A micro-electroporation/electrophoresis-based vaccine screening system reveals the impact of vaccination orders on cross-protective immunity

The constant emergence of mutated pathogens poses great challenges to the existing vaccine system. A screening system is needed to screen for antigen designs and vaccination strategies capable of inducing cross-protective immunity. Herein, we report a screening system based on DNA vaccines and a micro-electroporation/electrophoresis system (MEES), which greatly improved the efficacy of DNA vaccines, elevating humoral and cellular immune responses by over 400- and 35-fold respectively. Eighteen vaccination strategies were screened simultaneously by sequential immunization with vaccines derived from wildtype (WT) SARS-CoV-2, Delta, or Omicron BA.1 variant. Sequential vaccination of BA.1-WT-Delta vaccines with MEES induced potent neutralizing antibodies against all three viral strains and BA.5 variant, demonstrating that cross-protective immunity against future mutants can be successfully induced by existing strain-derived vaccines when a proper combination and order of sequential vaccination are used. Our screening system could be used for fast-seeking vaccination strategies for emerging pathogens in the future. [Display omitted] •A screening system is developed to rapidly identify effective vaccination strategies•This system employs DNA vaccines and micro-electroporation/electrophoresis (MEES)•MEES greatly strengthens the induction of both humoral and cellular immune responses•Cross-protective immunity is induced by rationally combining DNA vaccines and MEES Computational molecular modelling; Immune response; Immunology