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Vaccinia is a virus related to smallpox and is used to make the smallpox vaccine. As part of the normal post-vaccination healing process, a bump will form at the place on a person's skin where the vaccine was given (called the "vaccination site"). The bump will turn into a blister. It will fill with pus and start to drain. The blister will dry up and form a scab. After about two to three weeks, the scab will fall off and leave a small scar. Vaccinia is spread by touching the vaccination site before the scab has fallen off, or by touching items like bandages, clothes, sheets or towels that have touched the site. Therefore, it's important to cover the vaccination site with a porous bandage such as gauze, and to wash with soap and warm water right away if you accidentally touch the vaccination site or items that were in contact with it.

As with all vaccines, some people may experience adverse reactions or complications following vaccination for smallpox. These reactions range from mild to severe or even life-threatening. Vaccinia reactions are occasionally misidentified as infections with the smallpox virus — which was declared eradicated in 1980 — raising concern for bioterrorism. Having recently received a smallpox vaccine or having had close contact with someone else who recently received a smallpox vaccine can help distinguish between these two conditions. Specialized testing at public health laboratories might also be required.

Vaccinia infections can also occur through contact with domesticated animals in some parts of the world or through exposure to vaccinia strains used in laboratory settings. Vaccinia infections acquired in this way are usually localized and self-limited.

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