Effectiveness of safer smallpox vaccine demonstrated against monkeypox

March 10, 2004

A mild, experimental smallpox vaccine known as modified vaccinia Ankara (MVA) is nearly as effective as the standard smallpox vaccine in protecting monkeys against monkeypox, a study by researchers of the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health, has found. Monkeypox is used to test the effectiveness of a smallpox vaccine because of its similarity to the smallpox virus. The study appears in the March 11 issue of Nature.

"These findings are important to the search for a replacement vaccine for people with health conditions that would prevent them from using the current smallpox vaccine," says Anthony S. Fauci, M.D., director of NIAID. Currently, Dryvax is the only commercially available smallpox vaccine in the United States. "In addition, because an initial MVA injection may help lessen the side effects experienced from Dryvax, MVA may serve as an important pre-vaccine for large-scale vaccination efforts in the event of a bioterror threat involving smallpox."

NIAID's Bernard Moss, M.D., Ph.D., the senior author on the paper, adds, "This study shows that the MVA vaccine holds great promise as an alternative to the current vaccine. Although MVA may not quite equal Dryvax in its effectiveness, it did extraordinarily well, with all of the monkeys who were vaccinated with MVA surviving a potentially lethal monkeypox infection and, aside from a few minor lesions, showing no clinical signs of disease."

In a separate study published in the March 11 online early edition of the Proceedings of the National Academy of Sciences, Dr. Moss and colleagues found that, in addition to protecting healthy mice against a lethal form of the vaccinia virus, MVA protects mice with certain immune deficiencies as well. The researchers found that mice survived a deadly dose of vaccinia virus if they'd been immunized with MVA--even those mice that were lacking antibody-producing immune cells or special proteins that help alert killer T cells to an infection. The findings indicate that MVA may be a promising alternative to Dryvax in humans who are partially immunodeficient.

Licensed in 1931, Dryvax is made from a live form of vaccinia virus that, although related to the smallpox virus, cannot cause smallpox. (Smallpox is caused by the more dangerous variola virus. The ability to prevent smallpox by injecting a person with either cowpox or vaccinia virus was demonstrated by Edward Jenner in the late 18th century.) Dryvax and similarly effective vaccines made in other countries led to the eradication of smallpox in 1980.

While most reactions to the Dryvax vaccine are relatively mild, some people may have more serious complications. Individuals at risk for such complications include those with weakened immune systems or skin conditions such as eczema, infants less than 12 months of age and women who are pregnant. For this reason, a primary goal of health officials is to develop a vaccine that is as effective as Dryvax, but safer.

MVA is a highly weakened form of the vaccinia virus that cannot multiply and infect mammalian cells. Although MVA was tested for safety in humans at the time of its development in Germany in the 1960s, it has not been tested for effectiveness against smallpox. According to the Food and Drug Administration, humans cannot be exposed to smallpox to test a vaccine's effectiveness: such exposure is unethical because smallpox is an infectious, deadly disease; and it is unfeasible because smallpox has been eradicated. Therefore, animal studies, such as those involving monkeys and mice, are critical to the development of a replacement vaccine.

To compare MVA with Dryvax, the researchers divided 24 cynomologus monkeys (a type of monkey found in Southeast Asia, Borneo and the Philippines) into four groups of six. Group one received two MVA injections--one at the start of the study and the second two months later. Group two received the MVA vaccine at the start of the study and the Dryvax vaccine two months later. Group three received no injection at the start but received a Dryvax injection after two months. Group four, the control, received no vaccines. Immune responses were monitored throughout the immunization period, and then, later, after the monkeys were exposed to monkeypox.

After vaccinating the monkeys, researchers examined the number of lesions that formed on the animals' skin and the amount of time in which they healed. Monkeys that received Dryvax alone developed the characteristic fluid-filled skin lesions, while those that received MVA prior to Dryvax had much smaller lesions. Furthermore, those that received MVA alone had no skin lesions.

The researchers then looked for antibodies produced against two different forms of the poxvirus: intracellular mature virions (IMVs), virus particles thought to be responsible for transmitting the disease from one host to another; and extracellular enveloped virions, IMVs with an added outer membrane that play a large role in spreading the disease within the individual. To be effective, a vaccine needs to protect against both forms of the virus, and each form requires a different set of antibodies to destroy it. In addition to measuring antibodies, the scientists examined the production of killer T cells, special immune cells that attack cells already infected by the monkeypox virus.

Dr. Moss and his research team discovered that the immune responses elicited by the MVA vaccine were similar to those produced by Dryvax in regard to both antibodies and killer T cells.

Two months after the second vaccination, all 24 monkeys were exposed to monkeypox. Remarkably, all the immunized animals remained healthy with no signs of disease, except for a small number of lesions seen on several monkeys from the MVA-only group. The unvaccinated monkeys, however, had more than 500 lesions each and became seriously ill or died.

Dr. Moss and his team will continue their studies on monkeys to determine, among other things, the duration of protection offered by MVA versus Dryvax as well as the effect of dosage. In addition, NIAID is currently supporting clinical trials to evaluate the immune response to MVA in humans.

Other researchers involved in the study represented the Henry M. Jackson Foundation, Rockville, MD; the University of Pennsylvania, Philadelphia, PA; and the U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD.

Smallpox is a serious, frequently fatal infectious disease that generally spreads from person to person through the air and is marked by fever, head and body aches, rash and large, fluid-filled bumps on the skin. The last case of smallpox in the United States occurred in 1949, and the last case in the world was in 1977. However, the smallpox virus still exists in laboratories and represents a potential threat because it could be used by terrorists. Monkeypox is primarily a disease of animals, but more than a hundred human cases a year have been reported from central and western Africa. The first monkeypox outbreak occurred in the United States in June 2003 when several people were sickened by infected pet prairie dogs. Symptoms of monkeypox are similar to smallpox, though often milder.
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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.

References: PL Earl et al. Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox. Nature 428:182-5 (2004).

LS Wyatt et al. Highly attenuated smallpox vaccine protects mice with and without immune deficiencies against pathogenic vaccinia virus challenge. Proceedings of the National Academy of Sciences DOI: 10.1073/PNAS.0401165101 (published online March 11, 2004).

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

NIH/National Institute of Allergy and Infectious Diseases

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