Oral Vaccines Development

 

To generate serum antibodies, vaccines are typically injected parenterally (systemically) via intradermal, subcutaneous, or intramuscular routes. These immunization routes may also generate antibodies in the mucosa, since high levels of IgG present in the plasma will also diffuse into mucosal tissues and secretions. However, generation of local immune responses within the mucosa itself may be beneficial for generating protection against mucosal pathogens. Since the mucosal immune system is stimulated daily by large amounts of food and microbial antigens, co-administration of antigen with a mucosally active immune stimulant (called an “adjuvant”) is necessary to bypass normal mechanisms of oral tolerance and generate an immune response.

 

Mucosal adjuvants are usually applied directly to mucosal surfaces by oral, intragastric, or nasal instillation. Cholera toxin (CT) is the classic “gold standard” mucosal adjuvant. However, despite its efficacy in inducing immune responses, as little as 5 mg of oral CT causes secretory diarrhea in humans. Nasal or gastric immunization with antigen plus CT has also been associated with IgE-associated adverse effects and death following booster immunizations in experimental animals. These side effects make CT unacceptable for use as a mucosal adjuvant in humans. Alternatively, mixtures of cytokines such as IL-1, IL-12, and IL-18 have been shown to have strong adjuvant effects on nasal mucosa. Development of adjuvants that similarly enhance response to oral vaccines would be particularly attractive, offering the potential of needle-free, painless, and potentially less expensive administration than injected systemic vaccines.

 

Contrary to expectations for a protein ingested without adjuvant, Dr. Hales’s group found that repeated oral exposure to the plant proteinase bromelain induced strong, dose-dependent serum anti-bromelain antibody responses. Bromelain thus appears to serve as a self-adjuvant for induction of anti-bromelain antibodies. Using bromelain as a model, studies in the DHVI Program in Oral Vaccines are currently investigating the mechanisms responsible for the immunogenicity of antigens presented orally and determining whether the potential adjuvant activity of bromelain extends to co-administered or cross-linked antigens.