Designed DNA-Encoded IL-36 Gamma Acts as a Potent Molecular Adjuvant Enhancing Zika Synthetic DNA Vaccine-Induced Immunity and Protection in a Lethal Challenge Model

Abstract

Identification of novel molecular adjuvants which can boost and enhance vaccine-mediated immunity and provide dose-sparing potential against complex infectious diseases and for immunotherapy in cancer is likely to play a critical role in the next generation of vaccines. Given the number of challenging targets for which no or only partial vaccine options exist, adjuvants that can address some of these concerns are in high demand. Here, we report that a designed truncated Interleukin-36 gamma (IL-36 gamma) encoded plasmid can act as a potent adjuvant for several DNA-encoded vaccine targets including human immunodeficiency virus (HIV), influenza, and Zika in immunization models. We further show that the truncated IL-36 gamma (opt-36γt) plasmid provides improved dose sparing as it boosts immunity to a suboptimal dose of a Zika DNA vaccine, resulting in potent protection against a lethal Zika challenge.

The Role of IL-36 in Infectious Diseases: Potential Target for COVID-19?

“…Louis et al reported that a truncated IL-36g-encoded plasmid can act as a potent adjuvant for a DNA-encoded Zika virus (ZIKV) vaccine. Immunization with truncated IL-36g promoted antiviral T cell responses and protected mice from ZIKV challenge (68). Moreover, co-delivery of truncated IL-36g can also enhance antiviral immunity against HIV and influenza DNA vaccines (68).…”

Adjuvant Screen Identifies Synthetic DNA-Encoding Flt3L and CD80 Immunotherapeutics as Candidates for Enhancing Anti-tumor T Cell Responses

“…Vaccination with highly optimized DNA cancer vaccines and delivered by the CELLECTRA R electroporation (EP) device for cancer has been highly effective in the preclinical space (7)(8)(9)(10)(11) and results from a phase 2b clinical trial testing VGX-3100 for patients with cervical intraepithelial neoplasia showed this therapy to be safe, efficacious, and immunogenic (12). It has been well-documented that the specific targeting of immune cells by molecular adjuvants increases the immune response to viral associated antigens (13)(14)(15)(16), thus the potential exists to further increase the magnitude of the vaccine-elicited responses against tumor-associated antigens (TAAs) enabling tumor control.…”

DNA Vaccine Development at Pre- and Post-Operation Warp Speed

“…Hit by the COVID-19 epidemics, the world has come to realize the importance of efficient vaccines against viral infections. It is comforting that the contributing authors were working hard in this field before the epidemic broke out: all publications of this issue focus on the development of vaccines against viral infections, such as HIV by Kilpelainen et al [1], Louis et al [2], and Akulova et al [3]; human hepatitis C virus by Masalova et al [4]; Ebola virus by Bazhan et al [5]; Zika virus [2]; influenza by Hinkula et al [6] and Louis et al [2]; and Epstein-Barr virus by Wojtak et al [7].…”

“…The majority of studies presented in this issue used different forms of plasmid DNA: genes optimized for expression and/or consensus immunogens [2,3,7], polyepitope constructs [5], or plasmids with viral enhancers increasing protein expression and thus allowing one to reduce the DNA dose (Chapman & Rybicki [8]). A still more efficient way to ensure high-level expression of the immunogen is to use RNA/DNA layered alphavirus vectors, which provide a superior expression of immunogens in comparison with conventional plasmid DNA technology (Lundstrom [9]).…”

“…A recent development is the use of plasmid DNA to encode an adjuvant; for instance, a cytokine or another noncytokine immunomodulator with the power to enhance and shape the immune response. In this Special Issue, we see demonstrations of the efficient use of an immunomodulatory plasmid DNA encoding IL-36 gamma, giving a boost to an immune response against HIV, Zika virus, and influenza in mice [2]. The review by Shrestha & Grubor-Bauk gives an excellent example of the use of a novel cytolytic platform of DNA immunization based on truncated mouse perforin [10], whereas Hinkula et al [6] use a plasmid DNA encoding the TLR5 ligand flagellin as an immunomodulator which, if administered together with formalin-inactivated whole influenza A vaccine, increases the antibody response 200-fold, hemagglutination inhibition (HAI) titer by 100-fold, and the cellular response against flu by 40-fold.…”