Modulation of the immune response at systemic and mucosal sites by DNA vaccine adjuvants in HIV and influenza models

Since the discovery of the Human Immunodeficiency Virus type 1 (HIV-1) as the cause of Acquired Immunodeficiency Syndrome (AIDS) almost 30 years, nearly 25 million people have died from AIDS worldwide. HIV-1/AIDS is a pandemic and there currently is no vaccine or cure for the devastating disease. Regardless of the route of infection, the mucosa is the primary site of viral replication and amplification. Therefore, the generation of immune responses at mucosal sites by and HIV-1 vaccine is likely important. We aimed to modulate the immune response generated through systemic vaccination by incorporating plasmid DNA expressing cytokine or mucosal chemokine adjuvants. First, we examined the potential of IL-15 in combination with its high affinity receptor alpha chain (IL-15Ra) to augment immune responses when co-delivered with IL-15 through immunizations in mice. We found that IL-15Ra is a novel adjuvant in the absence of IL-15, increasing the potency of the CD8+ T cell responses, even in IL-15 knockout mice. However, little impact on mucosal immunity was observed. Therefore we chose three novel chemokines to examine for putative effects of mucosal immunity-CCL25 (Thymus Expressed Chemokine, TECK), CCL27 (Cutaneous T Cell Attracting Chemokine, CTACK), and CCL28 (Mucosa Associated Chemokine, MEC). Mice co-immunized with these mucosal chemokines and an HIV-1 gag antigenic plasmid, exhibited increased levels of both systemic and mucosal immune responses. In addition, these responses were physiologically relevant in that they protected from a lethal influenza challenge. To further test the efficacy in the standard model for HIV-1 vaccine studies, immunization were carried out in the rhesus macaque model. Immunizations with CCL27 and simian (SIV) constructs delivered with electroporation elicited potent, but similar cellular and humoral immune responses in the periphery. The effects of CCL27 as an adjuvant were observed at mucosal sites, as shown by increased cytokine expression in CD4+ T and CD8+ T cells from the lung as well as antigen specific IgA in the lung and fecal samples. We show for the first time that the incorporation of plasmid-encoded chemokines is capable of eliciting responses at mucosal sites in the rhesus macaque model