Grad Profile
Changing human response to vaccine

April 9, 2009

By Brette Ehalt

Respiratory Syncytial Virus (RSV) “is the most important cause of infectious lung disease in infants and small children worldwide, as well as the most common reason for infant hospitalization,” says veterinary microbiology PhD student John Mapletoft. “By the age of three, virtually all children have been exposed to RSV.”

That's why, for the past five years, Mapletoft has worked to develop a vaccine for this virus.

RSV is spread via small particle aerosols and fomites–those inanimate objects, like doorknobs, money, and toys, capable of carrying and transmitting microorganisms from one person to another. “The virus spreads so readily among children as they are constantly coughing and sneezing and playing with toys and each other, all without washing their hands,” Mapletoft adds.

He explains how, in America in the 1960s, researchers attempted to develop a vaccine against RSV. But instead of inducing protection, the vaccine primed the immune system for an exaggerated inflammatory response in the lungs, and the children who received the vaccine developed even more severe disease upon exposure to the virus. Some even died.

“My team's goal was to alter the host immune response induced by this vaccine into a safe, protective response,” he says.

Using a bovine version of the virus in calves and mice, Mapletoft's primary challenge was to discover the right combination of adjuvants–substances able to alter or enhance immune responses–to be mixed with the vaccine prior to administration.

“One version of the vaccine was delivered traditionally, using a needle, and the other was delivered up the nose to specifically target the respiratory system. But within the two versions, dozens of small variations in adjuvant combinations were tested in dozens of experiments here at VIDO.”

He then goes on to explain the body's immune responses in relation to RSV.

“In a nutshell, there are two types of immune response that can be induced by a vaccine or microbial pathogen. Th1-type responses are traditionally associated with cellular immunity. Cytotoxic T-cells are activated with the goal of specifically seeking out and killing infected cells. This response is particularly valuable when the pathogen lives inside our cells, like viruses do.”

Th2-type responses, he continues, are traditionally associated with humoral immunity. Pathogen-specific antibodies are produced with the goal of binding to pathogens, thereby blocking their activities and targeting the pathogen to be destroyed by the immune system. These responses are particularly valuable when the pathogen lives outside of our cells, like most bacteria do.

“As RSV is a virus, Th1 responses are necessary to kill infected cells and prevent it from spreading. For reasons that nobody completely understands, Th2 responses against RSV are associated with an exaggerated inflammatory response in the lungs, resulting in even more severe disease.”

Mapletoft's team successfully developed an adjuvant formulation that switches the immune response induced by the 1960s vaccine from Th2 to Th1, avoiding the exaggerated response and inducing safe, protective immunity. Because of the history of RSV, however, it is unlikely that Mapletoft's vaccine will ever be accepted for use in humans.

“We would have to go back and change the original RSV component of the vaccine … but the value of our work is that we took a harmful situation and made it safe.”

Brette Ehalt writes profiles of grad students for the College of Graduate Studies and Research.