GM-CSF Increases Mucosal and Systemic Immunogenicity of an H1N1 Influenza DNA Vaccine Administered into the Epidermis of Non-Human Primates

Abstract

BackgroundThe recent H5N1 avian and H1N1 swine-origin influenza virus outbreaks reaffirm that the threat of a world-wide influenza pandemic is both real and ever-present. Vaccination is still considered the best strategy for protection against influenza virus infection but a significant challenge is to identify new vaccine approaches that offer accelerated production, broader protection against drifted and shifted strains, and the capacity to elicit anti-viral immune responses in the respiratory tract at the site of viral entry. As a safe alternative to live attenuated vaccines, the mucosal and systemic immunogenicity of an H1N1 influenza (A/New Caledonia/20/99) HA DNA vaccine administered by particle-mediated epidermal delivery (PMED or gene gun) was analyzed in rhesus macaques.Methodology/Principal FindingsMacaques were immunized at weeks 0, 8, and 16 using a disposable single-shot particle-mediated delivery device designed for clinical use that delivers plasmid DNA directly into cells of the epidermis. Significant levels of hemagglutination inhibiting (HI) antibodies and cytokine-secreting HA-specific T cells were observed in the periphery of macaques following 1–3 doses of the PMED HA DNA vaccine. In addition, HA DNA vaccination induced detectable levels of HA-specific mucosal antibodies and T cells in the lung and gut-associated lymphoid tissues of vaccinated macaques. Importantly, co-delivery of a DNA encoding the rhesus macaque GM-CSF gene was found to significantly enhance both the systemic and mucosal immunogenicity of the HA DNA vaccine.Conclusions/SignificanceThese results provide strong support for the development of a particle-mediated epidermal DNA vaccine for protection against respiratory pathogens such as influenza and demonstrate, for the first time, the ability of skin-delivered GM-CSF to serve as an effective mucosal adjuvant for vaccine induction of immune responses in the gut and respiratory tract.

Recent insights into cutaneous immunization: How to vaccinate via the skin

“…By targeting the epidermal and dermal layers of the skin, powder injection efficiently exploits the unique immunology of the skin. It induces comparable or higher antibody titers compared to conventional vaccination and holds the potential to elicit cellular and mucosal immune responses [25,[121][122][123]. Moreover, powder injection might represent a convenient strategy for genetic immunization and holds great potential for a range of applications, such as the treatment of type 1 diabetes [124].…”

Vaccination Using Gene-Gun Technology

“…Gene-gun technology (aka "biolistic plasmid delivery") has been used for the delivery of plasmids encoding various types of antigens such as infl uenza [ 19 ] or tumor antigens [ 18 , 20 ]. Thus, the following protocols are appropriate for any preclinical gene gunbased immunization approach.…”

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

“…A genetic adjuvant is a protein with adjuvant properties that is encoded by the pDNA and hence is co-expressed with the antigen, bolstering the immune response towards this antigen. Examples are IL-12 or IL-15, IL-28B, the use of granulocyte macrophage colonystimulating factor (GM-CSF) or high-mobility-group-protein B1 (HMGB1) [72][73][74][75][76][77][78][79][80][81][82][83][84].…”