This report focuses on the role of immunization in the protection of laboratory workers who are engaged in research on hazardous pathogens (viruses, bacteria) and toxins; specifically, it focuses on the Special Immunizations Program (SIP), which is housed 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 staff that are at risk of exposure to hazardous pathogens and toxins and is the only such program in the United States. Its missions are (Boudreau, 2010)
To provide additional protection with vaccines to at-risk personnel.
To ensure the safety and well-being of participants through continuous medical evaluation.
To provide evaluation of and treatment for occupational exposures.
To collect vaccine safety and immunogenicity data to further medical research.
The SIP vaccines augment the protection provided by laboratory best practices, engineering controls, and personal protective equipment for working with hazardous pathogens and toxins. Most of the vaccines used in the SIP are not licensed by the Food and Drug Administration but have Investigational New Drug (IND) status. The administration of the vaccines is therefore considered to be part of a set of continuing clinical trials that involve intensive regulatory requirements.1 The SIP vaccines are available only in limited amounts and are
currently administered only at USAMRIID, and they must be stored, maintained, and tested periodically for potency (Boudreau 2010). Those factors and the regulatory requirements associated with the clinical protocols that guide the SIP make the special immunizations expensive. In the early 2000s, the high costs and limited availability of SIP vaccines led the Department of Defense (DOD) to restrict enrollment in the SIP of personnel working for or funded by non-DOD agencies unless the costs of participation for these personnel were covered by the non-DOD users. The result was that fewer non-DOD government and civilian academic researchers had access to SIP immunizations at the same time that the population of such researchers was undergoing a rapid expansion.
To address the cost and location issues in the program, a U.S. Homeland Security Council (HSC) policy coordinating committee (PCC) approved an expansion of the SIP in 2004. The U.S. Army Medical Research and Materiel Command (USAMRMC) and USAMRIID were directed to continue conducting an expanded program at Fort Detrick and at one or two new satellite locations. The HSC PCC directed that the program expansion be funded by cost sharing with fully burdened contributions from the using departments and agencies according to their percentage use of the program. However, the non-DOD user agencies did not set aside funds to pay for an expanded SIP accessible to all potential users, and at-risk researchers in non-DOD government and academic settings continued to work without immunization while potentially protective vaccines were available from DOD. In addition, some of the SIP vaccines are nearing the end of their lifespan and may need to be replaced.
In late 2008, 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 recommendation for the expansion of the SIP in the larger context of immunization of researchers working with potentially hazardous pathogens and toxins. The present report is the result of that examination.
This chapter sets the SIP and the U.S. biological defense (biodefense) program into context and provides a background for later chapters on specific elements of the program and committee findings and conclusions. The U.S. medical countermeasures enterprise, including military and civilian biodefense priorities and the state of potentially relevant vaccine research, development, and manufacturing, are continually changing. To the best of the committee’s knowledge, the information provided in this report is accurate at the time of publication. After briefing the sponsor, the committee made a limited number of factual corrections and clarifications, none of which affected the conclusions or recommendations.
THE CURRENT CONTEXT OF PATHOGEN RESEARCH
For more than 200 years, from the earliest discoveries of such luminaries as Edward Jenner, Robert Koch, and Louis Pasteur to the present day, scientists have conducted research on microorganisms and other pathogens that cause infectious diseases.2,3 Their research has produced vaccines and therapies that have greatly decreased the risks posed by infectious diseases. As a National Research Council committee noted in 2009, “it is not an exaggeration to attribute increased human lifespan and better human health to the research of legions of microbiologists and other biomedical researchers on the biology of bacteria and viruses and the toxins they produce” (NRC 2009: 21). Research on microorganisms improves our ability to prevent infectious disease outbreaks, to treat them more effectively when they occur, and to detect the pathogens and toxins more rapidly both in patients and in the environment.
Shortly after the September 11, 2001, attacks, the United States received a new impetus to support and conduct pathogen research when a second set of attacks occurred, this time involving the bacterium Bacillus anthracis, the etiologic agent of the disease anthrax. Since then, the nation’s capacity to conduct pathogen research has expanded substantially. According to a recent analysis of the biodefense budget, U.S. government civilian biodefense funding increased from $633.4 million in FY 2001 to a requested $6.5 billion in FY 2011, which brought the U.S. government investment during FY 2001–2011 to a total of $61.9 billion. In FY 2011, $4.7 billion of the requested $6.5 billion (over 70%) is for HHS, and 37% of this amount ($1.75 billion) is for the National Institutes of Health (NIH) to support research related to biodefense (Franco and Sell 2010).
An important outcome of the funding amplification has been an expansion of the research infrastructure. The number of biological safety level (BSL) 4 laboratories—which are used for research on the most dangerous pathogens, those that pose the highest risk of disease and for which no vaccine or therapy is available—increased from two before 1990 to at least seven in 2009, with a projected expansion to at least 134 (GAO 2009). Such laboratories are no
Edward Jenner is well known for his investigations on the use of cowpox vaccination to protect against smallpox, and Robert Koch formulated the criteria in “Koch’s postulates” to establish whether a specific microorganism causes a specific disease and isolated Bacillus anthracis, among other discoveries. Louis Pasteur discovered that the growth of microorganisms causes fermentation and investigated microbial theories of disease; he did early work on the development of rabies and anthrax vaccines.
For the purposes of this report, the committee generally uses pathogen to refer to a microorganism while its use of the term agent encompasses both microorganisms and microbial toxins. A fuller definition of pathogen may be found in Appendix B as well as in Casadevall and Pirofski (1999).
In 2009, six entities reportedly were operating seven BSL-4 laboratories (four federal, two academic, and one private nonprofit) that were registered with the CDC-USDA Select Agent program, and six BSL-4 laboratories were in various stages of planning and construction (GAO 2009).
longer limited to the federal government but now include facilities in academic institutions, state and local public health departments, and the private sector (GAO 2007). The number of the much more numerous BSL-3 laboratories is unknown, but they also underwent rapid expansion during that period (GAO 2009).5 Those increases in pathogen research laboratory capacity were made possible largely by the substantial influx of federal support already noted. For example, since 2003, the National Institute of Allergy and Infectious Diseases (NIAID) has supported the development of 11 Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases (RCEs) and 12 Regional Biocontainment Laboratories (RBLs). Each RCE comprises a consortium of universities and research institutions that serve a specific geographic region.6 In the RCE program alone, there are nearly 500 principal investigators, mostly new to biodefense, in almost 300 participating institutions.
CATEGORIZATION OF PATHOGENS AND MANAGEMENT OF PATHOGEN RESEARCH
The conduct and management of pathogen research have evolved in response to concerns about safety and, more recently, security. This evolution has produced a number of practice and procedure frameworks that incorporate consideration of the relative risks of research on hazardous infectious microorganisms due to their biological properties and their potential as biological weapons (bioweapons).
Over the last 25 years, best practices have been designed, articulated, and accepted to reduce the likelihood that research with hazardous pathogens will cause harm either to laboratory workers or to the public or the environment because of accidents or accidental releases. HHS published the first edition of its Biosafety in Microbiological and Biomedical Laboratories (BMBL) in 1984, and the fifth edition was issued in 2007 and revised in December 2009 (CDC/NIH 2009). Although not codified in formal regulations, the BMBL guidelines are widely used performance-based criteria for how modern pathogen research laboratories are expected to operate. BMBL from it inception has constituted a set of guidelines for laboratory safety in the academic, government, and public
Under the oversight system implemented for Select Agents (discussed in Section 1.2), the Centers for Disease Control and Prevention and the U.S. Department of Agriculture (USDA) have shared authorities and responsibilities for Select Agents and biocontainment laboratories, and USDA is responsible for authorizing and inspecting laboratories that work with animal and livestock pathogens, some of which are zoonotic Select Agents. Although the number of Select Agent BSL-3 facilities is known, other BSL-3 laboratories that do not work with Select Agents and are not required to register as such have been established in the public and private sectors.
Further information on the RCEs is available from NIAID (2010). Information on the RBLs is available from NIAID (2011). An additional RBL, the Pacific Regional Biocontainment Laboratory at the University of Hawaii at Manoa, remains in planning.
health communities. BMBL categorizes infectious pathogens and laboratory activities into four biosafety levels (BSL-1 through BSL-4) and establishes safety guidelines for each level on the basis of risk:
BSL-1 laboratories are designed for work with pathogens and toxins that do not consistently cause disease in healthy human adults.
BSL-2 laboratories are designed for work with pathogens and toxins that can be spread by puncture, absorption through mucus membranes, or ingestion.
BSL-3 laboratories are designed for work with pathogens and toxins that are capable of aerosol transmission and that may cause serious or lethal infection.
BSL-4 laboratories are designed for work with pathogens and toxins that pose a high risk of life-threatening disease, that are capable of aerosol transmission, and for which there is generally no available therapy or vaccine.
BSL-3 and BSL-4 laboratories are considered to afford “high” and “maximum” biological containment (biocontainment), respectively, for research on the most dangerous pathogens. They require specialized expertise to design, construct, commission, operate, and maintain, and workers in these laboratories must follow stringent safety procedures and use specialized safety equipment. High- and maximum-containment laboratories may also be necessary for some diagnostic and analytic services.
The BMBL guidelines are not regulations, but research on many pathogens is subject to regulatory oversight via other programs, such as the HHS-USDA Select Agent program.7 The program was created in 1996 by the Antiterrorism and Effective Death Penalty Act (Public Law 104-132), which was passed amid rising concerns about terrorism after a number of terrorist acts, including the Oklahoma City bombing. Before 2001, the statute governed primarily the transfer of biological pathogens and toxins between research laboratories. The act directed the secretary of HHS and the secretary of USDA to regulate the transport of biological agents that have the potential to pose severe threats to public, animal, or plant health and safety through their use in bioterrorism. The HHS secretary delegated that authority to the Centers for Disease Control and Prevention (CDC) and the USDA secretary to the Animal and Plant Health Inspection Service (APHIS). To ensure that the pathogens and toxins were transferred only between responsible parties, CDC and APHIS required that laboratories that transfer Select Agents be registered and that transfers be
reported to CDC and APHIS and conducted under a permitting system (42 CFR § 72.6; NRC 2009).
After the anthrax attacks of 2001, the regulations governing Select Agents were greatly expanded under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (Public Law 107-188, 116 Stat. 594 ) into a rigorous and formal oversight system to ensure that persons seeking to possess, use, or transfer Select Agents or Toxins have a lawful purpose. Among its requirements, the law
Requires all facilities possessing Select Agents to register with the secretary of HHS or USDA, not just facilities sending or receiving Select Agents. Registration is for 3 years, and facilities must demonstrate that they meet the requirements delineated in BMBL for working with particular Select Agents. Such requirements include having proper laboratory and personal protective equipment, precautionary signs, monodirectional and high-efficiency particulate air (HEPA) filtered ventilation, controlled access, and biosafety operations manuals. Facilities must describe the laboratory procedures that will be used, provide a floor plan of the laboratory where Select Agents will be handled and stored, and describe how access will be limited to authorized personnel. And facilities must describe the objectives of the work that requires use of Select Agents. Each facility must identify a responsible facility official who is authorized to transfer and receive Select Agents on behalf of the facility.
Restricts access to pathogens and toxins by persons who do not have a legitimate need and who are considered by federal law-enforcement and intelligence officials to pose a risk.
Requires transfer registrations to include information regarding the characterization of pathogens and toxins to facilitate their identification, including their source.
Requires the creation of a national database with information on all facilities and persons that possess, use, or transfer Select Agents.
Directs the secretaries of HHS and USDA to review and publish the Select Agents list biennially, making revisions as appropriate to protect the public.
Requires the secretaries of HHS and USDA to impose more detailed and different levels of security for different Select Agents on the basis of their assessed level of threat to the public.
The regulations are applicable to all federal, public, and private research institutions and individuals associated with the institutions that possess, handle, store, and conduct research activities and programs that use Select Agents and Toxins (42 CFR Part 732, 7 CFR Part 331, and 9 CFR Part 121). The Select
Agents list is maintained by CDC for human pathogens and toxins and by APHIS for plant and animal pathogens.8 The list (see Table 1.1), first introduced in 1997, has grown from 42 pathogens and toxins to the current 82, 40 pathogens are HHS-only agents, 32 are USDA-only agents (24 animal pathogens and eight plant pathogens), and 10 are zoonotic pathogens that overlap both HHS and USDA.
The criteria for including a particular pathogen or toxin on the Select Agents list address threats to public, animal, and plant health and safety but go further to include more security-oriented considerations. Historically, pathogens that had been previously weaponized by the United States or other countries have been considered to pose the greatest risks,9 including the ability to incapacitate affected people or cause highly lethal infections in a short period, lack of availability of preventive or therapeutic measures, ease of production, stability as an aerosol, and capability of being dispersed as small particles. The following considerations have generally been used as the basis for conferring Select Agent status on particular microorganisms. Some of them deal with health risks, others with potency or effectiveness as potential biological weapon (bioweapons):
Virulence, pathogenicity, or toxicity of the microorganism; its potential to cause death or serious disease.
Availability of treatments, such as vaccines or drugs, to control the consequences of a release or epidemic.
Transmissibility of the microorganism; its potential to cause an uncontrolled epidemic.
Ease of preparing the microorganism in sufficient quantity and stability for use as a biological terrorism (bioterrorism) agent, for example, the ability to prepare large quantities of stable microbial spores.
Ease of disseminating the microorganism in a bioterrorism event to cause mass casualties, for example, by aerosolization.
Public perception of the microorganism; its potential to cause societal disruption by mass panic.
Known research and development efforts on the microorganism by national bioweapons programs.
NIAID has also developed a classification of pathogens using a category A, B, and C system (Table 1.2). The system is used to set research priorities and
TABLE 1.1 Select Agents and Toxins
HHS SELECT AGENTS AND TOXINS
OVERLAP SELECT AGENTS AND TOXINS
Botulinum neurotoxin–producing species of Clostridium
Cercopithecine herpesvirus 1 (herpes B virus)
Clostridium perfringens epsilon toxin
Coccidioides posadasii/Coccidioides immitis
Crimean-Congo hemorrhagic fever virus
Eastern equine encephalitis virus
Lassa fever virus
Reconstructed replication-competent forms of the 1918 pandemic influenza virus containing any portion of the coding regions of all eight gene segments (reconstructed 1918 Influenza virus)
Shiga-like ribosome inactivating proteins
South American hemorrhagic fever viruses
Burkholderia mallei (formerly Pseudomonas mallei)
Burkholderia pseudomallei (formerly Pseudomonas pseudomallei)
Rift Valley fever virus
Venezuelan equine encephalitis virus
USDA SELECT AGENTS AND TOXINS
African horsesickness virus
African swine fever virus
Avian influenza virus (highly pathogenic)
Bluetongue virus (exotic)
Bovine spongiform encephalopathy prion
Classical swine fever virus
Ehrlichia ruminantium (heartwater)
Foot-and-mouth disease virus
Goat pox virus
Japanese encephalitis virus
Lumpy skin disease virus
Malignant catarrhal fever virus (Alcelaphine herpesvirus type 1)
Mycoplasma capricolum subspecies capripneumoniae (contagious caprine pleuropneumonia)
Mycoplasma mycoides subspecies mycoides small colony (MmmSC) (contagious bovine pleuropneumonia)
Peste des petits ruminants virus
Sheep pox virus
Swine vesicular disease virus
Vesicular stomatitis virus (exotic): Indiana subtypes VSV-IN2, VSV-IN3
Virulent Newcastle disease virus
Tick-borne encephalitis complex (flavi) viruses
Central European tick-borne encephalitis Far Eastern tick-borne encephalitis (formerly known as Russian spring and summer encephalitis)
Kyasanur Forest disease
Omsk hemorrhagic fever
Variola major virus (smallpox virus)
Variola minor virus (alastrim)
USDA PLANT PROTECTION AND QUARANTINE (PPQ)
SELECT AGENTS AND TOXINS
Peronosclerospora philippinensis (Peronosclerospora sacchari)
Phoma glycinicola (formerly Pyrenochaeta glycines)
Ralstonia solanacearum race 3, biovar 2
Sclerophthora rayssiae var zeae
Xylella fastidiosa (citrus variegated chlorosis strain)
SOURCE: Adapted from NRC 2009.
uses different criteria for classification. The criteria stress ease of dissemination, associated mortality after infection, potential for public health impact and social disruption, and required special action for public health preparedness. A larger universe of pathogens is included in the NIH assessment, and some pathogens on the NIH list are not captured on the Select Agents list.
It should be clear from the foregoing discussion that research with hazardous pathogens and toxins is associated with a risk of accidental exposure. Many of the laboratory workers, technicians, and others who are exposed to these pathogens and toxins are part of the broad military and public health enterprise to develop medical countermeasures against potential biological threat (biothreat) agents and emerging infectious diseases. However, the current view in the United States is that these risks are part of a necessary investment to protect public health, agriculture, and national security. In addition, risks to laboratory workers are mitigated by laboratory best practices, equipment, facilities, and in some cases the availability of additional protections in the form of vaccines, antibiotics, antiviral drugs, and antibodies. The USAMRIID SIP, which provides access to a limited set of IND vaccines to at-risk laboratory workers, is one tool in this web of protection.
CHARGE TO THE COMMITTEE
Given both the substantial expansion in research with hazardous pathogens since 2001 and current efforts to review national biodefense and infectious disease countermeasures programs, the HHS BARDA asked the National Research Council’s Board on Life Sciences to examine the SIP and its role in helping to protect researchers who work with highly hazardous pathogens. The SIP, administered by USAMRIID, provides access to licensed and investigational vaccines against selected highly hazardous pathogens and toxins for scientists, technicians, and other workers who may be exposed to these microorganisms as part of their employment.
TABLE 1.2 NIAID Category A, B, and C Priority Pathogens
Bacillus anthracis (anthrax)
Clostridium botulinum toxin (botulism)
Yersinia pestis (plague)
Variola major (smallpox) and other related pox viruses
Francisella tularensis (tularemia)
Viral hemorrhagic fevers
Burkholderia pseudomallei (melioidosis)
Coxiella burnetii (Q fever)
Brucella spp. (brucellosis)
Burkholderia mallei (glanders)
Chlamydia psittaci (Psittacosis)
Ricin toxin (from Ricinus communis)
Epsilon toxin of Clostridium perfringens
Staphylococcus enterotoxin B
Rickettsia prowazekii (typhus)
Foodborne and waterborne pathogens
Additional viral encephalitides
Emerging infectious disease threats, such as Nipah virus and additional hantaviruses
NIAID priority areas:
Tickborne hemorrhagic fever viruses
Tickborne encephalitis viruses
Yellow fever virus
Tuberculosis (TB), including drug-resistant TB
Other Rickettsia species
Severe acute respiratory syndrome–associated coronavirus (SARS-CoV)
Antimicrobial resistance, excluding research on sexually transmitted organismsa
Antimicrobial research, as related to engineered threats and naturally occurring drug-resistant pathogens, focused on development of broad-spectrum antimicrobials
Innate immunity, defined as the study of nonadaptive immune mechanisms that recognize and respond to microorganisms, microbial products, and antigens
Coccidioides immitis (added February 2008)
Coccidioides posadasii (added February 2008)
aNIAID Category C Antimicrobial Resistance—Sexually Transmitted Excluded Organisms Bacterial vaginosis, Chlamydia trachomatis, cytomegalovirus, Granuloma inguinale, Hemophilus ducreyi, hepatitis B virus, hepatitis C virus, Herpes simplex virus, human immunodeficiency virus, human papillomavirus, Neisseria gonorrhoeae, Treponema pallidum, Trichomonas vaginalis
SOURCE: NIAID 2009.
A committee of experts in such fields as pathogen research, infectious diseases, vaccine effectiveness and safety, vaccine manufacturing, regulatory affairs, biosafety and laboratory operations, and biological ethics (bioethics) was convened to address the charge given in Box 1.1. The committee met four times over 10 months to review information on the SIP, the broader context of research with highly hazardous human and animal pathogens, and stakeholder perspectives.
Committee on Special Immunizations Program for Laboratory Personnel Engaged in Research on Countermeasures for Select Agents
Statement of Task
A National Research Council (NRC) committee will examine technical issues related to a decision made by the U.S. Homeland Security Council (HSC) Policy Coordinating Committee (PCC) in 2004 to expand the United States Army Medical Research Institute of Infectious Diseases’ (USAMRIID’s) Special Immunizations Program (SIP) and the larger context of vaccination for researchers working with potentially dangerous pathogens. The purpose of an expanded immunizations program would be to provide additional protection for researchers engaged in developing next generation countermeasures against agents of bioterrorism, most of which are now identified as Select Agents (42 CFR Parts 72 and 73; 7 CFR Part 331; 9 CFR Part 121). People eligible for vaccination may be expanded beyond personnel in government laboratories belonging to the Department of Defense (DOD) to include personnel of other federal agencies (e.g., National Institutes of Health) as well as in academic laboratories conducting such research with federal funding and other settings in which exposure to Select Agents and other high-hazard pathogens may occur including some diagnostic, public health, or emergency response laboratories. The NRC committee will consider the needs outlined in 2004 for the HSC PCC along with information on the current status of the SIP (vaccine supplies and viability), the value of immunization beyond the current implementation of the SIP, and the growth of research on high hazard organisms since 2004. Questions the committee may consider include:
The committee will focus on the more general questions above to inform the U.S. government’s high level policy discussion on the role of vaccines in the context of research with high-hazard pathogens. The committee will not conduct a detailed analysis on the risk of each pathogen or the relative safety and efficacy of particular vaccines but may consult available data on these issues to address elements of the statement of task.
ORGANIZATION OF THE REPORT
The committee took a broad view in its deliberations, choosing to consider not only the increase in demand for the vaccines currently administered by the SIP but likely advances in vaccines, manufacturing, and regulatory science. Its discussions led the committee to consider and evaluate whether an effective researcher-immunization program should include options for broadening the scope of and products included in the SIP.
Chapter 2 discusses the history of the SIP and the role of vaccination as one component of safe laboratory practice in work with highly hazardous pathogens. The SIP arose as part of the U.S. Army’s historical bioweapons program at Fort Detrick, MD, but it now serves both civilian and military personnel and scientists conducting biodefense research at facilities other than USAMRIID. Chapter 2 also presents information on the frequency of laboratory exposures and the lessons that have been learned from experience in providing vaccinations to workers engaged in hazardous-pathogen research. Chapter 3 provides additional detail on the U.S. medical countermeasures enterprise, including research priorities and recommendations from recent reports, to provide a framework for a discussion of the current SIP. Chapters 4 and 5 discuss potential options relevant to the SIP in regulatory guidance and in vaccine development and manufacturing, respectively. Chapter 6 presents several options discussed by the committee for how the SIP might meet its goals. Chapter 7 presents the committee’s conclusions regarding the role of vaccines in protecting laboratory workers, the value of maintaining a program like the SIP to make the vaccines available, and how additional vaccines might be selected for inclusion. The committee suggests a framework for actions that could be considered over short, medium, and long terms to address some of the issues identified.