“The public health implications of this study are enormously important,” said Secretary Thompson. “We now know that in the unlikely event of an intentional release of smallpox, our stockpile of smallpox vaccine can be expanded fivefold as we had planned. The success of this study puts us one step closer to our goal of having enough vaccine for every American if needed to respond to a potential outbreak.”
Expanding the U.S. smallpox vaccine supply has been a high-priority of the HHS bioterrorism preparedness plan. In addition to expanding the existing supply of vaccine through dilution, HHS has contracted with Acambis Inc. to produce another 209 million doses of smallpox vaccine by the end of 2002. The combination of these efforts would bring the total number of doses in the smallpox vaccine stockpile to at least 286 million, and the Acambis contract gives the federal government the option to purchase even more vaccine quickly.
“These encouraging results suggest that we can do more with less and thereby extend our capacity to contain a potential smallpox outbreak,” said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), which funded the research. “Although the likelihood of a deliberate release of smallpox is very small, it is prudent to be prepared.”
The trial compared the full-strength vaccine with fivefold, as well as tenfold, dilutions in 680 young adults with no history of smallpox vaccination. More than 97 percent of all participants in the trial responded with a vaccine “take,” a blister-like sore at the injection site that serves as an indirect measure of the vaccine’s effectiveness.
A report describing these findings appears online today at The New England Journal of Medicine Web site (http://www.nejm.org). The article will appear in the April 25 print issue of the journal.
The virus that causes smallpox, Variola major, is among the most potentially dangerous biological weapons because it spreads from person to person and no effective treatment exists. Few people have full immunity to the virus anymore because in the absence of any new cases, the United States discontinued routine vaccinations three decades ago, and immunity is thought to wane over time in vaccinated individuals. Although public health officials declared smallpox successfully eradicated worldwide in 1980, in addition to the two authorized stocks of the virus secured in laboratories in the United States and Russia, unauthorized stores of the virus are believed to exist.
The smallpox vaccine used in this trial, known as Dryvax, was made by Wyeth Laboratories (Marietta, Pa.). The vaccine is freeze-dried, live vaccinia virus, a poxvirus related to smallpox virus. Before use, the vaccine is reconstituted with a sterile-water-based diluent. The current vaccine stockpile remains from 1982, when the company stopped making the vaccine.
Trial Results
The trial described in NEJM, led by co-chairs Robert B. Belshe, M.D., and Sharon E. Frey, M.D., of Saint Louis University, was conducted at three NIAID Vaccine Treatment and Evaluation Units in St. Louis, Baltimore, and Rochester, NY, and at the Respiratory Pathogens Research Unit in Houston. The four sites recruited all 680 volunteers during November 2001. Volunteers had to be between 18 and 32 years old and not previously vaccinated against smallpox. Participants were assigned at random to one of three groups: 106 received undiluted vaccine, 234 received a 1:5 dilution, and 340 received a 1:10 dilution.
The investigators administered the vaccine by pricking the skin 15 times with a tiny two-pronged needle, and then monitored the volunteers for 56 days after immunization to assess take rates and side effects. More than 97 percent (665) had a take after the first vaccination. Those who failed to develop a take within seven to nine days were revaccinated. About half of the 15 individuals who did not have an initial take responded to revaccination. Most who did not respond to revaccination had pre-existing antibody to vaccinia, indicating, Dr. Belshe said, they may have received smallpox vaccine before and been unaware of their previous vaccination history.
After one or two vaccinations, the investigators found no significant difference in the take rate of the three doses: 97 percent of volunteers who received undiluted vaccine had a take compared with 100 percent of those receiving the 1:5 dilution and 98 percent of those receiving the 1:10 dilution.
Besides the telltale blister and subsequent scar at the injection site, other adverse side effects were mostly mild to moderate and common among all dosages. Frequent side effects included swollen lymph glands, fever, headache, muscle aches, chills and “satellite” lesions near the primary lesion. The undiluted vaccine caused greater inflammation at the site of injection and more swollen lymph glands, whereas the diluted vaccines more often caused satellite lesions.
“Many clinicians may not realize that smallpox vaccination causes an acute illness in adults who’ve never received the vaccine before,” noted Dr. Belshe. “None of our volunteers experienced life-threatening reactions, but about a third had symptoms that were significant enough to make them change their normal daily activities.” As part of the study, NIAID hopes to develop Web-based education materials for clinicians.
Results of a much smaller, NIAID-funded pilot study--used to design the larger, multicenter trial--also appear online at the NEJM Web site today. This study, carried out at Saint Louis University, enrolled 60 healthy, vaccinia-naïve young adults and compared full-strength Dryvax with a 1:10 dilution and a 1:100 dilution. Dryvax, the study found, had maintained its potency from 1982. In addition, although individuals receiving the weakest dilution had a low take rate, 95 percent of volunteers who received undiluted vaccine and 70 percent of those who received the 1:10 dilution developed a take. The skin lesion correlated with measurable cellular and antibody-mediated immune responses. The lower take rate for the 1:10 dilution found in the pilot study may be due to the different lots of vaccine used. The vaccine lot used in the larger study had a higher initial concentration of virus than that of the pilot study.
Also appearing online at the same time as the reports describing the clinical trial results are three other smallpox-related articles, including a commentary by Dr. Fauci in which he calls for an open public dialogue to discuss what the U.S. vaccination policy against smallpox should be: pre-emptive vaccination for the entire population or a more restricted vaccination program tied to those most closely affected by an attack or high threat of an attack.
NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
Journal
New England Journal of Medicine