GAITHERSBURG, MD. — A more modern version of the smallpox vaccine appears to be safe and effective enough to use “where it is determined that there is a high risk of exposure to smallpox virus,” according to a Food and Drug Administration advisory panel.
At a meeting, members of the FDA's Vaccines and Related Biological Products Advisory Committee agreed that the ACAM2000 vaccine should be submitted to postmarketing studies that follow people who developed vaccine-associated myocarditis and determine risk factors for myocarditis.
The vaccine, which is derived from Dryvax, the currently licensed smallpox vaccine, is not being considered for use in the general population. Panelists emphasized the nature of the situations in which the risk-benefit profile of ACAM2000 would be considered favorable.
“This and Dryvax are the least-safe vaccines that we will have licensed in this country, and we have to weigh that against the risk of smallpox,” said the panel chair, Dr. Ruth A. Karron, professor in the department of international health at Johns Hopkins University, Baltimore.
The rate of myocarditis—one in about every 150 vaccine recipients—was “far and above” any serious adverse event of that magnitude associated with other vaccines, emphasized Dr. Jack Stapleton, professor and director of infectious diseases at the University of Iowa, Iowa City.
If this were a vaccine being considered for routine use in the general population, the risk of myocarditis seen in clinical trials would be unacceptable, added Dr. Monica Farley, professor of medicine at Emory University, Atlanta.
Some other well-documented complications of smallpox vaccination that date back to the era of routine smallpox vaccination include generalized vaccinia, eczema vaccinatum, postvaccinial encephalitis, inadvertent inoculation, fetal vaccinia, and death.
The panel was not asked to vote specifically on whether to approve the vaccine. The FDA typically follows the advice of its advisory panels, although that advice is not binding.
If approved by the FDA, the vaccine would not be made available commercially. Instead, it would be used for the national vaccine stockpile and for military personnel deployed to areas of the world where the threat of exposure to smallpox as a biologic weapon is considered high.
Acambis Inc. manufactures the vaccine, which was developed under a contract with the Centers for Disease Control and Prevention for stockpiling purposes. In fact, Acambis has already supplied 192.5 million doses to the U.S. Strategic National Stockpile, according to the company. There is a limited supply of Dryvax remaining, which is itself reserved for the military and laboratory workers.
The derivation of ACAM2000 from Dryvax uses modern cell culture techniques without animal serum. The vaccine is grown in a continuous cell line, which provides a predictable, standardized manufacturing process, according to Acambis.
Dryvax was compared with ACAM2000 in two multicenter, double-blind randomized studies of about 2,800 previously healthy adults. Those studies were designed to show that ACAM2000 was not inferior to Dryvax.
In one study of people aged 18–30 years who had never been vaccinated against smallpox, the “take rate” of a cutaneous response—a generally accepted surrogate of protection—was 96% among those who received ACAM2000 and 99% among those who received Dryvax, a difference indicating noninferiority.
In a second study of people aged 31–84 years who had been vaccinated against smallpox, however, the take rate was 84% among those who received ACAM2000, compared with 98% of those who received Dryvax.
The majority of side effects were inoculation site reactions and systemic symptoms, including vaccine site pain, lymph node pain, headache, fatigue, and myalgia.
In both studies, participants were closely monitored for myocarditis, which was diagnosed in 10 naive recipients (7 of whom were in the ACAM2000 treatment group). The myocarditis cases occurred at a mean of 11 days after receiving the vaccine and resolved in all but one case, according to Acambis.
In the study of people without prior vaccination, the rate of myocarditis was about one case per 145 vaccinations, which is higher than anticipated, according to the FDA. That study's myocarditis rate was greater than the military's rate, which a Department of Defense official at the meeting said has been about one case per 6,000 primary vaccinations.
If the vaccine is approved, Acambis would launch a Risk Minimization Action Plan (RiskMAP). That would include education of vaccinees and health care providers, expedited reporting of serious adverse events, and phase IV studies to assess the vaccine's safety profile, long-term outcomes, and myocarditis risk factors.