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Efficacy and Safety of Resurrected and Diluted Smallpox Vaccine

Smallpox vaccine tests indicate that existing stocks, diluted up to 10 times, remain effective, but widespread vaccination remains controversial.

Recent terrorist activity has rekindled intense interest in smallpox vaccination. Routine smallpox vaccination ceased in the U.S. 3 decades ago, and natural disease was declared eradicated worldwide in 1980. The immediacy of a terrorist smallpox threat and the expected side effects of universal vaccination are hotly debated, but available vaccine stocks -- currently about 15 million doses, with an additional 75 million recently discovered but as yet untested -- would be insufficient to immunize the U.S. population. NIH investigators studied the efficacy and safety of the 15 million doses, stocks of smallpox vaccine that were produced 30 years ago.

Initially, 60 healthy, vaccinia-virus-naive adults were inoculated with a vaccine-loaded bifurcated needle, pressed 15 times into the skin of the upper arm. Vaccine was administered in 3 different concentrations, each given to 20 subjects: undiluted (mean viral titer, 10^7.8 plaque-forming units/mL), diluted 1:10, or diluted 1:100. Efficacy was measured by development of the classic vesicle-to-pustule-to-eschar progression during the next 10 to 14 days. "Take" was confirmed by monitoring levels of neutralizing antibodies, interferon-gamma production, and cellular immune responses. Vaccine success rates were dose-dependent. Undiluted vaccine immunized 19 of 20 patients; the 1:10 dilution immunized 14 of 20, and the 1:100 dilution immunized only 3 of 20. Skin take (vesicle formation) correlated well with other immunologic responses. Doses of 10⁷ pfu were necessary to elicit a 95% response rate. Side effects, which were not serious, included fever, skin irritation, myalgias, and transient lab-test abnormalities in a few patients.

The same investigators conducted a companion study involving 680 patients to establish more precisely the extent to which available vaccine stocks could be diluted and remain effective. Exclusion criteria included pregnancy, evidence of immunodeficiency or eczema, recent live-virus vaccination, and recent receipt of blood products. As would be expected from the results of the previous study, undiluted vaccine (mean viral titer, 10^8.1 pfu/mL) and 5- and 10-fold dilutions were all immunologically effective, producing successful-vaccination rates ranging from 97.1% to 99.1 %. Fifteen subjects did not develop vesicles. Six of these subjects had preexisting neutralizing antibodies, and 1 had a confirmed history of childhood vaccination. Fourteen of the 15 were revaccinated with the same dilution, 7 successfully. The vaccine retained its titer for at least 7 days after reconstitution, confirming its stability. Side effects, again not serious, included pain, redness, and swelling at the vaccination site, satellite vesicles (more common with dilute vaccine), headaches, and fever in about 10% of vaccine recipients.

Comment: The question of whether to resume smallpox vaccination is extremely controversial. Attempts are under way to create recombinant vaccines, which would presumably have fewer serious adverse effects than the classic calf-derived vaccine. In the meantime, it is somewhat comforting that 150 million doses or more -- rather than 15 million -- may be available, should the need arise.

— Stephen G. Baum, MD

Published in Journal Watch Infectious Diseases April 25, 2002

Citation(s):

Frey SE et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med 2002 Apr 25; 346:1265-74.

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• Medline abstract (Free)

Frey SE et al. Dose-related effects of smallpox vaccine. N Engl J Med 2002 Apr 25; 346:1275-80.

• Original article (Subscription may be required)
• Medline abstract (Free)