Experimental Vaccine Protects Mice Against Deadly
1918 Flu Virus
Federal scientists have developed a vaccine that protects mice
against the killer 1918 influenza virus. They also have created
a technique for identifying antibodies that neutralize this virus,
a tool that could help contain future pandemic flu strains. These
findings are important, the researchers say, to understanding and
preventing the recurrence of the H1N1 influenza virus that caused
the 1918 pandemic and to protecting against virulent flu strains
in the future, including the H5N1 avian flu virus. Details of the
research are available online this week in Proceedings of the
National Academy of Sciences.
Gary J. Nabel, M.D., Ph.D., director of the Vaccine Research Center
(VRC) at the National Institute of Allergy and Infectious Diseases
(NIAID), part of the National Institutes of Health (NIH), led the
research team in developing the experimental vaccines and conducting
the immunological studies in mice. Terrence Tumpey, Ph.D., of the
Centers for Disease Control and Prevention (CDC) conducted vaccine
studies in mice involving the live, reconstructed 1918 flu virus
in a biosafety level 3-enhanced laboratory at the CDC in Atlanta — one
of four types of specialized biosafety labs where scientists study
contagious and potentially deadly materials under high-level safety
and contamination precautions designed to protect the researchers
and prevent microorganisms from entering the environment.
“Understanding why this influenza virus was so deadly is an extremely
important question,” says NIAID Director Anthony S. Fauci, M.D. “By
building upon earlier research where scientists successfully reconstructed
the 1918 pandemic flu strain, Dr. Nabel and his colleagues have
demonstrated that this virus is vulnerable to intervention. This
knowledge will help further our continued efforts to develop treatments
and vaccines to protect us against another deadly flu pandemic.”
The 1918-1919 influenza pandemic was the most deadly flu outbreak
in modern history, killing 50 million or more people worldwide.
“A key to containing pandemic flu viruses is to understand their
vulnerabilities and determine whether they can evade immune recognition,” says
Dr. Nabel. “What we learn about the H1N1 virus that caused the
1918 pandemic is pertinent to other pandemic viruses and to the
development of effective and universal vaccines.”
Using the genetic sequence information for the 1918 flu virus,
Dr. Nabel and his VRC colleagues created plasmids — small
strands of DNA designed to express specific characteristics — carrying
genes for the virus’ hemagglutinin (HA) protein, the surface protein
found in all flu viruses that allows the virus to stick to a cell
and cause infection. The researchers created two types of plasmids:
one to reflect the HA found in the original 1918 flu virus; the
other an altered HA protein designed to attenuate (weaken) the
virus.
Mice were then injected with a DNA vaccine containing both types
of plasmids to determine whether they would generate immune responses
to the 1918 virus. The researchers found significant responses
both in terms of production of T-cells, the white blood cells critical
in the immune system’s battle against invading viruses, as well
as the production of neutralizing antibodies.
To determine the vaccine’s protective effects, the CDC’s Dr. Tumpey
intranasally exposed a group of mice to live, reconstructed 1918
virus 14 days after they were immunized with the experimental DNA
vaccine. All 10 vaccinated mice survived the challenge with the
deadly virus. To explore how the vaccine protected the animals,
the researchers first depleted other mice of T-cells; however,
this had no effect on the immunity of the vaccinated mice to the
1918 virus. In contrast, the researchers discovered that transferring
antibody-rich immunoglobulin (IgG) from immunized mice to non-immunized
mice resulted in antibody levels in the animals at levels only
slightly lower than those that were immunized. Further, when the
animals were exposed to the reconstructed 1918 flu virus, 8 of
10 mice that received antibodies from the immunized mice survived;
none of the 10 mice that received IgG from the unvaccinated control
group survived.
“By using an existing pandemic flu strain, this research will
provide the basis for design of alternative vaccines against influenza
viruses with enhanced virulence,” says Dr. Tumpey.
Although the researchers are not discounting the potential role
T-cells may have in combating flu viruses, they concluded that
in this study, the experimental DNA vaccine protected the mice
by stimulating antibodies capable of neutralizing the 1918 flu
virus.
“Who would have imagined five years ago that we’d be able to create
a vaccine that protects against one of the deadliest forms of influenza
the world has ever seen?” adds Dr. Nabel. “It’s because the 1918
flu virus has been reconstructed that we are now able the further
understand it. Hopefully, this virus will help us to develop effective
vaccine strategies for current pandemic influenza virus threats.”
To evaluate the vaccine’s antibody-inducing capabilities while
minimizing exposure of lab personnel to the 1918 flu virus, Dr.
Nabel and his VRC colleagues also created artificial viruses, or
pseudoviruses, featuring the HA of the 1918 flu virus but stripped
of the ability to cause infection. The pseudoviruses were then
incubated with antibody-containing blood samples from the mice
immunized with the DNA vaccine and those that were not. The researchers
found that the antibodies from the immunized mice neutralized the
pseudoviruses while the blood samples from the mice that were not
immunized had no effect. This method was also effective in identifying
neutralizing antibodies to the H5N1 avian flu virus and could be
used to screen for monoclonal antibodies that may be used as an
antiviral treatment, according to Dr. Nabel.
“This technique would be very useful in defining evolving serotypes
of flu viruses like H5N1 to develop immune sera and neutralizing
monoclonal antibodies that may help to contain pandemic flu,” says
Dr. Nabel.
The study authors indicate that further testing will be needed
to determine whether DNA vaccination can confer immune protection
in people similar to that seen in the study mice. Additionally,
the use of DNA-based vaccines are being explored as a potential
strategy for creating vaccines to protect against the H5N1 avian
flu virus.
This research activity is part of a broader effort by the Department
of Health and Human Services to accelerate the development and
production of new technologies for influenza vaccines within the
U.S., including a $1 billion investment earlier this year to support
the advanced development of cell-based production technologies
for influenza vaccines and will help to modernize and strengthen
the nation’s influenza vaccine production by creating an alternative
to producing influenza vaccines in eggs.
NIAID grantee Adolfo García-Sastre, Ph.D., of the Mount Sinai
School of Medicine in New York, also contributed to the study through
his work in reconstructing the virus. In addition to Dr. Nabel,
other VRC scientists who contributed to the study include: Wing-Pui
Kong, Ph.D.; Chantelle Hood; Zhi-yong Yang; Ling Xu; and Chih-Jen
Wei.
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
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