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

Florian Wimmers; Allison R Burrell; Yupeng Feng; Hong Zheng; Prabhu S Arunachalam; Mengyun Hu; Sara Spranger; Lindsay Nyhoff; Devyani Joshi; Meera Trisal; Mayanka Awasthi; Lorenza Bellusci; Usama Ashraf; Sangeeta Kowli; Katherine C Konvinse; Emily Yang; Michael Blanco; Kathryn Pellegrini; Gregory Tharp; Thomas Hagan; R Sharon Chinthrajah; Alba Grifoni; Alessandro Sette; Kari C Nadeau; David B Haslam; Steven E Bosinger; Jens Wrammert; Holden T Maecker; Paul J Utz; Taia T Wang; Surender Khurana; Purvesh Khatri; Mary A Staat; Bali Pulendran

doi:10.1101/2023.01.28.23285133

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

medRxiv [Preprint]. 2023 Jan 31:2023.01.28.23285133. doi: 10.1101/2023.01.28.23285133.

Authors

Florian Wimmers^{1

2

3

4}, Allison R Burrell^{5

6}, Yupeng Feng¹, Hong Zheng^{1

7}, Prabhu S Arunachalam¹, Mengyun Hu¹, Sara Spranger⁵, Lindsay Nyhoff⁸, Devyani Joshi⁸, Meera Trisal¹, Mayanka Awasthi⁹, Lorenza Bellusci⁹, Usama Ashraf^{1

10}, Sangeeta Kowli^{1

11}, Katherine C Konvinse¹², Emily Yang^{1

13}, Michael Blanco¹⁴, Kathryn Pellegrini¹⁵, Gregory Tharp¹⁵, Thomas Hagan^{5

16}, R Sharon Chinthrajah¹⁷, Alba Grifoni¹⁸, Alessandro Sette^{18

19}, Kari C Nadeau¹⁷, David B Haslam^{5

16}, Steven E Bosinger^{15

20}, Jens Wrammert⁸, Holden T Maecker^{1

11}, Paul J Utz^{1

13}, Taia T Wang^{1

10

11}, Surender Khurana⁹, Purvesh Khatri^{1

7}, Mary A Staat^{5

16}, Bali Pulendran^{1

11

21}

Affiliations

¹ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA.
² Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tuebingen, Tuebingen, Germany.
³ DFG Cluster of Excellence 2180 'Image-guided and Functional Instructed Tumor Therapy' (iFIT), University of Tuebingen, Tuebingen, Germany.
⁴ German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵ Department of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁶ Department of Environmental and Public Health Sciences, Division of Epidemiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁷ Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
⁸ Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine.
⁹ Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, 20993, USA.
¹⁰ Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA 94305, USA.
¹¹ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
¹² Department of Pediatrics, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
¹³ Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁴ Stanford Genomics Service Center, Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ Yerkes National Primate Research Center, Atlanta, GA, USA.
¹⁶ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁷ Department of Medicine, Sean N. Parker Center for Allergy and Asthma Research, Stanford, CA 94305, USA.
¹⁸ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.
¹⁹ Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA 92037, USA.
²⁰ Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
²¹ Department of Pathology, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.

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.

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Abstract

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