Discovery Points Toward A Possible Universal Flu Vaccine

Discovery Points Toward A Possible Universal Flu Vaccine
Antibodies bind to a flu virus protein (grey) with their
variable regions (blue) forming an immune complex. The
antibodies' Fc region (red) will bind to immune cells.
Researchers think flu vaccines could be improved by including
immune complexes that contain antibodies with modified Fc
regions. (Credit: Rockefeller University)
Every year thousands of people die because of influenza, mostly 65 and older, and causes serious disease in many others. The virus makes for a difficult target for vaccines because its strains are so diverse, and new ones are constantly emerging. Types A and B cause seasonal flu epidemics. Influenza A viruses are further broken down into subtypes based in part on their surface proteins, which include hemagglutinin, the "H" in H1N1, for example. The subtypes are further divided into strains.
 
Currently, most flu vaccines are formulated to target a total of three or four viral strains: H1 and H3 influenza A viruses, plus influenza B virus strains. The strains are selected based on public health experts' predictions for the coming flu season. But sometimes they are wrong, rendering the shots ineffective. A universal flu vaccine has become something of a holy grail, and a number of strategies have been proposed to create it. Researchers now suggests a new alternative: chemical modifications to the Fc region of antibodies. These regions go on form complexes with vaccine antigens, which then modulate the evolving vaccine response. The research was published in the journal Cell.
 
The researchers first vaccinated healthy volunteers with a seasonal flu vaccine containing an inactivated strain of the H1N1 virus. They then tracked the volunteers' immune responses via blood samples, keeping an eye out for chemical modifications to antibodies against the hemagglutinin protein.
 
About seven days after the vaccination, they saw a spike in sialylated antibodies, meaning sialic acid, an important signaling molecule, had been added at a specific spot on the Fc region. The greater the sialylation, the better a person's response to the vaccine.
 
To tease apart how this chemical modification improves the immune response, the researchers used cell cultures and mice to study the effects of sialylated Fc regions binding to B cells. Their experiments revealed a complex interaction that ultimately pushes the B cells to produce antibodies with a higher affinity to their antigens. It begins when a sialylated Fc region binds to a receptor protein known as CD23 on the B cells, prompting CD23 to activate a second receptor, FcγRIIB, which, in turn, discourages B cells producing low affinity antibodies. In this way, the sialylation on Fc regions establishes a high threshold for the immune response, so that only B cells producing the highest affinity antibodies are activated. The result of the higher affinity was broad protection against H1 subtype influenza viruses.
 
The researchers then used this knowledge to improve the vaccine itself. They modified the H1N1 vaccine so it contained not only protein from the virus itself, but also sialylated antibodies against that protein.
 
When the researchers immunized mice with just the H1 protein from one strain or with the sialylated complexes containing the same viral protein, they found both offered equal protection against the same strain of flu. However, when they exposed them to strains expressing different versions of the H1 protein, only the sialylated immunizations offered protection.
 
"The new mechanism we have uncovered, by which a vaccine containing sialylated antibodies elicits broadly protective antibodies, could potentially be harnessed to reduce the tremendous morbidity and mortality caused by seasonal influenza virus infections," the researchers concluded. "We are now looking into applying this strategy toward improving existing vaccines; ideally, this would result in a vaccine that provides life long immunity against flu infections."
 
Based on material originally posted by Rockefeller University.
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