# Spatiotemporal Dynamic Immunomodulation by Infection‐Mimicking Gels Enhances Broad and Durable Protective Immunity Against Heterologous Viruses

## TL;DR

A new vaccine platform called IM-Gel mimics viral infections to boost strong and lasting immunity against multiple flu strains and SARS-CoV-2 variants.

## Contribution

The IM-Gel platform introduces a programmable, infection-mimicking vaccine design that enhances broad and durable immunity.

## Key findings

- IM-Gel with influenza antigen provides cross-protection against multiple flu subtypes with long-term immune responses.
- Combining IM-Gel with SARS-CoV-2 spike protein elicits strong cross-reactive antibody responses against various variants.
- The gel enables sustained lymph node retention of vaccine components, enhancing both humoral and cellular immunity.

## Abstract

Despite their safety and widespread use, conventional protein antigen‐based subunit vaccines face significant challenges such as low immunogenicity, insufficient long‐term immunity, poor CD8+ T‐cell activation, and poor adaptation to viral variants. To address these issues, an infection‐mimicking gel (IM‐Gel) is developed that is designed to emulate the spatiotemporal dynamics of immune stimulation in acute viral infections through in situ supramolecular self‐assembly of nanoparticulate‐TLR7/8a (NP‐TLR7/8a) and an antigen with tannic acid (TA). Through collagen‐binding properties of TA, the IM‐Gel enables sustained delivery and enhanced retention of NP‐TLR7/8a and protein antigen in the lymph node subcapsular sinus of mice for over 7 days, prolonging the exposure of vaccine components in both B cell and T cell zones, leading to robust humoral and cellular responses. The IM‐Gel system with the influenza A antigen confers cross‐protection against multiple influenza subtypes (H1N1, H5N2, H3N2, H7N3, and H9N2) with long‐term immune responses. Combination of the IM‐Gel with the SARS‐CoV‐2 spike protein also elicits strong cross‐reactive antibody responses against multiple SARS‐CoV‐2 variants (Alpha, Beta, NY510+D614G, Gamma, Kappa, and Delta). The IM‐Gel, as a programmable immunomodulatory material, provides a vaccine design principle for the development of next‐generation universal vaccines that can elicit broad and durable protective immunity against emerging viruses.

An infection‐mimicking gel (IM‐Gel) is developed that emulates the spatiotemporal immune dynamics of acute viral infections. By enabling sustained lymph node retention of vaccine components, IM‐Gel enhances humoral and cellular immunity, offering cross‐protection against influenza subtypes and SARS‐CoV‐2 variants. This programmable platform highlights a next‐generation approach for developing universal vaccines with broad and durable immunity.