NIH Scientists Target Future Pandemic Strains
of H5N1 Avian Influenza
Preparing vaccines and therapeutics that target a future mutant
strain of H5N1 influenza virus sounds like science fiction, but
it may be possible, according to a team of scientists at the National
Institute of Allergy and Infectious Diseases (NIAID), a component
of the National Institutes of Health (NIH), and a collaborator
at Emory University School of Medicine. Success hinges on anticipating
and predicting the crucial mutations that would help the virus
spread easily from person to person.
Led by Gary Nabel, M.D., Ph.D., director of the NIAID’s Dale and
Betty Bumpers Vaccine Research Center (VRC), the team is reporting
in the August 10, 2007 issue of the journal Science that
they have developed a strategy to generate vaccines and therapeutic
antibodies that could target predicted H5N1 mutants before these
viruses evolve naturally. This advance was made possible by creating
mutations in the region of the H5N1 hemagglutinin (HA) protein
that directs the virus to bird or human cells and eliciting antibodies
to it.
“What Dr. Nabel and his colleagues have discovered will help to
prepare for a future threat,” says NIH Director Elias A. Zerhouni,
M.D. “While nobody knows if and when H5N1 will jump from birds
to humans, they have come up with a way to anticipate how that
jump might occur and ways to respond to it.”
“Now we can begin, preemptively, to consider the design of potential
new vaccines and therapeutic antibodies to treat people who may
someday be infected with future emerging avian influenza virus
mutants,” says NIAID Director Anthony S. Fauci, M.D. “This research
could possibly help to contain a pandemic early on.”
Making a vaccine against an existing strain of H5N1 or any other
type of influenza virus is relatively routine. Typically, samples
of existing influenza virus strains are isolated and then grown
inside eggs or in cell cultures. The virus is then collected, inactivated,
purified and added to the other components of the vaccine.
A flu shot prompts a person’s immune system to detect pieces of
the inactivated virus present in the vaccine and make neutralizing
antibodies against them. Later, if that same person is naturally
exposed to a flu virus, these same antibodies should help fight
the infection.
Influenza viruses constantly mutate, however, and vaccines are
most effective against the highly specific strains that they are
made from. This makes it difficult to predict how effective a vaccine
made today will be against a virus that emerges tomorrow.
Dr. Nabel and his colleagues started their project by focusing
narrowly on mutations that render H5N1 viruses better able to recognize
and enter human cells. Bird-adapted H5N1 binds bird cell surface
receptors. But these receptors differ slightly from the receptors
on human cells, which in part explains why bird-adapted H5N1 can
infect but not spread easily between humans.
About a year ago, the research team began asking what mutations
help the virus shift its adaptability. They compared the structural
proteins on the surface of bird-adapted H5N1 influenza virus with
those on the surface of the human-adapted strain that caused the
1918 pandemic. They focused specifically on genetic changes to
one portion of the H5 protein — a portion called the receptor
binding domain. They showed that as few as two mutations to this
receptor binding domain could enhance the ability of H5N1 to recognize
human cells.
Additional mutations would likely need to accumulate for H5N1
to spread more easily from person to person, says Dr. Nabel. The
few mutations he and his colleagues identified are likely just
a subset of those, he emphasizes.
Moreover, they found that these mutations change how the immune
system recognizes the virus. Mouse antibodies that target H5N1
were up to tenfold less potent against the mutants. Dr. Nabel and
his colleagues used their knowledge of receptor specificity to
create vaccines and isolate new antibodies that might be used therapeutically
against human-adapted mutants.
They vaccinated mice with the material from viruses they altered
to contain the mutant receptors, and they discovered one broadly
reactive antibody that could neutralize both the bird- and human-adapted
forms of an H5N1 virus.
According to Dr. Nabel, their findings should contribute to better
surveillance of naturally occurring avian flu outbreaks by making
it easier to recognize dangerous mutants and identify vaccine candidates
that might provide greater efficacy against such a virus before
it emerges.
“Our findings build on elegant studies of the influenza HA protein
by structural biologists,” notes Dr. Nabel. “Insight into the structure
of the avian flu virus has enabled us to target a critical region
of HA that directs its specificity. Such a structure-based vaccine
design may allow us to respond to this future threat in advance
of an actual outbreak.”
NIAID is a component of the National Institutes of Health. NIAID
supports basic and applied research to prevent, diagnose and treat
infectious diseases such as HIV/AIDS and other sexually transmitted
infections, influenza, tuberculosis, malaria and illness from potential
agents of bioterrorism. NIAID also supports research on basic immunology,
transplantation and immune-related disorders, including autoimmune
diseases, asthma and allergies. News releases, fact sheets and
other NIAID-related materials are available on the NIAID Web site
at http://www.niaid.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov. |