SLU's Center for Vaccine Development receives $2.9 million to study new vaccine to combat TB

Saint Louis University School of MedicineJun 30 2015

Saint Louis University's Center for Vaccine Development has received a $2.9 million award from the Bill & Melinda Gates Foundation to study a new tuberculosis vaccine.

With the award, Daniel Hoft, M.D., Ph.D., director of the division of infectious diseases at Saint Louis University, will continue studying the role of a special subset of T cells - gamma/delta T cells - in fighting TB. An integral part of our immune system, T cells are a type of white blood cells that recognize the presence of a foreign invader in the body and destroy it or help other cells to initiate an attack.

Concentrated in the skin and mucosal surfaces, gamma/delta T cells in our immune system are the soldiers on the front line and mount a rapid response in protecting our bodies against invading pathogens. Gamma/delta T cells have direct protective effects but also serve as a bridge between innate immunity, which is a generic first response to all types of pathogens, and adaptive immunity, which recognizes, remembers and destroys specific pathogens.

Only 5 percent of T cells in the blood are gamma/delta T cells; most others are alpha/beta T cells. The major difference between gamma/delta and alpha/beta T cells is the molecule found on their surface, which fits to a specific antigen like a lock and key. These molecules, called T cell receptors (TCR), are encoded by different but similar genes that are either gamma/delta or alpha/beta gene pairs. Most scientists have focused on alpha/beta T cells as vaccine targets for inducing protection against tuberculosis.

With this funding, Hoft will explore using a type of gamma/delta T cells - gamma 9/delta 2 T cells - to marshal the immune system to fight TB by recognizing TB germs that live inside a group of white blood cells called macrophages throughout the infected person's body, and preventing uncontrolled pathogen growth.

TB is a massive world health problem. About a third of the world's population is infected with TB, meaning they have TB bacterium in their bodies that might not cause active disease. More than 1 million people die from TB each year.

We need a new approach to fight TB, Hoft says, because TB is becoming increasingly resistant to current therapies and many patients are sicker and more complicated to treat because they also are infected with HIV.

"We are in grave danger of all current TB preventive and curative measures becoming useless," Hoft said. "The goal of this investment is to develop novel vaccines with the potential to significantly reduce TB infection and disease. Success in achieving this goal could lead to important new public health tools worldwide."

Hoft's project will:

•Identify the specific TB antigens that induce protective gamma 9/delta 2 T cells
•Test a vaccine made from the specific gamma 9/delta 2 T cell-inducing TB antigens in an animal model
•Determine the sequences of gamma/delta T cell TCR that are most important in protecting against TB by comparing South Africans exposed to TB who did or didn't get infected

Funding of Hoft's work comes after a much anticipated clinical trial of a new TB vaccine didn't protect 2,800 South African infants from infection with TB or subsequent illness.

"It was the culmination of 15 years of research in thousands of labs world-wide, all focused on one strategy - to induce a strong immune response from alpha/beta T cells," Hoft said. "We've led the field in a different approach that shows gamma/delta T cells can be a relevant target for the development of a TB vaccine, and hope to accelerate our research with the ultimate goal of protecting people from TB."

The current TB vaccine, Bacille Calmette-Guerin (BCG), is given to infants who live in countries where TB is common, and protects them for five years from TB meningitis and death from TB. However, the vaccine is only about 50 percent effective in protecting adults from lung TB, the most common and most infectious form of the illness.

"We need something better," Hoft said.

With Hoft as overall PI, the research is expected to take three years and will include scientists from South Africa, the University of Illinois, Stanford University and Colorado State University.