Scientists at UB, the VA Medical Center and Roswell Park Cancer Institute have received a $2 million program project grant from the National Institutes of Health to perform research aimed at developing vaccines to prevent ear infections in children and respiratory tract infections in adults with chronic lung disease.

The four-year program includes three separate but related projects, all geared toward understanding the human immune response to the bacteria that cause these infections—information that will lead directly to the development of vaccines.

Timothy Murphy, professor of medicine and microbiology, and chief of infectious diseases at UB and the VA hospital, will direct the overall program and head one of the research projects.

Murphy has had a long-standing interest in ear infections and infections in adults with chronic lung disease. He holds several patents involving vaccines, including the P6 protein, which he discovered and has been studying for 15 years. It is a promising vaccine candidate for the prevention of infections caused by nonencapsulated strains of the bacterium Haemophilus influenzae and currently is being tested in early clinical trials in humans.

All three projects include studies of clinical samples emanating from a chronic obstructive pulmonary disease (COPD) study clinic conducted at the VA hospital by Murphy and Sanjay Sethi, UB associate professor of medicine, continuously since 1994. It is the longest running study clinic for COPD in the United States.

Approximately 25 million episodes of middle ear infections occur in children in the U.S. annually at an estimated cost of $3 billion.

"Children who experience recurrent ear infections suffer hearing loss at a time critical for acquiring speech and language," Murphy said. "This may lead to a delay in language development and to learning problems in school. For these reasons, there is a strong interest in developing vaccines to prevent ear infections.

"The same bacteria that cause ear infections are responsible for the respiratory tract infections seen in COPD," Murphy said, "so vaccines developed for these bacteria would be tested in both populations."

COPD is the fourth leading cause of death in the U.S and is responsible for an estimated $11 billion in health-care costs. Bacterial infections in patients with COPD lead to hospitalization, respiratory failure and death.

"Preventing infections in COPD would have a huge impact on the course of the disease," Murphy said.

His project consists of experiments to determine the human antibody response to the bacterium Moraxella catarrhalis, which is a common cause of ear infections in children and of lung infections in adults with COPD. This project will use a unique collection of samples obtained from the VA COPD study. A total of 110 veterans have been followed in the clinic.

"These samples provide a unique opportunity to learn about the immune human response to M. catarrhalis," Murphy said. "A variety of tests will be performed to learn exactly what type of immune response in humans allows a person to be protected from infection. This type of information is critical to evaluating the efficacy of any vaccine for M. catarrhalis tested in the future."

Yasmin Thanavala, cancer research scientist at Roswell Park, and Anthony Campagnari, UB associate professor of microbiology, each will direct one of the remaining projects.

Thanavala is an immunologist who has performed groundbreaking research in the development of vaccines for hepatitis, including the "potato vaccine" currently undergoing testing in humans. Her project involves detailed studies of the P6 protein, a promising vaccine candidate to protect against infections caused by H. influenzae, a common cause of recurrent ear infections in children and lung infections in adults with COPD.

Thanavala will study the human immune response to specific regions of the P6 molecule. She will introduce human lymphocytes (white blood cells) into mice that lack immune systems, creating an animal model with a human immune system. The mice will be immunized with P6 and the researchers will study the antibody response.

This is the "next best thing" to immunizing people, Murphy said, because the mice make human antibodies. As another part the project, researchers will collect lymphocytes from healthy donors and from adults with COPD and study the response of these cells to P6.

"These experiments will reveal valuable information about how humans respond to P6, which will help to determine its usefulness as a successful vaccine," Murphy said.

Campagnari is an internationally recognized authority in studies of the mechanisms of infection and the immune response to the bacterium M. catarrhalis. His project involves studies of an important molecule on the surface of the bacterium called lipooligosaccharide, or LOS. This molecule is critical to the bacterium's ability to attach to the human mucous membranes and to cause the inflammation seen in the ears of children and the airways of adults with COPD during infection.

"Understanding the specific mechanisms whereby the LOS molecule does this is the first step in designing novel strategies to prevent these deleterious effects of infection," Murphy said. "Dr. Campagnari will clone the genes that are responsible for making LOS and make mutant bacteria with altered LOS molecules. This will allow him to elucidate the role of LOS in infections."

In addition, samples from the COPD study clinic will be used to study the human immune response to the LOS molecule. Campagnari also will collaborate with Howard Faden, UB professor of pediatrics at Children's Hospital of Buffalo, to study samples obtained from children with ear infections.