Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia.

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.

Evaluation of BNT162b2 Covid-19 Vaccine in Children Younger than 5 Years of Age.

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.).

Etiologies of outpatient medically attended acute respiratory infections among young Ecuadorian children prior to the start of the 2020 SARS-CoV-2 pandemic.

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.

Evaluation of the BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age.

BACKGROUND: Safe, effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in children younger than 12 years of age. METHODS: A phase 1, dose-finding study and an ongoing phase 2-3 randomized trial are being conducted to investigate the safety, immunogenicity, and efficacy of two doses of the BNT162b2 vaccine administered 21 days apart in children 6 months to 11 years of age. We present results for 5-to-11-year-old children. In the phase 2-3 trial, participants were randomly assigned in a 2:1 ratio to receive two doses of either the BNT162b2 vaccine at the dose level identified during the open-label phase 1 study or placebo. Immune responses 1 month after the second dose of BNT162b2 were immunologically bridged to those in 16-to-25-year-olds from the pivotal trial of two 30-µg doses of BNT162b2. Vaccine efficacy against Covid-19 at 7 days or more after the second dose was assessed. RESULTS: During the phase 1 study, a total of 48 children 5 to 11 years of age received 10 µg, 20 µg, or 30 µg of the BNT162b2 vaccine (16 children at each dose level). On the basis of reactogenicity and immunogenicity, a dose level of 10 µg was selected for further study. In the phase 2-3 trial, a total of 2268 children were randomly assigned to receive the BNT162b2 vaccine (1517 children) or placebo (751 children). At data cutoff, the median follow-up was 2.3 months. In the 5-to-11-year-olds, as in other age groups, the BNT162b2 vaccine had a favorable safety profile. No vaccine-related serious adverse events were noted. One month after the second dose, the geometric mean ratio of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing titers in 5-to-11-year-olds to those in 16-to-25-year-olds was 1.04 (95% confidence interval [CI], 0.93 to 1.18), a ratio meeting the prespecified immunogenicity success criterion (lower bound of two-sided 95% CI, >0.67; geometric mean ratio point estimate, ≥0.8). Covid-19 with onset 7 days or more after the second dose was reported in three recipients of the BNT162b2 vaccine and in 16 placebo recipients (vaccine efficacy, 90.7%; 95% CI, 67.7 to 98.3). CONCLUSIONS: A Covid-19 vaccination regimen consisting of two 10-µg doses of BNT162b2 administered 21 days apart was found to be safe, immunogenic, and efficacious in children 5 to 11 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).

Medically Attended Outpatient Coronavirus Infections in Ecuadorean Children During the 20 Months Preceding Countrywide Lockdown Related to the SARS-CoV-2 Pandemic of 2020.

BACKGROUND: Human coronaviruses (HCoVs) cause respiratory tract infections during childhood manifesting as common colds, bronchiolitis, croup and pneumonia. In temperate geographies, HCoV activity peaks between December and March. The epidemiology and manifestations of HCoV infections have not been previously reported from Ecuador. METHODS: Children <5 years who presented with ≥2 symptoms consistent with an acute respiratory tract infection were eligible for enrollment. After obtaining informed consent, demographic data and details regarding the acute illness were recorded. Secretions collected with a nasopharyngeal swab underwent diagnostic testing using multiplex polymerase chain reaction. RESULTS: A total of 850 subjects were enrolled. A total of 677 (80%) tested positive for at least 1 pathogen, including 49 (7.2%) who tested positive for ≥1 HCoV type. HCoV-NL63 was the most frequent type detected (39%), followed by HCoV-OC43 (27%), 229E (22%) and HKU1 (12%). Nearly all subjects who tested positive for HCoV had nasal congestion or secretions (47/49; 96%). The most frequent syndromic diagnosis was common cold (41%), followed by bronchiolitis (27%). We found no association between the infecting HCoV type and subject's syndromic diagnosis (P > 0.05) or anatomic location of infection (upper vs. lower respiratory tract; P > 0.05). The 2018-2019 peak HCoV activity occurred from October to November; the 2019-2020 peak occurred from January to February. CONCLUSIONS: HCoVs were detected in ~7% of outpatient Ecuadorean children <5 years of age with symptoms of acute respiratory tract infection. The most frequently detected HCoV types, and the period of peak HCoV activity differed for the 2018-2019 and 2019-2020 seasons.