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 Chen 1,2,3,4,5,20 , Jing Guo 6,20, John Heath 7,20,
Tyler R. Prestwood8, Woo Joo Kwon8, Ashley R. Smith 2,3, Tran T. Nguyen9,
Karan R. Kathuria1, Elsa Sola 1, AbuBakr Sangare10, Vamsee Mallajosyula 1,
Ryan Furuichi Fong 1, Azam Mohsin 1, Lei Chen1, Oviya Siva2,3, Cindy Padilla11,
Mingdian Tan 12, Cornelia L. Dekker 13, Philip Grant1, Ying Lu14,
Harry B. Greenberg15, William H. Robinson8, Catherine Blish 11,
Shai S. Shen-Orr 16, Ahmad Salehi 17, Holden T. Maecker 1,9,
Purvesh Khatri 1,18, Paul J. Utz 8, Yueh-Hsiu Chien 5,19 &
Mark M. Davis 1,6
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.