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Group B Streptococcus (GBS) beta C protein elicits protective antibodies in experimental animals, making beta C protein an attractive component of a human GBS glycoconjugate vaccine. We determined whether natural exposure to beta C protein elicits antibodies in humans. Geometric mean concentrations (in micrograms per milliliter) of beta C-specific immunoglobulin (Ig) M and IgG as determined by enzyme-linked immunosorbent assay were similar in serum from 16 colonized (0.82 and 0.76, respectively) and 48 age-matched noncolonized (0.96 and 0.74, respectively) pregnant women. Serum from 3 women with beta C GBS bacteremia had significantly higher levels of IgM (6.0) and IgG (52.9) (P=.01 and 0.01, respectively). Invasive disease but not colonization elicits beta C-specific IgM and IgG. Copyright © 2007 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

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., Competing Interests: CONFLICT OF INTEREST DISCLOSURES: Dr Domachowske has received consulting fees from Sanofi; payment or honoraria from Sanofi; and has participated in data safety monitoring boards or advisory boards for AstraZeneca. Dr Hamrén, Dr Mankad, Ms Takas, and Ms Villafana are employees and shareholders of AstraZeneca. Ms Baronio is an employee of ClinChoice Inc and was contracted to AstraZeneca at the time of this analysis. Dr Basavaraju is a former employee of AstraZeneca. Drs Koen and Pannaraj have no conflicts of interest to declare. Dr Soler-Palacin has received research grants from Astellas, CSL Behring, Gilead, Grifols, Pfizer, Pharming, and Takeda; and consulting fees from CSL Behring, Grifols, Takeda, and UCB. Dr Mori has received grants from Abbvie GK, Asahi Kasei Pharma Corporation, Ayumi Pharmaceutical Corporation, CSL Behring K. K., Chugai Pharmaceutical Co. Ltd., Japan Blood Products Organization, Nippon Kayaku Co. Ltd., and UCB Japan Co. Ltd.; consulting fees from Daiichi Sankyo Company Ltd. and Taisho Pharmaceutical Co. Ltd; and payments or honoraria from AstraZeneca K. K., MSD K. K. and Sanofi K. K.

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants demonstrate predilection for different regions of the respiratory tract. While saliva-based reverse transcription-polymerase chain reaction (RT-PCR) testing is a convenient, cost-effective alternative to nasopharyngeal swabs (NPS), few studies to date have investigated whether saliva sensitivity differs across variants of concern., Methods: SARS-CoV-2 RT-PCR was performed on paired NPS and saliva specimens collected from individuals with acute coronavirus disease 2019 (COVID-19) symptoms or exposure to a COVID-19 household contact. Viral genome sequencing of NPS specimens and Los Angeles County surveillance data were used to determine the variant of infection. Saliva sensitivity was calculated using NPS-positive RT-PCR as the reference standard. Factors contributing to the likelihood of saliva SARS-CoV-2 RT-PCR positivity were evaluated with univariate and multivariable analyses., Results: Between June 2020 and December 2022, 548 saliva samples paired with SARS-CoV-2 positive NPS samples were tested by RT-PCR. Overall, saliva sensitivity for SARS-CoV-2 detection was 61.7% (95% CI, 57.6%-65.7%). Sensitivity was highest with Delta infection (79.6%) compared to pre-Delta (58.5%) and Omicron (61.5%) (P = 0.003 and 0.01, respectively). Saliva sensitivity was higher in symptomatic individuals across all variants compared to asymptomatic cases [pre-Delta 80.6% vs 48.3% (P < 0.001), Delta 100% vs 72.5% (P = 0.03), Omicron 78.7% vs 51.2% (P < 0.001)]. Infection with Delta, symptoms, and high NPS viral load were independently associated with 2.99-, 3.45-, and 4.0-fold higher odds of SARS-CoV-2 detection by saliva-based RT-PCR (P = 0.004, <0.001, and <0.001), respectively., Conclusions: As new variants emerge, evaluating saliva-based testing approaches may be crucial to ensure effective virus detection., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Little is known about the efficacy of COVID-19 vaccines during acute lymphoblastic leukemia therapy (ALL); data for COVID-19 vaccine immune responses in pediatric leukemia remain sparse. We conducted a single center study of patients aged 5-25 years undergoing ALL chemotherapy who received COVID-19 vaccination. Twenty-one patients were enrolled; efficacy was evaluable in 20. Twenty were vaccinated while receiving chemotherapy. Twenty received the BNT162b2 mRNA vaccine. Spike reactive antibodies (S-IgG) and/or T-cells (SRT) were detected in 16 of 20 (80%) vaccinated patients; 13 (65%) and 9 (45%) were positive for S-IgG and SRT, respectively. Six (30%) showed both spike reactive B and T-cell responses. Eleven of the 13 with S-IgG positivity were negative for anti-Nucleocapsid IgG, an antibody profile consistent with a vaccine induced immune response. All 13S-IgG+ patients showed neutralizing antibodies. SRT included CD4+ (7) and CD8+ (6) T-cells; both CD4+ and CD8+ SRT were seen in 4. SRT were multifunctional (producing multiple cytokines) in most patients (8 of 9); 4 showed SRT with triple cytokine and B-cell co-stimulatory responses, indicating a multimodal adaptive immune response. Immune responses were seen among patients vaccinated in the settings of lymphopenia (6 of 12) intensive chemotherapy (3 of 4), and Peg allergy (6 of 8). Sequencing revealed public CD4+ and CD8+ TCR sequences reactive to epitopes across the spike protein. In conclusion, COVID-19 vaccination induced B and/or T-cell responses in a majority of children and young adults undergoing ALL chemotherapy., (© 2024 UICC.)

Mucosal immunity may contribute to clearing SARS-CoV-2 infection prior to systemic infection, thereby allowing hosts to remain seronegative. We describe the meaningful detection of SARS-CoV-2-specific nasal mucosal antibodies in a group of exposed-household individuals that evaded systemic infection. Between June 2020 and February 2023, nasopharyngeal swab (NPS) and acute and convalescent blood were collected from individuals exposed to a SARS-CoV-2-confirmed household member. Nasal secretory IgA (SIgA) antibodies targeting the SARS-CoV-2 spike protein were measured using a modified ELISA. Of the 36 exposed individuals without SARS-CoV-2 detected by the RT-PCR of NPS specimens and seronegative for SARS-CoV-2-specific IgG at enrollment and convalescence, 13 (36.1%) had positive SARS-CoV-2-specific SIgA levels detected in the nasal mucosa at enrollment. These individuals had significantly higher nasal SIgA (median 0.52 AU/mL) compared with never-exposed, never-infected controls (0.001 AU/mL) and infected-family participants (0.0002 AU/mL) during the acute visit, respectively (both p < 0.001). The nasal SARS-CoV-2-specific SIgA decreased rapidly over two weeks in the exposed seronegative individuals compared to a rise in SIgA in infected-family members. The nasal SARS-CoV-2-specific SIgA may have a protective role in preventing systemic infection.

Pediatric COVID-19 vaccination is effective in preventing COVID-19-related hospitalization, but duration of protection of the original monovalent vaccine during SARS-CoV-2 Omicron predominance merits evaluation, particularly given low coverage with updated COVID-19 vaccines. During December 19, 2021-October 29, 2023, the Overcoming COVID-19 Network evaluated vaccine effectiveness (VE) of ≥2 original monovalent COVID-19 mRNA vaccine doses against COVID-19-related hospitalization and critical illness among U.S. children and adolescents aged 5-18 years, using a case-control design. Too few children and adolescents received bivalent or updated monovalent vaccines to separately evaluate their effectiveness. Most case-patients (persons with a positive SARS-CoV-2 test result) were unvaccinated, despite the high frequency of reported underlying conditions associated with severe COVID-19. VE of the original monovalent vaccine against COVID-19-related hospitalizations was 52% (95% CI = 33%-66%) when the most recent dose was administered <120 days before hospitalization and 19% (95% CI = 2%-32%) if the interval was 120-364 days. VE of the original monovalent vaccine against COVID-19-related hospitalization was 31% (95% CI = 18%-43%) if the last dose was received any time within the previous year. VE against critical COVID-19-related illness, defined as receipt of noninvasive or invasive mechanical ventilation, vasoactive infusions, extracorporeal membrane oxygenation, and illness resulting in death, was 57% (95% CI = 21%-76%) when the most recent dose was received <120 days before hospitalization, 25% (95% CI = -9% to 49%) if it was received 120-364 days before hospitalization, and 38% (95% CI = 15%-55%) if the last dose was received any time within the previous year. VE was similar after excluding children and adolescents with documented immunocompromising conditions. Because of the low frequency of children who received updated COVID-19 vaccines and waning effectiveness of original monovalent doses, these data support CDC recommendations that all children and adolescents receive updated COVID-19 vaccines to protect against severe COVID-19., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Danielle M. Zerr reports institutional support from Merck and consulting fees from AlloVir. Melissa S. Stockwell reports institutional support from the National Institutes of Health (NIH). Mary Allen Staat reports institutional support from NIH, Pfizer, Cepheid, and Merck and receipt of royalties from UpToDate for chapters on adoption and immunization. Jennifer E. Schuster reports institutional support from NIH, the Food and Drug Administration, and the State of Missouri, receipt of an honorarium from the Missouri chapter of the American Academy of Pediatrics (AAP) and participation on the advisory board of the Association of American Medical Colleges and the Association for Professionals in Infection Control and Epidemiology. Adrienne G. Randolph reports institutional support from NIH, royalties for UpToDate for work as a section editor, consulting fees from Inotrem, Inc. and ThermoFisher, Inc., receipt of honoraria from St. Jude Children’s Research Center and Volition, Inc., travel support from the International Sepsis Forum, participation on a data safety monitoring board for NIH and the Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia, serving as chair (2023–2024) of the International Sepsis Forum, and receipt of equipment from Illumina, Inc. (for institutional use). Pia S. Pannaraj reports institutional support from the National Institute on Allergy and Infectious Diseases, the National Institute of Child Health and Human Development, and AstraZeneca, receipt of honoraria from IDweek and Infectious Diseases in Children Symposium, payment for expert testimony from BBV Law Firm and Helsell Fetterman Law Firm, waiver of registration fee for IDweek meeting, uncompensated participation on three data safety monitoring boards 1) Phase II, Double-Blind, Multicenter, Randomized, Placebo-Controlled Trial to Assess the Safety, Reactogenicity and Immunogenicity of One or Two Doses of Multimeric-001 (M-001) Followed by One or Two Doses of an Influenza A/H7N9 Vaccine, 2) Therapeutic Fecal Transplant on the Gut Microbiome in Children with Ulcerative Colitis, and 3) Safety of Fecal Transplant in maintenance of pediatric Crohn's disease), and uncompensated services as president of the California Immunization Coalition and the AAP Committee on Infectious Diseases. Kanokporn Mongkolrattanothai reports institutional support from Gilead. Samina S. Bhumbra reports travel support from CDC to present a plenary lecture at the Conference on Emerging Infectious Diseases. Kathleen Chiotos reports institutional support from the Agency for Healthcare Research and Quality and travel support from IDWeek (2022), Society for Healthcare Epidemiology of America (2022), and Pediatric Academic Societies (2022). Bria M. Coates reports institutional support from the National Heart, Lung, and Blood Institute and the American Lung Association, payment for expert testimony from Triplett Woolf Garretson, and participation on a Sobi Data Safety Monitoring Board. Thomas J. Connors reports grant support from NIH. Melissa L. Cullimore reports institutional support from NIH. Heidi R. Flori reports receipt of consulting fees from Lucira Health for advisory role for rapid diagnostic devices for COVID-19. Shira J. Gertz reports ownership of Pfizer stock. Ivan Gonzalez reports receipt of honoraria from the Florida Chapter of AAP for educational infection control initiatives and travel support from the Florida Chapter of AAP for regional conference attendance. Judith A. Guzman-Cottrill reports receipt of a consulting contract from the Oregon Health Authority. Natasha B. Halasa reports receipt of investigator-initiated grants from Sanofi, Quidel, and Merck. Charlotte V. Hobbs reports receipt of consulting fees from Dynamed.com and royalties as a content reviewer for UpToDate.com. Janet R. Hume reports institutional support from NIH and uncompensated participation on a data safety monitoring board for a study at the University of Minnesota (Magnesium sulfate as adjuvant analgesia and its effect on opiate use by postoperative transplant patients in the pediatric intensive care unit). Satoshi Kamidani reports institutional support from NIH, Pfizer, Moderna, Meissa, and Bavarian Nordic and receipt of honoraria from AAP. Michele Kong reports institutional support from NIH and uncompensated service on the Board of Directors for Jefferson County Department of Health, Callahan Eye Hospital, University of Alabama at Birmingham, and KultureCity. Regina M. Simeone reports payments received by her spouse from a previously managed Pfizer investment, which was sold in April 2023. No other potential conflicts of interest were disclosed.

Background and Objectives: In June 2022, the mRNA COVID-19 vaccination was recommended for young children. We examined clinical characteristics and factors associated with vaccination status among vaccine-eligible young children hospitalized for acute COVID-19., Methods: We enrolled inpatients 8 months to <5 years of age with acute community-acquired COVID-19 across 28 US pediatric hospitals from September 20, 2022 to May 31, 2023. We assessed demographic and clinical factors, including the highest level of respiratory support, and vaccination status defined as unvaccinated, incomplete, or complete primary series [at least 2 (Moderna) or 3 (Pfizer-BioNTech) mRNA vaccine doses ≥14 days before hospitalization]., Results: Among 597 children, 174 (29.1%) patients were admitted to the intensive care unit and 75 (12.6%) had a life-threatening illness, including 51 (8.5%) requiring invasive mechanical ventilation. Children with underlying respiratory and neurologic/neuromuscular conditions more frequently received higher respiratory support. Only 4.5% of children hospitalized for COVID-19 (n = 27) had completed their primary COVID-19 vaccination series and 7.0% (n = 42) of children initiated but did not complete their primary series. Among 528 unvaccinated children, nearly half (n = 251) were previously healthy, 3 of them required extracorporeal membrane oxygenation for acute COVID-19 and 1 died., Conclusions: Most young children hospitalized for acute COVID-19, including most children admitted to the intensive care unit and with life-threatening illness, had not initiated COVID-19 vaccination despite being eligible. Nearly half of these children had no underlying conditions. Of the small percentage of children who initiated a COVID-19 primary series, most had not completed it before hospitalization., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Characterization of longitudinal SARS-CoV-2-specific antibody responses in children following infection and vaccination is needed to inform SARS-CoV-2 vaccine policy decisions for children, which may differ from adults., Methods: We enrolled individuals at the time of SARS-CoV-2 infection or vaccination for longitudinal serological testing and compared SARS-CoV-2-spike-specific IgG and neutralization activity in children and adults stratified by infection and vaccination status using enzyme-linked immunosorbent and virus neutralization assays., Results: Between June 2020 and December 2022, we collected sera from 669 participants aged 40 days to 55 years, including 330 unvaccinated individuals with laboratory-confirmed SARS-CoV-2 infection, 180 vaccinated SARS-CoV-2-naïve individuals, and 159 vaccinated previously infected individuals. Half (n = 330, 49.3%) were children. SARS-CoV-2-specific IgG and neutralization activity in children < 12 years old in response to infection persisted at higher levels than those of adults through at least 6 months (spike-specific IgG levels, 2.05 [95% CI: 1.4-3.1] times higher than adults; neutralizing activity, median 88.8 vs 75.2%, respectively, p = .04). In addition, all pediatric participants had significantly higher IgG levels compared with adults at 6 months following infection or vaccination, regardless of prior infection status. Vaccine-induced SARS-CoV-2-specific IgG responses in previously infected individuals persisted at higher levels than those from infection alone at 6 months (median AUC, children 5-11 years old, 9115 vs 368; adolescents 3613 vs 475; adults 1956 vs 263, all p < .001)., Conclusions: These data demonstrate the robust and persistent immunologic response of SARS-CoV-2 vaccination in children and emphasize the benefit of vaccination after SARS-CoV-2 infection., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Infants aged <6 months are not eligible for COVID-19 vaccination. Vaccination during pregnancy has been associated with protection against infant COVID-19-related hospitalization. The Overcoming COVID-19 Network conducted a case-control study during March 9, 2022-May 31, 2023, to evaluate the effectiveness of maternal receipt of a COVID-19 vaccine dose (vaccine effectiveness [VE]) during pregnancy against COVID-19-related hospitalization in infants aged <6 months and a subset of infants aged <3 months. VE was calculated as (1 - adjusted odds ratio) x 100% among all infants aged <6 months and <3 months. Case-patients (infants hospitalized for COVID-19 outside of birth hospitalization and who had a positive SARS-CoV-2 test result) and control patients (infants hospitalized for COVID-19-like illness with a negative SARS-CoV-2 test result) were compared. Odds ratios were determined using multivariable logistic regression, comparing the odds of receipt of a maternal COVID-19 vaccine dose (completion of a 2-dose vaccination series or a third or higher dose) during pregnancy with maternal nonvaccination between case- and control patients. VE of maternal vaccination during pregnancy against COVID-19-related hospitalization was 35% (95% CI = 15%-51%) among infants aged <6 months and 54% (95% CI = 32%-68%) among infants aged <3 months. Intensive care unit admissions occurred in 23% of all case-patients, and invasive mechanical ventilation was more common among infants of unvaccinated (9%) compared with vaccinated mothers (1%) (p = 0.02). Maternal vaccination during pregnancy provides some protection against COVID-19-related hospitalizations among infants, particularly those aged <3 months. Expectant mothers should remain current with COVID-19 vaccination to protect themselves and their infants from hospitalization and severe outcomes associated with COVID-19., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Regina M. Simeone reports payments received by her spouse from a previously managed Pfizer investment, which was sold in April 2023. Natasha Halasa reports grant support from Sanofi, Quidel, and Merck, and testing and vaccine donation for Sanofi; and an education grant for delivering a lecture. Satoshi Kamidani reports institutional support from the National Institutes of Health (NIH), Pfizer, Meissa, and Emergent BioSolutions; and honoraria from the American Academy of Pediatrics (AAP). Pia S. Pannaraj reports institutional support from AstraZeneca and NIH, payment for expert testimony, and unpaid service on the AAP’s Committee on Infectious Diseases and the California Immunization Coalition. Aline B. Maddux reports support from the International Severe Acute Respiratory and Emerging Infections Consortium for conference attendance. Charlotte V. Hobbs reports receipt of consulting fees from Dynamed.com for review of a clinical database and honoraria from bioMérieux for speaking at Biofire (bioMérieux) 2022. Julie A. Boom reports receipt of royalties from UpToDate, Inc. for chapter authorship. Michele Kong reports institutional support from NIH and KultureCity board membership. Jennifer E. Schuster reports institutional support from NIH and the Food and Drug Administration, consulting fees from the Association for Professionals in Infection Control and Epidemiology and the Association of American Medical Colleges, and honoraria from the Missouri American Academy of Pediatrics. Janet R. Hume reports institutional support from the National Institute of Child Health and Human Development and NIH, consulting fees from Entegrion, and uncompensated service on a data safety managing board for an institutional study at the University of Minnesota. Mary A. Staat reports institutional support from NIH, Merck, and Cepheid, and royalties from UpToDate, Inc. for unrelated subject matter. Emily R. Levy reports institutional support from the National Institute on Allergy and Infectious Diseases and consulting fees from the Health Resources and Service Administration Regional Pediatric Pandemic Network. Heidi R. Flori reports consulting fees from NOTA Laboratories and Lucira Health, unrelated to the current work; housing compensation from the Society of Critical Care Medicine for participation in the Pediatric Surviving Sepsis Campaign; and unfunded participation on a data safety monitory board for normoxia in cardiothoracic surgery and cyclodextrin in Niemann-Pick disease. Adrienne G. Randolph reports grant support from NIH for work related to COVID-19, royalties from UpToDate, Inc. for work as the Pediatric Critical Care Medicine section editor; honoraria from grand rounds presentations on multisystem inflammatory syndrome in children and sepsis; meeting attendance support from the International Sepsis Forum, participation on a data safety monitoring board for the NIH Grace Study; chair of the Families Fighting Flu International Sepsis Forum medical advisory board; and receipt of reagents from Illumina, Inc. No other potential conflicts of interest were disclosed.

Importance: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections (LRTIs) and infant hospitalization worldwide., Objective: To evaluate the characteristics and outcomes of RSV-related critical illness in US infants during peak 2022 RSV transmission., Design, Setting, and Participants: This cross-sectional study used a public health prospective surveillance registry in 39 pediatric hospitals across 27 US states. Participants were infants admitted for 24 or more hours between October 17 and December 16, 2022, to a unit providing intensive care due to laboratory-confirmed RSV infection., Exposure: Respiratory syncytial virus., Main Outcomes and Measures: Data were captured on demographics, clinical characteristics, signs and symptoms, laboratory values, severity measures, and clinical outcomes, including receipt of noninvasive respiratory support, invasive mechanical ventilation, vasopressors or extracorporeal membrane oxygenation, and death. Mixed-effects multivariable log-binomial regression models were used to assess associations between intubation status and demographic factors, gestational age, and underlying conditions, including hospital as a random effect to account for between-site heterogeneity., Results: The first 15 to 20 consecutive eligible infants from each site were included for a target sample size of 600. Among the 600 infants, the median (IQR) age was 2.6 (1.4-6.0) months; 361 (60.2%) were male, 169 (28.9%) were born prematurely, and 487 (81.2%) had no underlying medical conditions. Primary reasons for admission included LRTI (594 infants [99.0%]) and apnea or bradycardia (77 infants [12.8%]). Overall, 143 infants (23.8%) received invasive mechanical ventilation (median [IQR], 6.0 [4.0-10.0] days). The highest level of respiratory support for nonintubated infants was high-flow nasal cannula (243 infants [40.5%]), followed by bilevel positive airway pressure (150 infants [25.0%]) and continuous positive airway pressure (52 infants [8.7%]). Infants younger than 3 months, those born prematurely (gestational age <37 weeks), or those publicly insured were at higher risk for intubation. Four infants (0.7%) received extracorporeal membrane oxygenation, and 2 died. The median (IQR) length of hospitalization for survivors was 5 (4-10) days., Conclusions and Relevance: In this cross-sectional study, most US infants who required intensive care for RSV LRTIs were young, healthy, and born at term. These findings highlight the need for RSV preventive interventions targeting all infants to reduce the burden of severe RSV illness.

Protocols for the isolation of peripheral blood mononuclear cells (PBMCs) from whole blood vary greatly between laboratories, especially in published studies of SARS-CoV-2-specific T cell responses following infection and vaccination. Research on the effects of different wash media types or centrifugation speeds and brake usage during the PBMC isolation process on downstream T cell activation and functionality is limited. Blood samples from 26 COVID-19-vaccinated participants were processed with different PBMC isolation methods using either PBS or RPMI as the wash media with high centrifugation speed and brakes or RPMI as the wash media with low speed and brakes (RPMI+ method). SARS-CoV-2 spike-specific T cells were quantified and characterized via a flow cytometry-based activation induced markers (AIM) assay and an interferon-γ (IFNγ) FluoroSpot assay and responses were compared between processing methods. Samples washed with RPMI showed higher AIM + CD4 T cell responses than those washed with PBS and showed a shift away from naïve and towards an effector memory phenotype. The activation marker OX40 showed higher SARS-CoV-2 spike-induced upregulation on RPMI-washed CD4 T cells, while differences in CD137 upregulation were minimal between processing methods. The magnitude of the AIM + CD8 T cell response was similar between processing methods but showed higher stimulation indices. Background frequencies of CD69 + CD8 T cells were increased in PBS-washed samples and were associated with higher baseline numbers of IFNγ-producing cells in the FluoroSpot assay. Slower braking in the RPMI+ method did not improve detection of SARS-CoV-2-specific T cells and caused longer processing times. Thus, the use of RPMI media with full centrifugation brakes during the wash steps of PBMC isolation was found to be most effective and efficient. Further studies are needed to elucidate the pathways involved in RPMI-mediated preservation of downstream T cell activity., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: In a 2020 pilot case-control study using medical records, we reported that non-Hispanic Black children were more likely to develop multisystem inflammatory syndrome in children (MIS-C) after adjustment for sociodemographic factors and underlying medical conditions. Using structured interviews, we investigated patient, household, and community factors underlying MIS-C likelihood., Methods: MIS-C case patients hospitalized in 2021 across 14 US pediatric hospitals were matched by age and site to outpatient controls testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 3 months of the admission date. Caregiver interviews queried race/ethnicity, medical history, and household and potential community exposures 1 month before MIS-C hospitalization (case-patients) or after SARS-CoV-2 infection (controls). We calculated adjusted odds ratios (aOR) using mixed-effects multivariable logistic regression., Results: Among 275 case patients and 496 controls, race/ethnicity, social vulnerability and patient or family history of autoimmune/rheumatologic disease were not associated with MIS-C. In previously healthy children, MIS-C was associated with a history of hospitalization for an infection [aOR: 4.8; 95% confidence interval (CI): 2.1-11.0]. Household crowding (aOR: 1.7; 95% CI: 1.2-2.6), large event attendance (aOR: 1.7; 95% CI: 1.3-2.1), school attendance with limited masking (aOR: 2.6; 95% CI: 1.1-6.6), public transit use (aOR: 1.8; 95% CI: 1.4-2.4) and co-resident testing positive for SARS-CoV-2 (aOR: 2.2; 95% CI: 1.3-3.7) were associated with increased MIS-C likelihood, with risk increasing with the number of these factors., Conclusions: From caregiver interviews, we clarify household and community exposures associated with MIS-C; however, we did not confirm prior associations between sociodemographic factors and MIS-C., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Extracorporeal membrane oxygenation (ECMO) has been used successfully to support adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related cardiac or respiratory failure refractory to conventional therapies. Comprehensive reports of children and adolescents with SARS-CoV-2-related ECMO support for conditions, including multisystem inflammatory syndrome in children (MIS-C) and acute COVID-19, are needed., Design: Case series of patients from the Overcoming COVID-19 public health surveillance registry., Setting: Sixty-three hospitals in 32 U.S. states reporting to the registry between March 15, 2020, and December 31, 2021., Patients: Patients less than 21 years admitted to the ICU meeting Centers for Disease Control criteria for MIS-C or acute COVID-19., Interventions: None., Measurements and Main Results: The final cohort included 2,733 patients with MIS-C ( n = 1,530; 37 [2.4%] requiring ECMO) or acute COVID-19 ( n = 1,203; 71 [5.9%] requiring ECMO). ECMO patients in both groups were older than those without ECMO support (MIS-C median 15.4 vs 9.9 yr; acute COVID-19 median 15.3 vs 13.6 yr). The body mass index percentile was similar in the MIS-C ECMO versus no ECMO groups (89.9 vs 85.8; p = 0.22) but higher in the COVID-19 ECMO versus no ECMO groups (98.3 vs 96.5; p = 0.03). Patients on ECMO with MIS-C versus COVID-19 were supported more often with venoarterial ECMO (92% vs 41%) for primary cardiac indications (87% vs 23%), had ECMO initiated earlier (median 1 vs 5 d from hospitalization), shorter ECMO courses (median 3.9 vs 14 d), shorter hospital length of stay (median 20 vs 52 d), lower in-hospital mortality (27% vs 37%), and less major morbidity at discharge in survivors (new tracheostomy, oxygen or mechanical ventilation need or neurologic deficit; 0% vs 11%, 0% vs 20%, and 8% vs 15%, respectively). Most patients with MIS-C requiring ECMO support (87%) were admitted during the pre-Delta (variant B.1.617.2) period, while most patients with acute COVID-19 requiring ECMO support (70%) were admitted during the Delta variant period., Conclusions: ECMO support for SARS-CoV-2-related critical illness was uncommon, but type, initiation, and duration of ECMO use in MIS-C and acute COVID-19 were markedly different. Like pre-pandemic pediatric ECMO cohorts, most patients survived to hospital discharge., Competing Interests: Dr. Bembea’s institution received funding from the National Institute of Neurological Disorders and Stroke (R01NS106292) and Grifols Investigator Sponsored Research Grant. Drs. Bembea, Heidemann, Zinter, and Randolph received support for article research from the National Institutes of Health (NIH). Dr. Thiagarjan’s institution received funding from the U.S. Department of Defense (Peer Reviewed Medical Research Project Clinical Trial Award No. W81XWH2210301 Trial of Indication-based Transfusion of Red blood cells in Extracorporeal Membrane Oxygenation); he received funding from Society of Critical Care Medicine and the Extracorporeal Life Support Organization. Drs. Young’s, McCadden’s, Newhams’s, Kucuak’s, Mack’s, Fitzgerald’s, Rowan’s, Maddux’s, Kolmar’s, Heidemann’s, Schwartz’s, Kong’s, Crandall’s, Singh’s, Schuster’s, Hall’s, Wellnitz’s, Maamari’s, Gaspers’s, Nofziger’s, Cullimore’s, Halasa’s, McLaughlin’s, Pannaraj’s, Cvijanovich’s, Coates’s, Horwitz’s, Hobbs’s, Dapul’s, and Randolph’s institutions received funding from the U.S. Centers for Disease Control and Prevention (CDC). Dr. McCadden disclosed work for hire. Dr. Newhams’ institution received funding from the National Institute of Allergy and Infectious Diseases. Drs. Fitzgerald’s, Kong’s, Cullimore’s, Cvijanovich’s, and Randolph’s institutions received funding from the NIH. Dr. Rowan’s institution received funding from the National Heart, Lung, and Blood Institute (NHLBI) (K23HL150244). Dr. Maddux’s institution received funding from the National Institute of Child Health and Human Development (K23HD096018). Drs. Irby, Crandall, Singh, Wellnitz, Nofziger, Bradford, McLaughlin, Coates, Hobbs, and Zambrano received support for article research from the CDC. Dr. Schuster’s institution received funding from Merck. Dr. Hall received funding from Abbvie, Kiadis, and the American Board of Pediatrics. Dr. Wellnitz’s institution received funding from the University of Pennsylvania (prime sponsor NIH) and the University of Nebraska (prime sponsor Administration for Strategic Preparedness and Response). Dr. Gaspers received funding from Abbott Laboratories. Dr. Munoz’s institution received funding from Boston’s Children’s Hospital; he received funding from the University of Texas Health Science Center at Houston. Dr. Halasa’s institution received funding from Sanofi. Dr. McLaughlin received funding from expert witness fees from two entities. Dr. Pannaraj’s institution received funding from AstraZeneca and Pfizer. Dr. Coates’ institution received funding from the NHLBI and the American Lung Association; she received funding from Sobi. Drs. Hobbs and Randolph received funding from UpToDate. Dr. Hobbs received funding from Dynamed.com; she disclosed that she was a speaker for Biomerieux 2021–2022. Drs. Zambrano and Campbell disclosed government work. Dr. Randolph had full access to all the data in the investigation and takes responsibility for the integrity of the data and the accuracy of the data analysis. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Pregnancy poses a greater risk for severe COVID-19; however, underlying immunological changes associated with SARS-CoV-2 during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in unvaccinated pregnant and nonpregnant women with acute and convalescent COVID-19, quantifying 217 immunological parameters. Humoral responses to SARS-CoV-2 were similar in pregnant and nonpregnant women, although our systems serology approach revealed distinct antibody and FcγR profiles between pregnant and nonpregnant women. Cellular analyses demonstrated marked differences in NK cell and unconventional T cell activation dynamics in pregnant women. Healthy pregnant women displayed preactivated NK cells and γδ T cells when compared with healthy nonpregnant women, which remained unchanged during acute and convalescent COVID-19. Conversely, nonpregnant women had prototypical activation of NK and γδ T cells. Activation of CD4+ and CD8+ T cells and T follicular helper cells was similar in SARS-CoV-2-infected pregnant and nonpregnant women, while antibody-secreting B cells were increased in pregnant women during acute COVID-19. Elevated levels of IL-8, IL-10, and IL-18 were found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, we demonstrate perturbations in NK cell and γδ T cell activation in unvaccinated pregnant women with COVID-19, which may impact disease progression and severity during pregnancy.

Background: Pfizer-BioNTech COVID-19 vaccine received emergency use authorization for persons ≥ 16 years in December 2020 and for adolescents 12-15 years in May 2021. Despite the clear benefits and favorable safety profile, vaccine uptake in adolescents has been suboptimal. We sought to assess factors associated with COVID-19 non-vaccination in adolescents 12-18 years of age., Methods: Between June 1, 2021 and April 29, 2022, we assessed factors associated with COVID-19 non-vaccination in hospitalized adolescents ages 12-18 years enrolled in the Overcoming COVID-19 vaccine effectiveness network. Demographic characteristics and clinical information were captured through parent interviews and/or electronic medical record abstraction; COVID-19 vaccination was assessed through documented sources. We assessed associations between receipt of the COVID-19 vaccine and demographic and clinical factors using univariate and multivariable logistic regression and estimated adjusted odds ratios (aOR) for each factor associated with non-vaccination., Results: Among 1665 hospitalized adolescents without COVID-19, 56% were unvaccinated. Unvaccinated adolescents were younger (median age 15.1 years vs. 15.4 years, p < .01) and resided in areas with higher social vulnerability index (SVI) scores (median 0.6 vs 0.5, p < .001) than vaccinated adolescents. Residence in the Midwest [aOR 2.60 (95% CI: 1.80, 3.79)] or South [aOR 2.49 (95% CI: 1.77, 3.54)] US census regions, rarely or never receiving influenza vaccine [aOR 5.31 (95% CI: 3.81, 7.47)], and rarely or never taking precautions against COVID-19 [aOR 3.17 (95% CI: 1.94, 5.31)] were associated with non-vaccination against COVID-19., Conclusions: Efforts to increase COVID-19 vaccination of adolescents should focus on persons with geographic, socioeconomic, and medical risk factors associated with non-vaccination., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Multisystem inflammatory syndrome in children (MIS-C), linked to antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with considerable morbidity. Prevention of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) by vaccination might also decrease MIS-C likelihood., Methods: In a multicenter, case-control, public health investigation of children ages 5-18 years hospitalized from 1 July 2021 to 7 April 2022, we compared the odds of being fully vaccinated (2 doses of BNT162b2 vaccine ≥28 days before hospital admission) between MIS-C case-patients and hospital-based controls who tested negative for SARS-CoV-2. These associations were examined by age group, timing of vaccination, and periods of Delta and Omicron variant predominance using multivariable logistic regression., Results: We compared 304 MIS-C case-patients (280 [92%] unvaccinated) with 502 controls (346 [69%] unvaccinated). MIS-C was associated with decreased likelihood of vaccination (adjusted OR [aOR]: .16; 95% CI: .10-.26), including among children ages 5-11 years (aOR: .22; 95% CI: .10-.52), ages 12-18 years (aOR: .10; 95% CI: .05-.19), and during the Delta (aOR: .06; 95% CI: .02-.15) and Omicron (aOR: .22; 95% CI: .11-.42) variant-predominant periods. This association persisted beyond 120 days after the second dose (aOR: .08; 95% CI: .03-.22) in 12-18-year-olds. Among all MIS-C case-patients, 187 (62%) required intensive care unit admission and 280 (92%) vaccine-eligible case-patients were unvaccinated., Conclusions: Vaccination with 2 doses of BNT162b2 is associated with reduced likelihood of MIS-C in children ages 5-18 years. Most vaccine-eligible hospitalized patients with MIS-C were unvaccinated., Competing Interests: Potential conflicts of interest. J. E. S. reports institutional support from Merck for an RSV research study, unrelated to the current work. A. G. R. reports institutional support from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); royalties from UpToDate as the Pediatric Critical Care Section Editor; and participation on a data safety monitoring board (DSMB) for a National Institute of Child Health and Human Development (NICHD)–funded study. P. S. P. reports institutional support from AstraZeneca and Pfizer, consulting fees from Sanofi-Pasteur and Seqirus, payment from law firms for expert testimony, participation on a Division of Microbiology and Infectious Diseases DSMB (paid to author), and an unpaid leadership role in the California Immunization Coalition. R. A. N. reports institutional support from NIH for participation in a multicenter influenza study. S. K. reports institutional support from NIH and Pfizer. C. V. H. reports consulting fees from Dynamed (clinical database, reviewer) and honoraria from Biofire/Biomerieux, and funding from CDC to the University of Mississippi Medical Center. N. B. H. reports grants from Sanofi and Quidel and an educational grant from Genentech. N. Z. C. reports a speaker’s registration discount at the Society of Critical Care Medicine meeting and grants or contracts from the NIH, unrelated to this work and paid to their institution. S. S. B. reports receipt of an NIH, NIAID training grant during 1 September 2019–31 August 2020 (T32AI007637). M. L. C. reports grants or contracts unrelated to this work from the CDC, paid to their institution. H. R. F. reports grants or contracts unrelated to this work from the National Heart, Lung, and Blood Institute (NHLBI) and NICHD, paid to their institution; support for attending meetings and/or travel from the Society of Critical Care Medicine; participation on a DSMB for a cardiothoracic surgery trial—single center—and for intrathecal chemotherapy trial; an unpaid leadership or fiduciary role on the Michigan Thoracic Society Executive Committee and PALISI Network Executive Committee; other financial or nonfinancial interests in the Lucira Health advisory committee and Aerogen Pharma—advisor—unfunded. J. R. H. reports grants or contracts unrelated to this work from the NICHD, paid to their institution; participation on a DSMB for institutional study at the University of Minnesota, “Magnesium sulfate as adjuvant analgesia and its effect on opiate use by post-operative transplant patients in the pediatric ICU” (Magnesium sulfate as Investigational New Drug [IND] per the Food and Drug Administration [FDA]; no financial reimbursements). E. R. L. reports the following grants or contracts unrelated to this work and paid to their institution—AI 144301-01: An Observational Cohort Study to Determine Late Outcomes and Immunological Responses after Infection with SARS-CoV-2 in Children with and without MIS-C; and NIH AI 154470-01: Immunobiology of Influenza Virus-related Critical Illness in Young Hosts. E. H. M. reports an unpaid role as Vice President of the South Carolina Chapter of the American Academy of Pediatrics. L. S. reports conference attendance allowance from Medical University of South Carolina. Matthew Zinter reports the following grant or contract unrelated to this work: NHLBI K23HL146936. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Introduction: The balance of risks and benefits of COVID-19 vaccination in children is more complex than in adults with limited paediatric data resulting in no global consensus on whether all healthy children should be vaccinated. We sought to assess the safety, efficacy, and effectiveness of childhood vaccination against SARS-CoV-2, as well as better understanding perceptions of vaccination in parents and vaccine experts. Methods: We performed a literature review for COVID-19 vaccine safety, efficacy, effectiveness, and perceptions. We searched international safety databases for safety data and developed an electronic survey to elicit country-specific COVID-19 immunisation data, including vaccine regulations, policies, rates, and public attitudes solicited from vaccine experts. Results: Nine studies were included in the final safety analysis. Local reactions were frequently reported across all studies and vaccine types. Adverse events reported to surveillance systems tended to be non-serious, and commonly included injection site reactions and dizziness. Twenty-three studies reported immunogenicity, efficacy, and effectiveness data. There were nine randomised control trials of six different vaccine types, which showed seroconversion of neutralising antibodies in vaccinated children ranging from 88% to 100%. The vaccine efficacy for Pfizer and Moderna vaccines ranged from 88% to 100%. There were 118 survey responses representing 55 different countries. Reported vaccination rates ranged from <1% to 98%. Most respondents described “mixed opinions” regarding paediatric vaccination policies in their country. By region, a more positive public attitude towards vaccination correlated with higher vaccination rates. Discussion: In this mixed-methods review, we have found evidence that vaccination against COVID-19 in children is safe, efficacious, and effective. Overall, the combined evidence from both the literature review and survey highlights the need for further data on both the safety and effectiveness of COVID-19 vaccinations in children.

Pediatric oncology patients are at risk for poor outcomes with respiratory viral infections. Outcome data for COVID-19 in children and young adults with cancer are needed; data are sparse for obese/overweight and adolescent and young adult subgroups. We conducted a single center cohort study of COVID-19 outcomes in patients younger than 25 years with cancer. Candidate hospitalization risk factors were analyzed via univariable and multivariable analyses. Eighty-seven patients with cancer and COVID-19 were identified. Most were Hispanic/Latinx (n = 63, 72%). Forty-two (48%) were overweight/obese. Anticancer therapy included chemotherapy only (n = 64, 74%), chimeric antigen receptor T-cells (CAR-T, n = 7), hematopoietic stem cell transplantation (HSCT, n = 12), or CAR-T and HSCT (n = 4). There was no COVID-19 related mortality. Twenty-six patients (30%) required COVID-19 related hospitalization; 4 required multiple hospitalizations. Nine (10%) had severe/critical infection; 6 needed intensive care. COVID-19 resulted in anticancer therapy delays in 22 (34%) of 64 patients on active therapy (median delay = 14 days). Factors associated with hospitalization included steroids within 2 weeks prior to infection, lymphopenia, previous significant non-COVID infection, and low COVID-19 PCR cycle threshold value. CAR-T recipients with B-cell aplasia tended to have severe/critical infection (3 of 7 patients). A COVID-19 antibody response was detected in 14 of 32 patients (44%). A substantial proportion of COVID-19 infected children and young adults with cancer require inpatient management; morbidity may be high in B-cell immunodeficiency. However, a majority of patients can be taken through chemotherapy without prolonged therapy delays. Viral load is a potential outcome predictor in COVID-19 in pediatric cancer., (© 2022 UICC.)

Background: COVID-19 vaccinations are now recommended in the United States (U.S.) for children ≥ 6 months old. However, pediatric vaccination rates remain low, particularly in the Hispanic/Latinx population., Objective: Using the 4C vaccine hesitancy framework (calculation, complacency, confidence, convenience), we examined parental attitudes in the emergency department (ED) towards COVID-19 vaccination, identified dimensions of parental vaccine hesitancy, and assessed parental willingness to have their child receive the COVID-19 vaccine., Methods: As part of a larger multi-methods study examining influenza vaccine hesitancy, we conducted interviews that included questions about COVID-19 vaccine authorization for children. We used directed content analysis to extract qualitative themes from 3 groups of parents in the ED: Hispanic/Latinx Spanish speaking (HS), Hispanic/Latinx English speaking (HE), non-Hispanic/non-Latinx White English speaking (WE). Themes were triangulated with the Parent Attitudes about Childhood Vaccines (PACV) survey, where higher scores indicate increased vaccine hesitancy., Results: Factors influencing vaccine hesitancy were mapped to the 4C framework from 58 sets of interviews and PACVs. HE and HS parents, compared to WE parents, had less knowledge about COVID-19 and its vaccine, and more beliefs in COVID-19 vaccine myths. However, both HS and HE parent groups were more inclined to endorse COVID-19 vaccine effectiveness as a reason to have their children vaccinated. HS parents felt that COVID-19 increased their fear of illnesses in general and were worried about confusing COVID-19 with other infections. Median PACV scores of HS (Mdn = 20) and HE (Mdn = 20) parent groups were higher than of WE parents (Mdn = 10), but parental willingness to have their child receive COVID-19 vaccination was similar across groups., Conclusions: Higher COVID-19 vaccine hesitancy among HS and HE parents compared to WE parents may be attributed to insufficient knowledge about COVID-19, its vaccine, along with COVID-19 vaccine myths. Efforts to provide targeted vaccine education to different populations is warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Measures to limit SARS-CoV-2 transmission in 2020 reduced other viral infections. Among 7 US children's hospitals, invasive pneumococcal disease cumulative incidence decreased by 46% in 2020 vs 2017-2019. Limited droplet transmission of pneumococci and preceding viral pathogens may be responsible., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Infants younger than 6 months of age are at high risk for complications of coronavirus disease 2019 (Covid-19) and are not eligible for vaccination. Transplacental transfer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after maternal Covid-19 vaccination may confer protection against Covid-19 in infants., Methods: We used a case-control test-negative design to assess the effectiveness of maternal vaccination during pregnancy against hospitalization for Covid-19 among infants younger than 6 months of age. Between July 1, 2021, and March 8, 2022, we enrolled infants hospitalized for Covid-19 (case infants) and infants hospitalized without Covid-19 (control infants) at 30 hospitals in 22 states. We estimated vaccine effectiveness by comparing the odds of full maternal vaccination (two doses of mRNA vaccine) among case infants and control infants during circulation of the B.1.617.2 (delta) variant (July 1, 2021, to December 18, 2021) and the B.1.1.259 (omicron) variant (December 19, 2021, to March 8, 2022)., Results: A total of 537 case infants (181 of whom had been admitted to a hospital during the delta period and 356 during the omicron period; median age, 2 months) and 512 control infants were enrolled and included in the analyses; 16% of the case infants and 29% of the control infants had been born to mothers who had been fully vaccinated against Covid-19 during pregnancy. Among the case infants, 113 (21%) received intensive care (64 [12%] received mechanical ventilation or vasoactive infusions). Two case infants died from Covid-19; neither infant's mother had been vaccinated during pregnancy. The effectiveness of maternal vaccination against hospitalization for Covid-19 among infants was 52% (95% confidence interval [CI], 33 to 65) overall, 80% (95% CI, 60 to 90) during the delta period, and 38% (95% CI, 8 to 58) during the omicron period. Effectiveness was 69% (95% CI, 50 to 80) when maternal vaccination occurred after 20 weeks of pregnancy and 38% (95% CI, 3 to 60) during the first 20 weeks of pregnancy., Conclusions: Maternal vaccination with two doses of mRNA vaccine was associated with a reduced risk of hospitalization for Covid-19, including for critical illness, among infants younger than 6 months of age. (Funded by the Centers for Disease Control and Prevention.)., (Copyright © 2022 Massachusetts Medical Society.)

As the establishment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory in children remains largely unexplored, we recruited convalescent COVID-19 children and adults to define their circulating memory SARS-CoV-2-specific CD4 + and CD8 + T cells prior to vaccination. We analyzed epitope-specific T cells directly ex vivo using seven HLA class I and class II tetramers presenting SARS-CoV-2 epitopes, together with Spike-specific B cells. Unvaccinated children who seroconverted had comparable Spike-specific but lower ORF1a- and N-specific memory T cell responses compared with adults. This agreed with our TCR sequencing data showing reduced clonal expansion in children. A strong stem cell memory phenotype and common T cell receptor motifs were detected within tetramer-specific T cells in seroconverted children. Conversely, children who did not seroconvert had tetramer-specific T cells of predominantly naive phenotypes and diverse TCRαβ repertoires. Our study demonstrates the generation of SARS-CoV-2-specific T cell memory with common TCRαβ motifs in unvaccinated seroconverted children after their first virus encounter., Competing Interests: Declaration of interests SARS-CoV-2 serological assays (US Provisional Application #62/994252, 63/018457, 63/020503, and 63/024436) and NDV-based SARS-CoV-2 vaccines (US Provisional Application #63/251020) list F.K. as a co-inventor. F.A. is also a co-inventor of the serological assay patents. Patent applications were submitted by the Icahn School of Medicine at Mount Sinai. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2. F.K. has consulted for Merck and Pfizer (before 2020) and is currently consulting for Pfizer, Third Rock Ventures, Seqirus, and Avimex. F.K. laboratory collaborates with Pfizer on the animal models of SARS-CoV-2. P.G.T. is on the SAB of Immunoscape and Cytoagents, has consulted for JNJ, received travel support and/or honoraria from Illumina, 10X Genomics, and has patents on TCR discovery and expression. P.S.P. received research grants from Astra Zeneca and Pfizer and has served on advisory boards for Sanofi Pasteur and Seqirus., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Infants remain at high risk for severe coronavirus disease 2019 (COVID-19). Human milk contains high levels of protective SARS CoV-2 specific antibodies post-infection and primary vaccine series, but levels decline over time. We hypothesized that the COVID-19 booster vaccine augment antibody production and the protection afforded to human milk-fed infants. We prospectively enrolled pregnant or lactating mothers planning to receive COVID-19 vaccination. We measured human milk IgG, IgA, and IgM antibodies targeting the SARS CoV-2 receptor binding domain within the spike protein and human milk neutralization activity against SARS CoV-2 in 10 lactating mothers from pre-COVID-19 primary series vaccine to post-booster dose. Human milk SARS CoV-2 specific IgG increased significantly from pre- to post-booster levels (median OD 0.33 vs. 2.02, P = 0.002). The IgG levels post-booster were even higher than the peak level after the primary series (2.02 vs. 0.95, P = 0.03). The increase in SARS CoV-2 specific IgA levels was not significant (0.10 vs. 0.33, P = 0.23). There was a strong correlation between paired maternal blood and milk IgG and IgA levels (IgG rho 0.52, P < 0.001, IgA rho 0.31, P = 0.05). Post-booster neutralizing activity was elevated compared to pre-booster levels (66% vs. 12% inhibition, P = 0.002). COVID-19 vaccine booster elicits SARS CoV-2 specific antibodies in human milk at higher levels compared to the initial primary series. This finding suggests that three doses of COVID-19 mRNA vaccination leads to improved mucosal response in human milk and reinforces current guidance recommending all pregnant or lactating mothers receive full COVID-19 vaccine courses with a booster dose., Competing Interests: PP has received research funding from AstraZeneca and Pfizer for unrelated studies, consultant fees from Sanofi-Pasteur and Seqirus, and speaker fees from Nestle Nutrition Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bender, Lee, Cheng, Marentes Ruiz and Pannaraj.)

Longitudinal data comparing SARS-CoV-2 serology in individuals following infection and vaccination over 12 months are limited. This study compared the magnitude, decay, and variability in serum IgG, IgA, and neutralizing activity induced by natural infection ( n = 218) or mRNA vaccination in SARS-CoV-2 naïve ( n = 143) or experienced ( n = 122) individuals over time using enzyme-linked immunosorbent assays and an in vitro virus neutralization assay. Serological responses were found to be highly variable after natural infection compared with vaccination but durable through 12 months. Antibody levels in vaccinated, SARS-CoV-2 naïve individuals peaked by 1 month then declined through 9 months, culminating in non-detectable SARS-CoV-2-specific serum IgA. Individuals with both infection and vaccination showed SARS-CoV-2-specific IgG and IgA levels that were more robust and slower to decline than the other groups; neutralizing activity remained highest in this group at 9 months past vaccination. These data reinforce the benefit of vaccination after SARS-CoV-2 recovery.

Background: Spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant, which led to increased U.S. hospitalizations for coronavirus disease 2019 (Covid-19), generated concern about immune evasion and the duration of protection from vaccines in children and adolescents., Methods: Using a case-control, test-negative design, we assessed vaccine effectiveness against laboratory-confirmed Covid-19 leading to hospitalization and against critical Covid-19 (i.e., leading to receipt of life support or to death). From July 1, 2021, to February 17, 2022, we enrolled case patients with Covid-19 and controls without Covid-19 at 31 hospitals in 23 states. We estimated vaccine effectiveness by comparing the odds of antecedent full vaccination (two doses of BNT162b2 messenger RNA vaccine) at least 14 days before illness among case patients and controls, according to time since vaccination for patients 12 to 18 years of age and in periods coinciding with circulation of B.1.617.2 (delta) (July 1, 2021, to December 18, 2021) and omicron (December 19, 2021, to February 17, 2022) among patients 5 to 11 and 12 to 18 years of age., Results: We enrolled 1185 case patients (1043 [88%] of whom were unvaccinated, 291 [25%] of whom received life support, and 14 of whom died) and 1627 controls. During the delta-predominant period, vaccine effectiveness against hospitalization for Covid-19 among adolescents 12 to 18 years of age was 93% (95% confidence interval [CI], 89 to 95) 2 to 22 weeks after vaccination and was 92% (95% CI, 80 to 97) at 23 to 44 weeks. Among adolescents 12 to 18 years of age (median interval since vaccination, 162 days) during the omicron-predominant period, vaccine effectiveness was 40% (95% CI, 9 to 60) against hospitalization for Covid-19, 79% (95% CI, 51 to 91) against critical Covid-19, and 20% (95% CI, -25 to 49) against noncritical Covid-19. During the omicron period, vaccine effectiveness against hospitalization among children 5 to 11 years of age was 68% (95% CI, 42 to 82; median interval since vaccination, 34 days)., Conclusions: BNT162b2 vaccination reduced the risk of omicron-associated hospitalization by two thirds among children 5 to 11 years of age. Although two doses provided lower protection against omicron-associated hospitalization than against delta-associated hospitalization among adolescents 12 to 18 years of age, vaccination prevented critical illness caused by either variant. (Funded by the Centers for Disease Control and Prevention.)., (Copyright © 2022 Massachusetts Medical Society.)

Breastfeeding protects against mucosal infections in infants. The underlying mechanisms through which immunity develops in human milk following maternal infection with mucosal pathogens are not well understood. We simulated nasal mucosal influenza infection through live attenuated influenza vaccination (LAIV) and compared immune responses in milk to inactivated influenza vaccination (IIV). Transcriptomic analysis was performed on RNA extracted from human milk cells to evaluate differentially expressed genes and pathways on days 1 and 7 post-vaccination. Both LAIV and IIV vaccines induced influenza-specific IgA that persisted for at least 6 months. Regulation of type I interferon production, toll-like receptor, and pattern recognition receptor signaling pathways were highly upregulated in milk on day 1 following LAIV but not IIV at any time point. Upregulation of innate immunity in human milk may provide timely protection against mucosal infections until antigen-specific immunity develops in the human milk-fed infant., (© 2022. The Author(s), under exclusive licence to Society for Mucosal Immunology.)

Background: Age and obesity status are associated with severe outcomes among hospitalized individuals with COVID-19. It remains unclear whether age and obesity are risk factors for milder COVID-19 illness., Methods: We prospectively enrolled SARS-CoV-2-exposed individuals. Participants recorded symptoms for 28 days and were tested for SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR) and serology. Type, number, and duration of symptoms and SARS-CoV-2 laboratory parameters were compared by age and obesity status., Results: Of 552 individuals enrolled from June 2020 to January 2021, 470 (85.1%) tested positive for SARS-CoV-2 including 261 (55.5%) adults ≥18 years, 61 (13.0%) adolescents 12-17 years, and 148 (31.5%) children <12 years. Children had fewer symptoms (median 2 vs. 3, p < 0.001) lasting fewer days (median 5 vs. 7, p < 0.001) compared with adolescents/adults. Body mass index of 300 (63.8%) individuals classified with overweight or obesity (OWOB). Individuals with OWOB suffered more symptoms compared with individuals without OWOB (median 3 vs. 2, p = 0.037), including more cough and shortness of breath (p = 0.023 and 0.026, respectively). Adolescents with OWOB were more likely to be symptomatic (66.7% vs. 34.2%, p = 0.008) and have longer respiratory symptoms (median 7 vs. 4 days, p = 0.049) compared with adolescents without OWOB. Lower RT-PCR Ct values were found in children and symptomatic individuals compared with adolescent and adults and asymptomatic individuals, respectively (p = 0.001 and 0.022)., Conclusions: Adolescents and adults with OWOB experience more respiratory symptoms from COVID-19 despite similar viral loads. These findings underscore the importance of vaccinating individuals with OWOB., (© 2021 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Background: The increasing incidence of pediatric hospitalizations associated with coronavirus disease 2019 (Covid-19) caused by the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United States has offered an opportunity to assess the real-world effectiveness of the BNT162b2 messenger RNA vaccine in adolescents between 12 and 18 years of age., Methods: We used a case-control, test-negative design to assess vaccine effectiveness against Covid-19 resulting in hospitalization, admission to an intensive care unit (ICU), the use of life-supporting interventions (mechanical ventilation, vasopressors, and extracorporeal membrane oxygenation), or death. Between July 1 and October 25, 2021, we screened admission logs for eligible case patients with laboratory-confirmed Covid-19 at 31 hospitals in 23 states. We estimated vaccine effectiveness by comparing the odds of antecedent full vaccination (two doses of BNT162b2) in case patients as compared with two hospital-based control groups: patients who had Covid-19-like symptoms but negative results on testing for SARS-CoV-2 (test-negative) and patients who did not have Covid-19-like symptoms (syndrome-negative)., Results: A total of 445 case patients and 777 controls were enrolled. Overall, 17 case patients (4%) and 282 controls (36%) had been fully vaccinated. Of the case patients, 180 (40%) were admitted to the ICU, and 127 (29%) required life support; only 2 patients in the ICU had been fully vaccinated. The overall effectiveness of the BNT162b2 vaccine against hospitalization for Covid-19 was 94% (95% confidence interval [CI], 90 to 96); the effectiveness was 95% (95% CI, 91 to 97) among test-negative controls and 94% (95% CI, 89 to 96) among syndrome-negative controls. The effectiveness was 98% against ICU admission and 98% against Covid-19 resulting in the receipt of life support. All 7 deaths occurred in patients who were unvaccinated., Conclusions: Among hospitalized adolescent patients, two doses of the BNT162b2 vaccine were highly effective against Covid-19-related hospitalization and ICU admission or the receipt of life support. (Funded by the Centers for Disease Control and Prevention.)., (Copyright © 2022 Massachusetts Medical Society.)

COVID-19 vaccination is recommended for persons who are pregnant, breastfeeding, trying to get pregnant now, or who might become pregnant in the future, to protect them from COVID-19. § Infants are at risk for life-threatening complications from COVID-19, including acute respiratory failure (1). Evidence from other vaccine-preventable diseases suggests that maternal immunization can provide protection to infants, especially during the high-risk first 6 months of life, through passive transplacental antibody transfer (2). Recent studies of COVID-19 vaccination during pregnancy suggest the possibility of transplacental transfer of SARS-CoV-2-specific antibodies that might provide protection to infants (3-5); however, no epidemiologic evidence currently exists for the protective benefits of maternal immunization during pregnancy against COVID-19 in infants. The Overcoming COVID-19 network conducted a test-negative, case-control study at 20 pediatric hospitals in 17 states during July 1, 2021-January 17, 2022, to assess effectiveness of maternal completion of a 2-dose primary mRNA COVID-19 vaccination series during pregnancy against COVID-19 hospitalization in infants. Among 379 hospitalized infants aged <6 months (176 with COVID-19 [case-infants] and 203 without COVID-19 [control-infants]), the median age was 2 months, 21% had at least one underlying medical condition, and 22% of case- and control-infants were born premature (<37 weeks gestation). Effectiveness of maternal vaccination during pregnancy against COVID-19 hospitalization in infants aged <6 months was 61% (95% CI = 31%-78%). Completion of a 2-dose mRNA COVID-19 vaccination series during pregnancy might help prevent COVID-19 hospitalization among infants aged <6 months., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Adrienne G. Randolph reports institutional support from the National Institute of Allergy and Infectious Diseases and National Institutes of Health (NIH) and being the UpToDate Pediatric Critical Care Section Editor. Matt S. Zinter reports institutional support from the National Heart, Lung, and Blood Institute (NHLBI), NIH and the American Thoracic Society. Laura Smallcomb reports support from the Medical University of South Carolina for conference attendance. Jennifer E. Schuster reports institutional support from Merck. Ryan A. Nofziger reports institutional support from NIH. Emily R. Levy reports institutional support from NIH. Michele Kong reports institutional support from NIH. Satoshi Kamidani reports institutional support from NIH and Pfizer. Janet R. Hume reports institutional support from the National Institute for Child Health and Development, NIH, and serving on a data safety monitoring board for an institutional study of magnesium for analgesia in complex medical patients. Charlotte V. Hobbs reports consultant fees from BioFire (bioMérieux). Natalie Z. Cvijanovich reports institutional support from NIH. Bria M. Coates reports institutional support from NHLBI, NIH, the American Lung Association, and the American Thoracic Society. Kathleen Chiotos reports institutional support from the Agency for Healthcare Research and Quality and serving as the Society for Healthcare Epidemiology of America Research Network Chair. Samina S. Bhumbra reports receipt of an NIH, National Institute for Allergy and Infectious Diseases training grant. Pia S. Pannaraj reports institutional support from AstraZeneca and Pfizer, consulting fees from Sanofi-Pasteur and Seqirus, payment from law firms for expert testimony, serving in the Division of Microbiology and Infectious Diseases, and unpaid service on the California Immunization Coalition. Mary A. Staat reports institutional support from NIH and receipt of lecture fees from the American Academy of Pediatrics for PREP ID Course. Natasha B. Halasa reports grant support from Sanofi and Quidel and honoraria from Genentech. No other potential conflicts of interest were disclosed.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies have been detected in human milk up to 6 weeks post-coronavirus disease 2019 (COVID-19) vaccination. We evaluated SARS-CoV-2-specific antibodies, neutralization activity, effect of pasteurization, and persistence through 6 months after vaccination., Methods: This prospective longitudinal study enrolled 30 pregnant or lactating women. SARS-CoV-2 antibodies and neutralization capacity were analyzed using an enzyme-linked immunosorbent assay compared at prevaccination and 1, 3, and 6 months postvaccination, and through Holder pasteurization., Results: Human milk SARS-CoV-2-specific IgG levels peaked at 1 month postvaccination and persisted above prevaccination levels for at least 6 months (P = .005). SARS-CoV-2-specific IgA was detected at 1 and 3 months (both P < .001) but waned by 6 months compared with baseline (P = .07). Milk SARS-CoV-2-specific IgG and IgA correlated with serum IgG at the same time point (R2 = 0.37, P < .001 and R2 = 0.19, P < .001). Neutralization activity was seen in 83.3%, 70.4%, and 25.0% of milk samples at 1, 3, and 6 months postvaccination. Neutralization most strongly correlated with SARS-CoV-2-specific IgG (R2 = 0.57, P < .001). Pre- and postpasteurization samples showed similar IgG (0.84 vs 1.07, P = .36) and neutralizing activity (57.7% vs 58.7% inhibition, P = .27), but lower IgM and IgA levels postpasteurization (0.09 vs 0.06, P = .004 and 0.21 vs 0.18, P = .043)., Conclusions: The data suggest that human milk SARS-CoV-2-specific antibodies may be available to milk-fed infants for up to 6 months. In addition, donor milk from vaccinated mothers retain IgG and neutralizing activity., Competing Interests: FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose., (Copyright © 2022 by the American Academy of Pediatrics.)

Multisystem inflammatory syndrome in children (MIS-C) is a severe postinfectious hyperinflammatory condition, which generally occurs 2-6 weeks after a typically mild or asymptomatic infection with SARS-CoV-2, the virus that causes COVID-19 (1-3). In the United States, the BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine is currently authorized for use in children and adolescents aged 5-15 years under an Emergency Use Authorization and is fully licensed by the Food and Drug Administration for persons aged ≥16 years (4). Prelicensure randomized trials in persons aged ≥5 years documented high vaccine efficacy and immunogenicity (5), § and real-world studies in persons aged 12-18 years demonstrated high vaccine effectiveness (VE) against severe COVID-19 (6). Recent evidence suggests that COVID-19 vaccination is associated with lower MIS-C incidence among adolescents (7); however, VE of the 2-dose Pfizer-BioNTech regimen against MIS-C has not been evaluated. The effectiveness of 2 doses of Pfizer-BioNTech vaccine received ≥28 days before hospital admission in preventing MIS-C was assessed using a test-negative case-control design ¶ among hospitalized patients aged 12-18 years at 24 pediatric hospitals in 20 states** during July 1-December 9, 2021, the period when most MIS-C patients could be temporally linked to SARS-CoV-2 B.1.617.2 (Delta) variant predominance. Patients with MIS-C (case-patients) and two groups of hospitalized controls matched to case-patients were evaluated: test-negative controls had at least one COVID-19-like symptom and negative SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) or antigen-based assay results, and syndrome-negative controls were hospitalized patients without COVID-19-like illness. Among 102 MIS-C case-patients and 181 hospitalized controls, estimated effectiveness of 2 doses of Pfizer-BioNTech vaccine against MIS-C was 91% (95% CI = 78%-97%). All 38 MIS-C patients requiring life support were unvaccinated. Receipt of 2 doses of the Pfizer-BioNTech vaccine is associated with a high level of protection against MIS-C in persons aged 12-18 years, highlighting the importance of vaccination among all eligible children., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Jennifer E. Schuster reports institutional support from Merck for an RSV research study, unrelated to the current work. Adrienne G. Randolph reports institutional support from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), royalties from UpToDate as the Pediatric Critical Care Section Editor, and participation on a data safety monitoring board (DSMB) for a National Institute of Child Health and Human Development-funded study. Pia S. Pannaraj reports institutional support from AstraZeneca and Pfizer, consulting fees from Sanofi-Pasteur and Seqirus, payment from law firms for expert testimony, participation on a Division of Microbiology and Infectious Diseases DSMB, and an unpaid leadership role in the California Immunization Coalition. Ryan A. Nofziger reports institutional support from NIH for participation in a multicenter influenza study. Satoshi Kamidani reports institutional support from NIH and Pfizer. Charlotte V. Hobbs reports consulting fees from Dynamed and honoraria from Biofire/Biomerieux. Natasha B. Halasa reports grants from Sanofi and Quidel and an educational grant from Genentech. Natalie Z. Cvijanovich reports a speaker’s registration discount at the Society of Critical Care Medicine meeting. Samina S. Bhumbra reports receipt of an NIH, NIAID training grant during September 1, 2019–August 31, 2020. No other potential conflicts of interest were disclosed.

Objectives: Studies of household transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) focused on households with children are limited. We investigated household secondary attack rate (SAR), transmission dynamics, and contributing factors in households with children. Materials and Methods: In this prospective case-ascertained study in Los Angeles County, California, all households members were enrolled if ≥1 member tested positive for SARS-CoV-2 by polymerase chain reaction (PCR). Nasopharyngeal PCRs, serology, and symptom data were obtained over multiple visits. Results: A total of 489 individuals in 105 households were enrolled from June to December 2020. The majority (77.3%) reported a household annual income of <$50,000, and most (92.9%) were of Hispanic/Latinx ethnicity. Children <18 years old accounted for 46.9% index cases, of whom 45.3% were asymptomatic. Household index cases were predominantly children during low community transmission and adults during the high community transmission period (χ 2 = 7.647, p = 0.0036. The mean household SAR was 77.0% (95% CI: 69.4-84.6%). Child and adult index cases both efficiently transmitted SARS-CoV-2 within households [81.9%, (95% CI: 72.1-91.9%) vs. 72.4% (95% CI: 59.8-85.1%), p = 0.23]. Household income and pets were significantly associated with higher SAR in the multivariable analysis of household factors ( p = 0.0013 and 0.004, respectively). Conclusions: The SAR in households with children in an urban setting with a large ethnic minority population is much higher than previously described. Children play important roles as index cases. SAR was disproportionately impacted by household income. Vaccination and public health efforts need special focus on children and vulnerable communities to help mitigate SARS-CoV-2 spread., Competing Interests: PP has received consultant fees from Sanofi-Pasteur and Seqirus and also receives research funding from AstraZeneca and Pfizer for unrelated studies. AG has received consultant fees from Janssen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tanaka, Marentes Ruiz, Malhotra, Turner, Peralta, Lee, Jumarang, Perez, Navarro, Dien Bard, Gordon, Allen, Thomas and Pannaraj.)

Pfizer-BioNTech COVID-19 vaccine is authorized for use in children and adolescents aged 12-15 years and is licensed by the Food and Drug Administration (FDA) for persons aged ≥16 (1). A randomized placebo-controlled trial demonstrated an efficacy of 100% (95% confidence interval [CI] = 75.3%-100%) in preventing outpatient COVID-19 in persons aged 12-15 years (2); however, data among adolescents on vaccine effectiveness (VE) against COVID-19 in real-world settings are limited, especially among hospitalized patients. In early September 2021, U.S. pediatric COVID-19 hospitalizations reached the highest level during the pandemic (3,4). In a test-negative, case-control study at 19 pediatric hospitals in 16 states during June 1-September 30, 2021, the effectiveness of 2 doses of Pfizer-BioNTech vaccine against COVID-19 hospitalization was assessed among children and adolescents aged 12-18 years. Among 464 hospitalized persons aged 12-18 years (179 case-patients and 285 controls), the median age was 15 years, 72% had at least one underlying condition, including obesity, and 68% attended in-person school. Effectiveness of 2 doses of Pfizer-BioNTech vaccine against COVID-19 hospitalization was 93% (95% CI = 83%-97%), during the period when B.1.617.2 (Delta) was the predominant variant. This evaluation demonstrated that 2 doses of Pfizer-BioNTech vaccine are highly effective at preventing COVID-19 hospitalization among persons aged 12-18 years and reinforces the importance of vaccination to protect U.S. youths against severe COVID-19., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Natasha B. Halasa reports grants from Sanofi and Quidel outside of the submitted work. Jennifer E. Schuster reports grants from Merck outside of the submitted work. Pia S. Pannaraj reports grants from AstraZeneca and Pfizer outside of the submitted work, and personal fees from Seqirus and Nestle outside of the submitted work. No other potential conflicts of interest were disclosed.

Introduction: The infant gut microbiome is thought to play a key role in developing metabolic and immunologic pathways. Antibiotics have been shown to disrupt the human microbiome, but the impact they have on infants during this key window of development remains poorly understood. Through this study, we further characterize the effect antibiotics have on the gut microbiome of infants by looking at metagenomic sequencing data over time., Materials and Methods: Stool samples were collected on infants from a large tertiary care neonatal intensive care unit. After DNA extraction, metagenomics libraries were generated and sequenced. Taxonomic and functional analyses were then performed. Further directed specimen sequencing for fungal species was also performed., Results: A total of 51 stool samples from 25 infants were analyzed: seven infants were on antibiotics during at least one of their collection time points. Antibiotics given at birth altered the microbiome (PERMANOVA R 2  = 0.044, p  = .002) but later courses did not ( R 2  = 0.023, p  = .114). Longitudinal samples collected while off antibiotics were more similar than those collected during a transition on or off antibiotics (mean Bray-Curtis distance 0.29 vs. 0.63, Wilcoxon p  = .06). Functional analysis revealed four microbial pathways that were disrupted by antibiotics given at-birth ( p  < .1, folate synthesis, glycerolipid metabolism, fatty acid biosynthesis, and glycolysis). No functional changes associated with current antibiotic use were identified. In a limited sample set, we saw little evidence of fungal involvement in the overall infant microbiome., Conclusion: Through this study, we have further characterized the role antibiotics have in the development of the infant microbiome. Antibiotics given at birth were associated with alterations in the microbiome and had significant impact on the functional pathways involved in folate synthesis and multiple metabolic pathways. Later courses of antibiotics led to stochastic dysbiosis and a significant decrease in Escherichia coli . Further characterization of the infant mycobiome is still needed.

Background: There is increasing concern that persistent infection of SARS-CoV-2 within immunocompromised hosts could serve as a reservoir for mutation accumulation and subsequent emergence of novel strains with the potential to evade immune responses., Methods: We describe three patients with acute lymphoblastic leukemia who were persistently positive for SARS-CoV-2 by real-time polymerase chain reaction. Viral viability from longitudinally-collected specimens was assessed. Whole-genome sequencing and serological studies were performed to measure viral evolution and evidence of immune escape., Findings: We found compelling evidence of ongoing replication and infectivity for up to 162 days from initial positive by subgenomic RNA, single-stranded RNA, and viral culture analysis. Our results reveal a broad spectrum of infectivity, host immune responses, and accumulation of mutations, some with the potential for immune escape., Interpretation: Our results highlight the potential need to reassess infection control precautions in the management and care of immunocompromised patients. Routine surveillance of mutations and evaluation of their potential impact on viral transmission and immune escape should be considered., Competing Interests: Declaration of Competing Interests S.D.B. has consulted for Regeneron, Sanofi, and Novartis on topics unrelated to this study. S.D.B., and K.R. have filed provisional patent applications related to serological tests for SARS-CoV-2 antibodies. All other authors have no competing interests., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The progression and severity of COVID-19 vary significantly in the population. While the hallmarks of SARS-CoV-2 and severe COVID-19 within routine laboratory parameters are emerging, the impact of sex and age on these profiles is still unknown., Methods: A multidimensional analysis was performed involving millions of records of laboratory parameters and diagnostic tests for 178 887 individuals from Brazil, of whom 33 266 tested positive for SARS-CoV-2. Analyzed data included those relating to complete blood cell count, electrolytes, metabolites, arterial blood gases, enzymes, hormones, cancer biomarkers, and others., Findings: COVID-19 induced similar alterations in laboratory parameters in males and females. CRP and ferritin were increased, especially in older men with COVID-19, whereas abnormal liver function tests were common across several age groups, except for young women. Low peripheral blood basophils and eosinophils were more common in the elderly with COVID-19. Both male and female COVID-19 patients admitted to intensive care units displayed alterations in the coagulation system, and higher values for neutrophils, CRP, and lactate dehydrogenase., Conclusions: Our study uncovered the laboratory profiles of a large cohort of COVID-19 patients, which formed the basis of discrepancies influenced by aging and biological sex. These profiles directly linked COVID-19 disease presentation to an intricate interplay between sex, age, and immune activation., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pollution of the environment is increasing and threatens the health and wellbeing of adults and children around the globe. The impact of air pollution on pulmonary and cardiovascular disease has been well documented, but it also has a deleterious effect on reproductive health. Ulaanbaatar, the capital city of Mongolia, has one of the highest levels of air pollution in the world. During the extreme winters when temperatures routinely fall below -20 °C the level of air pollution can reach 80 times the WHO recommended safe levels. Heating mainly comes from coal, which is burned both in power stations, and in stoves in the traditional Ger housing. We studied the impact of air pollution on conception rates and birth outcomes in Ulaanbaatar using a retrospective analysis of health data collected from the Urguu Maternity hospital in Ulaanbaatar, Mongolia. Daily levels of SO 2 , NO 2 , PM 10 , and PM 2.5 were collected from the government Air Quality Monitoring Stations in Ulaanbaatar for the same period as the study. In January, the month of highest pollution, there is a 3.2-fold decrease in conceptions that lead to the successfully delivered infants compared to October. The seasonal variations in conceptions resulting in live births in this study in Ulaanbaatar are shown to be 2.03 ± 0.20 (10-sigma) times greater than those in the Denmark/North America study of Wesselink et al., 2020. The two obvious differences between Ulaanbaatar and Europe/North America are pollution and temperature both of which are extreme in Ulaanbaatar. The extreme low temperature is mitigated by burning coal, which is the main source of domestic heat especially in the ger districts. This drives the level of pollution so the two are inextricably linked. Infants conceived in the months of June-October had the greatest cumulative PM 2.5 pollution exposure over total gestation, yet these were also the pregnancies with the lowest PM 2.5 exposure for the month of conception and three months prior to conception. The delivered-infant conception rate shows a markedly negative association with exposure to PM 2.5 prior to and during the first month of pregnancy. This overall reduction in fecundity of the population of Ulaanbaatar is therefore a preventable health risk. It is of great consequence that the air pollution in Ulaanbaatar affects health over an entire lifespan including reproductive health. This could be remedied with a clean source of heating.

Background: Chagas disease is a pathogenic parasitic infection with approximately 8 million cases worldwide and greater than 300,000 cases in the United States (U.S.). Chagas disease can lead to chronic cardiomyopathy and cardiac complications, with variable cardiac presentations in pediatrics making it difficult to recognize. The purpose of our study is to better understand current knowledge and experience with Chagas related heart disease among pediatric cardiologists in the U.S., Methods: We prospectively disseminated a 19-question survey to pediatric cardiologists via 3 pediatric cardiology listservs. The survey included questions about demographics, Chagas disease presentation and experience., Results: Of 139 responses, 119 cardiologists treat pediatric patients in the U.S. and were included. Most providers (87%) had not seen a case of Chagas disease in their practice; however, 72% also had never tested for it. The majority of knowledge-based questions about Chagas disease cardiac presentations were answered incorrectly, and 85% of providers expressed discomfort with recognizing cardiac presentations in children. Most respondents selected that they would not include Chagas disease on their differential diagnosis for presentations such as conduction anomalies, myocarditis and/or apical aneurysms, but would be more likely to include it if found in a Latin American immigrant. Of respondents, 87% agreed that they would be likely to attend a Chagas disease-related lecture., Conclusions: Pediatric cardiologists in the U.S. have seen very few cases of Chagas disease, albeit most have not sent testing or included it in their differential diagnosis. Most individuals agreed that education on Chagas disease would be worth-while.

Testing efforts for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been burdened by the scarcity of testing materials and personal protective equipment for health care workers. The simple and painless process of saliva collection allows for widespread testing, but enthusiasm is hampered by variable performance compared to that of nasopharyngeal swab (NPS) samples. We prospectively collected paired NPS and saliva samples from a total of 300 unique adult and pediatric patients. SARS-CoV-2 RNA was detected in 32.2% (97/300) of the individuals using the TaqPath COVID-19 Combo kit (Thermo Fisher). Performance of saliva and NPS was compared against the total number of positives regardless of specimen type. The overall concordances for saliva and NPS were 91.0% (273/300) and 94.7% (284/300), respectively. The values for positive percent agreement (PPA) for saliva and NPS were 81.4% (79/97) and 89.7% (87/97), respectively. Saliva yielded detection of 10 positive cases that were negative by NPS. For symptomatic and asymptomatic pediatric patients not previously diagnosed with COVID-19, the performances of saliva and NPS were comparable (PPA, 82.4% versus 85.3%). The overall values for PPA for adults were 83.3% and 90.7% for saliva and NPS, respectively, with saliva yielding detection of 4 fewer cases than NPS. However, saliva performance for symptomatic adults was identical to NPS performance (PPA of 93.8%). With lower cost and self-collection capabilities, saliva can be an appropriate sample choice alternative to NPS for detection of SARS-CoV-2 in children and adults., (Copyright © 2021 American Society for Microbiology.)

Human milk contains a dynamic and complex site-specific microbiome, which is not assembled in an aleatory way, formed by organized microbial consortia and networks. Presence of some genera, such as Staphylococcus, Streptococcus, Corynebacterium, Cutibacterium (formerly known as Propionibacterium ), Lactobacillus , Lactococcus and Bifidobacterium , has been detected by both culture-dependent and culture-independent approaches. DNA from some gut-associated strict anaerobes has also been repeatedly found and some studies have revealed the presence of cells and/or nucleic acids from viruses, archaea, fungi and protozoa in human milk. Colostrum and milk microbes are transmitted to the infant and, therefore, they are among the first colonizers of the human gut. Still, the significance of human milk microbes in infant gut colonization remains an open question. Clinical studies trying to elucidate the question are confounded by the profound impact of non-microbial human milk components to intestinal microecology. Modifications in the microbiota of human milk may have biological consequences for infant colonization, metabolism, immune and neuroendocrine development, and for mammary health. However, the factors driving differences in the composition of the human milk microbiome remain poorly known. In addition to colostrum and milk, breast tissue in lactating and non-lactating women may also contain a microbiota, with implications in the pathogenesis of breast cancer and in some of the adverse outcomes associated with breast implants. This and other open issues, such as the origin of the human milk microbiome, and the current limitations and future prospects are addressed in this review., (Copyright © 2020 Fernández, Pannaraj, Rautava and Rodríguez.)

Objective: To investigate the effects of environmental cleaning and the installation of heat and moisture exchangers (HMEs) to reduce neonatal carbapenem-resistant Acinetobacter baumannii (CRAB) sepsis and colonization as well as antimicrobial use., Design: We conducted a 7-year, quasi-experimental study., Setting and Patients: All neonates admitted to a neonatal intensive care unit (NICU)., Methods: We compared the trends for CRAB sepsis and colonization before (period 1, 2011-2013) and after (period 3, 2015-2017) a 12-month intervention period in 2014 (period 2) to incorporate a combination of HME use and sodium hypochlorite cleaning (5,000 ppm in the NICU and 500 ppm in the neonatal environment) using interrupted time series analysis with segmented regression., Results: During the 7-year study period, 3,367 neonates were admitted to the NICU; the prevalence rates of CRAB sepsis and endotracheal CRAB colonization were 0.5 per 1,000 patient days, and 19.4 per 1,000 ventilator days. A comparison of period 1 to period 3 showed significant decreases in the percentages of both CRAB of A. baumannii sepsis (100% versus 11%) and endotracheal colonization (76% vs 52%) following the introduction of disposable HMEs and sodium hypochlorite cleaning (both P < .001). In period 3, compared with period 1, segmented regression analysis showed significant reductions in endotracheal CRAB colonization per 1,000 ventilator days (ie, change in level) and both carbapenem and colistin use (changes in both level and slope) (P < .001)., Conclusions: Interventions featuring environmental cleaning and use of HMEs led to a sustainable reduction of CRAB colonization coupled with a reduction in broad-spectrum antimicrobial use in the NICU.

Objective: The SENTINEL1 observational study characterized confirmed respiratory syncytial virus hospitalizations (RSVH) among U.S. preterm infants born at 29 to 35 weeks' gestational age (wGA) not receiving respiratory syncytial virus (RSV) immunoprophylaxis (IP) during the 2014 to 2015 and 2015 to 2016 RSV seasons., Study Design: All laboratory-confirmed RSVH at participating sites during the 2014 to 2015 and 2015 to 2016 RSV seasons (October 1-April 30) lasting ≥24 hours among preterm infants 29 to 35 wGA and aged <12 months who did not receive RSV IP within 35 days before onset of symptoms were identified and characterized., Results: Results were similar across the two seasons. Among infants with community-acquired RSVH ( N  = 1,378), 45% were admitted to the intensive care unit (ICU) and 19% required invasive mechanical ventilation (IMV). There were two deaths. Infants aged <6 months accounted for 78% of RSVH observed, 84% of ICU admissions, and 91% requiring IMV. Among infants who were discharged from their birth hospitalization during the RSV season, 82% of RSVH occurred within 60 days of birth hospitalization discharge., Conclusion: Among U.S. preterm infants 29 to 35 wGA not receiving RSV IP, RSVH are often severe with almost one-half requiring ICU admission and about one in five needing IMV., Competing Interests: E.J.A., J.P.D., E.A.F.S., L.R.K., M.L.F., P.S.P., C.M.E., R.C.W., L.I.W., R.Y., P.A.C., J.B.D., and N.H. are independent investigators who have received research support from AstraZeneca/MedImmune. J.P.D., E.A.F.S., L.R.K., and M.L.F. also received travel support from AstraZeneca/MedImmune to present the results of this or other research studies at scientific meetings. J.P.D., M.L.F., and P.S.P. have served on the speakers’ bureau for AstraZeneca/MedImmune. E.J.A., E.A.F.S., and J.P.D. have served as consultants to AbbVie; P.A.C. has received research support from AbbVie. S.J.M. is an independent statistical consultant to AstraZeneca. K.K.M. and C.S.A. are employees of AstraZeneca and hold stock. V.R.K. and C.P.R. were employees of AstraZeneca at the time this research was conducted. C.P.R. is a current employee of Sobi Inc., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Increasing evidence supports the importance of the breast milk microbiome in seeding the infant gut. However, the origin of bacteria in milk and the process of milk microbe-mediated seeding of infant intestine need further elucidation. Presumed sources of bacteria in milk include locations of mother-infant and mother-environment interactions. We investigate the role of mother-infant interaction on breast milk microbes. Shotgun metagenomics and 16S rRNA gene sequencing identified milk microbes of mother-infant pairs in breastfed infants and in infants that have never latched. Although breast milk has low overall biomass, milk microbes play an important role in seeding the infant gut. Breast milk bacteria were largely comprised of Staphylococcus, Streptococcus, Acinetobacter, and Enterobacter primarily derived from maternal areolar skin and infant oral sites in breastfeeding pairs. This suggests that the process of breastfeeding is a potentially important mechanism for propagation of breast milk microbes through retrograde flux via infant oral and areolar skin contact. In one infant delivered via Caesarian section, a distinct strain of Bifidobacteria breve was identified in maternal rectum, breast milk and the infant's stool potentially suggesting direct transmission. This may support the existence of microbial translocation of this anaerobic bacteria via the enteromammary pathway in humans, where maternal bacteria translocate across the maternal gut and are transferred to the mammary glands. Modulating sources of human milk microbiome seeding potentially imply opportunities to ultimately influence the development of the infant microbiome and health., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Kordy performed this work while at CHLA and is currently affiliated with Novartis. We confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Human milk microbes play an important role in infant health and disease. Emerging evidence shows that human milk viruses are also transmitted from the mother to the infant via breastfeeding. These viruses include eukaryotic viruses, bacterium-infecting viruses called bacteriophages, and other viral particles. Human milk viruses are instrumental in shaping the infant gut virome and microbiome. Eukaryotic DNA and RNA viruses contribute to pathogenic challenges and protection. Bacteriophages have the ability to kill bacteria or supply them with potentially beneficial gene functions, thereby shaping the microbiome. The early infant virome is dominated by bacteriophages that likely contribute to a highly dynamic microbiome in the early life. There is a critical window of early childhood growth with rapid maturation of metabolic, endocrine, neural, and immune pathways. The colonization of microbes in the infant body during this time plays an important role in the establishment and maturation of these pathways. The virome transmitted via breastfeeding may also be particularly important at these critical time points of immune development. More longitudinal studies of mother-infant pairs will help to better define the human milk virome and their functional impact on the development of the growing infant., (© 2020 Nestlé Nutrition Institute, Switzerland/S. Karger AG, Basel.)