Vaccines, Blood & Biologics

Protecting the immunocompromised patient by modeling a potentially fatal smallpox vaccine side effect

Smallpox vaccinations are generally safe, but for individuals who have immune system disorders there is a rare, but potentially fatal complication from this vaccine. However, thanks to research done by Food and Drug Administration scientists in the Center for Biologics Evaluation and Research (CBER), the vaccine may one day become much safer for people with these immune system disorders.

The smallpox vaccine is not made from smallpox (variola) virus, but rather from a live virus related to smallpox, called vaccinia. The live vaccinia vaccine is safe for most people. However, people who have certain immunodeficiency disorders are at risk for a serious side effect from the smallpox vaccine called progressive vaccinia (PV). In PV, the site of vaccination does not heal; instead, there is a slowly growing lesion at the injection site and eventual spread of the virus to other parts of the body, which, if not stopped by medical treatment eventually leads to death. People with PV have traditionally been treated with vaccinia immune globulin (VIG). VIG is a product made from antibodies obtained from people who have previously had the smallpox vaccine.

PV is often fatal if not treated, but 50 percent of PV cases can be successfully treated with VIG. Infants and children with certain immunodeficiency diseases are especially vulnerable to developing PV, even when treated with VIG.

However, while VIG has been used since the 1950s, it did not undergo placebo-controlled clinical trials, that is, it was not compared against “sugar pills” in patients with PV. The modern equivalent, vaccinia immune globulin intravenous (VIGIV) was licensed in 2005 based on safety data and on studies examining the achievable levels of vaccinia neutralizing antibodies in the plasma of patients administered VIGIV. Since clinical trials examining VIGIV efficacy in immunocompromised patients immunized with vaccinia would not be ethical, the way VIGIV works in such patients has not been well studied. The CBER scientists tried to remedy that problem by studying a PV-like illness in mice, and using that system to test a potentially improved therapy.

The scientists showed that a combination of VIGIV and the anti-viral drug cidofovir effectively treated PV and led to long-term, disease-free survival in mice with an immune system disorder called severe combined immunodeficiency. The treatment also prevented death from PV even when given a week after the mice received the vaccine. The results of this study suggest that an immunodeficient mouse model could be used to test other new therapies and provide further insights into how PV develops.

The development of a mouse model for PV is important because of the ethical restrictions on performing placebo-controlled clinical studies of this disease in humans. The so-called “animal rule1” enables test results from an animal model to be used in place of data from human studies when clinical trials are not ethical or feasible. The establishment of such an animal model is a time-consuming and difficult process, but it starts with the initial observation that the mouse model of the disease shares important characteristics with the human form of the disease. The results of the CBER study are a starting point for developing improved models of PV, and using these models to test therapeutics designed to help safeguard the immunocompromised population.

“Postexposure Prevention of Progressive Vaccinia in SCID Mice Treated with Vaccinia Immune Globulin”

Clinical and Vaccine Immunology, Jan. (2011) Vol 18, No. 1, p. 67-74


R.W. Fisher,1* J.L. Reed,1 P.J. Snoy,2 M.G. Mikolajczyk,1 M. Bray,3 D.E. Scott,sup>1 and M.C. Kennedy1

Laboratory of Plasma Derivatives, Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research CBER), Food and Drug Administration (FDA), Rockville, Maryland1; Division of Veterinary Services, Office of Management, CBER, FDA, Rockville, Maryland2; and Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Maryland3

Page Last Updated: 03/08/2012
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