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4/23/2002

Status of Nation's Smallpox Vaccine Reserve Improves

Kate Traynor

The potential national supply of smallpox vaccine jumped sharply at the end of March, thanks to newly released clinical study results and the unveiling of a previously undisclosed supply of vaccine.

An online article released early by the editors of the New England Journal of Medicine (NEJM) and scheduled for the April 25 issue gives evidence that the smallpox vaccine stocks controlled by the Centers for Disease Control and Prevention (CDC) remain potent.1 A second NEJM article indicates that a 5- or 10-fold dilution of the vaccine, Wyeth Laboratories's Dryvax, confers immunity to smallpox in previously unvaccinated, healthy adults.2

Diluting the vaccine fivefold would potentially allow CDC's 15.4 million doses to protect up to 77 million vaccinees.

  How is Dryvax Diluted and Administered?

The two New England Journal of Medicine articles described here offer a glimpse of the practical side of smallpox vaccination. In the smaller study, the reconstituted vaccine was described as "highly viscous and difficult to manipulate."1 Serial dilution of the vaccine resulted in "nonlinear" reductions in titer, which the study team said may have been due to the product's viscosity.

In the larger study, the lyophilized vaccine was diluted directly in the vial by adding 0.25, 1.25, or 2.5 mL of a diluent containing 50% glycerin and 0.21% phenol.2 After reconstitution, the vaccine was refrigerated for a week or less.

The vaccine was administered into the skin using a two-pronged needle that was pressed into the vaccinee's arm 15 times per dose. The inoculation site was covered with gauze that was held in place with a semipermeable adhesive membrane. This precaution was taken to lessen the chance that the vaccine recipients would inadvertently inoculate themselves or nearby people.

1. Frey SE, Newman FK, Cruz J et al. Dose-related effects of smallpox vaccine. N Engl J Med. 2002; 346:1275-80.

2. Frey SE, Couch RB, Tacket CO et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med. 2002; 356:1265-74.

Nearly coincident with the release of these study results was the news that Aventis Pasteur Inc. holds as many as 90 million doses of smallpox vaccine in storage. According to the Washington Post, which first announced the vaccine's existence on March 28, the Aventis product, a liquid, has been stored frozen for decades in 2-L bottles.

In separate press releases, Aventis and the Department of Health and Human Services (HHS) acknowledged the existence of the vaccine stash. Preliminary testing is underway to determine whether the vaccine, which the Washington Post reported is derived from the same vaccinia seed stocks as Dryvax, remains safe and effective. Aventis has agreed to donate its supply to HHS to add to the nation's vaccine stockpile, and HHS has said that it will accept the vaccine if it proves safe and effective in clinical studies.

HHS Secretary Tommy G. Thompson described the Aventis smallpox vaccine as a "safety net" for emergency use if there is a need to vaccinate Americans before a new form of the smallpox vaccine becomes available. HHS has contracted with Acambis Inc. to produce 209 million doses of a tissue-culture-derived smallpox vaccine before the end of this year.

The Dryvax vaccine described in the two NEJM articles was produced in 1982 or earlier. Dryvax is derived from the lymphatic fluid of bovine calves infected with a vaccinia virus strain that induces immunity against variola, the smallpox virus, in humans.

The initial dilution and potency study of CDC's Dryvax stocks began in 2000, under direction of the National Institute of Allergy and Infectious Diseases (NIAID). In this study, undiluted vaccine produced a vaccinia vesicle, an indirect indication of immunity, in 19 of 20 healthy adult volunteers who had not previously received the smallpox vaccine. In contrast, the vesicle developed in 14 of 20 volunteers who received a 10-fold dilution of the vaccine and in 3 of 20 who received a 100-fold dilution.

The second study, which NIAID also directed, took place last fall and enrolled 680 healthy adults who had not been previously vaccinated against smallpox. Half of the study volunteers received a 1:10 dilution of the vaccine. Of the remaining half, 106 received an undiluted vaccine dose, and 234 received a 1:5 vaccine dilution.

Overall, 665 (98%) of the second study's enrollees produced a vaccinia vesicle after receiving a single dose of the vaccine. According to the report, there was no difference in pustule size at the vaccination site among the three treatment groups at 13 and 14 days after vaccination. People who received an undiluted dose had a larger area of redness and swelling around the vaccination site than did those who received diluted vaccine. Satellite lesions, occurring away from the vaccination site, were more common among people who received diluted vaccine than among volunteers who received the undiluted product.

In the 2001 study, adverse reactions after smallpox vaccination were common. Thirty-six percent of the study participants said that they had felt ill enough to miss school or work or to otherwise alter their daily activities. Two study participants were deemed to have had a serious vaccine-related adverse event—one had severe headache and nausea, and another had extreme swelling and redness at the vaccination site.

Robert B. Belshe, M.D., who contributed to both NEJM articles, was quoted in an HHS press release as saying that "many clinicians may not realize that smallpox vaccination causes an acute illness in adults who've never received the vaccine before." He noted that none of the adverse reactions seen during the studies was life threatening.

The most common adverse events among the study participants included pain at the vaccination site, pustular or vesicular rashes, fever of at least 100 degrees F, headache, muscle aches, and chills.

1. Frey SE, Newman FK, Cruz J et al. Dose-related effects of smallpox vaccine. N Engl J Med 2002; 346:1275-80.

2. Frey SE, Couch RB, Tacket CO et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med 2002; 356:1265-74.

 Experts Ponder Resumption of Smallpox Vaccination

The seeming availability of enough smallpox vaccine to support a mass vaccination campaign focuses attention on whether Americans should be universally vaccinated against the disease, which was eradicated in the wild decades ago.

"Public health officials and other experts currently are debating whether preexposure mass vaccination programs should be undertaken and, if so, of whom and when," said Gerald McEvoy, Pharm.D., an assistant vice president of the ASHP Publications and Drug Information Systems Office and a member of the Society's Staff Task Force on Emergency Preparedness. McEvoy said the debate involves weighing "the potential risks and benefits in the context of a potential bioterroist release of the virus."

NIAID Director Anthony S. Fauci, M.D., writing in an editorial (PDF) for the April 25 New England Journal of Medicine (NEJM), noted that the known risks of smallpox vaccination include one or two deaths per million recipients and "probably hundreds of cases of generalized vaccinia, eczema vaccinatum, progressive vaccinia, and postvaccinial encephalitis per million recipients." According to Fauci, there is a "real possibility" that the smallpox virus will be used as an agent of bioterrorism, but the risk is "most likely very small." He emphasized the need for open and public debate about the risks and benefits of universal smallpox vaccination.

William J. Bicknell, M.D., of the Boston University School of Public Health, in a "Sounding Board" (PDF) column in the same issue of NEJM, used the phrase "logistical havoc" to describe the results of an emergency-preparedness exercise conducted last year that dealt with a simulated smallpox virus release. Bicknell said that, if sufficient supplies of smallpox vaccine exist, the product should be made available to members of the public who want to be vaccinated.

Bicknell noted that CDC has already vaccinated members of its smallpox-response teams.