Novel pathway for a mucosal TB vaccine

Lead author on the study is Shabaana A. Khader, PhD, of the Department of Pediatrics, University of Pittsburgh; co-authors are Terry D. Connell, PhD, professor of microbiology and immunology in UB's School of Medicine and Biomedical Sciences and researchers from the University of Rochester and the University of Alabama.

The new pathway was identified in animal studies using LT-IIb, a novel, mucosal adjuvant, developed by Connell, who has shown that LT-IIb dramatically boosts the potency of vaccines that are administered to mucous membranes. Adjuvants enhance the body's immune response against an antigen.

"This research demonstrates that the most effective vaccination against TB should target the IL-17 pathway," says Connell, former director of UB's Witebsky Center for Microbial Pathogenesis and Immunology.

"This observation is in stark contrast to the importance of the IFN-γ and T helper 1 pathways in combating TB infection in the body, which have been the traditional targets for TB vaccines," he says.

"While those pathways are essential in overcoming infection, this published study indicates that they are likely to be less important in vaccination to elicit immune protection against TB," he explains. The mechanisms that modulate IL-17-based protection are now being studied in laboratories around the world, he adds.

Connell's lab is leading the study of LT-IIb and similar adjuvants that are derived from a unique group of bacterial proteins that belong to the type II family of bacterial heat-labile enterotoxins (HLT). These HLT are similar in structure and toxicity to cholera toxin but interestingly, Connell notes, do not exhibit any detectible toxicities when employed as mucosal or systemic adjuvants.

"The adjuvants, which UB patented in 2008 have some unique characteristics," says Connell.

"Depending on the type of adjuvant, one can either enhance the body's ability to make antibodies or enhance the body's cytotoxic response. The great benefit of our type II HLT adjuvants is that these molecules can activate both pathways," he says. "We can direct the type of immune response to the vaccine that is desired, whether an antibody response or a cellular response, simply by choosing one or the other type II adjuvant."

Connell notes that there is a big push for development of mucosal vaccines against a number of pathogens in addition to TB that could be administered by some other route than injection. That's because in the developing world, where the need for TB vaccination is greatest, it's very difficult to store vaccines for long periods of time in conditions required for their stability, termed "the cold chain," which is routinely required to maintain the efficacy and safety of most, if not all, injectable vaccines.

"Clearly, for use in developing areas of the world, the most optimal vaccine and adjuvant mixture would not require the 'cold chain,'" says Connell. "Our mixtures of adjuvants and vaccines can be dried into a powder and stored on a shelf without refrigeration until needed."

At that point, the adjuvant/vaccine powder would be added to water sterilized by boiling; the solution could then be sprayed into the nose from an atomizer.

The emergence of drug-resistant strains of Mycobacterium tuberculosis, and the more than 1.7 million deaths each year attributable to the disease has provided a strong impetus for researchers to develop new methods to improve mucosal vaccines against tuberculosis. Connell says the next step for this collaborative research is to identify the cellular and molecular mechanisms that underlie the capacity of LT-IIb to induce IL-17-associated immune response to antigens and pathogens.

"Once those mechanisms, have been identified, new mutant HLT can be engineered to further optimize the capacity of these adjuvants to enhance desired immune responses to candidate TB vaccines," he says.

The research was funded by the National Institutes of Health and the Children's Hospital of Pittsburgh.