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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. Editor's summary: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines were instrumental in curbing the COVID-19 pandemic, the immunity elicited by these vaccines has been shown to wane over time, especially in older adults. Thus, mRNA vaccines, much like their protein counterparts, may benefit from the addition of an adjuvant. Here, Brook et al. showed that the BNT162b2 SARS-CoV-2 mRNA vaccine did not elicit IL-12p70, an important immune mediator, in human blood. Adjuvantation of the BNT162b2 SARS-CoV-2 mRNA vaccine with an mRNA encoding IL-12p70 amplified humoral and cellular immune responses, including in aged mice, and enabled a reduced dose of vaccine mRNA needed to achieve the same antibody response seen without adjuvantation. Moreover, limiting expression of IL-12p70 or spike antigen to muscle tissue, through the use of a multiorgan protection (MOP) sequence, maintained the benefit of adjuvantation with the potential advantage of avoiding side effects caused by systemic transcript expression. These data support further development of this mRNA-based adjuvant and of MOP platforms. —Courtney Malo [ABSTRACT FROM AUTHOR]

Vaccination can help prevent infection and can also be used to treat cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-B (NF-1B)- activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor immunoassay using primary human peripheral blood mononuclear cells. Screening on primary cells identified an imidazopyrimidine, dubbed PVP-037. Moreover, while PVP-037 did not overtly activate THP-1 cells, it demonstrated broad innate immune activation, including NF-1B and cytokine induction from primary human leukocytes in vitro as well as enhancement of influenza and SARS-CoV-2 antigen-specific humoral responses in mice. Several de novo synthesis structural enhancements iteratively improved PVP-037' s in vitro efficacy, potency, species-specific activity, and in vivo adjuvanticity. Overall, we identified imidazopyrimidine Toll-like receptor-7/8 adjuvants that act in synergy with oil-in-water emulsion to enhance immune responses. [ABSTRACT FROM AUTHOR]