Differential severity of SARS-CoV-2 variant infections in children and adults with COVID-19

Noah Brazer¹, Venice Servellita¹, Chengshi Jin², Abiodun Foresythe¹, Miriam Oseguera¹, Jenny Nguyen¹, Nanami Sumimoto¹, Hee Jae Huh³, Andries Feder⁴, Sanchita Bhattacharya⁵, Surabhi Bhaskar¹, Alicia Sotomayor-Gonzalez¹, Prachi Saldhi¹, Chris Choi⁶, Grace X Li⁶, Komal Gopchandani⁶, Ashley Tippett⁶, Hui-Mien Hsiao⁶, Mark D Gonzalez⁷, Dalia Gulick⁶, Colleen Kraft⁶, Vyjayanti Kasinathan⁶, Yun F Wayne Wang⁸, Pei Ying Chen⁹, Jessica Flores-Vazquez⁹, Krisha Patel⁴, Audrey R Odom John¹⁰, Jennifer K Spinler¹¹, Sridevi Devaraj¹², Ananth V Annapragada¹³, Ruth Ann Luna¹¹, Xiaowu Gai¹⁴, Jennifer Dien Bard¹⁴, Christina A Rostad¹⁵, Paul J Planet¹⁰, Ann A Lazar¹⁶, Charles Y Chiu¹⁷

Affiliations

¹ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
² Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94143, USA.
³ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
⁴ Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁵ Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Pediatrics, Division of Infectious Diseases, Emory University, Georgia, GA 30322, USA.
⁷ Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
⁸ Department of Pediatrics, Division of Infectious Diseases, Emory University, Georgia, GA 30322, USA; Grady Memorial Health Center, Atlanta, GA 30303, USA.
⁹ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
¹⁰ Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹¹ Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Division of Laboratory Medicine, Texas Children's Hospital and Department of Pathology & Immunology Baylor College of Medicine, Houston, TX 77030, USA.
¹³ E.B. Singleton Department of Radiology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
¹⁵ Department of Pediatrics, Division of Infectious Diseases, Emory University, Georgia, GA 30322, USA; Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
¹⁶ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94143, USA; Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA 94143, USA.
¹⁷ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: charles.chiu@ucsf.edu.

PMID: 40674918
DOI: 10.1016/j.jcv.2025.105833

Differential severity of SARS-CoV-2 variant infections in children and adults with COVID-19

Noah Brazer et al. J Clin Virol. 2025 Oct.

. 2025 Oct:180:105833.

doi: 10.1016/j.jcv.2025.105833. Epub 2025 Jul 7.

Authors

Affiliations

¹ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
² Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94143, USA.
³ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
⁴ Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁵ Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Pediatrics, Division of Infectious Diseases, Emory University, Georgia, GA 30322, USA.
⁷ Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
⁸ Department of Pediatrics, Division of Infectious Diseases, Emory University, Georgia, GA 30322, USA; Grady Memorial Health Center, Atlanta, GA 30303, USA.
⁹ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
¹⁰ Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹¹ Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Division of Laboratory Medicine, Texas Children's Hospital and Department of Pathology & Immunology Baylor College of Medicine, Houston, TX 77030, USA.
¹³ E.B. Singleton Department of Radiology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
¹⁵ Department of Pediatrics, Division of Infectious Diseases, Emory University, Georgia, GA 30322, USA; Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
¹⁶ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94143, USA; Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA 94143, USA.
¹⁷ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: charles.chiu@ucsf.edu.

PMID: 40674918
DOI: 10.1016/j.jcv.2025.105833

Abstract

We performed virus whole-genome sequencing of 6916 upper respiratory swabs from adults and children from March 2020 to May 2023 and collected clinical metadata to assess differences in SARS-CoV-2 variant severity and symptomatology. Multivariable logistic regression showed a severity peak with Delta, which had the highest likelihood of severe infection. In children, another peak was observed with BA.4/BA.5, which was associated with more severe infection than both prior (BA.1) and later (BQ.1, BF.7, and XBB) Omicron variants. In contrast, BA.4/BA.5 in adults was associated with less severe infection than BA.1. Genome-wide association studies revealed that nonstructural protein 5 (nsp5, also called 3C-chymotrypsin-like protease), the Paxlovid target, and the spike N-terminal domain were strongly associated with severity. Kmers (contiguous nucleotide sequences of a fixed length k) from these regions matched the prototype Wuhan sequence exactly, corroborating decreases in severity over time. One kmer in the spike gene region was conserved in Delta genomes, with the kmer retained in higher proportions in patients with more severe infection. Our results show, with the exception of Delta, decreases in severity associated with SARS-CoV-2 variant infection over time and underscore the potential utility of kmer monitoring to assess variant severity.

Keywords: COVID-19; Coronavirus; Delta; Epsilon; Omicron; Pediatric; Respiratory disease; Severe Acute Respiratory Syndrome; Severity; Symptoms; Variant of concern (VOC); Variant of interest (VOI); Virus whole-genome sequencing.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Charles Y. Chiu reports financial support was provided by National Institute of Child Health and Human Development. Charles Y. Chiu reports financial support was provided by Centers for Disease Control and Prevention. Paul J. Planet reports financial support was provided by Centers for Disease Control and Prevention. Charles Y. Chiu reports a relationship with Abbott Laboratories that includes: funding grants. Charles Y. Chiu reports a relationship with Delve Bio that includes: equity or stocks and funding grants. Charles Y. Chiu reports a relationship with Biomeme that includes: consulting or advisory. Charles Y. Chiu reports a relationship with Biomesense that includes: equity or stocks. Charles Y. Chiu reports a relationship with Flightpath Biosciences that includes: equity or stocks. Charles Y. Chiu reports a relationship with Mammoth Biosciences that includes: equity or stocks. Charles Y. Chiu reports a relationship with Poppy Health that includes: equity or stocks. Christina A. Rostad reports a relationship with Biofire Diagnostics Inc that includes: funding grants. Christina A. Rostad reports a relationship with GlaxoSmithKline Inc that includes: funding grants. Christina A. Rostad reports a relationship with MedImmune LLC that includes: funding grants. Christina A. Rostad reports a relationship with Janssen Pharmaceuticals Inc that includes: funding grants. Christina A. Rostad reports a relationship with Merck & Co Inc that includes: funding grants. Christina A. Rostad reports a relationship with Moderna Inc that includes: funding grants. Christina A. Rostad reports a relationship with Novavax Inc that includes: funding grants. Christina A. Rostad reports a relationship with PaxVax Corporation that includes: funding grants. Christina A. Rostad reports a relationship with Pfizer Inc that includes: funding grants. Christina A. Rostad reports a relationship with Regeneron Pharmaceuticals Inc that includes: funding grants. Christina A. Rostad reports a relationship with Sanofi Pasteur Inc that includes: funding grants. Christina A. Rostad has patent pending to Meissa Vaccines, Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Differential severity of SARS-CoV-2 variant infections in children and adults with COVID-19

Affiliations

Differential severity of SARS-CoV-2 variant infections in children and adults with COVID-19

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

Supplementary concepts

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous