Mice studies illustrate potential of chimp/human antibodies to protect against smallpox

Results from a new study indicate that hybrid laboratory antibodies derived from chimpanzees and humans may provide a potentially safe and effective way to treat the serious complications that can occur following smallpox vaccination--and possibly may even protect against the deadly disease itself. The study, led by researchers with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), appears online this week in the Proceedings of the National Academy of Sciences (PNAS).

A worldwide immunization program officially eradicated naturally occurring smallpox disease in 1980. However, concerns of a bioterror attack involving the highly contagious and fatal virus have prompted researchers to search for new smallpox vaccines and treatments.

The currently licensed smallpox vaccine consists of a live but weakened strain of vaccinia virus, a relative of the variola virus that causes smallpox. Vaccinia immunization has been proven effective in generating immunity against smallpox virus and other orthopoxviruses, including monkeypox and cowpox.

Although most reactions to the vaccinia virus are mild, the vaccine can cause serious and even life-threatening complications in individuals with weakened immune systems or skin conditions such as eczema, in infants younger than 12 months and in pregnant women. Health care providers currently treat smallpox vaccine complications with anti-vaccinia immune globulin (VIG)--pooled antibodies taken from the blood of individuals immunized with the smallpox vaccine. However, VIG is in short supply since the United States discontinued its public smallpox vaccination program in 1972.

NIAID-funded researchers have been working to develop alternatives to VIG based on antibodies they created in the laboratory. The study appearing online this week in PNAS details how senior authors Robert H. Purcell, M.D., co-chief of NIAID's Laboratory of Infectious Diseases, and Bernard Moss, M.D., chief of NIAID's Laboratory of Viral Diseases, and their collaborators developed hybrid antibodies from chimpanzees and humans that effectively inhibited the spread of both vaccinia and variola viruses in test tube experiments. Moreover, the hybrid antibodies proved more effective than VIG when tested in mice infected with vaccinia virus, even when given two days after virus exposure.

"This is an important finding in the race to develop effective measures against a potential bioterror attack involving the deadly smallpox virus," says NIH Director Elias A. Zerhouni, M.D.

"It is imperative that we have effective treatments available that everyone could use in the event of a bioterror attack," says NIAID Director Anthony S. Fauci, M.D. "This study shows that there are potential alternatives to existing treatments and perhaps to existing vaccines that we can use to enhance our arsenal of medical countermeasures."

Using a library of antibodies derived from the bone marrow of two vaccinia-immunized chimpanzees, the study researchers identified a pair of potent antibodies that target and neutralize the B5 protein, one of five key proteins responsible for cell-to-cell spread of infectious vaccinia virus. The researchers then combined the two chimp-derived antibodies with a human antibody to create two hybrid test antibodies, 8AH7AL and 8AH8AL. In test tube experiments, both antibody types prevented the spread of vaccinia virus. Further, the 8AH8AL antibody neutralized one strain of the smallpox-causing variola virus. The test involving the smallpox virus was performed at the Centers for Disease Control and Prevention in Atlanta.

The researchers then tested the effectiveness of the hybrid antibodies in mice. The control group--mice that were given the vaccinia virus but did not receive the antibodies--experienced continuous weight loss for five days after virus injection, which the researchers correlated with viral replication in the lungs. In contrast, mice injected with either of the two types of hybrid antibodies did not lose weight.

Since there was no difference in the protective abilities between the two hybrid antibodies, the researchers used 8AH8AL to determine the minimum effective dose. Groups of mice were given decreasing doses--90, 45 and 22.5 micrograms per mouse--of 8AH8AL or a single 5-mg dose of human VIG (two and a half times the recommended human dose on a weight basis) as a point of comparison. All five mice in the control group died or were sacrificed when their weight fell to 70 percent of their starting weight. All of the mice that were injected with 8AH8AL (even at the lowest dose) or with VIG were protected from death.

Further, mice that received a single 90-microgram dose of 8AH8AL two days after virus exposure experienced only slight weight loss followed by rapid recovery. Conversely, all five of the mice that received 5 mg of VIG 48 hours after virus exposure experienced much greater weight loss than those that received the hybrid antibody.

"This study demonstrated that the hybrid antibodies provide instant protection against the vaccinia virus and likely smallpox and are potentially more potent and more specific than the treatment we currently have available," says Dr. Purcell. The hybrid antibodies also offer a potentially significant advantage over VIG as a treatment for smallpox vaccination complications not only because VIG is in limited supply but because VIG lots may have different potencies and carry the potential to transmit other infectious agents, he adds.

According to Dr. Purcell, the hybrid antibodies should be tested in another animal model for effectiveness against the monkeypox virus, which closely mirrors smallpox but is less virulent in humans.

Currently, the smallpox virus exists in only two laboratories found in Atlanta, Georgia, and in Russia.

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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.

Reference: Z Chen et al. Chimpanzee/human mAbs to vaccinia virus B5 protein neutralize vaccinia and smallpox viruses and protect mice against vaccinia virus. Proceedings of the National Academy of Sciences (2006)DOI:10.1073/PNAS.0510598103.

Media Contact: Kathy Stover
(301) 402-1663
kstover@niaid.nih.gov

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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