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Update on Smallpox Vaccine

By Amesh A. Adalja, M.D., January 8, 2009

In the past few years, there have been several updates to the smallpox vaccine armamentarium, including the addition of a vaccine that appears to be safe for immunocompromised individuals. These developments are reviewed below.

The Original Smallpox Vaccine

Before 2001, Dryvax was the chief vaccine available for use against smallpox. It was produced in essentially the same manner as that employed in the 18th century by Edward Jenner, who obtained live vaccinia virus directly from the skin of a calf. Because Dryvax  contains live, replicating vaccinia virus, its utility has been limited by several important contraindications, including: 

  • use in the approximately 4% of the U.S. population that is immunocompromised and therefore at risk for disseminated vaccinia (the generalized spread of vaccinia throughout the body);1

  • use in the 10% to 15% of the U.S. population with atopic skin disease, because the vaccine may cause severe adverse events, including eczema vaccinatum, a condition in which vaccinia replicates in skin cells and produces a generalized and severe rash;2 and

  • use in those who have close contact with members of the populations specified above, because shedding may spread the vaccine strain of the virus.

Generation II: The Current Smallpox Vaccine

Difficulties with calf skin production led to the development of ACAM 2000, the vaccine currently in use. ACAM 2000 is manufactured by Acambis and has been procured by the U.S. government for the Strategic National Stockpile (SNS). It is fundamentally the same as Dryvax, but it has been modified to grow in Vero cells. It has an immunogenicity profile similar to that of the first generation vaccine and is contraindicated in the same populations as Dryvax.1

Vaccine in HIV-Infected Populations

In the course of the scale-up of vaccination in 2004, 10 patients with undiagnosed HIV infection were inadvertently vaccinated, with no adverse results. Importantly, 7 of the 10 vaccinees had prior immunization against smallpox and none had a CD4 count below 250 cells/mm3. In fact, there is only one report of a serious adverse outcome following vaccination of a patient with HIV: in 1984, a patient with a CD4 count of approximately 25 cells/mm3 was vaccinated and subsequently developed meningitis, disseminated lesions, and ulcerations that were treated successfully with Vaccinia Immune Globulin (VIG). It is assumed that many more HIV-infected persons have been vaccinated unknowingly and presumably without adverse effects in the past, since HIV testing did not start until the 1980s.1  It is suspected that CD4 counts below 200-300 cells/mm3, rather than HIV infection itself, may represent the true contraindication to smallpox vaccination in people with HIV infection.

Generation III Vaccines: Including All Populations

To expand the uptake of smallpox vaccination and avoid the potential dangers of a live vaccine, an approach using an inactivated, nonreplicating strain of the vaccinia virus was developed in the 1960s and 1970s. It was thought that prevaccination with modified vaccinia Ankara (MVA) might ameliorate the complications of vaccination with the full-strength standard live virus. While MVA has never been tested for efficacy during a smallpox outbreak, primate studies have shown adequate protection against monkeypox virus challenges following vaccination. However, vaccination failed to protect against monkeypox virus in immunocompromised SIV-infected macaques—the chimpanzee analog of HIV—with CD4 cell counts less than 300 per mm3, illustrating the crucial role of CD4 T-cell immunity.1 Given its success in monkeypox primate models—a good surrogate for smallpox—the vaccine’s development moved forward toward commercial availability.

The MVA vaccine will be manufactured by Bavarian Nordic under the trade name Imvamune. Bavarian Nordic recently released data from one clinical trial in which no increase in adverse events was observed among 300 HIV-infected patients with CD4 counts ranging from 250-700 cells/mm3. The company plans to release additional data on trials in patients with both HIV infection and atopic dermatitis in the latter part of 2009.4  Even before  the release of the latest data, the U.S. government had already procured 20 million doses of Imvamune for the SNS. This is an amount sufficient to cover the 10 million Americans who are unable to receive the standard vaccines and may eventually replace the standard vaccines entirely.3

Another vaccine based on a different attenuated strain of vaccinia, LC16m8, has been licensed for use in Japan since 1975. This vaccine has been administered to more than 50,000 children and has produced a smaller vaccination site lesion and fewer secondary symptoms than Dryvax.1

Comprehensive Vaccination Planning May Now Be Possible

As more data from Imvamume trials are released, further refinements of contraindications to vaccination are likely to follow. With the ability to immunize individuals for whom first- and second-generation vaccines are contraindicated, it now may be possible to develop a comprehensive smallpox vaccination plan that will not pose undue risk to individuals who are immunocompromised or who have atopic skin disease. This is an important milestone.


  1. Lucey DR, Breman JG, Henderson DA. Smallpox and bioterrorism. In: Lutwick LI, Lutwick SM. Beyond Anthrax. Chapter 2. New York: Humana Press; 2008.

  2. Engler RJM, Kenner J, Leung DYM. Smallpox vaccination: risk considerations for patients with atopic dermatitis. J Allerg Clin Immunol 2002;110:357-365.

  3. Firm says weakened smallpox vaccine has good safety profile. CIDRAP News. November 14, 2008. Accessed January 5, 2009.

  4. Bavarian Nordic reports successful safety data from Phase II study with IMVAMUNE® [news release] Kvitsgard, Denmark: Bavarian Nordic; November 5, 2008. Accessed January 5, 2009.