Abstract
Immunity by vaccination can protect human against heterologous viruses. However, protective abilities of artificial vaccines are still weaker than natural infections. Here we develop a kinetically engineered vaccine (KE-VAC) that mimics the multidimensional immunomodulation in natural infections via dynamic activation of antigen presenting cells with masked TLR7/8 agonist and sustained supplies of antigens and adjuvants to lymph nodes, leading to follicular helper T and germinal centre B cell activation in vaccinated mice. KE-VAC demonstrates superior efficacy than traditional alum and mRNA vaccines, achieving a 100% survival rate with increased neutralizing antibodies titers and polyfunctional CD8+ T cells, recognizing heterologous SARS-CoV-2 variants, and inducing broad and long-term protection against multiple strains of influenza viruses. Prime/boost vaccination with KE-VAC also protect aged ferrets from severe fever with thrombocytopenia syndrome virus infection, with no virus detected in any organs at day 6 p.i. The efficacy of KE-VAC across various pathogens thus highlights its potential as an effective vaccine against emerging infectious risks.