Multiple tandem copies of conserved gp41 epitopes incorporated in gag virus-like particles elicit systemic and mucosal antibodies in an optimized heterologous vector delivery regimen.

Induction of neutralizing antibodies to prevent HIV infection, especially at the mucosa, is a critical goal of future vaccines. In this study, we have designed chimeric HIV-gag virus-like particles (VLPs) that contain multiple copies of the two highly conserved gp41 membrane-proximal external region (MPER) epitopes, ELDKWA and NWFDIT, with the objective of generating high titers of MPER-specific antibodies. We have shown that the implementation of optimized vector design, delivery regimens and appropriate delivery methods is critical to significantly increase epitope-specific antibody titers.

Treatment of intravaginal HSV-2 infection in mice: a comparison of CpG oligodeoxynucleotides and resiquimod (R-848).

The mammalian innate immune system recognizes pathogens via a series of pattern-recognition receptors such as the toll-like receptors (TLR) that interact with pathogen-associated molecular patterns (PAMPs) and lead to the rapid activation of innate immune cells. In this study, we compared the efficacy of CpG ODN (a TLR9 agonist) and resiquimod (R-848; a TLR7/8 agonist) for topical immunoprophylaxis or immunotherapy of vaginal herpes simplex virus type 2 (HSV-2) infection in mice. Efficacy against HSV infection was observed with CpG ODN but less so with R-848, even after repeated administrations.

Mucosal delivery of CpG oligodeoxynucleotides expands functional dendritic cells and macrophages in the vagina.

Antigen-presenting cells (APC) are specialized sentinel cells that sense pathogens within tissues and then activate appropriate immune effector cells in lymphoid organs. Recent evidence, however, suggests that APC can also induce effector cells in non-lymphoid organs. The purpose of this study was to determine the effect of intravaginal (IVAG) delivery of CpG-oligodeoxynucleotide (ODN) on expansion of resident genital APC.

Toll-like receptor (TLR)-3, but not TLR4, agonist protects against genital herpes infection in the absence of inflammation seen with CpG DNA.

We previously demonstrated that delivery of CpG oligodeoxynucleotide (ODN) to vaginal mucosa induced an innate mucosal antiviral state that protected against intravaginal challenge with herpes simplex virus (HSV)-2. We report that mucosal, but not systemic, delivery of ligands for Toll-like receptor (TLR)-3, but not TLR4, induced protection against genital HSV-2 challenge that was not accompanied by the local inflammation and splenomegaly seen after treatment with CpG ODN. Surprisingly, TLR4 messenger (m) RNA expression was shown to be higher than that of TLR3 or TLR9 in murine genital mucosa.

Parameters of CpG oligodeoxynucleotide-induced protection against intravaginal HSV-2 challenge.

Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides within the context of certain flanking bases (CpG motifs) have been shown to induce potent innate and adaptive immune responses. Vaginal delivery of CpG ODN alone protects mice from vaginal herpes simplex virus type-2 (HSV-2) challenge. Here, we investigated the importance of timing of delivery, formulation, route and dose of vaginally administered CpG ODN in the prevention or treatment of intravaginal (IVAG) HSV-2 infection.