A century ago, exposure to infectious diseases often meant serious illness and—too often—even death. But because of medical and technological leaps, vaccines have disarmed many of these infectious agents.
Today vaccines help protect us from many diseases by stimulating our immune systems to fight off the germs we encounter in our daily lives. Effective vaccines already exist for several infectious diseases, such as polio, measles, and hepatitis, but vaccines for other harmful diseases have yet to be discovered.
Physician-researchers in the University of Minnesota Medical School’s Department of Pediatrics are working to develop vaccines for several of those diseases and reduce their burden on children and families everywhere.
And one group of University researchers, led by pediatric neuro-oncologist Christopher Moertel, M.D., and scientists John Ohlfest, Ph.D., and Walter Low, Ph.D., is investigating a different way to use vaccines—to treat, not prevent, a noncommunicable illness: brain cancer.
A new way of thinking
Vaccines generally contain a weakened or inactive form of the germ that causes a certain disease.When those germs are injected into our muscles or fatty tissue, they’re not potent enough to cause disease, but they are strong enough to trigger our immune systems to respond by producing “antibodies” to fight them off. Those antibodies stay with us so if we’re exposed to a live strain of the disease in the future, our bodies will be able to destroy the germs.
Moertel’s brain cancer vaccine works according to a similar principle, he says. The vaccine combines immune cells called dendritic cells from each patient with brain tumor antigen—a substance that prompts the immune system to produce antibodies—before giving them back to the patient.
The combination coaxes patients’ own immune systems to attack brain tumor cells and kill the cancer.
Currently, treating the types of brain cancers Moertel’s therapy is targeting—medulloblastoma, ependymoma, and glioblastoma—requires a combination of therapies, including extensive surgery, radiation therapy, and chemotherapy. This treatment regimen takes a toll on patients and can cause lasting side effects, especially in young children.
Because the experimental vaccine therapy uses patients’ own dendritic cells— found in small quantities mainly in the skin, lymph nodes, and inner lining of the nose, lungs, stomach, and intestines—it shouldn’t be so harsh, Moertel says.
“Effective immunotherapy for brain tumors could revolutionize the field by increasing cure rates while minimizing the side effects,” he says.
So far the vaccine has been successful in treating mice that have brain tumors. Now, with continued funding from the Children’s Cancer Research Fund and the Gateway Foundation, the team is gearing up to extend this treatment to both children and adults through a phase I clinical trial. Moertel expects the trial to begin this winter at the University, the sole location of the study.
“Patients at University of Minnesota Amplatz Children’s Hospital are at a place where leading-edge therapies—including innovative surgery, radiation therapy, chemotherapy, and immunotherapy—are brought from the lab to their bedside,” says Moertel, who is clinical director of the hospital’s Pediatric Neuro-Oncology Program, the first comprehensive research-based brain tumor program in the Midwest and one of only a few in the country.
Ensuring health through prevention
Vaccine research in other areas of the Department of Pediatrics focuses on the more traditional use of vaccines—to prevent infectious diseases.
Cytomegalovirus (CMV) is harmless to most healthy adults, but it can cause hearing loss and brain damage in fetuses whose mothers are infected for the first time during the pregnancy. It’s the second-leading cause of mental retardation after Down syndrome.
Mark Schleiss, M.D., head of the Division of Pediatric Infectious Diseases, is working to understand the biology behind CMV and develop strategies for preventing harm to newborns.
One of those strategies is to develop a vaccine for women of childbearing age, Schleiss says. But despite numerous efforts, researchers have not yet found a safe and effective vaccine to protect the developing fetus.
In the past year, Schleiss and his colleagues took a major step forward in tests involving an animal model of CMV. By deleting genes that allow the virus to evade immune system defenses, the team created a disabled live virus vaccine that reduced the risk of harm from CMV exposure to offspring during pregnancy while also reducing the risk of adverse effects from the immunization.
Schleiss hopes to build on these results to eventually perfect a vaccine that protects babies from CMV.
Opportunity for impact
Pediatrics professor Patricia Ferrieri,M.D., has been collaborating with colleagues at the University of Pittsburgh Medical School, Baylor College of Medicine, and Harvard Medical School on a vaccine for Streptococcus agalactiae or Group B streptococci (GBS). Like CMV, this bacterial pathogen threatens newborns and fetuses with serious infection if their mothers have the GBS bacterium.
A preliminary trial of a vaccine in nonpregnant women has shown a marked decrease in genital acquisition of GBS in those who received the vaccine. This holds promise for preventing the transmission of GBS from women of childbearing age to their babies, Ferrieri says.
Ferrieri has been instrumental in developing animal models of GBS infection that mimic the disease in newborn infants as part of an overall strategy to develop a way to protect mothers and their babies against this potentially fatal infectious disease. For several years, Ferrieri’s work has focused on specific GBS proteins that induce protective antibodies, and some of these proteins have been incorporated into experimental vaccines.
The entry of vaccine companies—with their use of molecular genetic approaches—into this research field has had a huge impact on the work, says Ferrieri, who directs the Clinical Microbiology Laboratory at University of Minnesota Amplatz Children’s Hospital.
“The opportunity has never been greater than now to move forward with these novel vaccine constructs,” she says.
Continuing the search
Edward Kaplan,M.D., a pediatric cardiologist and an infectious disease expert, is looking for ways to outwit yet another ubiquitous and elusive vaccine target: Group A streptococci.
Most commonly known as a cause of sore throat—some 5 to 7 million cases each year in the United States alone—Group A strep can also lead to heart damage, kidney disease, and necrotizing fascitis—the bacterium of “flesheating” fame. Yet after decades of searching, a Group A strep vaccine is still unavailable.
The challenge, Kaplan says, is the bacteria’s biodiversity.There are about 130 versions of Group A strep.That means it’s hard to decide which to vaccinate against.
Kaplan is working with P. Patrick Cleary, Ph.D., of the Medical School’s Microbiology Department on a promising approach to combating this disease.
“From a prevention, public-health point of view, everything is ripe for a vaccine,” says Kaplan, who is head of the Streptococcal Reference and Research Laboratory. “One of these days, such an important vaccine will be available.”