Colorado State University researchers have been awarded a five-year, $3 million grant from the National Institutes of Health to conduct a pioneering study to examine the long-term effectiveness and safety of tuberculosis vaccines. The scientists are determining if the most promising new vaccines – proven successful in short-term studies – can remain effective over the long term and if specific vaccines could actually be damaging to the lungs over time.
Researchers Ian Orme, professor of microbiology, and Randy Basaraba, associate professor and pathologist in the Department of Microbiology, Immunology and Pathology, are striving to provide the first fundamental scientific information regarding pathological changes in the lungs induced by tuberculosis vaccinations.
"This has not been looked at before and is the next important step in our tuberculosis vaccine research. We know that several tuberculosis vaccines seem to be effective in the short term, but there is not a lot known about how these work at the basic pathology level," said Orme, principal investigator of the study. "However, we are also going a step further with our research to look at the long-term safety and effectiveness of TB vaccines, another area which has previously received very little attention."
Several new TB vaccines are being developed that have the potential of curbing or eliminating the disease that kills more than 3 million people each year. However, there is not a lot known about how the vaccines actually protect people. For example, a vaccine could quickly work to inoculate someone against TB, but more research needs to be done to determine if the protection induced by the vaccine will last many years and whether the immunity that is expressed could be damaging to the lungs over this period of time.
"Even after years of research, we still do not know exactly how vaccines work in the lungs," said Basaraba. "This study will go a long way in filling those gaps in our knowledge and help determine which vaccines are the most effective over the long term in controlling, delaying or even preventing the development of TB."
The primary objectives of the Colorado State research project include:
- determining precisely how promising TB vaccines affect lung pathology;
- determining how the effectiveness and safety of these vaccines change over the long term; and
- determining how the lung pathology, effectiveness and safety of the vaccines differ when given in a post-exposure mode, or after someone contracts the bacterium but has not yet developed the disease.
In addition, the research will provide a framework for efficacy and safety testing of new tuberculosis vaccines for the future. The study will also produce results that can be used to create guidelines for testing which may reduce the time needed for approval of new vaccines.
"Most examinations of vaccine effectiveness are short-term studies and fail to address emerging questions of extreme importance regarding the long-term efficacy of promising new vaccines, as well as their long-term safety," said Orme.
The safety issue is currently of great concern to the researchers because of a newly emerging category of live vaccines derived from mutated TB bacteria. According to the Colorado State researchers, this new class of potential vaccines has great promise but also carries big risks. Previous studies have provided no long-term safety data about these types of vaccines.
With more than 8 million verifiable new cases of tuberculosis each year, there is an urgent need for more effective vaccines. Furthermore, recent data suggests that the current annual death rate of 3.3 million people per year due to the disease may be increasing. Nearly one-third of the world’s population, approximately 2 billion people, is believed to be infected with TB, the leading cause of death due to an infectious agent.
Due to the resurgence of the disease in recent years, there has been a concerted effort to develop a new vaccine against tuberculosis. The existing vaccine, BCG, has been used for many decades, but clinical trials have revealed a lack of effectiveness in adults. Chemotherapy has reduced death rates in recent years; however, this approach already is losing ground against the increasing numbers of TB strains expressing multi-drug resistance.
"Resolution of the TB epidemic will require improved vaccination strategies," said Orme. "A better understanding of how tuberculosis and its vaccines work at the cellular and molecular levels should enhance treatment approaches."
Orme is a world-renowned expert in TB research and has made major contributions to understanding the mechanisms at work in immunity to tuberculosis, resulting in 200 publications in medical journals. His TB-related work has generated more than $50 million in research support at Colorado State and led to several breakthroughs in the field.
Among other accomplishments, in recent years Orme has developed various models for the study of TB that are now widely used in vaccine and drug screening, work for which he was appointed a Fellow of the American Academy of Microbiologists in 2002. In addition to TB vaccine development, Orme also heads a research team working on a separate seven-year, $3.4 million NIH contract to screen the most promising TB treatment drugs.