When Steven Varga started learning about immunology, he often thought of the host immune system as an army ready to battle an invading pathogen. This analogy resonated with Varga, who supplemented his undergraduate biology studies with a second major in history—military history in particular.
“That’s ultimately what every immune response is all about,” says Varga, University of Iowa associate professor of microbiology and faculty in the Interdisciplinary Graduate Program in Immunology. “There’s an attacker and a defender, and it’s this ebb and flow of battle between the two that ultimately decides your fate, whether you live or die. Most of the time we live; sometimes pathogens can kill us.”
One of the most persistent of those “attackers,” and the focus of Varga’s lab, is respiratory syncytial virus (RSV).
According to the Centers for Disease Control, RSV is the most common cause of bronchiolitis (an inflammation of the small airways in the lung) and pneumonia in children under one year of age in the United States, and RSV is the leading cause of lower respiratory tract infection in infants worldwide. By the age of two, 95 percent of children have been infected with RSV at least once and, Varga says, by three years of age that number is almost 100 percent.
“I can guarantee that we have all been infected by RSV at least once, and generally multiple times,” says Varga. “There are few pathogens for which I can with certainty make that proclamation.”
For one to two percent of children under the age of two (about 125,000 children), their first RSV exposure lands them in the hospital with impaired breathing that turns out to be a severe lower respiratory tract infection. As the virus attacks the lungs, one of the body’s responses is to make mucus. Older children and adults easily cough this up, but young children sometimes can’t cough enough of it up (especially overnight, lying down horizontally in bed) and their airways become plugged.
"The child exhibits difficulty breathing,” says Varga, “and understandably the parents bring the child to the hospital to see a doctor."
Children hospitalized for a severe RSV infection run a much higher risk of developing asthma and allergies.
An RSV infection does not lead to the acquisition of immunity, and this makes RSV different from most other infections. We continue to be susceptible to repeated RSV infections throughout our lifetime. In young healthy adults, it usually produces only mild symptoms, similar to a common cold.
“You develop sniffles and a cough, maybe a low-grade fever, and you go to work,” says Varga, “and you infect your co-workers, and you move on with your life.”
But for the very young and for the elderly, RSV is a significant cause of disease. For many years most respiratory disease in the elderly was thought to be due to influenza. Now routine molecular analysis after a simple nasal swab can determine which pathogen is causing symptoms, and RSV comes up regularly in these screenings. And in non-pandemic years (i.e., excluding 2009’s H1N1 flu outbreak), RSV usually runs almost one to one with influenza in people over the age of 65 as a cause of severe respiratory tract infections.
RSV was first isolated in the 1950s, and its impact on children led scientists to develop a vaccine. By the mid-1960s, the United States had created a vaccine against RSV, but the attempt proved disastrous.
Nearly 80 percent of the children who received the vaccine required hospitalization (compared to only 5 percent of the control vaccine group) and two children died.
“That was the first time in the history of the United States that a vaccine had led to enhanced morbidity and mortality from the pathogen against which it was meant to provide protection,” says Varga.
Since the vaccine’s failure, the FDA has not allowed a license for an RSV vaccine.
What exactly went wrong? To begin to answer this question, Varga’s lab seeks to understand the mechanisms of the vaccine-enhanced disease by studying ways to regulate the host immune response as it tries to fight off RSV infection. Part of the immune response takes place in the lungs, which can produce mucus to protect its delicate tissue from foreign particles. Most of the time, we breathe particles into our lungs in relatively small quantities, so dust, mold, pollen, bacteria, or viruses don’t always trigger an immune response.
“But if enough of a certain pathogen enters the lungs, an immune response is tripped off,” says Varga. “If the immune response is too large, the lungs produce too much mucus, and airways become inefficient, sluggish, and inflamed. “This inflammatory response proves destructive to the host lung tissue and disrupts breathing.”
An immune response works something like the response to an alarm. But sometimes it works too well or too much. Imagine you burn a pizza in your oven. Your smoke detector sounds an alarm, which triggers an immediate house call from the fire department. In this situation, it would be helpful to dampen the response.
“The vaccine enhanced disease is thought to be an over-exuberant immune response,” says Varga. “What caused those children to be hospitalized and the two children to die was the immune response, which was larger and more nasty than was necessary to deal with the pathogen, and that’s what caused the excess damage to the lung tissue.”
An inflammation of the lungs causes much of the disease, Varga says, and a large fraction of the disease is probably attributable to the immune response, not simply to the death of cells that the virus infects. If the immune response is causing much of the disease, Varga and his colleagues might determine ways to alter that response or modulate it, such that our bodies could still effectively fight off the virus infection but not produce much disease.
“We are trying to find that balance,” says Varga.