Smallpox vaccine can be diluted and still be effective, expanding supply if needed

September 07, 2004

Diluted doses of a smallpox vaccine, originally manufactured in the 1950s and stored as a frozen preparation, are nearly 100 percent effective, allowing for expansion of the current stockpile if needed, according to an article in the September 8 issue of JAMA.

According to background information in the article, smallpox vaccination is an effective way to prevent the smallpox disease both before and after exposure to the virus. In 2002, the U.S. resumed limited vaccination, and in 2003 the military successfully inoculated more than 500,000 people. However, the current supply of the vaccine falls short of the Department of Health and Human Services goal of having one dose for every U.S. citizen, and the effectiveness of diluted doses in unclear.

Thomas R. Talbot, M.D., M.P.H., of Vanderbilt University School of Medicine, Nashville, Tenn., and colleagues injected 340 healthy volunteers with the smallpox vaccine in a double-blind, randomized controlled trial conducted between October 2002 and February 2003. Test subjects, aged 18 to 32 years, were given one of three strengths of the Aventis Pasteur smallpox vaccine (APSV): undiluted, a one to five dilution, or a one to ten dilution. The researchers followed up with the volunteers every three to five days until the injection site healed. Subjects also participated in one- and two-month evaluations and a six-month phone interview.

Of all the vaccinated individuals, 99.4 percent had successful vaccinations, defined by a vesicle or pustule at the inoculation site six to 11 days after injection. For subjects receiving an undiluted vaccine (n = 113), there was a 100 percent success rate. Those injected with the one to five dilution (n = 114) had a 98.2 percent success rate, while those receiving the one to ten dilution (n = 113) also had a 100 percent success rate of vaccination. Nearly all of the study volunteers (99.7 percent) reported at least one post vaccination symptom in the two weeks following vaccination, including vaccination site itching (96.8 percent) or pain (92.1 percent), fatigue (79.1 percent), muscle pain (78.2 percent), headache (75 percent), and fever (21.5 percent). One-fourth of the volunteers missed planned duties due to vaccine-related symptoms.

Reactogenicity (the capacity to produce adverse reactions) of the vaccine was not reduced with dilution and decreasing strengths of the vaccine. This study was conducted before reports of adverse events, including heart disease, were reported in February 2003 among civilian and military smallpox vaccine recipients. The authors report "although symptoms of cardiac disease were not actively sought from volunteers at follow-up, five volunteers reported cardiac symptoms 5 to 14 days post vaccination that resolved without [complications]."

The authors conclude: "The results of our study show that a frozen preparation of APSV has a high vaccination success rate and is an available option for smallpox vaccination of vaccinia-naïve persons, even at ten-fold diluted doses. This allows for amplification of the current smallpox vaccine stockpile [approximately 85 million doses of APSV], if needed."
(JAMA. 2004; 292:1205-1212. Available post-embargo at

Editor's note: This study was supported by the National Institute of Allergy and Infectious Diseases Division of Microbiology and Infectious Diseases Vaccine Trial and Evaluation Unit, and grants from the General Clinical Research Center of Vanderbilt University School of Medicine and University of Iowa. Co-author Dr. Crowe receives research funding from Aventis Pasteur, is a member of the Scientific Advisory Board of and received research funding from MedImmune, and is a consultant to Mapp and Syngenta Pharmaceuticals. Co-author Dr. Edwards receives research funding from Aventis Pasteur, MedImmune, and VaxGen.

The JAMA Network Journals

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