| Live H5N1 Avian Flu Virus Vaccines Show Protection
in Animal Studies
When tested in mice and ferrets,
experimental vaccines based on live, weakened versions of different
strains of the H5N1 avian influenza virus were well-tolerated and
protected the animals from a deadly infection with naturally occurring
H5N1 flu viruses. The findings, which appear in the September 12
issue of PLoS Medicine, are also encouraging, the researchers
say, because they demonstrate the ability to create a vaccine based
on one particular strain of the H5N1 flu virus that could potentially
protect against different emerging H5N1 flu strains.
Senior investigator Kanta Subbarao, M.D., M.P.H., and co-chief
Brian Murphy, M.D., both of the Laboratory of Infectious Diseases
at the National Institute of Allergy and Infectious Diseases (NIAID),
part of the National Institutes of Health (NIH), led the research.
The study was the result of a cooperative research and development
agreement between NIAID and MedImmune Inc., of Gaithersburg, Md.
“This is an excellent example of the NIH and industry working
together to find scientific solutions to potential public health
problems,” notes NIH Director Elias A. Zerhouni, M.D. “Developing
a vaccine that could protect against a potential influenza pandemic
is a top priority for all of us.”
“If an influenza pandemic were imminent or under way, we would
need a vaccine that could stimulate immunity quickly, preferably
with a single dose,” says NIAID Director Anthony S. Fauci., M.D. “The
encouraging findings of this study suggest that vaccines based
on live but weakened versions of the H5N1 avian influenza virus
may quickly stimulate protective immunity. We are further exploring
this live, attenuated vaccine strategy as one of several tools
that we hope to have available in the event of an influenza pandemic.”
As of September 8, 2006, there have been 244 confirmed human cases
of H5N1 infection and more than half of those were fatal, according
to the World Health Organization (WHO). Public health officials
worry that the H5N1 virus will evolve to become easily transmissible
among people, potentially sparking an influenza pandemic, because
humans have no pre-existing immunity to the H5N1 viruses.
The NIAID and MedImmune research team created three vaccines by
combining modified proteins derived from virulent H5N1 flu viruses
with proteins from an artificially weakened (attenuated) flu strain.
The virulent H5N1 viruses were isolated from human cases in Hong
Kong in 1997 and 2003, and Vietnam in 2004. The attenuated flu
vaccine strain, which also serves as the basis for MedImmune’s
FluMist® influenza vaccine, was lab-grown in progressively colder
temperatures (“cold-adapted”) to prevent the resulting vaccine
viruses from spreading beyond the relatively cool upper respiratory
tract. Large quantities of the resulting cold-adapted viruses were
grown in chicken eggs.
The safety of the vaccine viruses was evaluated in chickens and
mice. In chickens, the H5N1 vaccine viruses were not lethal, while
each of the three strains of the “wild-type” (naturally occurring)
H5N1 viruses were. Similarly, the vaccine viruses were not lethal
in mice, but the 1997 and 2004 strains of the wild-type H5N1 viruses
were. The 2003 strain of the H5N1 wild-type virus was not tested
in mice because the researchers found that the virus was lethal
in those animals only at very high doses. Because the wild-type
H5N1 viruses have been shown to replicate in animal lungs and brains,
the researchers tested the ability of the 1997 and 2004 strains
of the vaccine viruses to replicate in mice and ferrets as an additional
safety measure In mice, the vaccine viruses replicated in the respiratory
tract but did not spread to the animals’ brains. In ferrets,
the H5N1 vaccine viruses did not replicate in the lungs or the brain.
To evaluate the protective ability of the vaccines, the researchers
gave the mice a single dose of vaccine virus via nose drops. All
of these mice survived infection with the 1997 and 2004 H5N1 wild-type
viruses, including two more recent strains of the H5N1 virus found
circulating in Vietnam and Indonesia in 2005. Further, mice that
received a second dose of vaccine 28 days after the initial inoculation
demonstrated a stronger and more rapid immune response and almost
complete protection from respiratory infection when exposed to
the naturally occurring H5N1 viruses. Ferrets exhibited similar
results when given two doses of the vaccine viruses.
“It is impossible to predict how the H5N1 virus will evolve or
which strain, if any, will cause an influenza pandemic. To be prepared,
we need to select a vaccine capable of inducing an effective human
immune response against a range of H5N1 viruses that may emerge
in the future. This study shows that such cross-protection can
be achieved in small animals,” says Dr. Subbarao. “The next step
is to evaluate in people the safety and immune response induced
by these vaccines to see if they produce cross-reactive antibodies
that are likely to protect against different H5N1 viruses.”
In June 2006, NIAID and MedImmune launched a Phase 1 study to
evaluate the safety and immunogenicity of a live, attenuated H5N1
vaccine based on the 2004 H5N1 virus strain. The study, which is
being performed in an isolation unit at Johns Hopkins Bloomberg
School of Public Health Center for Immunization Research in Baltimore,
is evaluating the safety and immunogenicity of the vaccine in approximately
20 healthy individuals between the ages of 18 and 49. Results from
that study are not yet available.
The concept of using cold-adapted flu viruses to create flu vaccines,
as detailed in the study in PLoS Medicine, was developed
by scientists at NIAID and the University of Michigan School of
Public Health (http://www3.niaid.nih.gov/news/focuson/flu/research/prevention/flumist.htm).
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.
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.