TB research foundation announces vaccine grants

December 13, 2000

Tuberculosis Research Foundation announces first recipients of Vaccine Innovation Program (VIP) grants

The Sequella Global Tuberculosis Foundation today announced the first recipients of the inaugural series of VIP grants designed to fund high risk/high reward research that could inform international efforts to create successful new vaccines against tuberculosis. The awards were made possible by a grant from the Bill and Melinda Gates Foundation to develop an international Tuberculosis Vaccine Collaboration. Together the nine VIP grant recipients will receive more than $500,000 during the coming year.

"Each of the funded researchers proposed exceptionally innovative approaches to one aspect of tuberculosis vaccine development, including new adjuvants, delivery mechanisms, immunological approaches, and novel antigens. Any one of these proposals could result in a new approach to vaccination against tuberculosis, an infectious disease that kills more than two million people each year." said Dr. Carol A. Nacy, President of the Sequella Global Tuberculosis Foundation. A listing of the recipients with a synopsis of the projects is attached. More detailed information is available on the Foundation's website: http://www.sequellafoundation.org.

"Taken together, these projects represent the broad spectrum of issues confronting a new and effective tuberculosis vaccine. Our call for proposals generated a variety of projects that demonstrated the extraordinary creativity of the tuberculosis research community," Nacy added.

Sequella used a web-based system for recruiting and managing the proposal process. Application information was available only on the Foundation's website, applicants were encouraged to submit their applications electronically, and reviewers shared their comments via email. Nacy suggested that this is why more than half of the VIP grant recipients are located outside the United States, and also why it took less than 12 weeks from the date of the VIP announcement to the award of the grants.

The Sequella Global Tuberculosis Foundation was established in 1997 to bring the creativity and ingenuity of contemporary medical research to the tasks of tuberculosis diagnosis, prevention, and cure worldwide.

Vaccine Innovation Program Grants

Zhou Xing, McMaster University, Hamilton, Ontario, Canada
Dr. Xing's project was funded for its innovative use of an adenoviral-based delivery of TB DNA vaccine constructs. Such viruses have been used to carry DNA expressing other foreign proteins for the purpose of gene therapy, where multiple injections of the recombinant adenovirus is contemplated. Immune reactions to the adenovirus vector itself limited its usefulness in gene therapy. This is the first effort to use these viruses as a vector for a Mycobacterium tuberculosis antigen given once as a vaccine priming dose (and not anticipated to be given as multiple doses).

Glyn Hewinson, Veterinary Laboratories Agency, Surrey, United Kingdom
Dr. Hewinson's project was funded to enable this group to challenge with Mycobacterium bovis cows vaccinated previously with a heat-shock protein that has demonstrated efficacy in a murine model of TB disease. This will be the first time that the heat-shock protein DNA vaccine will be tested in a large animal, and may pave the way for further clinical development and assessment of protection against M. tuberculosis in humans.

Adrian V.S. Hill, Oxford, United Kingdom
Dr. Hill's work will identify immunologically important fragments (epitopes) of Mycobacterium tuberculosis proteins by sequencing the fragments eluted from Major Histocompatibility Complex (MHC) proteins on the surface of antigen-presenting cells from humans immune to TB. These MHC:epitope complexes dictate the direction and amplitude of the cellular and humoral response to TB. This approach may provide insight into epitopes that are universally recognized as important to the immune system by people with differing genetic backgrounds, and could assist in the selection of TB proteins (or fragments of proteins) for a broadly efficacious TB vaccine.

Donatus Dreher, University Hospital of Geneva, Geneva, Switzerland
Dr. Dreher's work will explore use of an invasion-deficient strain of Salmonella typhimurium to deliver genes for M. tuberculosis antigens that are expressed at reduced oxygen tensions or conditions as a vaccine for TB. The antigens included in the vaccine may mimic the intracellular antigens expressed by M. tuberculosis in individuals infected with latent tuberculosis. Use of Salmonella as a live vector for DNA expressing TB antigens is a novel approach to delivery of a TB vaccine.

Richard S. Kornbluth, University of California, San Diego, La Jolla, California
Dr. Kornbluth's work will explore important mechanisms used by the immune system to defend against M. tuberculosis. The hypothesis to be tested is that exogenous oligodeoxynucleotides containing CpG-rich immunostimulatory sequence (ISS) motifs (found in bacterial but not eukaryotic DNA) enhances immunity to M. tuberculosis and that antibodies to the CD40 ligand (anti-CD40L antibody) weakens this immunity. The results of these studies will indicate whether the induction of CD40L by mycobacterial antigens could serve as a surrogate marker of antimycobacterial immunity and if ISS should be advanced as an immunotherapy for the treatment of tuberculosis. The results could have important implications for improving and predicting the efficacy of TB vaccines.

Aharona Freedman, Albert Einstein College of Medicine, Bronx, New York

Dr. Freedman's project will explore the induction of humoral immunity to TB by purifying carbohydrate antigens (arabinomannan) and to develop carbohydate-conjugate vaccine candidates as well as synthesizing peptidomimetics. These constructs will then be used to vaccinate mice against lethal M. tuberculosis challenge. Her approach relies on eliciting a new protective antibody response, and differs from the more traditional approach of stimulating the cellular immune system to combat TB.

Richard Frothingham, Duke University Medical Center, Durham, North Carolina
Dr. Frothingham's study will use a murine model of TB to examine whether or not the protective effects of TB vaccination is lost following the depletion of certain immune system cells, particularly CD4 T lymphocytes, such as occurs with the progression to clinical AIDS of HIV-infected individuals. HIV/AIDS patients run a singularly high risk of succumbing to infection with M. tuberculosis. In fact, in many countries, tuberculosis is the leading cause of death in patients with AIDS. The characterization of this animal model of concomitant TB/AIDS may help us evaluate TB vaccines that could be useful in protecting HIV-infected people from TB.

Christopher C. Dascher, Brigham and Women's Hospital, Boston, Massachusetts
Dr. Dascher will continue studies that explore the role of CD1 antigens of Mycobacterium tuberculosis, lipid antigens, in protection against infection with tuberculosis when formulated as a vaccine. These lipid antigens will be combined with more traditional protein antigens, and the combination vaccine will be tested for efficacy in a guinea pig model of TB. These studies may result in a novel strategy for TB vaccination that is not being explored elsewhere.

Young-Chui Sung, Pohang University of Science and Technology, Pohang, Korea
Dr. Sung's project will determine the efficacy of a mutant form of Interleukin-12 (IL-12) as an adjuvant to stimulate effective murine immune responses to DNA vaccines for protection against TB. This mutant IL-12 has been shown to be substantially more effective in inducing Th1 and CTL responses to hepatitis C virus than the wild-type form. This new adjuvant form of IL-12 may be useful in augmenting the classically weak immunogenicity of DNA TB vaccines, many of which are being explored in animal models.


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