Adjuvantation of a SARS-CoV-2 mRNA vaccine with controlled tissue-specific expression of an mRNA encoding IL-12p70

Messenger RNA (mRNA) vaccines were pivotal in reducing severe acute respiratory syndrome 2 (SARS-CoV-2) infection burden, yet they have not demonstrated robust durability, especially in older adults. Here, we describe a molecular adjuvant comprising a lipid nanoparticle (LNP)–encapsulated mRNA encoding interleukin-12p70 (IL-12p70). The bioactive adjuvant was engineered with a multiorgan protection (MOP) sequence to restrict transcript expression to the intramuscular injection site. Admixing IL-12–MOP (CTX-1796) with the BNT162b2 SARS-CoV-2 vaccine increased spike protein–specific immune responses in mice. Specifically, the benefits of IL-12–MOP adjuvantation included amplified humoral and cellular immunity and increased immune durability for 1 year after vaccination in mice. An additional benefit included the restoration of immunity in aged mice to amounts comparable to those achieved in young adult animals, alongside amplification with a single immunization. Associated enhanced dendritic cell and germinal center responses were observed. Together, these data demonstrate that an LNP-encapsulated IL-12–MOP mRNA-encoded adjuvant can amplify immunogenicity independent of age, demonstrating translational potential to benefit vulnerable populations.