Delivery systems: a vaccine strategy for overcoming mucosal tolerance?

Antigens administered via the oral and, to a lesser extent, the nasal route are potentially able to invoke tolerance, resulting in a nonreactive immune response. This has been a hurdle for mucosal vaccine development and yet the desire to induce protective local and systemic responses, with pain-free and more convenient products, has been the impetus driving mucosal vaccine R&D. Nevertheless, few mucosal vaccines have reached the marketplace and products are still treated with caution, particularly where live organisms are utilized. In this review, we examine the use of delivery systems with adjuvant properties as key components in a vaccine strategy that does not require the use of live vectors to overcome tolerance and have exemplified their success in mucosal vaccines, concentrating on the nasal and oral routes of administration

Oral delivery of tetanus toxoid using vesicles containing bile salts (bilosomes) induces significant systemic and mucosal immunity

Protein antigens administered via the oral route are exposed to a hostile environment in the gastrointestinal tract, consisting of digestive enzymes and a range of pH (1-7.5). Using a delivery system can afford protection to entrapped components against degradation and permit delivery of antigen to the cells responsible for generating local and systemic immune responses. In this comparative study, mice were immunised orally with tetanus toxoid (40 or 200 μg dose/mouse, four doses in total) entrapped in non-ionic surfactant vesicles formulated with bile salts (bilosomes). The higher entrapped dose (BV-TT, 200 μg) induced IgG1 by study week 3 to similar levels to those observed with subcutaneous un-entrapped TT at the lower (<50 μg) dose. However, both bilosome formulations (BV-TT, low, and high doses), though not un-entrapped TT, caused a rise in the numbers of IgA positive plasma cells observed in the small intestine, primarily in the first 15 cm of the small intestine

Optimisation of a lipid based oral delivery system containing A/Panama influenza haemagglutinin

Vaccine antigens administered by the oral route are often degraded by gastric secretions during gastrointestinal transit. This necessitates larger and more frequent doses of antigen for vaccination. A delivery system, which overcomes this, is a lipid vesicle containing bile salts (bilosome), which prevents antigen degradation and enhances mucosal penetration. The effect of bilosome formulation modification on vaccine transit efficacy across the mucosa was determined. Specific antibody levels were assessed by end-point titre ELISA and the subclasses determined. Significant IgG1 titres were induced when the protein loading was doubled from 15 to 30 μg (P=0.009) and was equivalent to antigen administration by the subcutaneous route. No IgG2a was induced, indicating the generation of a TH2 response. Significant mucosal IgA levels were also observed with this treatment group (P=0.05)

Immune responses to a GnRH-based anti-fertility immunogen, induced by different adjuvants and subsequent effect on vaccine efficacy

A modified GnRH peptide (CHWSYGLRPG-NH2) was conjugated to tetanus toxoid and formulated with different adjuvants (non-ionic surfactant vesicles, aluminium hydroxide, Quil A, PLGA (poly(lactide-co-glycolide)/triacetin), and Quil A/PLGA). A comparison of the anti-fertility efficacy of the formulations was made by examining specific antibody levels, antibody subclasses, endocrine ablation and gonadal atrophy. The production of IgG2b antibody provided the best correlation for castration. PLGA was considered the most effective adjuvant as it produced a consistent anti-fertility response in all the treated animals

Transferrin conjugation confers mucosal molecular targeting to a model HIV-1 trimeric gp140 vaccine antigen☆

The generation of effective immune responses by mucosal vaccination without the use of inflammatory adjuvants, that compromise the epithelial barrier and recruit new cellular targets, is a key goal of vaccines designed to protect against sexually acquired pathogens. In the present study we use a model HIV antigen (CN54gp140) conjugated to transferrin (Tf) and evaluate the ability of the natural transferrin receptor CD71 to modulate immunity. We show that the conjugated transferrin retained high affinity for its receptor and that the conjugate was specifically transported across an epithelial barrier, co-localizing with MHC Class II+ cells in the sub-mucosal stroma. Vaccination studies in mice revealed that the Tf-gp140 conjugate elicited high titres of CN54gp140-specific serum antibodies, equivalent to a systemic vaccination, when conjugate was applied topically to the nasal mucosae whereas gp140 alone was poorly immunogenic. Moreover, the Tf-gp140 conjugate elicited both IgG and IgA responses and significantly higher gp140-specific IgA titre in the female genital tract than unconjugated antigen. These responses were achieved after mucosal application of the conjugated protein alone, in the absence of any pro-inflammatory adjuvant and suggest a potentially useful and novel molecular targeting approach, delivering a vaccine cargo to directly elicit or enhance pathogen-specific mucosal immunity