Development and Availability of BW Vaccines

David Robinson
Battelle Memorial Institute

Columbus, Ohio.
          Since the terrorist attacks of September 2001 and the subsequent mailing of letters containing weaponized anthrax spores, the US Government has revamped its strategy for the development and delivery of vaccines and other biologically based therapeutics intended to protect against exposure to agents of biological warfare (BW) interest. While the basic precepts of the Food and Drug Administration (FDA), the US regulatory agency for biologics and drugs, remain, the US Government has recognized that the products intended to protect against BW agents are unique from scientific, regulatory and economic standpoints. Of course, they have the liability concerns related to adverse events military population deployed to areas outside of the inherent with any vaccine. Additionally, the perceived at risk populations are not only the US but also the civilian population residing in the US. The combination of compliance with the FDA regulations, expansion of the perceived at risk populations, and the singular characteristics of the products intended to protect against intentional aerosol exposures, present unusual dilemmas for the developer and the government.

          Certainly, a major shift in the focus of BW defense products has been the acknowledgement that the products may be used in the civilian community. Prior to the letter mailings, the primary development and funding for BW defense products was the responsibility of the Department of Defense (DoD). Since then the focus has shifted to the civilian, government agencies including the Department of Health and Human Services (HHS) and the newly organized, Department of Homeland Security (DHS). Each involved part of the US federal government, the DoD, HHS and DHS, has different goals and missions and executes its programs differently. The DHS has established the Strategic National Stockpile (SNS) which contains vaccines along with other emergency supplies. DoD is restricted to research and development on products and procedures for use by military personnel, while the HHS and DHS are involved in providing research and development on products and procedures for the general population.As only a single example, military populations are more homogenous in age and state of physical health than the US population as a whole. The funding changes that expanded the HHS and DHS roles in BW defense will lead researchers to develop products for young and old and for individuals suffering from chronic disease conditions.

          The major threat from the classical BW agents is usually thought of as aerosol exposure. Certainly, a number of well publicized incidents have been the result of intentional contamination of foodstuffs, while assassinations have been carried out with injections of ricin. However, the potential for widespread disease requires the generation of aerosols with the resulting exposure by the pulmonary route. As an effective weapon, the delivery by aerosol is necessary regardless of the mechanism of transmission of the naturally occurring disease. Other mechanisms are too cumbersome to be effective in producing sufficient casualties to degrade the performance of a military unit, for instance. A possible exception to this is variola (smallpox) virus. Variola spreads readily from person to person by the aerosol route once the index cases have become contagious.

          Since the expected route of exposure is pulmonary, the BW defense products are intended to protect against exposure to the agent by this route although the natural disease may be predominantly spread by other mechanisms. Examples of non-aerosol routes include ricin, botulinum toxins and arthropod borne viral infections. Natural exposures to both ricin and the botulinum toxins occur through the gastrointestinal tract as a result of ingestion of the toxins, but aerosol exposures may be even more effective in producing debilitating disease. The alphaviruses, Venezuelan Equine Encephalitis (VEE), Eastern Equine Encephalitis (EEE), and Western Equine Encephalitis (WEE), are on most lists of BW agents. Since these viruses are transmitted by mosquitoes under natural conditions, protection against disease as a result of transmission by aerosol can present unique problems. During the natural transmission by the arthropod vector, the virus enters the blood stream and the initial cycle of replication occurs in the hematopoetic system. Russian scientists have found that VEE virus can spread directly from an aerosol exposure to the nasal pharynx to the brain by way of the nerves. The VEE antibody titer in serum may not be the appropriate measure of protection, as it is in the naturally occurring disease, given this mechanism of spread by the virus.

          The identification of an at risk population requiring the protection afforded by immunization is also a difficult process. Most of the diseases caused by the agents of interest are of limited public health concern in developed countries under normal circumstances. The use of vaccines when no disease is occurring is a risk-benefit decision for the individual vaccine recipient. The unpredictability of the success of immunization programs is well illustrated by the failure of the US vaccinia program which was targeted to healthcare providers. These knowledgeable and well trained individuals made the decision that the risks associated with receiving the vaccination were greater than the risk of contracting smallpox. Of course, a second factor in the decision could have been that vaccinia will produce significant protection from smallpox when given up to four days following exposure to variola virus.

          The regulatory issues surrounding these agents also complicate the development process. The licensure of a vaccine requires not only proof of safety but also proof of efficacy which requires the use of fully virulent agents. Since these agents have potential as BW weapons, the US government has designated them as Select Agents and promulgated a series of laws and regulations regarding the possession, use, transfer within the US, and import from outside of the US. Additionally, the regulations contain requirements for registration of the facility, risk assessments, safety plans, security plans, emergency response plans, training, transfers, record keeping, inspections and notifications. The HHS and the Department of Agriculture have separate but largely integrated procedures to restrict access to human and animal pathogens. DoD is studying a separate set of regulations to govern work funded by DoD with these agents. These laws and regulations have been the basis for the prosecution of investigators in the US who have allegedly violated these regulations.

          The FDA has recognized that vaccines and therapeutics intended to prevent or treat disease resulting from aerosol exposures to BW agents are unique from a licensure perspective. The common circumstance is that the products cannot be tested in adequate and well-controlled field studies in a human population suffering from the disease. The infections do not occur naturally at rates that permit such prospective trials to be conducted, and studies involving the administration of potentially lethal or permanently disabling materials to humans are not ethical. In acknowledgement of this, the FDA has published final rules for the approval of new drug and biological products based on animal data when efficacy studies in humans cannot be ethically conducted and field trials are not feasible (Federal Register 67: 37988-37998, May 31, 2002). This rule calls for the development of supporting data in two animal species, only one of which can be a rodent. There are a number of other stipulations including that the manifestations of the disease in the animal model are reasonably well understood and resemble those seen in humans, and that the pharmacokinetics of the prophylactic or therapeutic product in the animal models must be analogous to that seen in humans.

          Economic implications also negatively affect the development of products intended to protect against BW agents. Since the diseases do not occur naturally to any extent the size of the market is difficult to estimate. Other than the US military, the currently licensed anthrax vaccine [Anthrax Vaccine Adsorbed (AVA or BioThrax®)] has enjoyed a limited marketplace outside of the US, in veterinarians, and in personnel employed in woolen mills and laboratories. Certainly, the potential markets for the various products are generally small and unpredictable and as such make planning for testing and production difficult.

          Since the usage of the products cannot be estimated, balancing the production, storage, and replenishment of the product as a component of any stockpile will become a management nightmare. All biological products have a specific dating period. At the end of the dating period the material will need to be destroyed and replaced with fresh material. Since the biological materials have no other use than for BW defense, the rotation of the stock to keep it in date is not an option. The logical solution would seem to point to replacement of a portion of the stockpile each year with freshly produced material with regulated destruction of the shortest dated product. This will require a continual funding stream to pay for the manufacture and supply of the new product and the destruction of the old material. On a positive note, this will also provide for the maintenance of a “warm” manufacturing base to provide surge capacity in the event of an emergency.

          While the availability of vaccines and other biologics for BW agent is an unmet need, major vaccine producers have been reluctant to become involved in the program. As has been pointed out by many authors, the profit margins for vaccines are dependent on a continuing market for the product to amortize the cost of development and testing. To meet the needs for biodefense products will require incentives from governments or other sources of public funds to convince established firms to enter the market. These incentives could take the form of a guaranteed market for a specified quantity of the product over a set period of time. Only with this or similar incentives will the requirement for a stockpile of biological products to prevent or treat morbidity and mortality following a BW terrorist event be fulfilled.

Ed. Note: Dr. David Robinson, D.V.M., Ph.D., is a Senior Vice President, Battelle Memorial Institute.