BUFFALO, N.Y. – A new pathway for improving vaccines
against tuberculosis has been discovered by microbiologists at the
University at Buffalo in collaboration with researchers at other
universities, according to a paper in the journal Mucosal
Immunology, published by the Nature group.
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
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
“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,
“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
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.