Texas, Brazilian Scientists Collaborate on Novel TB Vaccine

The National Institutes of Health has awarded a $3.4 million grant to the Southwest Foundation for Biomedical Research (SFBR) to study a vaccine for tuberculosis (TB), one of the leading killers of young adults worldwide, causing 3 million deaths annually.

Dr. John VandeBerg, director of the SFBRs SouthwestNational PrimateResearchCenter, will be the primary investigator under the four-and-a-half year grant, which supports the efforts of an international team of investigators.

Dr. Celio Lopes Silva of the University of Sao Paulo [in Brazil] has taken a novel approach to designing this vaccine, which is intended to be both preventive and therapeutic, and it has already shown impressive preliminary results in mice, VandeBerg said. Its exciting for us to carry forward his work on a vaccine that could eventually save millions of lives.

The World Health Organization (WHO) considers TB among its top three priorities for infectious diseases urgently in need of research. The others are malaria, which kills more than 1 million people annually, and AIDS, which causes more than 3 million deaths each year. The bacterium that causes tuberculosis infects 2 billion people, or nearly a third of the worlds population. While the vast majority maintain latent infections that are not contagious and do not cause health problems, each year approximately 8 million develop the active, infectious disease, and 2 million to 3 million die from tuberculosis. Experts believe 10 million Americans are infected with the TB bacterium, and of those, about 10 percent will get sick with the disease.

TB is an infectious disease that primarily attacks the lungs, although it can attack any part of the body. Symptoms of the active disease typically include a bad cough that lasts three weeks or longer, pain in the chest, coughing up blood, fatigue, weight loss, loss of appetite, chills, fever, and night sweats.

TB infections in the United States began declining in the 1940s, when effective antibiotic treatments were introduced. However, infections have been on the rise since the mid-1980s for a number of reasons, including the AIDS epidemic HIV and TB are common co-infections and patients failure to comply with the lengthy course of treatment, which can last up to a year. These factors have contributed to TBs increasing resistance to antibiotics, adding to the seriousness of the disease and increasing the need for an effective vaccine.

One TB vaccine, the BCG vaccine, is already used in some countries, but it has several shortcomings, including poor efficacy in adults, wide variation in its efficacy in children, and interference with the TB skin test. The Silva vaccine may have the ability to overcome these problems because of its novel design, including its own built-in booster mechanism.

VandeBerg said the grant, awarded by the NIHs National Institute of Allergy & Infectious Diseases, has two major purposes: to test the Silva vaccine for its ability to prevent infection, and to test it as a therapy against an already active infection. Scientists also expect to advance the medical communitys understanding of the bodys natural immune response to TB infection as well as how this vaccine affects that immune response and to determine the appropriate vaccine dosage.

The possibility of a vaccine that is both preventive and therapeutic could be a major advance for global health, said VandeBerg. This vaccine could potentially be used to help control the disease in the millions of people already suffering from active tuberculosis, and it could be used to prevent billions more from becoming infected with the bacterium in the future.

Silvas vaccine is based on heat shock protein 65 (hsp65), which is isolated from the TB bacterium and stimulates an immune response when injected into animals or people. While scientists have attempted for decades to develop TB vaccines centered on hsp65, Silva added some new twists.

For one, he uses microspheres of biodegradable materials that encapsulate the hsp65 protein and delay its release into the body. However, the microspheres also contain the hsp65 DNA, which is much smaller in size and can immediately escape from the microspheres. The DNA quickly starts to produce the protein, stimulating the bodys primary immune response. Then, a few weeks later, after the various layers of the microsphere melt away, the hsp65 protein itself is released into the body, essentially providing a booster shot that stimulates a secondary immune response.

For added punch, Silva also incorporated a glycolipid to the vaccine formula, which enhances the bodys own immune response to TB infection.

Silva and his team have successfully tested the vaccine in various animal models, but not in non-human primates, whose immune characteristics are more similar to humans. SFBRs primate center is known worldwide for the quality of its primate-based research.

This study will utilize the primate centers rhesus monkey population. Rhesus monkeys are the nonhuman primates most susceptible to developing tuberculosis. They are also the most commonly used animal model in research on HIV. This combination of characteristics will enable scientists to study the vaccines effect on TB infection alone and in cases involving TB and HIV co-infection.

The Foundations laboratory facilities, including two new biosafety level 3 facilities capable of handling nonhuman primates, are also ideally suited to the project. VandeBerg believes this study will establish the expertise, technologies and other capabilities of the Southwest National Primate Research Center to collaborate with investigators from all over the world who need to test novel TB vaccines and drug treatments.

In addition to VandeBerg and Silva, other collaborators on this research project include Dr. Maria da Glória Bonecini de Almeida of the Oswaldo Cruz Foundation, Brazilian Ministry of Health, and Drs. Luis Giavedoni, Ana Cristina Leandro, Gene Hubbard and Edward Dick, all with SFBR. Bonecini de Almeida, Giavedoni and Leandro are immunologists who will study the animals natural immune response to the TB bacterium and to the vaccine. They also will determine the extent of immunological protection provided by the vaccine. Hubbard and Dick will provide pathology support to determine the effectiveness of the vaccine to prevent infection and to eradicate TB bacteria from the lungs and other tissues. Veterinary support will be directed by Dr. Melissa de la Garza, also with SFBR.

Source: Southwest Foundation for Biomedical Research