Vaccines and Bioterrorism
I. Bioterror Threats and Vaccines for Anthrax and Smallpox

The 2001 anthrax attacks in the United States illustrated the major threat posed by agents of bioterrorism. Since vaccines have the potential to provide long-term immunity against bioterror pathogens, their development and production are important components of preparedness efforts. Both the U.S. Department of Defense (DoD) and the Department of Health and Human Services (HHS) consider the development of safe and efficacious vaccines a priority. Former U.S. Army Major General Dr. Philip K. Russell identifies three functions of vaccines in civilian bioterrorism defense: control of an epidemic/prevention of global pandemic, general prophylaxis, and pre-epidemic prophylaxis for first responders, lab workers, and health care providers.¹

Despite their potentially critical value, there are several challenges facing the development and deployment of bioterror vaccines.² First, potential agents of bioterrorism are many, and it is difficult for government officials and public health authorities to anticipate which pathogens are likely to be used in an attack. Furthermore, the U.S. lacks the infrastructure and manufacturing capacity to produce mass quantities of vaccines on short notice, and complications related to financing and allocation hinder vaccine development and the preparation of distribution plans. Recent highly publicized controversies regarding vaccine safety may also dampen public support for vaccination programs in an emergency.

Because of the unique risks involved with service in the armed forces, members of the military are obvious candidates for bioterror vaccination programs. The military is smaller and more contained than the general population, and its hierarchical organization facilitates the administration of vaccines. Accordingly, those serving in many high-risk positions within the military are required to receive vaccines against smallpox and anthrax. Vaccine development and procurement is central to the DoD biodefense program, and the Pentagon is one of the primary financial sponsors of bioterrorism vaccine development. The DoD also manages the Joint Vaccine Acquisition Program (JVAP), an initiative devoted to accelerating the development and production of bioterror vaccines. ³

Key Vaccines in Production: Anthrax and Smallpox

Though licensed vaccines exist against yellow fever, Japanese encephalitis, tuberculosis, cholera, plague, anthrax, and smallpox, a number of potential agents of bioterror still lack vaccines. This group includes tularemia, rift valley fever, Ebola, ricin, botulism and staphylococcal enterotoxin. Anthrax and smallpox are considered the most profound threats, and the government has devoted tremendous resources towards improving the existing vaccines against these pathogens.

Caused by the spore-forming bacterium Bacillus anthracis, anthrax infections can occur cutaneously, gastrointestinally, or through inhalation. Symptoms vary according to the route of transmission: inhalational anthrax, the most serious form, initially displays as cold-like symptoms, but progresses into severe breathing problems, shock, and usually death. Anthrax is not contagious and cannot be transmitted person-to-person, yet--as the mail attacks of 2001 demonstrated--it presents a grave threat to public health and order.

Though antibiotics are somewhat effective in anthrax treatment, vaccination remains a vital component of anthrax preparedness.⁵ Biothrax is the only anthrax vaccine currently licensed in the U.S. ⁶ Produced by Emergent BioSolutions (formerly BioPort) since 1970, it is typically administered in a six-dose series over 18 months and requires additional annual boosters. Critics of Biothrax link the vaccine to "Gulf War Syndrome," a poorly understood condition reported by a number of Persian Gulf War combat veterans, some of whom received the vaccine.⁷ Most experts have discounted the link, however, and the FDA maintains that the vaccine is safe and effective.

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, with the aim of reducing adverse events, developing a more efficient delivery model, and augmenting available supplies.⁷ Critics observed that VaxGen was a small biopharmaceutical company that had never obtained licensure for a 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 and contracted additional doses of the original Biothrax vaccine. In May 2008, VaxGen sold its experimental vaccine to Emergent BioSolutions, the producer of Biothrax.⁸ Two months later, the National Institute of Allergy and Infectious Diseases (NIAID) awarded Emergent BioSolutions two grants--totaling $4.5 million--for the development of the second-generation anthrax vaccine as well as a botulism vaccine. Still in development, this new anthrax vaccine is similar to the current Biothrax formulation, but is fortified with an adjuvant intended to augment recipients' immune response, eliminating the need for a six-dose series.⁹

Improving the smallpox vaccine is another biodefense funding priority. A highly contagious disease capable of causing fever, malaise, and pustules on the face and body, smallpox was declared eradicated in 1977 after an extensive international vaccination campaign.^{10, 11} The only known remaining stores of smallpox are contained 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 for its bioweapons program, concerns persist over the existence of unaccounted samples that could be used in a bioterror attack.¹²

The first "modern" smallpox vaccine, Dryvax, has been produced by Wyeth Pharmaceuticals since the late 19th century.¹³ In recent years, over one million military personnel have been vaccinated with Dryvax. Though rare, side effects can include brain swelling, aggressive eczema, and a dangerous pox infection in immunocompromised individuals. In 2003, HHS campaigned to vaccinate emergency heath care workers with Dryvax, but the effort failed amid concerns over the vaccine's safety and skepticism regarding the gravity of bioterror threats.¹⁴

In February 2008, the military announced that it would abandon Dryvax in favor of ACAM2000, a second-generation smallpox vaccine produced by Acambis in collaboration with the CDC.^{17, 18} Licensed in September 2007, ACAM2000 is laboratory-cultured (Dryvax, in contrast, was derived from the lymph of cattle), allowing for rapid, large-scale production. ACAM2000's safety profile is comparable to that of Dryvax, though myocarditis--an inflammation of the heart and muscle lining--occurs in approximately 1 in 175 first-time smallpox vaccine recipients. The FDA has required that Acambis continue to monitor the safety of its vaccine through controlled studies in the military population, enhanced surveillance for myocarditis, and the establishment of a myocarditis registry.

In June 2007 the U.S. government awarded a $500 million contract to Bavarian Nordic A/S to develop 20 million doses of its experimental smallpox vaccine, Imvamune.¹⁵ Bavarian Nordic expects that Imvamune will be safer than previous vaccines, particularly for recipients with compromised immune systems. Clinical trials data thus far indicate that Imvamune generates an immune response faster than do currently used 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 2010.¹⁶

NIAID is also funding efforts to develop a modified vaccinia Ankara (MVA) vaccine for smallpox. The vaccine does not cause lesions and is considered to be potentially safer than traditional smallpox vaccines. Phase II clinical trials for both healthy individuals and people with compromised immune systems are currently taking place.¹⁹

-- By Katelin Hoskins, University of Pennsylvania (hoskinsk@nursing.upenn.edu); Updated July 2010.

Continue to II. Obstacles to Bioterror Vaccine Development

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¹ Russell PK. (1999). Vaccines in civilian defense against bioterrorism. Emerging Infectious Diseases, 5(4): 531-533.
² Ibid.
³ Cohen J & Marshall E. (2001). Vaccines for biodefense: A system in distress. Science, 294: 498-501.
⁴ Center for Disease Control and Prevention. (2003). Anthrax Q&A: Signs and Symptoms. Available at http://www.bt.cdc.gov/agent/anthrax/faq/signs.asp.
⁵ Lipton E. (2006). Bid to stockpile bioterror drugs stymied by setbacks. New York Times. Available at http://www.nytimes.com/2006/09/18/washington/18anthrax.html.
⁶ Weiss MM, Weiss PD & Weiss JB. (2007). Anthrax vaccine and public health policy. American Journal of Public Health, 97(11): 1945-1951; http://www.bioport.com/.
⁷ Ibid.
⁸ Roos, Robert. 2008. VaxGen sells anthrax vaccine to rival firm. CIDRAP, May 7.
⁹ Anthrax vaccine maker wins NIAID grant. 2008. CIDRAP, July 29.
¹⁰ CDC. (2007). Smallpox Disease Overview. Available at http://www.bt.cdc.gov/agent/smallpox/overview/disease-facts.asp.
¹¹ Cohen J & Marshall E. (2001). Vaccines for biodefense: A system in distress. Science, 294: 498-501.
¹² Roos R (2008). CDC retires one old smallpox vaccine, keeps another. Center for Infectious Disease Research and Policy. http://www.cidrap.umn.edu/cidrap/content/bt/smallpox/news/mar0708dryvax.html.
¹³ http://www.fda.gov/CbER/vaccine/smallpox.htm.
¹⁴ Ibid.
¹⁵ http://www.bavarian-nordic.com/imvamune
¹⁶ Bavarian Nordic. Imvamune. http://www.bavarian-nordic.com/biodefence/smallpox/imvamune.aspx (accessed June 22, 2010)
¹⁷ US military switching to new smallpox vaccine. Center for Infectious Disease Research and Policy. Available at http://www.cidrap.umn.edu/cidrap/content/bt/smallpox/news/feb0808smallpox.html.
¹⁸ http://www.acambis.com/default.asp?id=1189.National Institute of Allergy and Infectious Disease. (2010). Smallpox Research.
¹⁹ http://www.niaid.nih.gov/topics/smallpox/Pages/research.aspx (accessed June 22).