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.
Highlights
Current influenza vaccines protect against homologous viruses but are less effective against antigenic variants and provide little, if any, protection against a different subtype
In this study we assessed the systemic and mucosa immunogenicity of an influenza (A/New Caledonia/20/99) HA DNA vaccine administered by particle-mediated epidermal delivery (PMED or gene gun) in rhesus macaques
We evaluated whether co-administration of the GM-CSF genetic adjuvant could augment the immunogenicity of the particle-mediated delivery (PMED) HA DNA vaccine
Summary
Current influenza vaccines protect against homologous viruses but are less effective against antigenic variants and provide little, if any, protection against a different subtype. DNA vaccines have afforded significant protection against heterologous challenges with genetically drifted strains (e.g., heterosubtypic immunity) in animal models, an outcome that may be due to their ability to induce robust CD8+ cytotoxic T lymphocyte (CTL) responses against more conserved regions of the virus [1,2,3,4,5]. Such responses may not prevent infection per se, but could reduce viral load, mediate faster viral clearance, reduce morbidity, and, importantly for a viral pandemic, prevent mortality. 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
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