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Publication
bioRxiv

Cytokine Regulation of Human Antibody Responses to Influenza Vaccines

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  • August 8, 2025
  • Mark M. Davis, Stanford University School of Medicine
Topic/Product:
Immunology, Inflammation, Inflammation Panel 250, Vaccine
Disease Area:
Influenza
Sample Type:
Organoid Supernatants - Spleen

Abstract

Studies show that human vaccine responses widely vary. Here, we analyzed data measuring 66 cytokines from 4 different inactivated influenza vaccine (IIV) cohorts over 5 seasons (N=581) and identified a significant correlation between baseline/day 0 serum IL-18 and IFN-β concentrations and the vaccine-specific antibody response on day 28, suggesting these factors may have an adjuvant-like effect. To investigate this further, we tested the impact of 19 cytokines on the development of anti-influenza antibody response when administered together with the IIV vaccine in human tonsil and spleen organoids. We found that Type I IFNs (IFN-β and others), IL-21, IL-12, IL-10, but not IL-18 or IFN-γ, enhanced the antibody response. The live attenuated influenza vaccine (LAIV) induced a stronger antibody response than the inactivated one in organoids. Adding a single cytokine, IFN-β, to IIV stimulation recapitulated most of the live vaccine-specific cytokine activation program. It increased the antibody response of the inactivated vaccine to that of the LAIV. Two other antibody-boosting cytokines, IL-12 and IL-21, were induced by LAIV but not by Type I IFNs, indicating different cytokines can affect different pathways leading to a robust antibody response. We then generated cytokine mRNA lipid nanoparticles (LNPs) to test the effect of cytokines on IIV response in a mouse model of immunization. We found that IL-21-LNPs augmented the quantity and breadth of the antibody responses, while IFN-β LNPs enhanced durability. These findings identified parallel cytokine pathways regulating human vaccine responses and provide a rationale for using cytokines as adjuvants to mimic the effectiveness of live-attenuated vaccines without the risk of viral replication.

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Authors & Affiliations

Guangbo (Bill) Chen, Jing Guo, John Heath, Tyler Prestwood, Woo Joo Kwon, Ashley Smith, Tran T. Nguyen, Elsa Sola, AbuBakr Sangare, Vamsee Mallajosyula, Ryan Ichiro Furuichi Fong, Azam Mohsin, Lei Chen, Oviya Siva, Cindy Padilla, Mingdian Tan, Cornelia L. Dekker, Philip Grant, Ying Lu, Harry B. Greenberg, William H. Robinson, Catherine Blish,  Shai Shen-Orr, Ahmad Salehi, Holden T. Maecker,  Purvesh Khatri, Paul J. Utz, Yueh-hsiu Chien, Mark M. Davis

1 Institute for Immunology, Transplantation and Infection (ITI), Stanford University School of Medicine, Palo Alto, CA, USA 2Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA 3Center for Immunology, Medical College of Wisconsin, Milwaukee, WI, USA 4 Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA 5Hematopoiesis and Immunobiology Program, Versiti Blood Research Institute, Milwaukee, WI, USA 6Department of Microbiology and Immunology, Stanford University School of Medicine, Palo Alto, CA, USA 7Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA 8The Human Immune Monitoring Center (HIMC), Stanford University School of Medicine, Palo Alto, CA, USA 9Department of Biology, Stanford University Medical School, Stanford, CA, USA 10 Department of Pediatrics (Infectious Diseases), Stanford University School of Medicine, Palo Alto, CA, USA 11 Asian Liver Center, Department of Surgery, Stanford University Medical School, Stanford University, Palo Alto, California 94305, USA 12Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA

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Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

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Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.