Virus-like particle display of the SARS-CoV-2 receptor-binding domain using a modular tag/catcher system enhances immunogenicity of a DNA vaccine in mice

The COVID-19 pandemic highlighted the critical need for adaptable, rapid-response vaccine platforms. While mRNA vaccines enabled fast and scalable development, their stringent cold-chain requirements limited global accessibility. DNA vaccines offer a similarly fast and flexible vaccine design, but require far less complex manufacturing and distribution conditions, which is an advantage during a pandemic response. However, DNA vaccines have generally shown low immunogenicity in humans, which has hindered their clinical translation. Therefore, strategies that can enhance the potency of DNA vaccines are critical for realizing the full potential of this platform. Here, we apply a modular Tag/Catcher capsid virus-like particle (cVLP) technology to improve the immunogenicity of a DNA vaccine expressing the SARS-CoV-2 receptor-binding domain (RBD). Specifically, by administering a mixture of two plasmids, one encoding the RBD antigen and the other encoding a cVLP scaffold, each fused to a complementary Tag/Catcher binding partner, we induce in vivo assembly of cVLPs displaying multiple copies of the RBD antigen. In comparison to a control DNA vaccine encoding soluble RBD, the modular cVLP-display approach enhances both neutralizing antibody titers and RBD-specific CD8 + T-cell responses in mice. These findings demonstrate that the modular Tag/Catcher approach for cVLP display offers a widely applicable strategy for enhancing the immunogenicity of DNA vaccines, which could be combined with ongoing advances in DNA delivery for additive or synergistic benefit. Incorporating the Tag/Catcher cVLP technology may thus help establish the DNA platform as a viable tool for pandemic preparedness and cost-effective immunization in humans and animals.