Systems immunology analysis of human immune organoids identifies host-specific correlates of protection to different influenza vaccines

Zachary W Wagoner¹, Timothy B Yates¹, Jenny E Hernandez-Davies¹, Suhas Sureshchandra¹, Erika M Joloya¹, Aarti Jain², Rafael de Assis², Jenna M Kastenschmidt¹, Andrew M Sorn¹, Mahina Tabassum Mitul¹, Ian Tamburini³, Gurpreet Ahuja⁴, Qiu Zhong⁴, Douglas Trask⁵, Marcus Seldin³, D Huw Davies¹, Lisa E Wagar⁶

Affiliations

¹ Department of Physiology & Biophysics, University of California, Irvine, Irvine, CA, USA; Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Center for Virus Research, University of California, Irvine, Irvine, CA, USA; Vaccine R&D Center, University of California, Irvine, Irvine, CA, USA.
² Department of Physiology & Biophysics, University of California, Irvine, Irvine, CA, USA; Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Vaccine R&D Center, University of California, Irvine, Irvine, CA, USA.
³ Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA, USA.
⁴ Department of Pediatric Otolaryngology, Children's Hospital of Orange County, Orange, CA, USA; Department of Otolaryngology-Head and Neck Surgery, University of California, Irvine, Orange, CA, USA.
⁵ Department of Otolaryngology-Head and Neck Surgery, University of California, Irvine, Orange, CA, USA.
⁶ Department of Physiology & Biophysics, University of California, Irvine, Irvine, CA, USA; Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Center for Virus Research, University of California, Irvine, Irvine, CA, USA; Vaccine R&D Center, University of California, Irvine, Irvine, CA, USA. Electronic address: lwagar@hs.uci.edu.

PMID: 39986275
PMCID: PMC11974613 (available on 2026-04-03)
DOI: 10.1016/j.stem.2025.01.014

Systems immunology analysis of human immune organoids identifies host-specific correlates of protection to different influenza vaccines

Zachary W Wagoner et al. Cell Stem Cell. 2025.

. 2025 Apr 3;32(4):529-546.e6.

doi: 10.1016/j.stem.2025.01.014. Epub 2025 Feb 21.

Authors

Affiliations

¹ Department of Physiology & Biophysics, University of California, Irvine, Irvine, CA, USA; Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Center for Virus Research, University of California, Irvine, Irvine, CA, USA; Vaccine R&D Center, University of California, Irvine, Irvine, CA, USA.
² Department of Physiology & Biophysics, University of California, Irvine, Irvine, CA, USA; Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Vaccine R&D Center, University of California, Irvine, Irvine, CA, USA.
³ Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA, USA.
⁴ Department of Pediatric Otolaryngology, Children's Hospital of Orange County, Orange, CA, USA; Department of Otolaryngology-Head and Neck Surgery, University of California, Irvine, Orange, CA, USA.
⁵ Department of Otolaryngology-Head and Neck Surgery, University of California, Irvine, Orange, CA, USA.
⁶ Department of Physiology & Biophysics, University of California, Irvine, Irvine, CA, USA; Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Center for Virus Research, University of California, Irvine, Irvine, CA, USA; Vaccine R&D Center, University of California, Irvine, Irvine, CA, USA. Electronic address: lwagar@hs.uci.edu.

PMID: 39986275
PMCID: PMC11974613 (available on 2026-04-03)
DOI: 10.1016/j.stem.2025.01.014

Abstract

Vaccines are an essential tool to significantly reduce pathogen-related morbidity and mortality. However, our ability to rationally design vaccines and identify correlates of protection remains limited. Here, we employed an immune organoid approach to capture human adaptive immune response diversity to influenza vaccines and systematically identify host and antigen features linked to vaccine response variability. Our investigation identified established and unique immune signatures correlated with neutralizing antibody responses across seven different influenza vaccines and antigens. Unexpectedly, heightened ex vivo tissue frequencies of T helper (Th)1 cells emerged as both a predictor and a correlate of neutralizing antibody responses to inactivated influenza vaccines (IIVs). Secondary analysis of human public data confirmed that elevated Th1 signatures are associated with antibody responses following in vivo vaccination. These findings demonstrate the utility of human in vitro models for identifying in vivo correlates of protection and establish a role for Th1 functions in influenza vaccination.

Keywords: adaptive immunity; humoral immunity; immune organoids; lymphoid tissues; predictive modeling; systems immunology; vaccines.

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Conflict of interest statement

Declaration of interests L.E.W. is the co-inventor of a patent on immune organoid technology assigned to Stanford University, “Systems and Methods to Model Adaptive Immune Responses.”

References

1. Pollard AJ, and Bijker EM (2021). A guide to vaccinology: from basic principles to new developments. Nat. Rev. Immunol 21, 83–100. 10.1038/s41577-020-00479-7. - DOI - PMC - PubMed
1. Koff WC, Gust ID, and Plotkin SA (2014). Toward a Human Vaccines Project. Nat. Immunol 15, 589–592. 10.1038/ni.2871. - DOI - PubMed
1. Koff WC, Burton DR, R.Johnson P, Walker BD, King CR, Nabel GJ, Ahmed R, Bhan MK, and Plotkin SA (2013). Accelerating Next Generation Vaccine Development for Global Disease Prevention. Science 340, 1232910. 10.1126/science.1232910. - DOI - PMC - PubMed
1. Plotkin SA (2023). Recent updates on correlates of vaccine-induced protection. Frontiers in Immunology 13, 1081107. 10.3389/fimmu.2022.1081107. - DOI - PMC - PubMed
1. Plotkin SA (2010). Correlates of Protection Induced by Vaccination. Clin. Vaccine Immunol CVI 17, 1055–1065. 10.1128/CVI.00131-10. - DOI - PMC - PubMed

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Systems immunology analysis of human immune organoids identifies host-specific correlates of protection to different influenza vaccines

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Systems immunology analysis of human immune organoids identifies host-specific correlates of protection to different influenza vaccines

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