August 2004
Smallpox
OVERVIEW
Smallpox is a disfiguring and potentially deadly infectious disease caused by the Variola major virus. Before smallpox was eradicated, there were two forms of the disease worldwide: Variola major, the deadly disease, and Variola minor, a much milder form. According to some health experts, over the centuries smallpox was responsible for more deaths than all other infectious diseases combined. The disease spreads in any climate and during all seasons. Although a worldwide immunization program eradicated smallpox disease decades ago, small quantities of smallpox virus officially still exist in two research laboratories in Atlanta, Georgia, and in Russia.The last naturally occurring case of smallpox was reported in 1977. In 1980, the World Health Organization declared that smallpox had been eradicated. Currently, there is no evidence of naturally occurring smallpox transmission anywhere in the world.
THE MICROBE
Scientists have not studied variola virus well because of the hazards associated with potential exposure. In addition, by international agreement, smallpox may only be studied at the Centers for Disease Control and Prevention (CDC) high containment facility or one in the former USSR (Union of Soviet Socialist Republics), and experiments must be approved in advance by an international committee. Vaccinia virus, however, used to make a smallpox vaccine and closely related to variola, has been studied thoroughly. There is one major difference between the two viruses: vaccinia can infect several types of living beings, while variola infects only humans naturally and cynomolgus monkeys under highly artificial laboratory conditions.Researchers are now investigating vaccinia as a possible way to deliver genes from other viruses to make new vaccines.
TRANSMISSION
Smallpox is highly contagious. In most cases, people get smallpox by inhaling droplets of saliva, which are full of virus, during face-to-face contact with an infected person. When someone becomes infected, they do not immediately feel sick or shed virus to their household contacts. In addition, they have no symptoms for 10 to 12 days. After the virus has multiplied and spread throughout the body, a rash and fever develop. This is the "illness" portion of the disease, and it's when someone is most infectious. In short, someone who becomes infected is not going to be ill until 10 to 12 days later.Some risk of transmission lasts, however, until all scabs have fallen off. Contaminated clothing or bed linens also can spread the virus. Those caring for people with smallpox need to use special safety measures to ensure that all bedding and clothing from the infected person are cleaned appropriately with bleach and hot water. Caretakers can use disinfectants such as bleach and ammonia to clean contaminated surfaces.
SYMPTOMS
Symptoms of smallpox infection usually appear within 7 to 17 days after exposure to the virus, and on average appear after 12 days. The first symptoms of smallpox may be difficult to distinguish from other flu-like illnesses and include- High fever
- Tiredness, malaise
- Headache, backache
Rash
A characteristic rash, most prominent on the face, arms, and legs, follows 2 to 3 days after the first symptoms. The rash starts with flat red lesions (sores) that develop at the same rate. After a few days, the lesions become filled with pus, and they begin to crust early in the second week. Scabs develop and then separate and fall off after about 3 weeks.TREATMENT
There is no proven treatment for smallpox. People with the disease can benefit from intravenous fluids and medicine to control fever or pain as well as antibiotics for any secondary bacterial infections that may occur. If an infected person gets the smallpox vaccine within 4 days after exposure to the virus, it may lessen the severity of illness or even prevent it. The majority of people with smallpox recover, but death may occur in up to 30 percent of cases. Those who do recover are often left with disfiguring scars.Research to evaluate new antiviral agents is ongoing. Early results from laboratory studies suggest that the drug cidofovir may fight against the smallpox virus. (In 1996, the Food and Drug Administration [FDA] approved the use of cidofovir to treat cytomegalovirus infections.) Scientists are doing studies with animals to better understand the drug’s ability to treat smallpox. In addition, the National Institute of Allergy and Infectious Diseases (NIAID) has applied to FDA to use the antiviral drug cidofovir as an experimental treatment for smallpox in the event of a bioterrorist-initiated re-emergence.
PREVENTION
To prevent the spread of smallpox, health care providers must- Isolate infected people
- Vaccinate close contacts of infected people
Vaccine
The currently licensed smallpox vaccine, which consists of a laboratory strain of vaccinia virus, is highly effective in preventing infection. Medical experts believe that the vaccine may lessen the severity of, or even prevent, illness in unvaccinated people if given within 4 days of exposure to the virus.The smallpox vaccine helps the body develop immunity to smallpox. The vaccine is made from a “pox”-type virus related to smallpox. The smallpox vaccine contains live vaccinia virus—unlike many other vaccines that use killed virus. The vaccine does not contain the smallpox virus and cannot transmit smallpox (http://www.bt.cdc.gov/agent/smallpox/vaccination/facts.asp ).
Few data exist showing just how long vaccinia vaccines protect people against smallpox infection. Therefore, those vaccinated against the smallpox virus before 1972 may be susceptible to the disease. U.S. health officials are inoculating health care workers and those who will be on the front lines of medical care should there be a smallpox outbreak. Military and other high-risk groups (for example, scientists who work with vaccinia and other orthopoxviruses related to Variola major ) have been getting the vaccine since the United States stopped routine smallpox vaccinations in 1972.
Getting the vaccine
Health care providers do not use a hypodermic needle, usually used for vaccinations, to give the smallpox vaccine. Instead, they use a tiny, two-pronged needle that is dipped into the vaccine solution. When removed, the needle keeps a droplet of the vaccine. The needle is used to prick the skin, usually in the upper arm, a number of times within a few seconds. The pricking is not deep, but it will cause a sore spot and one or two droplets of blood to form.
If the vaccination is successful, a red and itchy bump develops at the vaccine site in 3 or 4 days.
- In the first week, the bump becomes a large blister, fills with pus, and begins to drain
- During the second week, the blister begins to dry up and a scab forms
- In the third week, the scab falls off, leaving a small scar
Reactions and complications
The vaccine often causes fever as well as large skin reactions at the vaccination site. These reactions usually go away, leaving only the telltale smallpox vaccine scar.
The vaccine, however, can cause several complications, some life-threatening, particularly in people with immune deficiencies and skin disorders. Based on reactions to smallpox vaccines in the past, CDC estimates that between 14 and 52 people out of every 1 million people vaccinated for the first time will have potentially life-threatening complications that require medical attention including
- Eczema vaccinatum (EV)—spread of vaccinia skin lesions to areas of the body once or presently afflicted by eczema
- Progressive vaccinia—uncontrolled spread of the vaccinia virus to adjacent and underlying tissues resulting in tissue death
- Postvaccinal encephalitis—spread of the vaccinia virus to the central nervous system that is probably made worse by an over-response by the immune system
Health care providers treat certain serious complications with anti-vaccinia immune globulin—pooled antibodies taken from people recently immunized with the smallpox vaccine. Because the United States discontinued routine smallpox vaccination programs in 1972, vaccinia immune globulin (VIG) is in extremely short supply. A government-funded program to produce sufficient VIG to treat all predicted cases of complications is underway. In addition, NIAID-funded researchers are trying to develop replacements for VIG based on antibodies made in the laboratory. Cidofovir also may be used in some situations. Neither drug is currently licensed for this purpose, and they may have side effects of their own.
NIAID RESEARCH
NIAID supports research on the diagnosis, prevention, and treatment of infections caused by microbes, including those that have the potential for use as biological weapons. The research program to address biodefense includes both short- and long-term studies to design, develop, evaluate, and approve specific tools (diagnostics, treatments, and vaccines) needed to defend against possible bioterrorist-caused disease outbreaks.Recently, NIAID launched the Atopic Dermatitis and Vaccinia Network (ADVN), a nationwide research group that seeks to reduce the risk of EV, a severe and potentially deadly complication of smallpox immunization. EV occurs almost exclusively in people with a history of atopic dermatitis (AD), a chronic, itchy skin condition commonly referred to as eczema. While uncommon, EV can develop when AD patients are given the smallpox vaccine or come into close personal contact with people who recently received the vaccine. If untreated, EV can kill between 1 and 6 percent of those affected. In children younger than 2 years of age, health experts estimate that EV can kill up to 30 percent.
Vaccine Supply and Strength
Expanding the U.S. smallpox vaccine supply is a high priority of the bioterrorism preparedness plan. Results from an NIAID study show that the existing U.S. supply of smallpox vaccine—15.4 million doses—could successfully be diluted up to five times and retain its potency, effectively expanding the number of individuals it could protect from the contagious disease. The vaccine, called Dryvax, had been stored since production stopped in 1983.The trial compared the full-strength vaccine with fivefold, as well as tenfold, dilutions in 680 young adults with no history of smallpox vaccination. More than 97 percent of all participants in the trial responded with a vaccine “take,” a blister-like sore at the injection site that serves as an indirect measure of the vaccine’s effectiveness. A new study has been conducted to determine how effective the diluted Dryvax is in people who have been previously vaccinated against smallpox.
In addition to Dryvax, NIAID is sponsoring clinical trials of another vaccine against smallpox called APSV. Eighty million doses of APSV, a different formulation of a vaccinia smallpox vaccine produced by Aventis Pasteur, had been in storage for 40 years. In on-going studies, researchers are testing various concentrations of APSV in adults who have never received vaccinia.
NIAID also conducts and supports research studies to develop and test a safer, weakened form of smallpox vaccine based on modified vaccinia Ankara (MVA) vaccine. MVA is being developed for use in people who are at risk for complications from Dryvax vaccination, for example, those who are HIV positive or have eczema. Unlike Dryvax, MVA is unable to grow in human cells and therefore cannot form a lesion at the site of vaccination. A recent NIAID study showed that MVA is nearly as effective as the standard smallpox vaccine in protecting monkeys against monkeypox (an orthopoxvirus). (Monkeypox is used to test the effectiveness of a smallpox vaccine because of its similarity to the variola viruses.)
Microbe biology
Variola and vaccinia belong to the Orthopoxvirus genus of poxviruses. Scientists who have sequenced the genes of several strains of variola and vaccinia have- Found that genes for structural, membrane, and inner proteins appear to vary little among orthopoxviruses
- Identified some of the genes responsible for virus growth in human cells
Treatment
In collaboration with the U.S. Department of Defense (DoD), NIAID has screened more than 500 compounds against smallpox and related viruses. In addition, NIAID supports studies that evaluate experimental antiviral compounds in a number of mouse models of vaccinia and cowpox (another member of the orthopoxvirus family).NIAID also supports mousepox virus and rabbitpox virus models. Compounds that are effective in these small-animal models are given priority for evaluation by DoD researchers in the monkeypox primate model.
In addition to collaborating with DoD scientists, NIAID is working with scientists at other federal agencies, such as CDC and the Department of Energy, to develop and test at least three antiviral drugs against smallpox and determine whether existing antiviral compounds and those being developed are effective against variola virus. In addition to those treatment studies, NIAID is collaborating on studies to
- Extend the usefulness of the currently available older smallpox vaccine, Dryvax
- Help develop a safer, sterile smallpox vaccine using modern technology
- Explore developing a vaccine that can be used safely in all segments of the population
- Increase scientific knowledge about the genome of variola and related viruses
MORE INFORMATION
National Library of MedicineMedlinePlus
8600 Rockville Pike
Bethesda, MD 20894
1-800-338-7657
http://www.nlm.nih.gov/medlineplus
Centers for Disease Control and Prevention
1600 Clifton Road
Atlanta, GA 30333
1-888-232-3228
http://www.bt.cdc.gov
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857
1-888-INFO-FDA (1-888-463-6332)
http://www.fda.gov/oc/opacom/hottopics/bioterrorism.html
U.S. Department of Defense
http://www.defenselink.mil
U.S. Department of Energy
1000 Independence Avenue, SW
Washington, DC 20585
1-800-dial-DOE (1-800-342-5363)
http://www.energy.gov
World Health Organization
Avenue Appia 20
1211 Geneva 27
Switzerland
(00 41 22) 791 21 11
http://www.who.int
NIAID is a component of the National Institutes of Health (NIH), which is an agency of the Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, 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.
Prepared by:
Office of Communications and Public Liaison
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892
 |
Department of
Health and Human Services |
 |
National Institutes
of Health (NIH) Bethesda, Maryland 20892 |
 |
NIAID Home | ![[ Go to FirstGov Web Site ]](/peth04/20041018225930im_/http://www.niaid.nih.gov/graphics/footer/firstgov_sm.gif){kind=small} |