By pinpointing the window of opportunity when the human immune response to a particular pathogen peaks, scientists in the US have developed a much faster way to isolate the highly specific antibodies needed to make flu vaccines. The discovery may also lead to new and faster ways to produce vaccines and therapies to fight many other diseases.
The study is the work of researchers at Emory University School of Medicine, in Atlanta, Georgia, and Oklahoma Medical Research Foundation (OMRF), in Oklahoma City, and is published in the 30th April advanced online issue of Nature.
Co-author, Dr Rafi Ahmed, director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar, said:
“This method could find broad application towards almost any infectious disease.”
Corresponding author Dr Patrick Wilson, immunology researcher at the OMRF, said:
“With just a few tablespoons of blood, we can now rapidly generate human antibodies that can be used for immunization, diagnosis and treatment of newly emerging strains of influenza.”
“In the face of a disease outbreak, the ability to quickly produce infection-fighting human monoclonal antibodies would be invaluable,” he added.
The human body’s most effective way of fighting disease is to be equipped with antibodies that can sense and neutralize invading pathogens. This is the principle of vaccination: expose the body to a safe dose of the pathogen, the immune system detects it, and starts making antibodies against it. Then when the “real” pathogen that is circulating (for instance seasonal flu) comes along, the immune system is ready to defend against the attack.
For the flu virus, experts get together every year to try and predict exactly which strains are going to be circulating in the coming season, and the vaccine manufacturers can then prepare the flu shots. You can’t use last year’s vaccination formula because the flu virus, which is actually a range of strains, mutates as it passes around the world, from community to community, and last year’s antibodies no longer recognize the new strains.
There are currently two ways to “manufacture” the antibodies that are put in the vaccines. The first way is like finding a needle in a haystack. Scientists use blood from people who have been exposed to the specific strain the vaccine is destined for, and then “sift” through all the similar antibodies until they find the one that is specific to that strain. This takes a long time, and in the meantime the virus is out there, evolving into new strains. The scientists also use models to try and predict the direction the mutations will take, but this can add to the timescale.
The second way to make antibodies for flu vaccines is to infect mice with the flu, take their antibody producing cells, make them suitable for humans, and use this “hybrid” to make antibodies. This way is faster, but less safe, because the human body could reject the mouse part of the hybrid in unforeseen ways.
The key discovery in this study, is that there is a window of opportunity following exposure to a pathogen where the antibodies against that pathogen peak in the bloodstream, and this makes it much easier to find them.
In this study the researchers were able to pinpoint the exact influenza specific IgG+ antibody-secreting cell (ASC) circulating in blood plasma following a flu booster shot. They found that about 7 days after the vaccination, there was a small window of opportunity where there is a high level of this specific plasma cell in the body, accounting for about 6 per cent of B cells in the blood.
B cells are white blood cells that make antibodies. The immune system has different B cells ready to make antibodies against a range of pathogens that the body has been exposed to in the past.
The researchers were able to distinguish these ASCs from influenza-specific IgG+ memory B cells that peaked 14 to 21 days after vaccination and averaged 1 per cent of all B cells. Memory B cells are what remain as a long term record of the exposure. The B cells that make the antibodies (the ASCs) recede, leaving just the memory cells as a record that the immune system has experience of fighting that pathogen in the past.
By pinpointing this window of opportunity when the ASCs levels peak, the researchers found that as much as 80 per cent of the purified ASCs harvested at this point were influenza specific (they had a specific effect on B-cell receptors).
They were able to sift through this much smaller pool of ASCs and produce over 50 human monoclonal antibodies (mAbs) that bound to the three target flu strains with high affinity. Monoclonal antibodies (mAbs) are highly specific antibodies (they bind to one strain of pathogen only) derived from a single parent immune cell (hence “clone”). The timescale from vaccination to mAbs production was one month, much faster than conventional methods.
The researchers concluded that:
“The panel of influenza-virus-specific human mAbs allowed us to address the issue of original antigenic sin (OAS): the phenomenon where the induced antibody shows higher affinity to a previously encountered influenza virus strain compared with the virus strain present in the vaccine.”
They found that OAS is not common among normal healthy adults receiving the flu shot, as was previously believed. If you look at the right time, within the window of opportunity, you can see there is a highly specific response to the current strain, which only later recedes and gets lost among all the earlier “memories” of previous strains.
While this study was part of a research effort to fight influenza, it has potential applications to any pathogen for which a vaccine exists, such as anthrax and smallpox.
“Vaccines can activate the immune system, but they need time to take effect, and many offer less than 100 percent protection and carry risks of side effects,” said Dr Stephen Prescott, president of the OMRF.
“With further research and testing, this new method might allow a nurse going into the center of an outbreak to receive a shot to keep her safe from infection. Soldiers in the field could keep a shot of anti-anthrax in their packs in case of a biological attack,” he added.
The method also has potential to help people fight newly acquired and chronic diseases, by taking their antibodies, boosting them and giving them back again, or even to provide passive immunity against future infection.
“Rapid cloning of high-affinity human monoclonal antibodies against influenza virus.”
Jens Wrammert, Kenneth Smith, Joe Miller, William A. Langley, Kenneth Kokko, Christian Larsen, Nai-Ying Zheng, Israel Mays, Lori Garman, Christina Helms, Judith James, Gillian M. Air, J. Donald Capra, Rafi Ahmed & Patrick C. Wilson.
Nature advance online publication 30 April 2008.
DOI:10.1038/nature06890
Sources: Oklahoma Medical Research Foundation, Emory University, journal abstract.
Written by: Catharine Paddock, PhD