GM-CSF increases mucosal and systemic immunogenicity of an H1N1 influenza DNA vaccine administered into the epidermis of non-human primates.
BACKGROUND
The 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.


RESULTS
Macaques 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
These 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.
Loudon
Peter T
PT
PowderMed Ltd., Oxford, UK.
Yager
Eric J
EJ
Lynch
Debbie T
DT
Narendran
Amithi
A
Stagnar
Cristy
C
Franchini
Anthony M
AM
Fuller
James T
JT
White
Phil A
PA
Nyuandi
Julia
J
Wiley
Clayton A
CA
Murphey-Corb
Michael
M
Fuller
Deborah H
DH
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis* / Q000097:blood; D004817:Epidermis / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007111:Immunity, Cellular / Q000187:drug effects; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D008253:Macaca mulatta; D009092:Mucous Membrane / Q000187:drug effects*; D013601:T-Lymphocytes / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology
D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D019444:Vaccines, DNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor