6]), and antibiotic prescriptions (23·6% [3·8-39·3]). Among infants with chronic lung disease, congenital heart disease, or extreme preterm birth in MEDLEY, nirsevimab serum exposures were similar to those found in the pooled data; exposures were above the target in more than 80% of the overall MEDLEY trial population (94%), including infants with chronic lung disease (94%) or congenital heart disease (80%) and those born extremely preterm (94%). INTERPRETATION: A single dose of nirsevimab protected healthy infants born at term or preterm from medically attended RSV LRTI, associated hospital admission, and severe RSV. Pharmacokinetic data support efficacy extrapolation to infants with chronic lung disease, congenital heart disease, or extreme prematurity. Together, these data suggest that nirsevimab has the potential to change the landscape of infant RSV disease by reducing a major cause of infant morbidity and the consequent burden on caregivers, clinicians, and health-care providers. FUNDING: AstraZeneca and Sanofi.

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BACKGROUND: Implementation of respiratory virus prevention measures requires detailed understanding of regional epidemiology; however, data from many tropical countries are sparse. We describe etiologies of ambulatory pediatric acute respiratory tract infections (ARTI) in Ecuador immediately preceding the onset of the SARS-CoV-2 pandemic. METHODS: Children < 5 years presenting to a designated study site with an ARTI were eligible. Informed consent was obtained. Demographic and clinical data were recorded. A nasopharyngeal swab was collected, processed, and analyzed using multiplex polymerase chain reaction (PCR) for common respiratory pathogens. Rhinovirus/enterovirus positive samples were further characterized by genomic sequencing. RESULTS: A total of 820 subjects were enrolled in the study between July 2018 and March 2020. A total of 655 (80%) samples identified at least one pathogen. Rhinoviruses (44%) were most common, followed by enteroviruses (17%), parainfluenza viruses (17%), respiratory syncytial virus (RSV) (15%), and influenza viruses (13%). Enterovirus D68 was the most common enterovirus detected and was among the leading causes of bronchiolitis. Seasonal RSV and influenza virus activity were different along the coast compared with the highlands. CONCLUSIONS: Ongoing regional surveillance studies are necessary to optimize available and emerging pathogen-specific preventative measures.

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