On the left is an electron micrograph of influenza virus, magnified about one million times. The virus is embedded in a dense medium, so the medium appears dark and the virus proteins appear light. The spike-like projections of hemagglutinin (HA) and neuraminidase (NA) are evident. One HA trimer is in a white oval. On the right is a blown-up outline of the HA next to a representation of what the actual HA molecule looks like. Attached to it are three copies (one per protein subunit) of a fragment of antibody CH65. Image: Courtesy of Stephen C. Harrison. |
Some
vaccines are once-in-a-lifetime; others need a booster shot or two to
maintain their potency. And then there’s the flu vaccine, which only
lasts a year. Strains of influenza virus change so much from
year-to-year that new vaccines must be developed annually to target the
strains of virus that are most likely to cause illness. But Howard
Hughes Medical Institute (HHMI) scientists have now discovered a human
antibody that recognizes many different flu strains. Understanding more
about this antibody may help scientists design a longer-lasting vaccine
against the influenza virus.
The research is published in the August 8, 2011, issue of the Proceedings of the National Academy of Sciences.
To
find the antibody, Stephen C. Harrison, an HHMI investigator at Harvard
Medical School and Children’s Hospital, Boston, took advantage of the
diversity of the human immune system.
When
given the flu vaccine, every person’s body will produce slightly
different antibodies, which are immune system molecules that recognize
and remember pathogens, such as viruses. Antibodies are small compared
to the flu virus, but they need only recognize one piece of the virus’s
outer shell to be effective. This means that within the human
population, there’s great diversity when it comes to antibodies that
recognize flu. For example, some people will produce an antibody against
one bit of the virus, while others have antibodies that recognize a
different viral snippet, and so on.
Strains
of flu virus differ from one another largely in the genes that code for
surface molecules called glycoproteins, which are the primary targets
of the body’s immune system in defending against flu viruses. Like a
coat of armor, the hemagglutinin and neuraminidase surface proteins stud
the tiny influenza virus particle. When the virus mutates, it
essentially “changes coats,” altering the shape of its exterior surface
and becoming unrecognizable to the human (or animal) immune system. This
is the essence of immune evasion, a hallmark of influenza.
To
study how the immune system determines which antibodies to produce,
Harrison and collaborators at Duke University, turned to a new
technology that lets scientists quickly scan the molecules in a person’s
immune cells.
“What
this allows us to do is get a snapshot of the different kinds of
antibodies being made in a person in response to a vaccine,” says
Harrison.
While
the research team was taking such snapshots of immune cells, they found
an antibody they weren’t expecting—one that recognized multiple strains
of the flu virus.
There’s
one part of the influenza virus that doesn’t mutate—the binding area
that recognizes receptors on human cells. If this receptor pocket
mutates, the virus is no longer infectious. Scientists had previously
believed that antibodies couldn’t target this small area with such
specificity.
“It
has been assumed that because antibodies have a larger contact area
than most virus receptors,” says Harrison, “an antibody might target
that receptor binding area, but it would still also recognize
surrounding, changeable areas.”
This means if that surrounding area mutated, the antibodies wouldn’t bind.
But
the new antibody that the researchers isolated—dubbed CH65—binds so
tightly to the receptor pocket that it appears not to be strongly
affected if the surrounding area mutates. When collaborators at the U.S.
Food and Drug Administration tested the new antibody against 36 flu
strains that have arisen between 1988 to 2007, they found that the
antibody recognized and blocked 30 of those strains.
While
this knowledge could theoretically be used to develop a vaccine that
stimulates production of the CH65 antibody, this could just push viruses
to mutate in the area around the binding pocket. If this occurs, the
vaccine would eventually become obsolete. Instead, Harrison would like
to use CH65 to probe how the immune system chooses which antibodies to
produce. If one person can make the broad CH65 antibody, why can’t
everyone? Can scientists learn to coax the human immune system to
produce CH65?
“Our
goal,” he says, “is to understand how the immune system selects for
antibodies and use that information to get better at making a vaccine
that will take you in a direction that favors breadth over specificity.”
Harrison
is now collaborating with HHMI investigator Nikolaus Grigorieff at
Brandeis University to get structural information on antibodies as they
evolve in the immune system after vaccine administration. By taking
structural snapshots of antibodies over time, they may be able to deduce
a pattern in how the immune system selects which antibody structures to
favor.
Others,
however, may use CH65 in a more direct clinical setting. “Some
scientists are thinking about therapeutic antibodies, which can be
administered to patients with severe flu cases, or compromised immune
systems, as a way of fighting the virus,” says Harrison. “And this
antibody is a very interesting molecule to consider for that.”
Filed Under: Drug Discovery
