Interleukin 12 (IL-12) in COVID-19 Vaccines

Interleukin 12 is a cytokine with wide-reaching effects in the innate and adaptive immune system. Of considerable interest for intervention purposes is the ability of IL-12 to link innate resistance and adaptive immunity. Recently, IL-12’s unique ability to influence the production of interferon-γ and cause differentiation to Th1 cells has been harnessed to create a vaccine against COVID-19, the novel coronavirus pandemic caused by the SARS-CoV-2 virus.

IL-12 expression regulates the innate immune response during infection and is ultimately responsible for determining the length and type of the following adaptive immune response. Similarly, IL-12 promotes differentiation in naive CD4+ helper T cells into the Th1 phenotype. Th1 T cells then go on to produce IFN-γ and facilitate cell-mediated immunity.

IL-12 can drive interferon-γ (IFN-γ) production in dendritic cells (DCs), NK cells, macrophages, and T cells. The production of IL-12 is induced by microbial peptides, and its role in shaping the adaptive immune response means that it is a key player in coordinating both innate and adaptive immunity. This fascinating cytokine sits at the intersection of two major immune functions, and thus has become a target for therapeutic intervention.

IL-12 is a heterodimeric cytokine which is encoded by two genes: IL-12A (also called p35) and IL-12B (p40). Following protein synthesis, the active heterodimer— termed ‘p70’— and homodimer p40 are assembled. IL-12 is comprised of four alpha helices, as seen in the figure above. IL-12 and IL-23 both contain a p40 subunit.

Once IL-12 binds to its receptor, the signal is transduced via the JAK/STAT pathway. Ultimately, the binding of IL-12 triggers the up-regulation of BOLA2, PSME2, MTAP, CA1, GSTA2, RALA, CNN2, CFL1, TCP1, HNRNPDL, MIF, AIP, SOD1, PPIA and PDCD4 in helper T cells.

Ustekinumab is a human monoclonal antibody which targets the p40 subunit found in both IL-12 and IL-23. It is primarily used in the treatment of psoriasis and ulcerative colitis. Both of these diseases are autoimmune in nature, and blocking p40 is thought to dampen the immune response to autoantigens.

An IL-12 plasmid vaccine for COVID-19 has been developed and is currently awaiting FDA approval. The prophylactic, developed by OncoSec, utilizes a modified SARS-CoV-2 S glycoprotein (also called the spike protein) to activate an innate immune response. The benefit of IL-12 comes in strengthening the innate immune response, and skewing it to a Type-1 immune response. The Type-1 response favours cytotoxic functions for effector cells and cytokines. Thus, the IL-12 present in the microenvironment ameliorates the functions of immune cells and allows for an augmented response to the SARS-CoV-2 S antigen.

The TAVO™ technology that the vaccine is based on has shown promising results in cancer, where it has been able to induce a renewed immune response to tumours which were previously able to suppress effector immune cell functions.