Mucosal immunity provides an important defense mechanism against a wide variety of pathogens. In this regard, the mucosal surfaces of the gastrointestinal, respiratory and genitourinary tracts are continuously exposed to foreign antigens, including potentially infectious bacterial, viral and sometimes parasitic organisms. Mucosal immune responses protect against such challenges and have distinct and specialized characteristics.
For example, the principal immunoglobulin produced by the mucosal immune system is secretory IgA. Specialized antigen uptake cells in the Peyer's Patches of intestinal tract or nasopharyngeal lymphoid tissues, termed microfold or M cells, transport antigen to the underlying mucosal associated lymphoid tissues (MALT). In other areas of the mucosal epithelium, such as the pseudo-stratified airway epithelium, dendritic cells serve as antigen-presenting cells and migrate to local lymph nodes or MALT. Antigen processing and presentation occurs in the MALT, resulting in activation of antigen-specific IgA B cells. The subsequent trafficking and recirculation of the activated IgA-B cells to other components of the mucosal immune system, e.g., the respiratory, intestinal and genital tracts, provides for disseminated local mucosal IgA responses throughout the “Common Mucosal System.” Thus, the mucosal immune system is uniquely suited to respond to the types of antigenic challenge encountered by mucosal surfaces, and may provide the most effective type of immune response against particular pathogens. Accordingly, antigen delivery mechanisms which target the mucosal immune system provide an attractive means for achieving immunity.
Attempts have been made to use bioadhesive polymers for the mucosal delivery of drugs. Bioadhesives are synthetic and naturally occurring materials able to adhere to biological substrates for extended time periods. For example, Carbopol and polycarbophil, both synthetic cross-linked derivatives of poly(acrylic acid), display excellent adhesion properties in vitro. However, performance of these bioadhesives has not been duplicated in vivo. Additionally, such bioadhesives may cause local irritation. Hence, few bioadhesive delivery systems are commercially available.
Attention has therefore turned to the development of bioadhesive delivery systems based on naturally occurring substances, such as lectins and fimbrial proteins. These bioadhesives adhere to mucosal cell surfaces via receptor-mediated mechanisms. Another natural bioadhesive is hyaluronic acid, also known as hyaluronan. Hyaluronic acid is a naturally occurring mucopolysaccharide consisting of residues of D-glucuronic and N-acetyl-D-glucosamine. Hyaluronic acid is found in the extracellular tissue matrix of vertebrates, including in connective tissues, as well as in synovial fluid and in the vitreous and aqueous of the eye. Hyaluronic acid has been shown to be bioadhesive both in vivo and in vitro.
Esterified derivatives of hyaluronic acid have been used to produce microspheres that are biocompatible and biodegradable. See, e.g., Cortivo et al., Biomaterials (1991) 12:727-730; European Publication No. 517,565. These microspheres have been used for the mucosal delivery of a number of substances. See, e.g., International Publication No. WO 96/29998. For example, Richardson et al., Int. J. Pharm. (1995) 115:9-15), describe the vaginal delivery of calcitonin in rats. Additionally, Illum et al., J. Controlled Rel. (1994) 29:133-141 and European Publication No. 517,565 describe the use of hyaluronic acid ester microspheres for the intranasal delivery of insulin in sheep.
However, the use of hyaluronic acid derivatives to deliver vaccine antigens has not heretofore been described.