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NIAID Role in Smallpox Research

NIAID supports basic, preclinical, and clinical research needed to advance product development for biodefense and emerging infectious diseases. Product development goals in this arena have shifted from a “one bug-one drug” approach to a more flexible strategy that is applicable to a broad spectrum of infectious diseases. Specifically, this broad-spectrum approach is being used to develop products effective against a variety of pathogens and toxins; find technologies that can be widely applied to improve multiple classes of products; and establish platforms that can reduce the time and cost of creating new products. This is evident in both the treatment and vaccine research NIAID has supported for smallpox, outlined below.

Vaccine Supply and Strength

The last naturally occurring case of smallpox was reported in 1977. In 1980, the World Health Organization declared that smallpox had been eradicated. The Dryvax vaccine was used in smallpox eradication, and the United States has enough of its successor, Acam2000, available to vaccinate the population in the case of a terrorist attack. Prior to availability of Acam2000, a NIAID-supported clinical trial that found that Dryvax could successfully be diluted up to five times and retain its effectiveness. These findings helped expand the number of individuals Dryvax could protect until sufficient doses of Acam2000 were made for the entire U.S. population.

People with weakened immune systems or skin conditions, such as atopic dermatitis, or eczema, are at increased risk for serious side effects from Dryvax and Acam2000. NIAID is pursuing the development of new, safer smallpox vaccines that could be used to protect these groups. One of the most promising is being developed by the biotechnology company Bavarian Nordic and uses a vaccine platform technology known as Modified Vaccinia Ankara – Bavarian Nordic (MVA-BN). NIAID supported early advanced development work for this important vaccine, with initial efforts largely focused on the liquid formulation. NIAID support spanned preclinical evaluation through Phase II clinical trials. The trials assessed the vaccine in healthy participants, HIV-positive volunteers, and people with atopic dermatitis or a history of atopic dermatitis. These studies evaluated factors such as safety, immunogenicity, duration of protection, and route of vaccination. The vaccine was transitioned to the Biomedical Advanced Research and Development Authority (BARDA) for advanced development. In 2013, Canada and the European Union approved the vaccine (under the trade names IMVAMUNE and IMVANEX) for use in the general population, including people with weakened immune systems or atopic dermatitis. As of August 2014, 24 million doses were delivered to the U.S. Strategic National Stockpile (SNS) for use among these groups.

NIAID also supported a project to develop a freeze-dried, or lyophilized, version of the vaccine. Compared to the current liquid formulation, the lyophilized version is more stable with a longer shelf life. NIAID has transitioned this project to the U.S. Department of Health and Human Services Biomedical Advanced Research and Development Authority (BARDA) for further development.

NIAID is supporting studies to identify adjuvants that can be used to decrease the number of vaccinations needed to provide protection and explore MVA as a platform technology to provide protection against more than one disease.


Although smallpox vaccines have been developed and procured for the SNS, they cannot completely prevent disease or attenuate the illness if given too late following exposure. Smallpox antivirals are needed for treatment or post-exposure prophylaxis. Early results from laboratory studies suggest that the drug cidofovir may be an effective treatment against the smallpox virus. (In 1996, the Food and Drug Administration [FDA] approved the use of cidofovir to treat cytomegalovirus infections.) NIAID-supported scientists are doing studies with animals to better understand the drug's ability to treat smallpox.

Based on encouraging study results, NIAID applied to FDA to use cidofovir as an experimental treatment for smallpox in the event of a bioterrorist-initiated re-emergence. Although it is effective against smallpox, cidofovir must be given intravenously and its use often results in life-threatening kidney toxicity. To circumvent the drug delivery and toxicity problems, NIAID has supported the development of brincidofovir, a derivative of cidofovir that can be given orally instead of by intravenous injection and that may have fewer side-effects. NIAID has supported brincidofovir from discovery through three Phase 1 clinical studies. In addition to its activity against smallpox, brincidofovir has activity against several other viruses that can infect humans, including herpes, adeno and polyoma viruses.

NIAID has also provided support from discovery through Phase 2 clinical development for a second therapeutic for smallpox, tecovirimat. Tecovirimat has a different mechanism of action from that of cidofovir or brincidofovir and is specifically active against smallpox and closely related members of the poxvirus family.

NIAID has successfully transitioned both brincidofovir and tecovirimat to BARDA for further clinical development.

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Last Updated December 11, 2014