Common cold viruses are an inconvenience for most of us, but they can have deadly consequences for patients recovering from a bone marrow transplant.
Researchers at Seattle’s Fred Hutchinson Cancer Research Center are reporting the discovery of five naturally occurring immune proteins, or antibodies, that have the potential to block one of those viruses. It is an advance that could eventually save the lives of patients who lose protection from many common viruses gained during childhood when they receive a transplant.
In a paper published on April 20 in the open access journal mAbs, a team of researchers led by Fred Hutch immunologist Dr. Justin Taylor describe how they isolated five different antibodies that, in lab dish studies, potently protect against human parainfluenza virus type III, or HPIV3.
Despite its name, parainfluenza is unrelated to seasonal flu. Biologically, parainfluenza viruses are more closely related to those responsible for measles, mumps and rubella.
A ubiquitous virus, HPIV3 can cause serious respiratory infections in infants with weakened immune systems. It infects just about all of us by the age of 8, usually causing a mild head cold. But it also infects about 18% of cancer patients who receive bone marrow or blood stem cell transplants, posing a significant risk of death. If it starts replicating deep in the lungs of an immunocompromised patient, there is a 40% chance it will be fatal.
“The purpose of this research is to give clinicians a tool to help prevent or treat parainfluenza infections. Right now, they have nothing, and as a result about a thousand transplant patients die of it in the U.S. every year,” said Taylor.
“It is extremely tragic when one of our transplant patients achieves a cure for their cancer and then dies with a respiratory virus that, in you or me, would just be a common cold,” said the paper’s lead author, Dr. Jim Boonyaratanakornkit, who treats infectious disease patients at the Hutch’s clinical care partner, Seattle Cancer Care Alliance, and is a research associate in Taylor’s lab.
The new report is the culmination of several years of studies aimed at identifying, from human blood and tissues samples, protective antibodies against parainfluenza virus. The first potent antibody, which the scientists call PI3-EI2, was isolated from the blood of a donor in an elaborate laboratory process developed by Taylor’s team. Initially, they identified 25 different antibodies that bound to the parainfluenza virus, but they later winnowed that down to just one that showed promise of neutralizing it.
They later used a high-throughput process developed by their Hutch colleague, Dr. Andrew McGuire, to look for more candidates, expanding their search to include tonsil and spleen tissues that are rich in antibody-producing blood cells, called B cells. They came up with four more antibodies, each of them as potent or more potent than the first against parainfluenza.
“We found that tonsils in particular were chock-full of B cells that neutralized the virus,” Boonyaratanakornkit said.
Coincidentally, recent research has shown that adults who have had tonsillectomies as children — an extremely common procedure among baby boomers — have a higher long-term risk of respiratory infections. Once one of the most common surgical procedures, tonsillectomies fell out of favor in the 1970s as doctors cited a lack of evidence that they were beneficial.
To confirm that antibodies to parainfluenza virus are also capable of blocking it in mammals, the researchers tested that first potent antibody in cotton rats, rodents that — unlike mice — are susceptible to parainfluenza. Rats given an injection of the antibody, and then challenged a day later with a snort of HPIV3, were protected from significant lung infection.
The initial goal of Taylor’s and Boonyaratanakorkit’s research is to see whether laboratory-manufactured copies of these potent antibodies — known as monoclonal antibodies — could be formulated into a drug that could be injected into transplant patients to prevent or treat parainfluenza.
A monoclonal antibody drug, palivizumab, is used to treat severe cases of respiratory syncytial virus, or RSV, a common and sometimes dangerous respiratory virus in children that also threatens immunocompromised patients. Encouragingly, the researchers found that the ability of the parainfluenza antibody to suppress that virus was better than palivizumab’s potency in suppressing RSV. While the drugs and diseases are different, the strategy to fight the viruses is similar.
Boonyaratanakornkit is taking the lead within Taylor’s lab on the next phase of this research. Ultimately, the goal is to discover and develop an array of potent antibodies against several different viral diseases that threaten immunocompromised patients. These could be formulated into a single “cocktail” that could be infused or injected into transplant patients to prevent or treat opportunistic infections that take advantage of their weakened immune state.
“The list of infections they are susceptible to is pretty well-known, and for most of the viral infections there aren’t preventative or therapeutic options,“ Taylor said. “We hope to change that in the next few years.
“We’ve started with HPIV3, but our aim is to have tools to prevent or treat several other infections in the next few years.”
A pioneer in the new field of B-cell engineering, Taylor is developing ways to genetically modify a patient’s own B-cells to produce antibodies of choice, so that a person can self-generate these protective proteins without requiring a vaccine or repeat infusions of expensive monoclonal antibodies.
Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs.
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