A new method for swiftly producing proteins to fight infections could mean the difference between life and death during future pandemics. Researchers report in Nature today that they have perfected a way to manufacture monoclonal antibodies capable of destroying diseases such the avian flu, which have the ability to swap genes with human flu varieties and jump from birds to people.
Their research is a dramatic advance, because it marks the first time that scientists were able to rapidly generate the disease-killing proteins, according to study co-author Patrick Wilson, an immunologist at the Oklahoma Medical Research Foundation (OMRF) in Oklahoma City. He says that researchers could one day spare scores of lives and nip potential epidemics in the bud by whipping up a treatment within a month from natural antibodies that survivors developed against the threatening disease.
Until now, he says, it took as long as three months to produce enough monoclonal antibodies to protect huge populations, because the immune system only pumps out small quantities in response to infections.
Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, called the new work a "significant advance," noting in a statement that it "opens the way to producing [monoclonal antibodies] that potentially could be used diagnostically or therapeutically" for the flu as well as other infectious diseases such as hepatitis C and the human immunodeficiency virus (HIV), which can lead to full-blown AIDS.
The new technique, pioneered by Wilson and fellow researchers at the Emory University School of Medicine in Atlanta, saves time by using antibodies produced by so-called B cells (white blood cells that produce and then ferry them to infection sites to battle invading germs) in response to vaccines instead of to actual infections.
According to Wilson, monoclonal antibodies from (deliberately infected) animals were routinely used in the first half of the 20th century to try to treat diphtheria (an upper-respiratory illness that killed roughly 15,000 people annually in the early 1920s until a vaccine was formulated against it in 1924) and tetanus (a potentially fatal infection also known as lockjaw, because one of the muscles it destroys is in the jaw). There were, however, compatibility issues: The human immune system in most cases viewed the animal antibodies as alien and rejected them—or lacked the ammunition to destroy them, thereby making patients sicker.
To avoid these problems, researchers have been trying to perfect and speed up procedures for extracting monoclonal antibodies from humans, replicating them in a lab, and then injecting them into victims suffering from the diseases they were formed to fight. The key to collecting these antibodies has been to remove B cells that bear them from survivors of, say, a particular flu strain—or alternatively, someone who has been vaccinated against the flu (because the flu vaccine contains a weakened version of the virus).
Until now, scientist have run into problems trying to recreate large enough quantities quickly enough to spare lives. Wilson says the process traditionally has taken so long that by the time enough new B cells were generated, the flu strain targeted already had mutated into a form no longer vulnerable to the captured crop of antibodies.
In the new method, the researchers isolated B cells from humans who had been vaccinated against—and therefore had built up specific antibodies to—the seasonal flu. But instead of prodding extracted B cells to proliferate, Wilson says, the teams simply plucked the antibody-producing genes from them and inserted those into existing B-cell lines, thereby increasing their protein output.
The type of B cells that the scientists tapped for the coveted proteins are known as antibody-secreting plasma cells (ASCs). ASCs are among the first-line defenders that the immune system sends out when it detects an infection (including weakened vaccine versions). These cells are tasked with scoping out potential danger and signaling the backup germ fighters required to knock out invading armies. ASCs are short-lived, because they serve more as scouts than as combat soldiers.
The teams found that up to 80 percent of the ASCs that they isolated during their peak (seven days after vaccination) contained monoclonal antibodies to the flu strain they had injected.
"The reason this is so exciting is that the same kind of B cell could be present in people [who] have primary infections," says Wilson, noting that researchers thus far have only showed this works with antibodies created in response to vaccines. The team now plans to test the method on people infected with the flu or another virus.
Antonio Lanzavecchia, director of the Institute for Research in Biomedicine in Bellinzona, Switzerland, stresses that the effectiveness of Wilson's technique depends on the relatively short time span during which ASCs are active.
Lanzavecchia believes that his own research is more promising: He has harvested antibodies against both severe acute respiratory syndrome (SARS) and avian flu using so-called memory B cells, which are immune cells that store antibodies from all vaccines and previously beaten viruses—and remain in the blood permanently.
"If you have a spontaneous disease, you have only a short window of time where you can get [ASCs]," he says, "so targeting memory B cells [from someone who has beaten the illness] may be an advantage."
The problem is, Wilson says, that a person has relatively few memory B cells—"on the order of one in thousands"—making the process of extracting antibodies from them a time-consuming task, because they first must be located.
"We are making new antibodies that [are potentially more effective because they] are binding to very specific strains of a virus," he says. He adds that the new technique might also be employed to pin down the flu strain someone has by testing the effectiveness of extracted antibodies against it.
Wilson says that the new technique could become widely available in a few years if it is proved safe and effective during human clinical trials.