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.