Summary

This report focuses on the role of immunization for the protection of laboratory workers engaged in research on hazardous pathogens (including viruses, bacteria, and toxins) and specifically on the Special Immunizations Program (SIP), which is located at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, as part of the U.S. Army Medical Research and Materiel Command (USAMRMC). The SIP provides immunizations to laboratory personnel who are at risk of exposure to hazardous pathogens and is the only such program in the United States. Its mission is to provide additional protection through vaccines to at-risk personnel, to ensure the safety and well-being of program participants through continuous medical evaluation, to provide evaluation and treatment of occupational exposures, and to collect safety and immunogenicity data to further medical research on these vaccines.

The SIP is designed to augment the protection provided by other components of laboratory biosafety, including best practices, engineering controls, and personal protective equipment for working with hazardous pathogens. The vaccines offered within the SIP include both products licensed by the Food and Drug Administration and vaccines that have not been licensed and remain under Investigational New Drug (IND) status. The administration of these IND vaccines is, therefore, considered to be part of the ongoing clinical trials necessary to meet regulatory requirements. The SIP IND vaccines are available in limited amounts and are currently administered only at Fort Detrick, MD.

Currently, the SIP includes IND vaccines against botulinum toxins, the equine encephalitides (eastern, western, and Venezuelan), Rift Valley fever, Q fever, and tularemia, and licensed vaccines for protection against anthrax, hepatitis B, Japanese encephalitis, rabies, smallpox, and yellow fever.



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Summary This report focuses on the role of immunization for the protection of laboratory workers engaged in research on hazardous pathogens (including viruses, bacteria, and toxins) and specifically on the Special Immunizations Program (SIP), which is located at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, as part of the U.S. Army Medical Research and Materiel Command (USAMRMC). The SIP provides im- munizations to laboratory personnel who are at risk of exposure to hazardous pathogens and is the only such program in the United States. Its mission is to provide additional protection through vaccines to at-risk personnel, to ensure the safety and well-being of program participants through continuous medical evaluation, to provide evaluation and treatment of occupational exposures, and to collect safety and immunogenicity data to further medical research on these vaccines. The SIP is designed to augment the protection provided by other com- ponents of laboratory biosafety, including best practices, engineering controls, and personal protective equipment for working with hazardous pathogens. The vaccines offered within the SIP include both products licensed by the Food and Drug Administration and vaccines that have not been licensed and remain under Investigational New Drug (IND) status. The administration of these IND vaccines is, therefore, considered to be part of the ongoing clinical trials necessary to meet regulatory requirements. The SIP IND vaccines are available in limited amounts and are currently administered only at Fort Detrick, MD. Currently, the SIP includes IND vaccines against botulinum toxins, the equine encephalitides (eastern, western, and Venezuelan), Rift Valley fever, Q fever, and tularemia, and licensed vaccines for protection against anthrax, hepa- titis B, Japanese encephalitis, rabies, smallpox, and yellow fever. 1

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2 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH In 2004, when biodefense research was undergoing a rapid expansion, a U.S. Homeland Security Council Policy Coordinating Committee (HSC PCC) approved an expansion of the SIP in an effort to provide access to the program for government and civilian academic researchers. The SIP was to be funded by fully burdened contributions by the departments and agencies making use of the program according to percentage use. After 5 years of experience with the new arrangement, the Biomedical Advanced Research and Development Authority (BARDA), in the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services (HHS), asked the National Research Council to examine technical issues related to the HSC PCC recommendations regarding the expansion of the SIP, and to con - sider the larger context of vaccination for researchers who work with potentially hazardous biological agents (i.e., bacteria, viruses, and biological toxins) (see Box 1.1 for the full Statement of Task). The committee formed by the National Research Council examined the history and current operation of the SIP as well as the principles of biosafety and historical data on exposures and laboratory-acquired infections (LAI) when working with hazardous pathogens and toxins. Those data demonstrate that although incidents of laboratory-acquired infections have decreased markedly over time as biosafety procedures, primary biocontainment systems, personal protective equipment, and facilities engineering have improved, the risk has not been reduced to zero, and infections do continue to occur sporadically. Researchers working with pathogens having a very low infectious dose (that is, those pathogens for which exposure to a very small quantity of the microbe can cause a disease) such as Venezuelan equine encephalitis virus, Brucella melitensis, Brucella abortus, Francisella tularensis, and Coxiella burnetii, may be particularly at risk. The committee also considered the regulatory frameworks under which SIP vaccines are administered and how additional vaccines now available in the United States or other countries might be considered for in - clusion in the SIP. Finally, the committee considered other factors that might influence the development and manufacturing of new vaccines for the SIP. As a result of its deliberations, the committee arrived at a series of findings and corresponding recommendations about the SIP and the general role of im - munization in the context of hazardous pathogen research in the United States. HISTORICAL VALUE OF THE SPECIAL IMMUNIZATIONS PROGRAM The SIP has played a significant historical role in offering additional pro - tection to laboratory workers involved in U.S. biodefense research. The lessons that have been learned through the program have advanced the practice of biosafety. Despite advances in other components of biosafety, immunization remains an integral component of an occupational safety program for people

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3 SUMMARY who work with highly hazardous pathogens. Immunizations with certain IND vaccines, such as those currently offered in the SIP, remain an important com - ponent of an overall biosafety program for laboratory workers at risk of expo - sure to hazardous pathogens. Recommendation 1: Special Immunizations Program IND vaccines should be offered to laboratory workers on a voluntary basis, subject to risk assessments and informed consent. The use of immunizations should never be a substitute for careful adherence to all biosafety best practices, 1 but should be considered a component of an overall biosafety program. EXPANSION OF THE SPECIAL IMMUNIZATIONS PROGRAM TO MEET CIVILIAN NEEDS AS WELL AS MILITARY NEEDS The SIP is the only formal program in the United States, and probably in the world, that exists to provide vaccines (both licensed and investigational) to at-risk laboratory workers and other occupationally exposed personnel work - ing with hazardous pathogens. USAMRMC has the history, personnel, clinic facilities, protocols, standard operating procedures, and regulatory infrastruc - ture needed to successfully administer, monitor, and document immunizations provided through the SIP. While the SIP generally functions well for the USAMRIID military users, it has not met the anticipated needs of customers beyond USAMRIID, particularly personnel involved in civilian biodefense countermeasures and public health research. Recommendation 2: Federal agency stakeholders should modify the SIP to ensure that immunizations are readily available and accessible to all at-risk research workers, including those working on civilian as well as military projects. Recommendation 3: In order to generate a specific list of pathogens for priority attention for inclusion in the SIP, a strategic review and system- atic assessment on a pathogen-by-pathogen basis should be undertaken by the government stakeholders. The assessment should consider the characteristics of each pathogen and toxin and the characteristics of the threat posed by it, incorporating both military and civilian stakeholder perspectives. The SIP should not be a static program but instead should be enabled to evolve with respect to the vaccines that it offers. 1 Biosafety best practices include laboratory practices, use of personal protective equipment, and engineering controls.

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4 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH STATUS OF VACCINES CURRENTLY ADMINISTERED IN THE SPECIAL IMMUNIZATIONS PROGRAM The IND vaccines currently used in the SIP were developed and manu- factured largely in the 1970s and 1980s under standards that would likely be different from those required today. From the individual laboratory worker’s perspective, a vaccine with a good safety profile and strong immunogenicity might well be expected to provide protection despite as-yet unproven efficacy in humans. From a societal perspective, use of IND vaccines in laboratory workers permits the ongoing collection of safety and immunogenicity data on new vaccines, and these data could someday be of substantial value in a future national biodefense emergency. Although meritorious in concept, the use of IND vaccines in the SIP is not ideal for several reasons: the vaccines are older products that have not been produced for many years, the safety and immu- nogenicity profiles of some of the vaccines are less than optimal, and immu - nization under the required Phase II clinical trial protocols places substantial cost and regulatory burdens on the program. The committee found that these vaccines could still nonetheless be beneficial for at-risk personnel and where options for immunization with newer or superior vaccines do not yet exist. The committee observed that it is important to evaluate the use of these SIP IND vaccines carefully case by case so that they are made available for researchers for whom the benefits of immunization outweigh the risks (as judged by ap - propriately conducted risk assessments). Recommendation 4: The SIP should offer the safest and most effective vaccines available, which would include use of licensed vaccines, where available, and/or replacing older vaccines in the SIP with newer IND vaccines that have substantially improved manufacturing, quality control, safety, and immunogenicity profiles. The safety and immunogenicity of all vaccines used in the SIP should be studied carefully, as these data may have substantial value in a potential future national biodefense emergency. SOURCES OF NEW VACCINES FOR THE SPECIAL IMMUNIZATIONS PROGRAM Numerous vaccine candidates of potential value to the SIP either are under development in the United States or abroad or are already licensed for use in other countries. Investigational vaccines developed in the United States that have proven valuable in other countries where the diseases are endemic may also be available. Recommendation 5: As research on medical countermeasures continues, new vaccine products should be systematically incorporated into the SIP

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5 SUMMARY and older or outdated products for similar applications should be consid- ered for removal. Products currently licensed for use in other countries, but not yet in the United States, could also be used to fill gaps in the SIP armamentarium. Such newly developed and/or imported products could replace the older IND products currently administered. These additional products could also expand the SIP to include vaccines against additional pathogens and toxins that reflect evolving national military and civilian medical countermeasures (MCM) priorities. REGULATORY CHALLENGES CONCERNING THE SPECIAL IMMUNIZATIONS PROGRAM The committee found that vaccines in the SIP typically have no or ex - tremely limited commercial value, and therefore do not attract the interest of the biopharmaceutical industry. As a result, there is a need to explore regulatory and manufacturing options for these vaccines. There is also a need to consider regulatory options for vaccines already in use or in development outside the United States that could be considered for inclusion in an expanded SIP. Recommendation 6: The Food and Drug Administration and other rel- evant regulatory authorities should explore new administrative and regula- tory pathways to facilitate the development and licensure of SIP vaccines. Options might include a form of “restricted” or “conditional” licensure or an “exceptional circumstances” pathway (similar to that available in Europe). U.S. government (HHS, DOD) vaccine production and procure- ment plans should be designed to take full advantage of the SIP program and to consider SIP vaccine needs. GOVERNANCE OF THE SPECIAL IMMUNIZATIONS PROGRAM The SIP appears to lack a governance structure that enables regular strate- gic review of the investigational and licensed vaccines included in the program and to lack mechanisms to address identified gaps in vaccines. Recommendation 7: If the SIP is to serve effectively as an immunization program for all at-risk researchers working with hazardous pathogens, the committee recommends that the governance of the SIP be revised to develop processes for shared priority-setting and operational oversight by key stakeholders from civilian (HHS, USDA) as well as military (DOD) and other agencies. The revised system should build upon the wealth of SIP expertise available at USAMRMC.

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6 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH MANAGEMENT OF THE SPECIAL IMMUNIZATIONS PROGRAM The committee identified several obstacles faced by civilian biodefense re - search workers that prevented ready access to SIP vaccines. Paramount among these are cost and travel. Recommendation 8: All biodefense contracting and granting agencies should consider covering the cost of immunizing at-risk research work- ers, so that this cost is not borne solely by the institutions working on government-supported programs. The committee supports the idea of central SIP administration but recommends that the SIP explore options for having a small number of satellite clinic locations around the country to reduce travel and inconvenience for other participating institutions (provided that they are able to adhere to the IND protocols).