New Method Enables Researchers to Make Human SARS Antibodies Quickly
Human antibodies that thwart the SARS virus in mice can be mass-produced
quickly using a new laboratory technique developed by an international
research team collaborating with the National Institute of Allergy
and Infectious Diseases (NIAID), one of the National Institutes
of Health. The new technique could become an important tool for
developing a cocktail of SARS-specific antibodies that might help
protect people recently exposed to the SARS virus or at high risk
of exposure. The technique could also make possible the development
of a similar approach to prevent or treat other illnesses, such
as HIV/AIDS and hepatitis C.
The report describing these findings appears in the July 11, 2004,
online issue of Nature Medicine.
"While much has been accomplished in our quest for a vaccine
against SARS, a vaccine may provide little benefit to someone already
infected," says Anthony S. Fauci, M.D., director of NIAID.
"Human SARS antibodies could offer a double benefit: they could
be used as a potent frontline defense for health care workers and
others at high risk of exposure and as an effective treatment for
those individuals newly exposed to the virus." Currently, there
is no specific effective treatment for SARS.
SARS is caused by a coronavirus, a family of viruses named for their
spiky, crown-like appearance. Highly contagious, SARS typically
begins with flu-like symptoms, such as fever, headache and muscle
aches, and generally progresses to pneumonia. In the 2003 global
outbreak, more than 8,000 people were infected with SARS, 9 percent
of whom died. In April 2004, a small outbreak in China is suspected
to have begun as a result of negligent laboratory practices.
In the current study, Elisabetta Traggiai, Ph.D., and Antonio Lanzavecchia,
M.D., from the Institute for Research in Biomedicine, Bellinzona,
Switzerland, together with an international research team, generated
human antibodies against SARS far more quickly and efficiently than
with current methods. Moreover, collaborators Kanta Subbarao, M.D.,
and Brian Murphy, M.D., both in NIAID's Laboratory of Infectious
Diseases, demonstrated for the first time that these human SARS
antibodies, when injected into mice, effectively prevent the virus
from multiplying in the respiratory system.
"The antibodies from people who have recovered from SARS may
target different parts of the virus than antibodies generated by
other animals, such as mice," says Dr. Subbarao. "For
this reason, human antibodies antibodies from recovered patients
that may have a proven effectiveness in fighting the disease are
considered most desirable for a possible serotherapy against SARS."
Antibodies are made by special immune system cells called B cells
that, to do their job, must first be switched on. In nature, this
occurs when the body encounters a new or repeat foreign "invader."
In the laboratory, researchers conventionally accomplish this by
exposing the B cells to Epstein Barr virus (EBV), a herpes virus
that infects B cells, which in turn activates them. Unfortunately,
this process is very inefficient, and only one or two B cells out
of one hundred are activated this way.
Dr. Lanzavecchia and his research team added a new ingredient to
the mix that significantly boosts efficiency. Beginning with B cells
from a recovered SARS patient, the researchers added a short stretch
of synthetic DNA that mimics DNA found in bacteria and viruses.
From 30 to 100 percent of the B cells in this case called "memory"
B cells because they had been exposed to the SARS virus before were
switched back on, enabling them to churn out SARS antibodies at
a fast pace. In only a few weeks, the researchers screened hundreds
of antibodies and obtained 35 that could neutralize the SARS virus
in the laboratory. All the neutralizing antibodies targeted a key
SARS protein, the spike protein, found on the virus surface.
Furthermore, when Drs. Subbarao and Murphy injected one of the neutralizing
antibodies into mice, they found that these antibodies effectively
thwarted the SARS virus from multiplying in the lower respiratory
tract, which includes the lungs, and, to a lesser extent, in the
upper respiratory tract, which includes the nasal cavity. According
to Dr. Subbarao, these results are very promising because replication
of SARS in the lungs of humans can result in pneumonia.
A primary benefit of the new activation technique is that it generates
a large pool of prospective antibodies from which to choose, so
only the most effective SARS fighters can be chosen for use in a
possible immune serum. Because viruses can mutate, however, more
than one antibody will most likely be needed to achieve the optimal
protection or treatment, the researchers contend.
The researchers' next goal is to find additional antibodies against
the SARS virus, focusing on those that attach most readily to the
virus, are most potent against the virus, and can attach to more
than one site on the spike protein. Before the antibodies might
be made available for clinical use, researchers need to test them
for their effectiveness in other laboratory animals, such as non-human
primates, as well as in human clinical trials.
NIAID is a component of the National Institutes of Health, an
agency of the U.S. Department of Health and Human Services. 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 transplantation
and immune-related illnesses, including autoimmune disorders, asthma
and allergies. Press releases, fact sheets and other NIAID-related
materials are available on the NIAID Web site at http://www.niaid.nih.gov.
Reference: E Traggiai et al. An efficient method to make human monoclonal
antibodies from memory B cells: potent neutralization of SARS coronavirus.
Nature Medicine. Published online July 2004. DOI: 10.1038/nm1080.