Faster and cheaper vaccine manufacture based on modern technologies is increasingly needed to effectively mitigate the burden of disease caused by highly contagious and mutagenic pathogens, such as influenza viruses. This study describes an approach to synthetically engineer a new influenza vaccine system by antigenic modularization of a carrier viral capsomere, coupled with microbial processing of the sub-unit vaccine. This approach leads to a system optimized with respect to both biological and process criteria. Murine polyomavirus VP1 protein, which self assembles into a pentameric sub-unit capsomere of a virus-like particle (VLP), was engineered to inhibit VLP assembly and to allow modular insertion of influenza M2e antigen at multiple sites within the protein. The yield, solubility, and immunogenicity of the resulting modular capsomeres could be optimized by varying the module insertion site and the number of M2e modules per site. This study demonstrated, for the first time, an innovative strategy of inserting multiple antigenic modules, up to 45 M2e modules, in a single capsomere. Modularization of M2e antigen was shown to improve its immunogenicity by more than an order of magnitude over that attained by immunization with an equivalent mass of non-modularized M2e peptide. Vaccination of mice using modular capsomeres induced high antigen-specific antibody levels suggestive of protective efficacy. This modular vaccine design approach, inspired by synthetic biology approaches to new system development, is conducive to technologies rapidly adaptable to pathogenic variations. (C) 2012 Elsevier Ltd. All rights reserved.