Integrative mapping of preexisting influenza immune landscapes predicts vaccine response
Stephanie Hao, … , Thushan I. de Silva, Adriana Tomic
Stephanie Hao, … , Thushan I. de Silva, Adriana Tomic
Published July 15, 2025
Citation Information: J Clin Invest. 2025;135(18):e189300. https://doi.org/10.1172/JCI189300.
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Clinical Research and Public Health Clinical Research Immunology Virology

Integrative mapping of preexisting influenza immune landscapes predicts vaccine response

Abstract

BACKGROUND Predicting individual vaccine responses is a substantial public health challenge. We developed Immunaut, an open-source, data-driven framework for systems vaccinologists to analyze and predict immunological outcomes across diverse vaccination settings, beyond traditional assessments.METHODS Using a comprehensive live attenuated influenza vaccine (LAIV) dataset from 244 Gambian children, Immunaut integrated prevaccination and postvaccination humoral, mucosal, cellular, and transcriptomic data. Through advanced modeling, our framework provided a holistic, systems-level view of LAIV-induced immunity.RESULTS The analysis identified 3 distinct immunophenotypic profiles driven by baseline immunity: (a) CD8+ T cell responders with strong preexisting immunity boosting memory T cell responses; (b) mucosal responders with prior influenza A virus immunity developing robust mucosal IgA and subsequent influenza B virus seroconversion; and (c) systemic, broad influenza A virus responders starting from immune naivety who mounted broad systemic antibody responses. Pathway analysis revealed how preexisting immune landscapes and baseline features, such as mucosal preparedness and cellular support, quantitatively dictate vaccine outcomes.CONCLUSION Our findings emphasize the power of integrative, predictive frameworks for advancing precision vaccinology. The Immunaut framework is a valuable resource for deciphering vaccine response heterogeneity and can be applied to optimize immunization strategies across diverse populations and vaccine platforms.FUNDING Wellcome Trust (110058/Z/15/Z); Bill & Melinda Gates Foundation (INV-004222); HIC-Vac Consortium; NIAID (R21 AI151917); NIAID CEIRR Network (75N93021C00045).

Authors

Stephanie Hao, Ivan Tomic, Benjamin B. Lindsey, Ya Jankey Jagne, Katja Hoschler, Adam Meijer, Juan Manuel Carreño Quiroz, Philip Meade, Kaori Sano, Chikondi Peno, André G. Costa-Martins, Debby Bogaert, Beate Kampmann, Helder Nakaya, Florian Krammer, Thushan I. de Silva, Adriana Tomic

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Figure 2

Vaccine response immune signatures defining LAIV responder types.

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Vaccine response immune signatures defining LAIV responder types. (A) Po...
(A) Polar plot summarizing scaled median expression of key immune features in CD8+ T cell responders (group 1, green). CD8+ T cell responders are characterized by robust influenza B virus HA–specific CD8+ IFN-γ responses and limited humoral immunity, with median feature values represented in the polar plot and fold-change comparisons shown in the adjacent box plot. (B) Polar plot for mucosal responders (group 2, orange) illustrating strong mucosal IgA responses, particularly stalk-specific (cH7/3 IgA) and H3N2 virus HA–specific IgA antibodies and influenza B virus–specific responses. Box plots detail fold changes (shown as log10) for various immune features, highlighting systemic (influenza B virus HAI) and mucosal immune activation (IgA). (C) Polar plot depicting systemic, broad influenza A virus responders (group 3, purple), showing elevated systemic antibody responses to multiple influenza A virus strains (e.g., H1, H3), as well as cross-reactive IgG and antibody-dependent cellular cytotoxicity activity. Box plots show fold-change values (log10) for each immune marker across responder groups. (D) Integrated radar plot comparing scaled median immune expression profiles across all responder groups (CD8+ T cell responders in green, mucosal responders in orange, systemic broad influenza A virus responders in purple), emphasizing distinct immune feature distributions. This integrative visualization highlights the unique baseline and postvaccination immune landscapes that define each responder profile. Box plots denote minimum to maximum values, and points are all individuals within the group. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA Kruskal-Wallis test with Dunn’s multiple-comparison test to adjust for multiple testing.