A new tuberculosis vaccine engineered by UCLA scientists specifically for HIV-positive people has been shown to be safer and more potent than the current TB vaccine in preclinical studies.

A more effective TB vaccine may help curtail the global spread of the disease, especially in HIV-positive people, for whom tuberculosis is the leading cause of death worldwide.

"The AIDS and tuberculosis epidemics are now so intertwined in many parts of the world that we can't win the fight against one of these diseases without also taking on the other," said principal investigator Dr. Marcus Horwitz, a professor of medicine and of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA.

The current TB vaccine, known as BCG, is administered to newborns in most countries in the world. However, in HIV-positive people, the vaccine can cause serious and even fatal disease later in life if HIV weakens the immune system, allowing the vaccine to multiply unchecked and spread throughout the body.

To address this problem, Horwitz and his team used an innovative method to limit the number of times the new vaccine can replicate itself in the body - just enough to stimulate the immune system to produce T cells to fight future infection with the TB bacillus but not enough to overwhelm the immune system if it subsequently becomes weakened by HIV.

The scientists' research shows that the new vaccine better protected guinea pigs from tuberculosis than the current vaccine. Guinea pigs are highly susceptible to infection with Mycobacterium tuberculosis, the bacterium that causes most cases of tuberculosis in humans, and they develop tuberculosis remarkably similar to the disease in humans. The researchers also showed that the new vaccine is much safer than BCG in a severely immunocompromised animal host - mice with severe combined immunodeficiency (SCID), which completely lack an immune system.

While the vaccine could be administered to anyone, it is specifically designed to be given to HIV-positive newborns and adults whose immune systems are still relatively intact and are therefore able to mount a good immune response to the vaccine, including persons on antiretroviral therapy.

The next step, according to researchers, is to test the vaccine in humans. It will take several years of further study before the vaccine is available to the public.

In devising the new vaccine, Horwitz and his team modified the current BCG vaccine, which is a weakened form of a bacterium closely related to the one that causes tuberculosis. First, to make it more potent and induce a stronger immune response, the scientists engineered the vaccine so that it would produce large amounts of a key protein of Mycobacterium tuberculosis called mycolyl transferase.

Second, to make the vaccine safer, the team altered the BCG vaccine so that it was only capable of multiplying a few times after it was injected into the body. To do this, the researchers eliminated the vaccine's ability to acquire iron from the host; iron is an essential nutrient for the vaccine to multiply. Technically, researchers used a genetic "knock-out" technique to render iron-scavenging molecules, called siderphores, inoperative. The new recombinant BCG vaccine was named rBCG(mbtB)30.

The scientists then preloaded the new vaccine in the lab with just enough iron to allow it to replicate a few times in the host. When this stored iron was used up, the vaccine was no longer able to multiply.

"This is one of the first vaccines developed to replicate only a few times in the host and the first to do so by eliminating the vaccine's ability to acquire iron in the host," said study author Michael V. Tullius, an assistant researcher in the UCLA Department of Medicine's division of infectious diseases.

"Preloading the vaccine with a specific amount of iron allows us control over the vaccine's safety and effectiveness in the host," said Horwitz, a specialist in infectious diseases.

The authors note that since iron is a key nutrient needed by all bacteria to thrive, this approach may be applicable to other live bacterial vaccines for diseases such as anthrax, tularemia and Legionnaires' disease.

"Tuberculosis is of the biggest concern to people with HIV. At the same time, the only existing tuberculosis vaccine, BCG, should not be used in people with HIV because it poses a health risk by itself," said Ulrich Fruth, of the World Health Organization's Initiative for Vaccine Research. "It would be wonderful news if this new vaccine, if it can be shown to be safe and efficacious in people with HIV, could help overcome this Catch-22."

About 2 billion people in the world harbor Mycobacterium tuberculosis, mostly in a latent state, and about 9 million people develop active tuberculosis each year. Approximately 12 million people throughout the world are infected with both Mycobacterium tuberculosis and HIV - about a third of all persons infected with HIV. These co-infected people have the greatest susceptibility of developing active tuberculosis, the major opportunistic infection in AIDS patients.

The study was funded by the National Institutes of Health.

Additional authors include Günter Harth, Saša Masleša-Galic, and Barbara J. Dillon, all of the division of infectious diseases at the David Geffen School of Medicine at UCLA.

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