7
Conclusions and Recommendations

Biomedical research on infectious pathogens inescapably carries a small but finite risk of infection. With the widespread adoption of well-engineered biocontainment facilities and equipment, effective personal protective gear, and rigorous training, the frequency and number of serious incidents in the United States have decreased substantially. The committee was charged with examining the role of vaccinations in providing protection, in addition to those measures.

7.1
THE ROLE OF VACCINES IN PROTECTING RESEARCH WORKERS

The Special Immunizations Program (SIP) is unique in its mission, filling an important niche in biosafety not currently covered by any other programs in the United States. It is the only mechanism whereby certain vaccines against highly hazardous pathogens and toxins are made available to laboratory-based and field-based workers who may be exposed to these pathogens and toxins. The types of workers for whom SIP vaccination is most relevant include not only laboratory researchers but also animal technicians working to develop next-generation medical countermeasures (MCM) for military and civilian use, personnel engaged in the manufacture of biodefense vaccines and human and veterinary vaccines against zoonotic diseases, and scientists and laboratory technicians engaged in field studies of the ecology and epidemiology of hazardous pathogens. Scientists in public health diagnostic laboratories may be another potential community of SIP users (although currently the New York State Department of Health has the only state health laboratory that participates in the program).

The committee examined historical data on incidents of laboratory-acquired



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7 Conclusions and Recommendations Biomedical research on infectious pathogens inescapably carries a small but finite risk of infection. With the widespread adoption of well-engineered biocontainment facilities and equipment, effective personal protective gear, and rigorous training, the frequency and number of serious incidents in the United States have decreased substantially. The committee was charged with examining the role of vaccinations in providing protection, in addition to those measures. 7.1 THE ROLE OF VACCINES IN PROTECTING RESEARCH WORKERS The Special Immunizations Program (SIP) is unique in its mission, filling an important niche in biosafety not currently covered by any other programs in the United States. It is the only mechanism whereby certain vaccines against highly hazardous pathogens and toxins are made available to laboratory-based and field-based workers who may be exposed to these pathogens and toxins. The types of workers for whom SIP vaccination is most relevant include not only laboratory researchers but also animal technicians working to develop next-generation medical countermeasures (MCM) for military and civilian use, personnel engaged in the manufacture of biodefense vaccines and human and veterinary vaccines against zoonotic diseases, and scientists and laboratory tech- nicians engaged in field studies of the ecology and epidemiology of hazardous pathogens. Scientists in public health diagnostic laboratories may be another potential community of SIP users (although currently the New York State Department of Health has the only state health laboratory that participates in the program). The committee examined historical data on incidents of laboratory-acquired 129

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130 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH infections, reports of Select Agent loss and release events, the history of biosafety practices, and lessons learned from occupational health and safety immunization programs such as the SIP. The committee noted that accidents and containment failures can occur even in highly regulated environments with trained personnel, and that some types of procedures (such as those involving sharps or aerosol exposures of animals), and some pathogens (such as those that have particu - larly low infectious doses) can present the greatest increased risk of infection to workers. The committee endorsed the concept that immunizations are not a substitute for other biosafety practices—such as appropriate training, personal protective equipment, and engineering controls—but that vaccines can serve as an important adjunct. The committee also endorsed the idea that immuniza - tions should be offered to workers when safe and effective products exist and that employers have an ethical mandate to follow best practices in biosafety, including the provision of vaccines where warranted. The committee considered the use of both licensed and Investigational New Drug (IND) status vaccines in the setting of occupational immunization. Licensed products have generally undergone larger-scale clinical trials, and their safety and efficacy profiles are well known. The IND vaccines used in the SIP remain in extended Phase II clinical trials. However, the clinical protocols under which these vaccines are administered have produced a wealth of data on human safety, immunogenicity, and probable efficacy, including long-term medical monitoring of SIP enrollees. The committee noted that publications analyzing data collected through the SIP have improved the understanding of immune responses to investigational vaccines and have helped to provide guidelines for the safe conduct of pathogen research and the management of laboratory infections. The committee views these publications as an important resource provided by the program, and encourages the SIP to analyze and make such data available to the research community. Although the IND vaccines currently used within the SIP were developed and manufactured largely in the 1970s and 1980s under standards that would probably be different from those applied today, the committee noted that these vaccines may be offered when beneficial to at-risk personnel and when options for immunization with newer or superior vaccines do not exist. The committee emphasized the importance of conducting appropriate risk assessments and maintaining informed-consent procedures to ensure that IND vaccines are offered only to workers who are both at risk and medically eligible to receive such them. The committee endorsed the view that immunizations with SIP IND vaccines should be given on a voluntary basis. Immunizations with certain IND vaccines, such as those currently offered in the SIP, remain an important component of an overall biosafety program for laboratory workers who are at risk for exposure to hazardous pathogens.

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131 CONCLUSIONS AND RECOMMENDATIONS Recommendation 1: Special Immunizations Program IND vaccines should be offered to laboratory workers on a voluntary basis, subject to risk as - sessments and informed consent. The use of immunizations should never be a substitute for careful adherence to all biosafety best practices, but should be considered a component of an overall biosafety program 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. 7.2 FOR WHICH PATHOGENS WOULD IT BE HIGHLY DESIRABLE TO HAVE VACCINES, AND WHICH PATHOGENS SHOULD RECEIVE PRIORITY ATTENTION? The committee examined publicly available priority lists from the Depart - ment of Defense (DOD) and the Department of Health and Human Services (HHS) for the development of new medical countermeasures and additional information on vaccines available or in development in the United States and abroad. The committee chose not to attempt to create a prescriptive list of pathogens against which the SIP should acquire new vaccines. Rather, the com- mittee suggested a framework for evaluating which pathogens should receive priority attention for inclusion of a vaccine against them in the SIP. This frame - work should be based on an evaluation of two core criteria: the characteristics of the pathogen or toxin and the characteristics of the threat that it poses. The characteristics of the pathogen that should be considered in making the judgment include infectious dose, transmission potential (including aerosol transmission), and case fatality rate, so that pathogens that have low infectious doses, high transmissibility, and substantial morbidity and mortality from in - fection would receive higher priority. The relevant characteristics of the threat that will influence which pathogens should be included in the SIP include the presence of the pathogen on government priority threat lists (which are largely generated by the intelligence community), which pathogens researchers are most actively working on, the availability or development status of vaccines, and the existence of effective anti-infective therapeutics directed against the pathogen. Historical information about the occurrence of and frequency of laboratory infections with the pathogen should also be considered. An overarching conclusion reached by the committee is that the SIP lacks clear and sufficient processes for governance, priority-setting, and strategic review to enable it to continue to adapt and evolve as needs change. The com- mittee judged that a strategic review and systematic assessment of vaccines to be included in the SIP based on the above framework and incorporating stake -

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132 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH holder perspectives of both military and civilian agencies should be undertaken. This detailed assessment was beyond the scope of the present study. 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 over time with respect to the vaccines that it offers. 7.3 ADVANTAGES AND DISADVANTAGES OF THE USE OF INVESTIGATIONAL VACCINES AS THEY HAVE BEEN USED IN THE SPECIAL IMMUNIZATIONS PROGRAM In concept, the use of IND vaccines for protection of at-risk laboratory workers has substantial merit. From the individual laboratory worker’s perspec- tive, 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 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 cur- rently 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 immunogenicity profiles of some of the vaccines are less than optimal (for example, the vaccine against Venezuelan equine encephalitis virus, VEE TC-83, is associated with a demonstrated 20% rate of systemic adverse events [Pittman et al. 1996]), and immunization under the required Phase II clinical trial protocols poses substan- tial cost and regulatory burdens on the program. 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 those researchers for whom the ben - efits of vaccination outweigh the risks (as judged by appropriately conducted risk assessments). The committee also concluded that if or when newer, safer, or improved vaccines become available against pathogens that are included in the SIP, the replacement vaccines should be incorporated into the program to phase out the older or less efficacious ones. That conclusion reemphasizes the overarching need for the SIP to incorporate clear procedures for undertaking periodic reviews and assessments of the vaccines used in the program, the pathogens against which the vaccines are directed, and the existence and state of development of other relevant MCM products.

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133 CONCLUSIONS AND RECOMMENDATIONS 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. 7.4 VACCINE DEVELOPMENT AND SUPPLY WITHIN AND BEYOND THE EXISTING SPECIAL IMMUNIZATIONS PROGRAM Given its emphasis on the importance of shared governance and program flexibility, the committee went on to consider recent developments in vaccine production and in regulatory processes that might affect the SIP. It noted that the modest scale of the current SIP user base means that only a limited number of immunization doses are required for its immediate needs. Newer pilot manu- facturing technologies, such as flexible, single-use bioreactors, may improve the cost and speed of manufacturing such small-scale quantities of vaccines. Flex - ible platform approaches to vaccine development may, in the future, also reduce the time and expense needed to develop new products and take them through to advanced development and licensure. If a future emerging threat dictates the need for a particular SIP vaccine, the experience gained in the manufacture and human trials of that vaccine candidate product through the SIP may help to shorten the timeline needed to mount a full MCM response. The committee also observed that potential new vaccines to be included in the SIP could come from national U.S. MCM development efforts (for example, the plague vaccine whose advanced development is being managed by the Joint Vaccine Acquisition Program) or from vaccines that are currently licensed by countries other than the United States. The committee noted the procurement initiatives put forward by HHS and DOD to support industry partnerships in vaccine development, which potentially include small biotechnology companies and large pharmaceutical manufacturers. The committee encourages the federal agencies, when they are making major U.S. investments in this area, to consider the immunization needs of the SIP and of the frontline biodefense researchers who help to develop these next-generation MCM. The committee also encourages the Food and Drug Administration (FDA) and other relevant bodies to explore potential new regulatory pathways that might more easily enable use of relevant SIP vaccines to reduce some of the substantial regulatory burden associated with the current IND clinical protocols.

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134 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH Recommendation 5: As research on medical countermeasures continues, new vaccine products should be systematically incorporated into the SIP 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 infectious pathogens and toxins that reflect evolving national military and civilian medical countermeasures (MCM) priorities. 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. 7.5 GENERAL OBSERVATIONS REGARDING THE ROLE OF IMMUNIZATIONS IN THE CONTEXT OF RESEARCH WITH HAZARDOUS PATHOGENS The committee noted that the SIP is a unique program and is the only im- munization program in the United States that supports researchers who work with hazardous pathogens by providing both licensed and IND vaccines. The committee emphasized the value of maintaining a program like the SIP. The committee also observed that the SIP sits at a critical intersection of military and civilian MCM research and development efforts. However, the committee observed that the SIP, as currently structured and managed, appears to lack a coordinated civilian and military stakeholder perspective on policy, management, and funding: Indeed, when the full vaccine MCM pathways are considered, there are important synergies but still important differences between the military and civilian programs, as summarized in Table 7.1. With the expansion of the MCM enterprise and the shifting nature of national security and public health threats, the mandate for countermeasures now extends well beyond DOD to include substantial investments by civilian research and public health agencies. The history and expertise available at U.S. Army Medical Research and Materiel Command (USAMRMC) in establishing and operating the SIP remain extremely valuable and provide a strong foun -

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135 CONCLUSIONS AND RECOMMENDATIONS TABLE 7.1 Synergies and Differences Betweem Military and Civilian Medical Countermeasures Pathways That Affect the Special Immunizations Program R&D Manufacturing Regulation Delivery Military Historically New DOD request for Changes made in The SIP is informationa had primary last two decades to currently housed role for biologics-based MCM conform to FDA in and operated regulations by DOD Civilian Expansion of New HHS request for Investigational There is no proposalb focused on influenza public bio- vaccine use independent preparedness production and request for regulated under civilian SIP proposalc on centers for research FDA program advanced development aU.S. Department of the Army 2010. bHHS 2009a. cHHS 2011. dation that can be built upon to create an effective 21st century occupational immunization program to support hazardous pathogen research. 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. The committee noted that agency demand for research worker vaccination should be proportional to the investments that agencies are making in relevant research, development, diagnostic, and surveillance programs. However, the current structure of the SIP appears inefficient for laboratory workers and public health practitioners who are not affiliated with the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). There appears to be limited harmonization with the needs of stakeholders such as the National In - stitute of Allergy and Infectious Diseases, the Centers for Disease Control and Prevention, the Biomedical Advanced Research and Development Authority (BARDA), the U.S. Department of Agriculture, the Department of Homeland Security, vaccine manufacturers, and the Association of State and Territorial Laboratory Directors. The IND status of many SIP vaccines also increases the regulatory burden and creates complex logistics for program administration, because continuing medical monitoring is required to document safety and immunogenicity. While the program provides a wealth of information, the IND

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136 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH documentation and reporting requirements greatly increase program costs com- pared to the costs of administering licensed products. Storage and maintenance of the existing IND vaccine stockpiles present yet another challenge. Although Chemical Biological Medical Systems has been maintaining the stocks on a year- to-year basis, no long-term mechanism has been identified. It is not clear which other organization would take its place, and no funds have been allocated for this expense. Despite previous reviews of the SIP and a 2004 Homeland Secu - rity Council Policy Coordinating Committee decision to expand the program under a fully burdened cost-sharing arrangement, the committee expressed concerns about the continuing financial stability of the SIP and about access to SIP immunizations for all at-risk personnel who handle hazardous pathogens. The committee offers the following suggestions to address aspects of those concerns, although it recognizes that these may present additional costs: • The committee encourages agencies awarding contracts and grants (by HHS, BARDA, and others) to cover the costs of immunizing personnel in those cases where such SIP immunizations are appropriate on the basis of risk so that the costs are not borne by institutions working on government-supported programs. Costs per person to participate in the SIP include an annual enrollment fee of approximately $10,000, additional program costs that vary depending on the vaccine(s) ad- ministered (which range from several hundred to several thousand dollars each, depending on the vaccine and the number of doses required), and travel to USAMRIID to receive medical exams and im - munizations.1 A given laboratory might seek to immunize more than one person, compounding the expense and making cost a potentially significant burden on laboratory budgets. • The committee noted that the 2004 evaluation undertaken by the SIP subgroup included recommendations for several regional SIP immu - nization sites throughout the United States. The committee encour- ages this concept to be revisited. The committee supports the idea of central SIP administration but suggests that a small number of satellite clinic locations could reduce travel and cost issues for other participat- ing institutions. A limited expansion closely administered by USAM - RMC would avoid the compliance issues previously experienced when immunizations took place at 117 locations. • One method to help achieve an expansion of SIP immunization loca - tions is the use of additional IND mechanisms, such as investigator- initiated INDs or treatment INDs, that would be held by investigators at other government or academic institutions, contingent on a continu- ing strong commitment by the additional investigators for collection 1 As noted in Chapter 3, no charge is assessed for the IND vaccine itself.

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137 CONCLUSIONS AND RECOMMENDATIONS of complete and standardized data and fulfillment of responsibilities under the IND. Alternatively, co-investigators under the USAMRMC IND could be recruited; this would be the equivalent of a multisite clinical trial under a single protocol, a very common practice in the development of vaccines and drugs. As a result, the committee offers a final recommendation: 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).

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