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New Smallpox Vaccine Licensed

By Eric Toner, M.D., September 7, 2007

On September 1, 2007, the U.S. Food and Drug Administration (FDA) announced the approval of ACAM2000TM, a cell based smallpox vaccine.1 The vaccine was developed and manufactured by Acambis plc, of Cambridge, UK and Cambridge, MA under a contract with the U.S. Centers for Disease Control and Prevention (CDC). Prior to licensure, the CDC had already purchased 192.5 million doses of the vaccine for inclusion in the Strategic National Stockpile (SNS) under a Food and Drug Administration (FDA) Investigational New Drug (IND) application. At this point, ACAM2000TM accounts for the majority of smallpox vaccine in the American stockpile, which is said to contain enough vaccine to protect the entire U.S. population (~300 million) in the event of a smallpox outbreak. ACAM2000TM will also be used to protect those working in laboratories with orthopoxviruses and by the Department of Defense in its ongoing smallpox vaccination program for the U.S military. To date, Acambis has delivered a total of more that 200 million doses of the ACAM2000TM to 15 countries.2

The only other currently licensed smallpox vaccine in the U.S. is Dryvax (Wyeth), which was approved in 1931 but last manufactured in the U.S. in 1982. The vaccinia virus used in the ACAM2000TM is the New York City Board of Health (NYCBH) strain, derived from the Dryvax. The two vaccines have comparable safety and efficacy profiles. The primary difference between them is that the ACAM2000TM is produced using cell culture technology which enables both large-scale and more rapid production, and improved quality consistency. Currently, Acambis is negotiating with the CDC for a “warm-base” manufacturing contract, to ensure a long-term manufacturing capability for the vaccine within the U.S.

Live Virus Vaccines

Both licensed vaccines contain live vaccinia virus, a poxvirus related to the variola virus (the causative agent of smallpox). Vaccination causes a localized cutaneous vaccinia infection. The induced immune response to the vaccinia infection cross-protects against variola. Because the vaccines cause active cutaneous infections, spread of the infection to other sites and other people can occur. Vaccinia infection can be serious if it involves the eye (leading to keratitis) or if it afflicts people with immuno-suppression or atopic dermatitis. Therefore, vaccination is contraindicated in these groups.3 Other rare but serious adverse reactions to the vaccine include myopericarditis and encephalitis.

The Threat of Smallpox

Smallpox, which was estimated to have killed 300 million people in the first two thirds of the twentieth century, was declared eradicated by a World Health Assembly of the WHO in 1980. Routine vaccination for smallpox ended in the U.S. in 1972 and globally in 1980. While no variola virus exists in nature anymore (since humans were the only natural reservoir), small stockpiles of the virus are maintained in U.S and Russian government laboratories for research purposes. Prior to the breakup of the Soviet Union, industrial-scale production of variola virus for use as a biological weapon was reported. There is concern that covert stockpiles of the virus or even covert production programs may still exist.4 Smallpox is associated with a 30% case fatality rate and there is no effective treatment.1 In addition, smallpox is contagious, spreading from person to person by close contact. For these reasons, smallpox is classified as a Category A agent of bioterrorism.

Another New Vaccine

While ACAM2000TM provides a source for smallpox vaccine should an epidemic occur, it does not provide a solution to the problem of vaccinating those in the population for whom the vaccine is contraindicated. Another vaccine, Modified Vaccinia Ankara (MVA), manufactured under the name InvamuneR by Bavarian Nordic has been developed but is not yet licensed in the U.S. MVA is made from a live but non-replicating modified vaccinia virus that induces a satisfactory immune response.5 HHS has contracted for 20 million doses of Invamune under Project Bioshield to be used, in the event of an emergency, in people with contraindications to ACAM2000.6


  1. FDA press release. September 1, 2007. Accessed September 6, 2007.

  2. Acambis press release. August 31, 2007. Accessed September 6, 2007.

  3. CDC smallpox website. Accessed September 6, 2007.

  4. Henderson DA, Inglesby TV, Bartlett JG, et al. for the Working Group on Civilian Biodefense. Smallpox as a biological weapon: medical and public health management. JAMA. 1999;281(22):2127-2137. Accessed September 6, 2007.

  5. Bavarian-Nordic, Invamune webpage. Accessed September 6, 2007.

  6. American Academy of Allergy, Asthma and Immunology website. Accessed September 6, 2007.