Systems biological assessment of the temporal dynamics of immunity to a viral infection in the first weeks and months of life.

• Type of Material: Article
• Authors: Bali Pulendran, Emory University; Florian Wimmers, Stanford University; Allison R Burrell, Cincinnati Children’s Hospital Medical Center; Yupeng Feng, Stanford University; Hong Zheng, Stanford University; Prabhu S Arunachalam, Stanford University; Mengyun Hu, Stanford University; Sara Spranger, Cincinnati Children’s Hospital Medical Center; Lindsay Nyhoff, Emory University; Devyani Joshi, Emory University; Meera Trisal, Stanford University; Mayanka Awasthi, Center for Biologics Evaluation and Research, Food and Drug Administration; Lorenza Bellusci, Center for Biologics Evaluation and Research, Food and Drug Administration; Usama Ashraf, Stanford University; Sangeeta Kowli, Stanford University; Katherine C Konvinse, Stanford University; Emily Yang, Stanford University; Michael Blanco, Stanford University; Kathryn Pellegrini, Yerkes National Primate Research Center; Gregory Tharp, Yerkes National Primate Research Center; Thomas Hagan, Cincinnati Children’s Hospital Medical Center; Sharon R Chinthrajah, Sean N. Parker Center for Allergy and Asthma Research, Stanford; Alba Grifoni, La Jolla Institute for Immunology (LJI); Alessandro Sette, La Jolla Institute for Immunology (LJI); Kari C Nadeau, Sean N. Parker Center for Allergy and Asthma Research, Stanford; David B Haslam, Cincinnati Children’s Hospital Medical Cente; Steven Bosinger, Emory University; Jens Wrammert, Emory University; Holden T Maecker, Stanford University; Paul J Utz, Stanford University; Taia T Wang, Stanford University; Surender Khurana, Center for Biologics Evaluation and Research, Food and Drug Administration; Purvesh Khatri, Stanford University; Mary A Staat, Cincinnati Children’s Hospital Medical Center
• Language: English
• Date: 2023-01-31
• Publisher: medRxiv
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1101/2023.01.28.23285133
• Title of Journal or Parent Work: medRxiv
• Grant/Funding Information: This work was supported by NIH grants U01 AI144673-01 (principal investigator M.A.S.). Work in the laboratory of B.P. is supported in part by the NIH (R01 AI048638, U19 AI057266 and U19 AI167903), Bill and Melinda Gates Foundation, Open Philanthropy and the Violetta L. Horton and Soffer Endowments to B.P. F.W. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) grants EXC2180-390900677 (Germany’s excellence strategy) and 503745673 (Emmy Noether Program). The sequencing data at Stanford were generated with instrumentation purchased with NIH funds (S10OD025212 and 1S10OD021763). Next-generation sequencing services were provided by the Emory NPRC Genomics Core, which is supported in part by NIH P51 OD011132. Sequencing data were acquired on an Illumina NovaSeq6000 funded by NIH S10 OD026799. The antibody neutralization work described in this manuscript was supported by FDA’s MCMi grant #OCET 2021-1565 and FDA’s Perinatal Health Center of Excellence (PHCE) project grants #GCBER005 and GCBER008 to S.K. The autoantibody work was supported by NIHs funds (R01 AI125197, RECOVER OTA-21-15B, and R38 HL143615) and philanthropic support from the Sean N Parker Center COVID-19 Research Fund and the Henry Gustav Floren Trust. This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00016 to A.G. and 75N9301900065 to A.S. The funders had no role in study design, data collection, analysis, interpretation, writing, the decision to publish, or preparation of the manuscript. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
• Keywords: Systems biological assessment

Abstract

The dynamics of innate and adaptive immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to SARS-CoV-2 infection in infants and young children in the first weeks and months of life by analyzing blood samples collected before, during, and after infection with Omicron and Non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, were stably maintained for >300 days. Antigen-specific memory B cell (MCB) responses were durable for 150 days but waned thereafter. Somatic hypermutation of V-genes in MCB accumulated progressively over 9 months. The innate response was characterized by upregulation of activation markers on blood innate cells, and a plasma cytokine profile distinct from that seen in adults, with no inflammatory cytokines, but an early and transient accumulation of chemokines (CXCL10, IL8, IL-18R1, CSF-1, CX3CL1), and type I IFN. The latter was strongly correlated with viral load, and expression of interferon-stimulated genes (ISGs) in myeloid cells measured by single-cell transcriptomics. Consistent with this, single-cell ATAC-seq revealed enhanced accessibility of chromatic loci targeted by interferon regulatory factors (IRFs) and reduced accessibility of AP-1 targeted loci, as well as traces of epigenetic imprinting in monocytes, during convalescence. Together, these data provide the first snapshot of immunity to infection during the initial weeks and months of life.