Intranasal Immunization with CpG Oligodeoxynucleotides as an Adjuvant Dramatically Increases IgA and Protection Against Herpes Simplex Virus-2 in the Genital Tract

Abstract

Development of vaccines capable of preventing the transmission or limiting the severity of sexually transmitted viruses, such as HSV and HIV, will likely be dependent on the induction of potent long-lasting mucosal immune responses in the genital tract. Recently, synthetic oligodeoxynucleotides (ODN) containing immunostimulatory CpG motifs were shown to serve as potent adjuvants for the induction of mucosal immune responses. Here, we show that intranasal immunization with CpG ODN, plus recombinant glycoprotein B (rgB) of HSV-1, results in significantly elevated levels of specific anti-gB IgA Abs in vaginal washes that remained high throughout the estrous cycle. Additionally, dramatically elevated numbers of specific IgA Ab-secreting cells were present and persisted in the genital tract in response to intravaginal (IVAG) HSV-2 challenge. HSV-2-specific CTL were observed at moderate levels in the spleens of CpG or non-CpG ODN-immunized mice. In contrast, strong CTL responses were observed locally in the genital tissues of both groups following IVAG HSV-2 challenge. Interestingly, mice immunized intranasally with rgB plus CpG ODN, but not non-CpG ODN, were significantly protected following IVAG HSV-2 challenge. Measurement of virus in protected CpG-immunized mice revealed a log lower level of replication within the first few days after infection. In conclusion, these results indicate that intranasal immunization with CpG ODN plus protein mediates immunity in the female genital tract capable of protecting against a sexually transmitted pathogen.

NADPH-Oxidase may Contribute to IL-12 Production in Macrophages Stimulated with CpG Phosphorothioate Oligodeoxynucleotides.

“…[12][13][14] However, the molecular mechanism responsible for the immunostimulatory effects of CpG-ODN is not yet fully understood. Recently, Yi et al 9,10) reported that the activation of murine B cells and macrophages by CpG-ODN was linked to ROS generation, and IL-6 secretion was suppressed by addition of ROS scavenger.…”

Intranasal immunization with synthetic peptides corresponding to the E6 and E7 oncoproteins of human papillomavirus type 16 induces systemic and mucosal cellular immune responses and tumor protection

“…Even though literature reports described DNA vaccines based on the E7 protein or the immunodominant CTL epitopes to be effective in generating HPV-specific systemic immunity [30], prevalence of antigen specific T cell responses at distant mucosal sites has not been investigated in detail. Similarly, the efficacy of delivering the E7 protein along with CpGoligodeoxynucleotide (ODN), a strong immunomodulatory agent [38][39][40][41], for priming systemic but not mucosal immune responses was reported by Tae-Yoon Kim et al, [31]. One recent report described intranasal immunizations with an adeno-associated virus (AAV2) vector construct expressing the codon-optimized major capsid gene L1 (L1H) from HPV-16 to induce long-lasting humoral and cellular immune responses [42].…”

Adaptive immune responses fail to provide protection against genital HSV‐2 infection in the absence of IL‐15

“…-/-mice fails to provide protection against HSV-2 challenge It is documented that intranasal immunization provides protection against subsequent intravaginal (IVAG) HSV-2 challenge in normal mice [36,37] (Fig. 3).…”