Human Antibodies Protect Mice
from Avian Flu
An international team of scientists, including researchers from
the National Institute of Allergy and Infectious Diseases (NIAID),
part of the National Institutes of Health, report using antibodies
derived from immune cells from recent human survivors of H5N1 avian
influenza to successfully treat H5N1-infected mice as well as protect
them from an otherwise lethal dose of the virus.
“The possibility of an influenza pandemic, whether sparked by
H5N1 or another influenza virus to which humans have no natural
immunity, is of serious concern to the global health community,” says
NIAID Director Anthony S. Fauci, M.D. “If the success of this initial
study is confirmed through further laboratory and clinical trials,
human monoclonal antibodies could prove to be valuable therapeutic
and prophylactic public health interventions for pandemic influenza.”
The research, to be published May 29 in PLoS Medicine,
represents a three-way collaboration among Kanta Subbarao, M.D.,
and her coworkers at NIAID; Antonio Lanzavecchia, M.D., and colleagues
from the Institute for Research in Biomedicine, Bellinzona, Switzerland;
and Cameron Simmons, Ph.D., from the Oxford University Clinical
Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City,
Vietnam.
Four Vietnamese adults diagnosed with H5N1 influenza infection
between January 2004 and February 2005 agreed to donate blood soon
after they had recovered from their illness. In Switzerland, Dr.
Lanzavecchia extracted antibody-producing white blood cells, called
memory B cells, from the Vietnamese samples and treated them with
a process he developed so that they rapidly and continuously produced
large amounts of antibody. Next, researchers in Dr. Subbarao’s
lab screened 11,000 antibody-containing samples provided by the
Swiss team and found a handful able to neutralize H5N1 influenza
virus. Based on these results, Dr. Lanzavecchia purified the B
cells and ultimately created four monoclonal antibodies (mAbs)
that secrete H5N1-specific neutralizing antibodies.
Dr. Subbarao and her coworkers first tested whether the human
H5N1 mAbs could protect mice from severe H5N1 infection. Groups
of five mice received either of two human H5N1 mAbs at one of three
dosages or human mAbs against diphtheria or anthrax. One day later,
the mice were exposed through their noses to lethal doses of H5N1
influenza virus.
All the control mice — those receiving non H5N1 mAbs — rapidly
developed severe illness and died within a week. In contrast, all
the mice that received the first H5N1 mAb tested — regardless
of dose — survived, while 80 percent of mice receiving the
highest dose of the second H5N1 mAb survived. Additional tests
showed that mice receiving either of the two protective H5N1 mAbs
had levels of virus in the lungs that were 10 to 100 times lower
than those in control mice, and little or no virus moved beyond
the lungs.
The investigators also tested the therapeutic potential of the
human H5N1 mAbs. Using blood products from influenza survivors
is an old idea, the researchers note. During the flu pandemic of
1918-19, for example, physicians took serum from recovered flu
patients and gave it to new victims; recent historical research
indicates that those blood transfusions, when given early in the
illness, sometimes saved recipients’ lives.
In their study, Dr. Subbarao and her colleagues infected groups
of mice with a lethal dose of an H5N1 virus that had circulated
in Vietnam in 2004. A total of 60 mice were given one of the four
H5N1 mAbs at 24, 48 or 72 hours after infection while a control
group received non-influenza mAbs. All the mice in the control
group died within 10 days of infection, while 58 of the 60 treated
mice survived. All four H5N1 mAbs conferred robust protection.
Most surprisingly, says Dr. Subbarao, the survival rate was excellent
even when treatment was delayed for three days.
Spurred by these results, the NIAID investigators next tested
whether the H5N1 mAbs might be used to treat mice infected with
a related but distinct H5N1 virus. Although the four mAbs used
in the experiment originated after infection with the 2004 H5N1
virus, three of them nevertheless prevented the mice from dying
when given 24 hours after they were infected with a 2005 H5N1 virus.
This suggests, the researchers say, that human mAbs may provide
broad protection against variant H5N1 viruses — a desirable quality
in any therapeutic aimed at the constantly evolving flu virus.
Taken together, the findings from this international collaboration
are encouraging, says Dr. Subbarao. They show that fully human
mAbs with potent H5N1 influenza virus neutralizing ability can
be rapidly generated from the blood of convalescent patients and
that these mAbs work well to both treat H5N1 infection and prevent
death from such infection in a mouse model. The authors plan to
take the research forward by scaling up the production of H5N1
mAbs and, if the technique proves safe and effective in additional
animal tests, to evaluate these human mAbs in clinical trials in
humans.
For more information on influenza see http://www3.niaid.nih.gov/news/focuson/flu.
Also visit http://www.PandemicFlu.gov for
one-stop access to U.S. Government information on avian and pandemic
flu.
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.
|