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Vaccines against Potential Agents of Bioterrorism The 2001 anthrax attacks in the United States demonstrated clearly the severe threat posed by agents of bioterrorism. Given their ability to provide advance and long-lasting protection against the pathogens likely to be used in bioterror attacks, vaccines are an important component of preparedness efforts. Retired U.S. Army Major General Dr. Philip K. Russell identifies three potential uses of vaccines in civilian bioterrorism defense: control of a smallpox epidemic and prevention of global pandemic, post-exposure prophylaxis against anthrax (coupled with antibiotics), and pre-exposure prophylaxis for first responders, lab workers, and health care providers.1 Development of safe and efficacious vaccines is a priority of both the U.S. Department of Defense (DoD) and the Department of Health and Human Services (HHS). Despite these potential uses, there are several challenges facing the use of vaccines in civilian bioterrorism defense.2 First, government leaders and public health authorities are unable to anticipate which pathogens would be used in an attack, and there are numerous potential agents in contrast to the number of vaccines in development. Also, the U.S. lacks the infrastructure and manufacturing capacity to produce mass quantities of vaccines on short notice, and issues with cost and dosing hinder vaccine development and potential distribution programs. Building public support for vaccination through educational programs may also pose challenges given recent, well-publicized controversies regarding vaccine safety. Members of the military are also likely participants in bioterror vaccination programs, and their presence presents different challenges. The military population is smaller and contained, designed around strict systems of authority that result in a reduced role for individual autonomy. Vaccines are a cornerstone of the Department of Defense biodefense program, with the Pentagon serving as a major funder of bioterrorism vaccine development.3 The DoD's Joint Vaccine Acquisition Program (JVAP) has targeted several vaccines against bioweapons in an attempt to fill industry gaps and accelerate production. Key Vaccines in Production: Anthrax and Smallpox Of potential agents of bioterrorism, licensed vaccines exist for yellow fever, Japanese encephalitis, tuberculosis, cholera, plague, anthrax, and smallpox. No licensed, marketed vaccines exist for tularemia, rift valley fever, ebola, ricin, botulism, or staphylococcal enterotoxin. In recent years, massive government resources have been mobilized to improve anthrax and smallpox vaccines. Anthrax is a disease caused by the spore-forming bacterium Bacillus anthracis; infections can occur in three forms: cutaneous (skin), gastrointestinal, and inhalation.4 Symptoms depend on the route of disease transmission. Symptoms of inhalation anthrax, the most serious, initially resemble a common cold but may progress to severe breathing problems and shock; it is usually fatal. Anthrax is not contagious and cannot be transmitted person to person, yet as indicated by the mail attacks of 2001, it presents a serious bioterror threat. Antibiotics are available for anthrax treatment, vaccination is a key component of anthrax preparedness planning.5 Biothrax, made by the company BioPort, is the only licensed anthrax vaccine in the U.S. and has been available since 1970.6 Typically, it is administered in a six-dose series over 18 months and requires yearly boosters. Military personnel serving in high-risk areas have been required to receive the vaccine. Though it is FDA approved as safe and efficacious, there are many strong opponents to Biothrax and as-yet-unproven allegations of a link to "Gulf War Syndrome," a variety of symptoms reported by Persian Gulf War combat veterans who received the anthrax vaccine. To increase supplies, reduce adverse events, and develop a more efficient delivery model, in November 2004 the government awarded an $878 million contract to VaxGen for the production of 75 million doses of a second-generation anthrax vaccine.7 Critics observed that VaxGen was a small biopharmaceutical company that had never made a licensed vaccine; its first major project, an AIDS vaccine candidate, failed in clinical testing in 2003. After several setbacks in the research and development process, the Department of Health and Human Services (HHS) cancelled VaxGen's contract in December 2006. Even after VaxGen's government contract for a new vaccine, BioPort lobbied aggressively for another opportunity. In May 2005, HHS awarded BioPort a $122 million contract for 5 million additional doses of its anthrax vaccine. A second contract for an additional 5 million doses was awarded in May 2006. In September 2007, HHS awarded a 3-year, $400 million contract for Biothrax. Regarding Biothrax, research is underway to reduce the number of required doses, minimize side effects and, improve shelf life. Other strategies currently funded by DoD include preclinical development of a patch-based anthrax vaccine.8 The major funding priority involves smallpox, a highly contagious disease capable of causing fever, malaise, and pustules over the entire body.9 The first "modern" smallpox vaccine, Dryvax, made by Wyeth Pharmaceuticals, has been used since the late 19th century.10 Following an extensive international vaccination campaign, the World Health Organization (WHO) declared smallpox eradicated in 1977, one of premier achievements in the history of public health.11 The only known remaining samples of smallpox are stored at the Centers for Disease Control and Prevention (CDC) in Atlanta, GA, and at the State Research Center of Virology and Biotechnology in Novosibirsk, Siberia. Because the Soviet Union produced large amounts of smallpox in its bioweapons program, concerns persist over the existence of unaccounted samples that could be utilized in a bioterror attack.12 In recent years, over one million military personnel have been vaccinated with Dryvax. Though rare, side effects of vaccination can be severe, including brain swelling, aggressive eczema, and a dangerous pox infection in individuals with weakened immune systems, with a small risk of death. In 2003, HHS campaigned to vaccinate emergency heath care workers with Dryvax, but the effort largely failed amid concerns over the vaccine's safety and skepticism over the gravity of bioterror threats.13 To improve the safety of smallpox vaccines, particularly for those with weakened immune systems, officials in June 2007 awarded a $500 million contract to Bavarian Nordic A/S to develop 20 million doses of its smallpox vaccine, IMVAMUNE.14 Clinical trials to date indicate that IMVAMUNE generates an immune response faster than other vaccines. Phase II studies have been completed in healthy subjects, subjects with atopic dermatitis, and subjects with HIV. A Phase III study is expected to commence in 2009.15 In February 2008, the military announced a switch to ACAM2000, a second-generation smallpox vaccine made by Acambis in collaboration with CDC.16, 17 The FDA licensed ACAM2000 in September 2007. It is grown in laboratory cell cultures and is manufactured with modern cell culture technology, allowing for rapid and large-scale production. ACAM2000's safety profile is comparable to that of Dryvax, with no significant difference in the rate of serious adverse events. One specific concern is myocarditis, inflammation of the heart and muscle lining; it occurs in approximately 1 in 175 first-time smallpox vaccine recipients. The FDA is requiring that Acambis take several specific steps to monitor safety, including post-marketing controlled studies in the military population, conducting enhanced surveillance for myocarditis, and establishing a myocarditis registry. The DoD currently intends to discard remaining stocks of Dryvax as new vaccines take its place in the national stockpile. -- By Katelin Hoskins, University of Pennsylvania (hoskinsk@nursing.upenn.edu) Continue to II. Obstacles Facing Bioterror Vaccine Development
1Russell PK. (1999). Vaccines in civilian defense against bioterrorism. Emerging Infectious Diseases, 5(4): 531-533. |
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