Human Antibodies that Block Human and Animal
SARS Viruses Identified
An international team of investigators has identified the first
human antibodies that can neutralize different strains of the virus
responsible for outbreaks of severe acute respiratory syndrome
(SARS). The researchers used a mouse model and in vitro assays
(lab tests) to test the neutralizing activity of the antibodies.
The research team was led by scientists from the National Cancer
Institute (NCI) and the National Institute of Allergy and Infectious
Diseases (NIAID), both parts of the National Institutes of Health,
and included collaborators from the U.S. Army (USAMRIID), academic
institutions in the United States, Switzerland, and Australia.
The research findings appear in the July 2, 2007, early online
edition of the Proceedings of the National Academy of Sciences.
SARS outbreaks occurred in humans in 2002-2003 and again in 2003-2004,
and each outbreak was thought to have occurred when the virus jumped
from an animal host to humans. Therefore, it appears that animal
strains of the virus may be capable of triggering a future human
outbreak.
“This study is important because the viral strain that caused
the outbreak in people in 2002 probably no longer exists in nature,” explains
Kanta Subbarao, M.D., NIAID, whose laboratory verified the efficacy
of the anti-SARS antibodies in animal models. “What we need to
prove for any vaccine, therapeutic, antibody, or drug is that it
is effective not only against the strain of SARS virus isolated
from people, but also against a variety of animal strains, because
animals will be a likely source for re-emergence of the SARS virus.”
The research team was led by Dimiter S. Dimitrov, Ph.D., head
of the Protein Interaction Group at NCI’s Frederick, Md., campus.
When the first SARS outbreak occurred in 2002, Dimitrov responded
to the public health crisis by applying his laboratory’s expertise
in how viruses enter cells, which was gained in the study of HIV,
to understand how this new virus enters and exploits human cells.
Their research into the spike glycoprotein, the part of the virus
that binds and allows entry into human cells, provided the knowledge
needed to identify several human antibodies against the SARS virus.
“Our researchers at NCI Frederick have an extraordinary breadth
of expertise, ranging far beyond cancer to areas such as AIDS research,
advanced biotechnology, and vaccine manufacturing,” said NCI Director
John E. Niederhuber, M.D. “We are realizing, as never before, that
cancer is a model for many diseases, and NCI's research is a rich
resource to our NIH colleagues and the biomedical research community
at large.”
Dimitrov and his colleagues identified two human antibodies that
bind to a region on the SARS virus’ spike glycoprotein that is
called the receptor binding domain (RBD). One of the antibodies,
called S230.15, was found in the blood of a patient who had been
infected with SARS and later recovered. The second antibody, m396,
was taken from a library of human antibodies the researchers developed
from the blood of 10 healthy volunteers. Because humans already
have immune cells that express antibodies that are very close to
those that can effectively neutralize the SARS virus, m396 could
be fished out from healthy volunteers. Dimitrov’s team next determined
the structure of m396 and its complex with the SARS RBD and showed
that the antibody binds to the region on the RBD that allows the
virus to attach to host cells.
If the antibodies were successful in binding to the SARS RBD,
they would prevent the virus from attaching to the SARS coronavirus
receptor, ACE2, on the outside of human cells, effectively neutralizing
it. When tested in cells in the laboratory, both antibodies potently
neutralized samples of the virus from both outbreaks. The antibodies
also neutralized samples of the virus taken from wild civets (a
cat-like mammal in which strains of the virus were found during
the outbreaks), though with somewhat lower potency.
The investigators next tested the antibodies in a mouse model
of SARS virus infection. Mice were given an injection of one of
the two antibodies and then were exposed 24 hours later either
to samples of the SARS virus from one of the two outbreaks or to
virus isolated from civets. Mice that received m396 or S230.15
were fully protected from infection by SARS from humans, the researchers
found. Similar to the experiments in cells in the laboratory, mice
that received either antibody were also protected against infection
by SARS from civets, though not completely.
Further analysis of the structure of m396 and its interactions
with experimental mutations in the SARS virus receptor binding
area suggested that the antibody can successfully neutralize all
known forms of the virus. “This antibody neutralizes all strains
of SARS we tested and is likely to neutralize all strains of the
virus with known sequences,” said Dimitrov. “There are no other
reports for such antibodies available.”
“This elegant research leaves us better prepared for the possible
re-emergence in people of viruses similar to those that caused
more than 8,000 documented SARS cases and nearly 800 deaths in
2002-2003,” noted NIAID Director Anthony S. Fauci, M.D. “This work,
which could help inform the development of therapeutics, vaccines,
and diagnostics, is a pre-emptive strike against a pathogen with
the potential to re-emerge.”
The discovery of two effective antibodies has the advantage that
a newly emergent variation of the SARS coronavirus might be insensitive
to neutralization with one, but still susceptible to the other. “Our
results demonstrate novel potential antibody-based therapeutics
against SARS that could be used alone or in combination...these
human antibodies could be also used for diagnosis and as research
reagents in the development of vaccines and inhibitors,” summarized
the authors.
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