Abstract
Human vaccine responses vary widely, but the determinants remain incompletely defined. Here we analyzed 66 cytokines across four inactivated influenza vaccine (IIV) cohorts over five seasons (n = 581) and identified baseline serum interleukin (IL)-18 and interferon (IFN)-β as correlates of day 28 antibody responses. To test causality, we evaluated 19 cytokines in human tonsil and spleen organoids and found that type I IFNs, IL-21 and IL-12, but not IL-18 or IFNγ, enhanced antibody production. The addition of IFNβ to IIV recapitulated key features of the live-vaccine cytokine program. IL-12 and IL-21 defined a parallel pathway independent of type I IFNs, with IL-12 inducing IL-21 in humans, unlike in mice. Delivery of IL-21 or IFNβ via mRNA lipid nanoparticles in vivo promoted long-lived plasma cell formation. Together, these findings define parallel pathways that regulate vaccine immunity. Our approach unites high-throughput organoid testing and human cohort studies, establishing a human-centric platform to identify adjuvant candidates.
Authors and Affiliations
Guangbo Chen¹˒²˒³˒⁴˒⁵˒²⁰, Jing Guo⁶˒²⁰, John Heath⁷˒²⁰, Tyler R. Prestwood⁸, Woo Joo Kwon⁸, Ashley R. Smith²˒³, Tran T. Nguyen⁹, Karan R. Kathuria¹, Elsa Sola¹, AbuBakr Sangare¹⁰, Vamsee Mallajosyula¹, Ryan Furuichi Fong¹, Azam Mohsin¹, Lei Chen¹, Oviya Siva²˒³, Cindy Padilla¹¹, Mingdian Tan¹², Cornelia L. Dekker¹³, Philip Grant¹, Ying Lu¹⁴, Harry B. Greenberg¹⁵, William H. Robinson⁸, Catherine Blish¹¹, Shai S. Shen-Orr¹⁶, Ahmad Salehi¹⁷, Holden T. Maecker¹˒⁹, Purvesh Khatri¹˒¹⁸, Paul J. Utz⁸, Yueh-Hsiu Chien⁵˒¹⁹, and Mark M. Davis¹˒⁶
¹ Institute for Immunology, Transplantation and Infection (ITI), Stanford University School of Medicine, Palo Alto, CA, USA
² Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
³ Center for Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
⁴ Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
⁵ Hematopoiesis and Immunobiology Program, Versiti Blood Research Institute, Milwaukee, WI, USA
⁶ Department of Microbiology and Immunology, Stanford University School of Medicine, Palo Alto, CA, USA
⁷ Department of Bioengineering, Stanford University, Stanford, CA, USA
⁸ Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA
⁹ The Human Immune Monitoring Center (HIMC), Stanford University School of Medicine, Palo Alto, CA, USA
¹⁰ Department of Biology, Stanford University, Stanford, CA, USA
¹¹ Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA
¹² Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Palo Alto, CA, USA
¹³ Department of Pediatrics (Infectious Diseases), Stanford University School of Medicine, Palo Alto, CA, USA
¹⁴ Department of Biomedical Data Science, Stanford University School of Medicine, Palo Alto, CA, USA
¹⁵ Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA
¹⁶ Ruth and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel
¹⁷ Donor Network West, San Ramon, CA, USA
¹⁸ Division of Computational Medicine, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA
¹⁹ Program in Immunology, Stanford University School of Medicine, Palo Alto, CA, USA
²⁰ These authors contributed equally: Guangbo Chen, Jing Guo, John Heath.