2
History of the Special Immunizations Program and Lessons Learned from Occupational Immunization Against Hazardous Pathogens

2.1
HISTORICAL PATHOGEN AND COUNTERMEASURES RESEARCH AND THE ORIGINS OF THE SPECIAL IMMUNIZATIONS PROGRAM

Research involving hazardous pathogens has been a component of the U.S. military scientific enterprise for many years. In 1941, Secretary of War Henry L. Stimson suggested that a program be initiated to investigate “the present situation and future possibilities” of both offensive and defensive biological warfare (biowarfare) (Covert 2000). In 1942, President Roosevelt authorized Secretary Stimson to establish a civilian agency to take the lead on all aspects of the biowarfare effort. The War Research Service (WRS), under George W. Merck, in the civilian Federal Security Agency was tasked to begin development of the U.S. biowarfare program with both offensive and defensive objectives. WRS organized a research and development (R&D) program in the Department of War and requested that the Army assume responsibility for the large-scale R&D program in November 1942. Construction and operation of laboratories and pilot plants at Camp Detrick (now Fort Detrick), in Frederick, MD, began in April 1943 (Covert 2000).1

The risk to scientists, laboratory technicians, and other staff from exposure to high-risk pathogens was recognized during the planning of the R&D program, as discussed in greater detail in Section 2.4. Arnold G. Wedum joined the U.S. biowarfare program in 1946 and served as the director of industrial health

1

In addition to Cutting Edge: A History of Fort Detrick, Maryland, 4th Edition (Covert 2000), information on the history of Fort Detrick and on the historical offensive and defensive U.S. biological weapons programs may be found in Medical Aspects of Chemical and Biological Warfare (U.S. Department of the Army 1997) and Medical Aspects of Biological Warfare (U.S. Department of the Army 2007).



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2 History of the Special Immunizations Program and Lessons Learned from Occupational Immunization Against Hazardous Pathogens 2.1 HISTORICAL PATHOGEN AND COUNTERMEASURES RESEARCH AND THE ORIGINS OF THE SPECIAL IMMUNIZATIONS PROGRAM Research involving hazardous pathogens has been a component of the U.S. military scientific enterprise for many years. In 1941, Secretary of War Henry L. Stimson suggested that a program be initiated to investigate “the present situa - tion and future possibilities” of both offensive and defensive biological warfare (biowarfare) (Covert 2000). In 1942, President Roosevelt authorized Secretary Stimson to establish a civilian agency to take the lead on all aspects of the bio - warfare effort. The War Research Service (WRS), under George W. Merck, in the civilian Federal Security Agency was tasked to begin development of the U.S. biowarfare program with both offensive and defensive objectives. WRS organized a research and development (R&D) program in the Department of War and requested that the Army assume responsibility for the large-scale R&D program in November 1942. Construction and operation of laboratories and pilot plants at Camp Detrick (now Fort Detrick), in Frederick, MD, began in April 1943 (Covert 2000).1 The risk to scientists, laboratory technicians, and other staff from exposure to high-risk pathogens was recognized during the planning of the R&D pro - gram, as discussed in greater detail in Section 2.4. Arnold G. Wedum joined the U.S. biowarfare program in 1946 and served as the director of industrial health 1 In addition to Cutting Edge: A History of Fort Detrick, Maryland, 4th Edition (Covert 2000), information on the history of Fort Detrick and on the historical offensive and defensive U.S. biological weapons programs may be found in Medical Aspects of Chemical and Biological Warfare (U.S. Department of the Army 1997) and Medical Aspects of Biological Warfare (U.S. Department of the Army 2007). 21

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22 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH and safety at Fort Detrick until 1972. Pathogen research conducted at Fort Detrick during the period of the offensive biowarfare program often involved high concentrations of microorganisms, aerosol challenge experiments involv - ing laboratory animals, and pilot production of high-risk pathogens and toxins. Those operations placed laboratory workers at substantial risk for exposure and disease, particularly because the availability of treatments, including antibiotics and antiviral drugs, was severely limited at the time. Beginning in the 1950s, the United States operated a parallel program at Fort Detrick that conducted re - search on defensive measures against biological weapons (bioweapons) (Rusnak et al. 2004c). The United States maintained its offensive bioweapons program from 1943 to 1969, when it was discontinued under President Nixon; the de - fensive research program continued. The Special Immunizations Program (SIP) at Fort Detrick began as an immunization program to provide an additional measure of protection of labo - ratory workers against occupational infections. A Special Procedures Section performed medical examinations on personnel assigned to work in the bio- warfare sections, saved blood samples—which also allowed the detection of asymptomatic infections, and maintained records. In 1962, the Special Proce - dures Section became the SIP. Both licensed and investigational vaccines were used as part of the overall safety program to protect Fort Detrick personnel. Immunization of laboratory workers was mandatory,2 and the use of investiga- tional vaccines was considered essential for occupational safety when licensed vaccines were not available. The occupational health and safety of laboratory workers had the highest priority in the Fort Detrick industrial health and safety program, and proce - dures were implemented to support the biological safety (biosafety) goals. An - nual medical examinations were provided for all Fort Detrick employees, and immunizations were provided for all laboratory personnel. The serum storage and collection program conducted annual serologic testing to detect serocon - version. Every infection was treated as laboratory-acquired until proved other- wise. All medical treatment and hospitalization were provided at no expense to infected workers. Reporting of exposures was encouraged and was not subject to disciplinary action. An active disease surveillance program provided a quick response to exposures that enabled both immediate medical care and the op - 2 Use of investigational vaccines in the SIP was considered outside Army Regulation AR 70-25, Use of Volunteers as Subjects of Research (U.S. Department of the Army 1990). That regulation, initially formulated in 1962 and last revised in 1990, states that voluntary informed consent is nec - essary in administering an investigational product to a human subject in the conduct of a research study. Additional information on the use of human subjects in Army research can be found in Chapter 24 of Medical Aspects of Biological Warfare, “Ethical and Legal Dilemmas in Biodefense Research” (U.S. Department of the Army 2007).

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23 HISTORY OF SPECIAL IMMUNIZATIONS portunity to assess the causes and effects of incidents, and it modeled corrective actions that were needed to prevent recurrence of incidents. 3 Over time, the SIP extended the use of its investigational vaccines to labo - ratory workers involved in biological defense (biodefense) research projects throughout the United States and Canada at 117 external sites. In 1972, federal regulation of biologics was transferred to the Food and Drug Administration (FDA), and in 1987 a memorandum of understanding (MOU) between the Department of Defense (DOD) and FDA that allowed the exempt use of in- vestigational biologics in the SIP or Force Health Protection Program ended. 4 Shortly thereafter, the SIP underwent marked change. Beginning in 1997, the SIP was required to adhere to FDA current Good Clinical Practice guidelines (cGCP); this requirement led to compliance with FDA-mandated cGCP and current Good Manufacturing Practice (cGMP). The maintenance of multiple extramural vaccination locations was discon- tinued in 1999 when these sites could no longer meet the rigorous regulatory requirements necessary for monitoring investigational vaccines. In 2000, FDA placed the SIP tularemia and Q fever vaccination protocols on clinical hold until reports on their use in 1963–1998 were submitted and their safety and immunogenicity data analyzed. During that time, 11 tularemia and nine Q fever protocols were reviewed, and new protocols were written for seven of the SIP vaccines (Boudreau 2010). 2.2 THE HISTORY OF VACCINE PRODUCTION FOR THE SPECIAL IMMUNIZATIONS PROGRAM 2.2.1 Origin and Evolution of the Salk Institute’s Government Services Division The Salk Institute’s Government Services Division (GSD) was the site of process development and manufacture of most of the vaccines now used in the SIP. In 1897, Richard M. Slee established Pocono Biological Laboratories in 3 The data collected by the SIP have also been used to study the long-term health outcomes of participants receiving investigational vaccines (for example, Pittman et al. 2004, 2005a,b). 4 An MOU was established in 1964 between DOD and the Department of Health, Education, and Welfare (now the Department of Health and Human Services, which houses the National Institutes of Health). The MOU was updated in 1974 and again in 1987 (52 Federal Register 33472-33474, September 3, 1987, “Memorandum of Understanding Between the Food and Drug Administration and the Department of Defense, Concerning Investigational Use of Drugs, Antibiotics, Biologics, and Medical Devices by the Department of Defense”). The MOU established in 1987 between FDA and DOD states that “DOD has been able to carry out effectively its responsibilities for national security without compromising the intent of the above-cited statutes and regulations; and that certain exemptions, relieving the DOD from the need to meet the ordinary requirements of the Investigation New Drug (IND) and Investigational Device Exemption (IDE) regulations are no longer necessary” (52 Fed. Reg. 33473 [1987], emphasis added).

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24 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH Swiftwater, PA, to manufacture and distribute smallpox vaccine. That decision was influenced by his work with George Sternberg (surgeon general of the Army in 1893–1902 and a pioneer in infectious diseases) and his studies at the Pasteur Institute in France. In 1930, the National Drug Company, a Division of Richardson-Merrell Inc. of Philadelphia, purchased the Swiftwater facility; in 1950, the Vick Chemical Co. purchased the property. The Swiftwater facility was subsequently donated to the Salk Institute in California, and part of the facility was then purchased by the Canadian firm of Connaught Laboratories Ltd. on January 3, 1978. However, the GSD, which had been built and operated by the Merrell National Laboratories of the National Drug Company to that point, was retained by the Salk Institute. The buildings were later acquired by sanofi pasteur (and its predecessor companies), which acquired Connaught in 1989 and now owns and operates the Swiftwater facility (Widmer 2000, sanofi pasteur 2010). The Salk Institute continued to operate the GSD facility at Swiftwater, however, until the GSD’s closure in 1998. 2.2.2 Relationship of the U.S. Army with the Salk Institute A 1991 report from the General Accounting Office (GAO; now the Gov - ernment Accountability Office) examined details of the Army’s relationship with the Salk Institute (GAO 1991). The U.S. Army issued a request for pro - posal to Merrell National Laboratories in March 1977 for a 5-year contract to research techniques for making vaccines against biological agents and to conduct other vaccine production research. Because Merrell had the only facil - ity capable of making vaccines that were not commercially available and had received similar Army contracts since 1960, the Army decided that the pro - posed contract should be a sole-source contract. However, before the request for proposal’s closing date, Merrell informed the Army that it was donating its Swiftwater facility, where the work would be performed, to the Salk Institute. According to Army contract officials (GAO 1991), Merrell had given the Army the opportunity to purchase the Swiftwater facility, but the Army had declined. Salk sold the commercial biological manufacturing operations at the Swiftwater facility to Connaught Laboratories, but retained a laboratory building where Merrell’s Army work had been conducted and established the GSD as a sepa - rate nonprofit entity to operate the facility. In October 1977, Salk submitted a proposal in response to the Army’s solicitation. The proposal was accepted, and Salk was awarded a 5-year contract that was effective on January 1, 1978. Salk later received two additional 5-year contracts from the Army to operate the Swiftwater facility. The three multiyear contracts awarded to Salk as part of the Biological Defense Research Program (BDRP) by the U.S. Army Medical Research and Development Command (USAMRDC; now USAMRMC) were valued at $75.4 million. Under those contracts, Salk was “to develop, produce, and test biological vaccines and to produce other biological products such as

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25 HISTORY OF SPECIAL IMMUNIZATIONS cell cultures and diagnostic reagents” (GAO 1991: 2). Salk’s 15-year contract period with the Army for biologics production thus ran from January 1978 through September 1993. Vaccines in storage in 1991 at the Salk Institute are indicated in Table 2.1. Salk produced most of these vaccines; some were pro - duced by Merrell. According to the 1991 GAO report, the Army considered Salk’s GSD vaccine production facility “a vital part” of the BDRP. Major General Philip K. Russell, the commander of the USAMRDC in 1989, stated that Salk was “a national resource” and “was vital to the defense of the United States and its allies against potential biowarfare weapons” (GAO 1991: 9). At the time of the 1991 GAO report, the Army’s in-house capabilities were not sufficient to meet its demand for vaccines to counter biowarfare agents (GAO 1991). The report stated, however, that some Army officials had told GAO that the Army could improve and expand its in-house capabilities to meet its needs, and GAO’s analysis agreed with this. At that time, the Walter Reed Army Institute of Research (WRAIR) was remodeling a facility to meet FDA requirements for producing human vaccines. The facility, now called the Pilot Bioproduction Facility (PBF), was constructed to produce small cGMP- compliant lots of infectious disease vaccines for use in clinical trials. However, to develop and produce vaccines to protect against biowarfare threat agents, the WRAIR facility would have needed to be upgraded to the biosafety level 3 (BSL-3) containment level available at the Salk facility. WRAIR officials stated that after such improvements, their facility could produce sufficient quanti - ties of attenuated virus vaccines to meet Army requirements (GAO 1991). TABLE 2.1 Dates of Manufacture of Vaccines in Storage at the Salk Institute in 1991 Vaccine Dates of Manufacture Tularemia 1962, 1964, and 1985 Q fever, phase 1, inactivated 1970 Q fever, chloroform and methanol residue, inactivated 1988 Chikungunya, live, attenuated 1985 Junin candidate I, live, attenuated 1988 and 1989 Rift Valley fever, live, attenuated 1988 Smallpox (TSI vaccinia strain) 1990 and 1991 Rift Valley fever, inactivated 1978, 1979, and 1989 Hepatitis A 1990 Venezuelan equine encephalitis, TC83, live, attenuated 1968, 1970, 1971, and 1972 Eastern equine encephalitis, inactivated 1969, 1970, and 1989 Western equine encephalitis, inactivated 1981 Venezuelan equine encephalitis, C84, inactivated 1980 and 1981 SOURCE: GAO 1991.

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26 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH The PBF remains in operation but was not upgraded to BSL-3 and remains at BSL-2 capability (WRAIR 2010). In the 1990s, the Army did renovate two laboratory suites at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) to meet FDA’s requirements for the production of bulk botulinum toxoids. This facility was operated by Salk under its Army contract. In addition, the Army had established an agreement with the National Institutes of Health (NIH) to reimburse it for the renovation and operation of a wing of an NIH-owned drug production facility that was contractor-operated. That facility would be used by NIH’s contractor to produce bulk anthrax vaccine. The bulk botulinum toxoid and anthrax vaccine produced by USAMRIID and NIH facilities were then shipped to a commercial supplier (the Michigan De - partment of Public Health) to be tested, processed into individual doses, and packaged. Those actions were taken by the Army to increase botulinum toxoid and anthrax vaccine production capabilities for Operation Desert Shield and Operation Desert Storm (GAO 1991). 2.2.3 Closing of the Salk Institute Government Services Division In the late 1990s, the Salk Institute GSD ceased operations at its Swift- water, PA facility. Although the laboratory at its peak in the early 1990s had employed a staff of 110 to study and develop vaccines for the U.S. Army, it came under criticism for using $14 million of government money for research on vaccine production for pathogens that were not validated biowarfare threat agents. This research included work on Chikungunya, Junin, and Rift Valley fever viruses (GAO 1991). Following the 1991 GAO report, funding lines were separated for biodefense and infectious diseases. In 1996, Salk lost its sole-source contract to develop vaccines, and in 1998, the Army awarded its biodefense vaccine contract to DynPort Vaccine Company; in September 1998, it was announced that the Salk GSD facility would be closed. DynPort manages countermeasures R&D through contractual mechanisms, including advanced development of a recombinant plague vaccine and a recombinant botulinum toxin vaccine, both originally developed at USAMRIID, but it does not main - tain laboratory facilities of its own (DVC LLC 2011). Stocks of the vaccines produced by Salk under Investigational New Drug (IND) authority were later transferred to the control of DOD’s Chemical Biological Medical Systems, and these stocks remain the primary source of investigational vaccines used in the SIP. With the closure of the Salk facility, no new stocks of those vaccines have been produced, and options for the production of new IND vaccines that might be added to the SIP remain limited. These issues are explored in more detail in Chapter 5. Table 2.2 presents key events in the history of the SIP through 2000. More recent developments and the current operation of the SIP are described in Chapter 3.

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27 HISTORY OF SPECIAL IMMUNIZATIONS TABLE 2.2 Milestones in the History of the SIP, 1940s–1990s Decade Important Events 1940s Opening of biological warfare laboratories at Fort Detrick Establishment of Fort Detrick industrial health and safety program Operation of Special Procedures Section 1950s Continuation of offensive and defensive bioweapons research 1960s SIP vaccination expanded to multiple external sites Merrell facility in Swiftwater produces vaccines under Army contract U.S. offensive bioweapons research ends (1969), but defensive research continues 1970s Swiftwater facility donated to Salk Institute Salk Institute GSD in Swiftwater produces vaccines under Army contract 1980s DOD–FDA MOU allowing exempt use of investigational vaccines ends 1990s SIP vaccination at external sites ends Salk contract with Army ends Salk GSD closes Army vaccine contract established with DynPort 2.3 THE ROLE OF IMMUNIZATION IN RESEARCH WITH HAZARDOUS PATHOGENS AND LESSONS LEARNED 2.3.1 Laboratory Risk of Infection by Select Agents, Emerging Disease-Causing Pathogens, and Other Hazardous Pathogens History suggests that often the first case of a laboratory-associated infection (LAI) is associated with the discovery and isolation of the causative agent of an emerging infectious disease, and infections are also a risk during the period of follow-on research involving animal experimentation and larger volumes of the pathogen. Exposure to materials that may contain infectious pathogens is the principal laboratory risk posed to workers who handle the materials or who work in laboratories where research with infectious pathogens is conducted. Even when containment procedures and appropriate microbiological practices are followed, occasional breaches can raise the risk of LAIs to a high level in research involving hazardous pathogens such as Select Agents. The transmission of potentially high-risk agents in a biocontainment labo - ratory will most likely occur through direct routes, such as accidental percuta - neous inoculation. Research involving animals and sharp instruments (such as syringes and needles) creates some of the most hazardous conditions. Exposure through respiratory, mucosal, and oral routes, such as in accidents or in the conduct of procedures that generate aerosols, also poses significant risks for laboratory workers. The potential for aerosol formation may be particularly

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28 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH important to consider, and may be less obvious to detect that incidents such as needlesticks or animal scratches. BMBL notes, “procedures and equipment used routinely for handling infectious agents in laboratories, such as pipetting, blenders, non-self contained centrifuges, sonicators and vortex mixers are proven sources of aerosols” (CDC/NIH 2009: 14). The first recorded LAIs with a number of pathogens that are classified today as Select Agents include, for example, • Burkholderia mallei (glanders) in 1898—syringe or needle exposure (Riesman 1898). • Vibrio cholerae (cholera) in 1894—pipette exposure (Kisskalt 1915). • Brucella spp. (brucellosis) in 1897—syringe or needle exposure (Birt and Lamb 1899; Meyer and Eddie 1941). Tables 2.3 and 2.4 provide information on the sources of exposure and types of accidents associated with laboratory infections from the 19th century to 1974. 2.3.2 Biosafety and the Role of Vaccines in Protecting Laboratory Workers Biosafety is the laboratory discipline that seeks to ensure the safe handling and containment of infectious pathogens and other hazardous biological mate - rials. The objective of biosafety is to reduce or eliminate exposure of laboratory workers, other persons, and the outside environment to potentially hazardous pathogens and toxins. A risk assessment of the hazardous characteristics of TABLE 2.3 Sources of Exposure for 3,921 Laboratory-Associated Infections from the End of the 19th Century Through 1974, Listed by Percentage of Total Source No. % Worked with agent 827 21.1 Unknown or not indicated 767 19.6 Accidents 703 17.9 Animal and ectoparasite 659 16.8 Aerosol 522 13.3 Clinical specimen 287 7.3 Human autopsy 75 1.9 Discarded glassware 46 1.2 Intentional infection 19 0.5 Other 16 0.4 Total 3,921 100 SOURCE: Adapted from Pike 1976.

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29 HISTORY OF SPECIAL IMMUNIZATIONS TABLE 2.4 Laboratory-Associated Infections Resulting from Various Types of Accidents from the End of the 19th Century Through 1974 Type of Accident No. % Needle or syringe exposure 177 25.2 Spill or spray exposure 188 26.7 Sharps injuries 112 15.9 Pipetting by mouth 92 13.1 Animal bite or scratch 95 13.5 Other 3 0.4 Not indicated 36 5.1 Total 703 99.9 SOURCE: Pike 1976. the infectious pathogens and toxins and the protocols that investigators carry out in the conduct of their research also determine the extent of laboratory containment that is used. The basic concepts and principles that define biosafety as a laboratory discipline were developed at the U.S. Army Biological Research Laboratories at Fort Detrick during the period 1943–1969 under the leadership of Arnold G. Wedum, director of Industrial Health and Safety. Dr. Wedum developed a risk assessment paradigm for identifying exposure and infection risks associ - ated with a proposed research protocol and for selecting control measures that would provide for the safe handling of high-risk pathogens and toxins in the Fort Detrick biodefense program (Wedum et al. 1972). The paradigm described the basic elements of a risk assessment, which included • The number and severity of reported LAIs. • Infective dose for humans. • Potential for exposure to infectious pathogens and toxins in conduct - ing protocols (for example, aerosols and contact with contaminated surfaces) or operating equipment (for example, needle stick exposure). • Results of studies to determine the number of microorganisms released into the air during common laboratory techniques. • Infection of cagemates by inoculated animals. • Excretion of the infectious agent in urine, feces, or saliva of inoculated animals. • Hazards peculiar to the animal species. • Increased susceptibility by gender. • Availability and use of specific therapy or effective vaccines.

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30 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH The infective dose of a bacterial or viral pathogen that can cause disease by inhalation is typically small. For example, the inhalation of about 10 mi - croorganisms of Francisella tularensis or Coxiella burnetii can cause disease in humans (Hornick et al. 1966). The Fort Detrick industrial health and safety program developed the foun - dation on which the principles of biosafety that protect laboratory workers, the environment, and the public from exposure to infectious microorganisms that are handled and stored in the laboratory are based: risk assessment, standard microbiological practices, containment, and facility safeguards. The technical proficiency of laboratory workers in using safe microbiological practices and biocontainment equipment and good habits that sustain excellence in the per- formance of those practices have also become important elements of the risk assessment paradigm (CDC/NIH 2009). 2.3.3 Incidents of Laboratory-Associated Infections and the Utility of Prophylactic Immunizations for Researchers: Experience from Fort Detrick and the Centers for Disease Control and Prevention Several analyses of laboratory exposures and infections have been under- taken that draw on the wealth of data available at USAMRIID and through the SIP. A review of the period 1943–1969 encompasses the Fort Detrick biowarfare program, during which workers handled concentrated samples of pathogens and conducted aerosol experiments, procedures that placed them at relatively higher risk of exposure. This period also overlaps with improvements in biosafety practices, such as the introduction of biosafety cabinets (BSCs) in 1950, and with the introduction of several investigational vaccines (Rusnak et al. 2004b). A decrease in anthrax cases was observed after 1946, attributed at least in part to the use of long-sleeved gowns and taped gloves. While 23 cases of cutaneous anthrax occurred in 1944 and 1945, two cases occurred during 1948–1952 after the change in biosafety practice. These biosafety measures were not fully protective, however, and a fatal case of inhalational anthrax oc - curred in 1951. Only three cases were observed during the 18 years from 1952 to 1969, following introduction of the anthrax vaccine. The authors also note that changes in biosafety practices and the introduction of BSCs contributed to a reduction in infections with Burkholderia mallei, for which a vaccine was not available. On the other hand, laboratory infections with Francisella tularensis continued after the introduction of BSCs and despite the use of the partially protective Foshay vaccine, with an average of 15 infections per year occurring during 1953–1959. Laboratory infections declined significantly, however, after the introduction of a live tularemia vaccine in 1959. Similarly, the introduction of BSCs reduced but was not sufficient to eliminate infections with Coxiella burnetii (Q fever) and with Venezuelan equine encephalitis (VEE) virus, which

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31 HISTORY OF SPECIAL IMMUNIZATIONS continued at an average of 3.4 cases per year and 1.9 cases per year, respective - ly.5 As with tularemia, the number of cases declined further after introduction of the Q fever vaccine in 1965 and the VEE TC-83 vaccine in 1963 (Rusnak et al. 2004b). As a result, the authors conclude, “most laboratory-acquired infections from agents with higher infective doses (e.g., anthrax, glanders, and plague) were prevented with personal protective measures and safety training alone. Safety measures (including BSCs) without vaccination failed to suffi - ciently prevent illness from agents with lower infective doses in this high-risk research setting” (Rusnak et al. 2004b). Biosafety practices and engineering controls have continued to advance since 1969, and an analysis of USAMRIID laboratory exposures and infections was also undertaken for the period 1989–2002, during which biodefense re - search continued to be conducted (Rusnak et al. 2004a). During this period, 234 individuals were evaluated for potential exposures to 289 pathogens; five infec - tions occurred—with Burkholderia mallei, Coxiella burnetii, vaccinia virus, VEE virus, and Chikungunya virus. Potential exposures largely occurred by aerosol or percutaneous routes, with 19% of the exposures occurring while working with animals; needlesticks continued to occur at a rate of approximately 1.7 per year. The 182 potential exposures to bacterial and rickettsial pathogens largely involved Bacillus anthracis (123 exposures), Yersinia pestis (23), and Coxiella burnetii (10), with smaller numbers of exposures to Burkholderia spp., Brucella spp., and F. tularensis. The 107 potential exposures to viral pathogens involved a larger number of viruses, with the most common potential exposures being to VEE virus (21), Rift Valley fever virus (20), and Hantavirus (11). Most of the individuals evaluated for potential exposure were vaccinated (where licensed or investigational vaccines were available), but vaccination breakthroughs did occasionally occur, for example, in the cases of C. burnetii, VEE, and vaccinia infections. In addition to biosafety practices and immunizations, USAMRIID also administered post-exposure prophylaxis where this was determined to be warranted based on risk assessments. Of note, the infection with C. burnetii re- portedly occurred in a researcher working with high concentrations of pathogen in the context of a leaking BSC (Rusnak et al. 2004a). The bioweapons and medical countermeasures research programs con- ducted at Fort Detrick have substantially advanced the community’s knowledge about the safe conduct of research with highly hazardous pathogens and have documented the value of offering immunization to those working with such pathogens. As discussed above, significant decreases in cases of LAI were often observed following the introduction of immunization or the introduction of a 5 Dataon yearly rates of infection with C. burnetii and VEE viruses were not available for the period before BSCs were introduced in 1950.

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32 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH more immunogenic vaccine, particularly in the cases of pathogens with low infective doses. For example (Rusnak et al. 2004c), • F. tularensis: “The most notable decrease in infections was seen after vaccination was begun against tularemia. The rates of typhoidal tulare- mia decreased from 5.7 cases to 0.27 cases per 1000 at-risk employees with the introduction of NDBR 101 live, attenuated tularemia vaccine in the 1960s.” • C. burnetii: “From 1943 to 1965, Q fever was the third most frequent disease seen (55 cases diagnosed between 1950–1965). Only 1 con- firmed case of Q fever has been diagnosed since use of the vaccine in 1965.” • VEE: “During the 13 years from 1950–1962, 39 cases of VEE were diagnosed, versus only 4 suspected or proven breakthrough infections in the 7 years after the use of the vaccine (1963–1969) and only 1 case from 1989 to 2002 (14 years).“ The role of vaccines in preventing laboratory infections is also vividly demonstrated by the case of yellow fever. Between the isolation of yellow fever virus in 1927 and availability of a vaccine against this highly lethal disease in 1931, there were 32 LAIs (5 fatal) among laboratory workers. The routine use of vaccines for protection of laboratory workers completely obviated this problem (Sawyer 1932). The Fort Detrick experience in immunizing workers with investigational vaccines for high-risk pathogens and toxins is indicated in Table 2.5 (years 1943–1969). Data of relevance to laboratory infections have also been compiled by the CDC for years 2003–2009 based on reporting of “loss” and “release” informa - tion. According to guidance issued by the CDC and the Animal and Plant Health Inspection Service, loss is defined as “failure to account for select agent or toxin” while release is defined as “a discharge of a select agent or toxin out- side the primary containment barrier due to a failure in the containment system, an accidental spill, occupational exposure, or a theft. Any incident that results in the activation of a post-exposure medical surveillance/prophylaxis protocol should be reported as a release” (CDC/APHIS 2008). Dr. Richard Henkel of the CDC Division of Select Agents and Toxins (DSAT) told the committee that the DSAT received 395 reports of releases of Select Agents between 2003 and 2009. Seven reports informed the DSAT of the occurrence of LAIs: four with B. melitensis, two with F. tularensis, and one with an unspecified Coccidioides species. The CDC will publish an in-depth analysis of these events. Table 2.6 provides information based on surveys from 1930 to 2009 on the number of reported LAIs that were caused by infectious pathogens that are now regulated as Select Agents. In addition to these reviews, the commit-

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33 HISTORY OF SPECIAL IMMUNIZATIONS TABLE 2.5 Fort Detrick Experience in Immunizing Workers with Investigational Vaccines Against High-Risk Pathogens and Toxins, 1943–1969 Years Assessmenta Investigational Vaccine Administered Anthrax whole-cell vaccine 1944–1951 Limited to no protection; changes in practices provided protection Brucella early vaccine 1943–1952 No protection candidates BSCsb were available in 1950; practices Cell-free anthrax antigen 1952–1969 vaccine and BSCs provided protection; vaccination recommended for protocols with high potential for aerosolization Phenolized tularemia vaccine 1945–1959 Ameliorated symptoms of disease; did not (Foshay vaccine) prevent infection after exposure; cases continued to occur after introduction of BSCs in 1950c Live tularemia vaccine 1959–1969 Immediate decrease in infections; use of BSCs provided limited protection, perhaps related to work with lyophilized culturesc Q fever vaccine 1965–1969 Vaccination prevented infections; BSCs provided limited protection from 1950 to 1965c Early VEE vaccine candidates 1950–1962 No protective benefits Live VEE TC-83 vaccine 1963–1969 Provided potential protection; BSCs provided limited protectionc Bivalent botulinum AB 1944–1959 Provided potential protection toxoid Pentavalent botulinum 1959–1969 Provided potential protection ABCDE toxoid SOURCES: Wedum 1996; Rusnak et al. 2004b. aMeasures such as decreases in observed numbers of LAIs are taken as indicative of potential protection. b BSCs were first introduced at USAMRIID under Dr. Wedum. The several classes of BSCs (I, II, III) offer various degrees of biological containment through directed airflow, filters, and other technologies and thus are suitable for safe laboratory work with different types of organisms. cProbable cause of limited protection associated with BCSs was failure to maintain user technical proficiency. tee examined the reports of several recent incidents of pathogen exposures in laboratory workers: • As referenced above, a laboratory worker at USAMRIID became in- fected in 2000 with Burkholderia mallei and contracted glanders; a vaccine against B. mallei is not available. The case investigation noted

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34 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH TABLE 2.6 Laboratory-Associated Infections with Pathogens Now Classified as Select Agents Period of LAI Report 1930–19781,2,3 1979–20044 2005–20095 Select Agents Viruses Cercopithecine herpesvirus 21 10 Crimean-Congo hemorrhagic fever 8 EEE 4 Ebola 1 4 Lassa 2 1 Marburg 25 2 Monkeypox Hemorrhagic fever viruses 368 9 Flexal Guanarito Junin 21 1 Machupo 1 1 Sabia 2 Central European encephalitis Far Eastern encephalitis Kyasanur Forest disease 133 Omsk hemorrhagic fever 5 4 Russian spring and summer encephalitis 8 Hendra Nipah 66 Rift Valley fever 47 Venezuelan equine encephalitis 146 1 Bacteria Coccidioides speciesa 93 1 1(?) 280 177 Coxiella burnetii 225 3 1 Francisella tularensis 181 10 Rickettsia prowazekii 72 Rickettsia rickettsii 40 1 Bacillus anthracis Brucella spp. 426 143 3 B. abortus 3 B. melitensis B. suis 3 Burkholderia mallei Burkholderia pseudomallei SOURCES: 1Pike 1978; 2Pike 1979; 3Leifer et al. 1970; 4Harding and Byers 2006; CDC, unpub- lished material, Nov. 2010; 6Paweska et al. 2008. aCoccidioides immitis and Coccidioides posadasii were only recently defined as separate species based on genomic analysis.

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35 HISTORY OF SPECIAL IMMUNIZATIONS that the worker did not consistently follow appropriate biosafety and laboratory procedures and was likely exposed while handling labora - tory equipment without gloves (CDC 2000). • In 2002, an unvaccinated laboratory worker in Texas contracted cuta - neous anthrax. The exposure likely occurred by handling a sample vial without gloves; the vial had not been cleaned with household bleach (sodium hypochlorite) and its lid contained Bacillus anthracis spores. Other personnel in the laboratory were also working with B. anthracis while unvaccinated (CDC 2002a,b). • In 2005, three laboratory workers at Boston University contracted tularemia (one confirmed and two probable cases). The laboratory was working with the live, attenuated vaccine strain of Francisella tularen- sis, but the exposure may have occurred during routine lab procedures as a result of the stock being contaminated with a virulent wild-type strain. Inconsistent adherence to biosafety procedures may also have contributed to the exposure (Barry 2005). • In 2006, a laboratory worker at Texas A&M University was infected with Brucella. The likely route of exposure was ocular during a proce- dure to clean an aerosol test chamber. That same year, three laboratory workers were also exposed to Coxiella burnetii as measured by serum antibodies, although they did not develop clinical illness (GAO 2007, Kaiser 2007). • Two cases of infection with Brucella melitensis in 2006 were reported from clinical laboratories in Indiana and Minnesota. 146 workers at both labs were reportedly exposed due to a practice of handling un - identified isolates on open benchtops (CDC 2008a). The CDC re- ported the potential exposures of multiple clinical laboratory workers to attenuated Brucella abortus in 2007. Although no cases of infection were reported, the exposures again occurred due to laboratory han- dling practices. A vaccine against Brucella spp. is not available in the United Stats (CDC 2008c). • Multiple cases of laboratory-associated exposures and infections to vaccinia virus have been reported. The CDC reviewed 5 cases of laboratory exposures to vaccinia (2005–2007, occurring in Connecti - cut, Iowa, Maryland, Pennsylvania, and New Hampshire), primarily associated with needlestick injuries. Three of the researchers were unvaccinated, one had received vaccination 10 years prior, and one had received an unsuccessful vaccination.6 A case of vaccinia virus in- fection in an unvaccinated laboratory worker in Virginia was reported in 2008. The CDC’s Advisory Committee on Immunization Practices recommends that workers handling non-highly-attenuated orthopox 6 As judged by failure of a lesion to form at the vaccination site (CDC 2008b).

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36 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH viruses, including vaccinia virus, receive immunization every 10 years with the licensed vaccine (CDC 2008b, 2009). • In 2009, an unvaccinated laboratory worker at USAMRIID became infected with Francisella tularensis. In this case, the worker had con- tracted an unrelated case of tularemia in 1992 and positive serum titers had suggested that she retained a level of immunity (NRC 2010). • Also in 2009, a fatal case of plague due to an attenuated strain of Yer- sinia pestis was reported in a laboratory worker, the first known fatal case of laboratory-acquired plague in the United States. Although the strain was attenuated, the researcher had potentially complicating health factors. The route of exposure to the pathogen was unclear, although inconsistent glove wearing while handling bacterial cultures may have contributed (CDC 2011b). Summary information regarding the numbers of Select Agent loss and re - lease reports is presented in Table 2.7. The types and numbers of Select Agents in the loss and release reports are presented in Table 2.8. As observed in Table 2.7, reports of Select Agent releases increased from 2003 to 2009. The committee noted that that may be attributable, at least in TABLE 2.7 Select Agent and Toxin Potential Loss and Release Reports in the United States, 2003–2009 Year of Report No. Loss Reports No. Release Reports 2003 3 0 2004 8 8 2005 12 9 2006 6 21 2007 5 52 2008 15 113 2009 17 192 Total 66 395 SOURCE: CDC, unpublished material, Nov. 2010. TABLE 2.8 Type and Number of Pathogens and Toxins Noted in Reports of Potential Loss and Release, 2003–2009 No. Reports of No. Reports of Type Potential Loss Potential Release Toxins 8 21 Fungi 2 30 Bacteria 50 303 Rickettsia 4 17 Viruses 10 51 Total agents (reports) 74 (66) 422 (395) SOURCE: CDC, unpublished material, Nov. 2010.

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37 HISTORY OF SPECIAL IMMUNIZATIONS part, to the broad definition of a release event and to the expansion in Select Agent research since 2001. Tables 2.9 and 2.10, respectively, present the types of laboratory events that resulted in the reported loss or release of Select Agents. Even in regulated research environments where hazardous pathogens and toxins are handled, the tables demonstrate that errors still occur and such incidents as failure of the primary containment system, spills, and sharps injuries can potentially expose personnel to infectious agents. Those data demonstrate that although incidents of LAI have decreased markedly as biosafety procedures have improved, risk has not been reduced to zero and some infections continue to occur. Other reviews have also noted that the risks of laboratory exposures and LAIs have been reduced but not eliminated (Kimman et al. 2008; Jahrling et al. 2009) and a recent analysis observed that the use of some forms of personal protective equipment and containment systems reduces worker dexterity (Sawyer et al. 2007). Despite training and precautions, accidents such as needlesticks, animal scratches, and broken equipment will occasionally happen, and may result in breaches of personal protective equipment or containment systems. As demonstrated TABLE 2.9 Activity Resulting in Potential Loss Events, 2003–2009 No. Potential Loss Activity Events Inventory discrepancy 35 Sample lost or discarded 12 Shipment or transportation issue 19 Total loss events 66 SOURCE: CDC, unpublished material, Nov. 2010. TABLE 2.10 Activity Resulting in Potential Release Events, 2003–2009 No. Potential Release Activity Events Animal bite or scratch 11 Needlestick or sharps injury 46 Equipment mechanical failure 23 Personal protective equipment failure 12 Loss of containment 196 Procedural issue 30 Spill 77 Total release events 395 SOURCE: CDC, unpublished material, Nov. 2010.

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38 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH by several of the cases noted above, workers may also fail to rigorously follow biosafety procedures. The standard practices employed by a particular research or clinical laboratory may potentially expose workers as well. As a recent NRC committee noted, “human actions are probably the weakest link in biosafety” (NRC 2010: 34). It has been noted that there is a level of risk associated with any high- containment laboratory. As the numbers of BSL-3 and -4 laboratories have expanded and the numbers of researchers working with hazardous pathogens such as Select Agents have increased, concerns have been raised that this expan- sion translates to an increased potential number of exposures and LAIs (GAO 2007). The same report also notes a disincentive to report exposure incidents due to scrutiny from funding agencies and concerns about public perception. The publicity surrounding the 2006 exposures of researchers at Texas A&M University to Brucella and to C. burnetii and subsequent CDC investigation pro- vide some context for these discussions and again demonstrate that exposures to pathogens may occur even in settings with highly trained and experienced personnel. A recent discussion of biosafety has noted the difficulty in trying to evalu - ate the effectiveness of various forms of biosafety practice, observing that “the regulations do not exactly specify the level of protection that they aim to af- ford, for example, in terms of diminishing exposure of the laboratory workers below a threshold level of infectivity. Furthermore, it is clear that the physical containment classes 1 to 4 afford increasing levels of containment, but it is not sufficiently clear and scientifically supported to what extent they provide effec - tive protection with regard to prevention of infection of laboratory personnel, prevention of airborne escape, etc.” (Kimman et al. 2008: 421). In this context, it is also difficult to clearly separate the role of immunization in preventing or reducing laboratory infections from the roles played by personal protective equipment or physical containment. However, the historical reviews of LAIs and recent examples of laboratory exposures to pathogens indicate to the committee that immunization has played a role in reducing LAIs, particularly for pathogens having low infective doses where BSCs alone are insufficient. Researchers working with pathogens such VEE virus, Brucella melitensis, Bru- cella abortus, Francisella tularensis, and Coxiella burnetii may be particularly vulnerable. Additional experience demonstrating the utility of vaccination in reducing LAIs comes from the National Institute for Occupational Safety and Health, which operates the national hepatitis surveillance program that is used to esti - mate the number of hepatitis B virus (HBV) infections in health-care workers. The program estimated that 800 health-care workers became infected with HBV in 1995—a 95% decline from the 17,000 new infections estimated in 1983. That result was considered to be due to the federal requirement for the immunization of health-care workers with the hepatitis B vaccine and the use

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39 HISTORY OF SPECIAL IMMUNIZATIONS of standard precautions and other measures required by the Occupational Safety and Health Administration bloodborne pathogens standard (29 CFR § 1910.1030) (NIOSH 1999). In sum, the Fort Detrick experience, the data provided by DSAT, and re- views of recent laboratory incidents demonstrate that exposures to infectious pathogens, and LAIs, can occur even in the most highly regulated research environments where high-risk pathogens, such as Select Agents, are handled. Although the data indicate substantial progress in biosafety since the 19th century, the committee concluded that immunization remains a valuable and necessary additional safeguard in the practice of safe science. 2.4 LESSONS LEARNED FROM THE FORT DETRICK OCCUPATIONAL HEALTH AND SAFETY PROGRAMS A variety of important lessons learned from these experiences have helped to shape the field of biosafety and safe laboratory practice: • When a pathogen or toxin that may cause disease is studied in the laboratory, it is logical to expect that sooner or later some laboratory worker will become infected with it. • Class III BSC systems can operate without LAIs in whole-body and head-only aerosol studies that use repetitive procedures with stable, well-trained, and well-disciplined workers. • Research using repetitive procedures is less hazardous than research requiring frequent changes in technique and equipment. • Pathogens with low infective doses (such as F. tularensis, VEE, C. burnetii, and B. melitensis) increase the risk of infection from aerosol exposures. • In the absence of effective immunization, it is not possible to do basic research using Class I BSCs with a highly infective pathogen without LAIs. As a result of advances in biosafety equipment, research with highly infective pathogens is conducted with other types of BSCs (e.g., Class II and Class III BSCs). • Analysis of disease surveillance data and lessons learned can provide guidance for making improvements in safe laboratory practices, re - search protocols, and the use of containment equipment. • Current biodefense research to satisfy FDA requirements under the animal rule for product licensure (discussed further in Section 4.2.3) will require frequent animal inoculation and aerosol experiments to test the efficacy of biodefense vaccines and other medical counter- measures. That research will probably present an increased risk of exposure of laboratory workers.

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40 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH TABLE 2.11 BMBL Recommendations for the Use of Investigational Vaccines for the Immunization of Laboratory Workers Who Handle High- Risk Pathogens and Toxins Agent Vaccine Recommendation Botulinum toxin Pentavalent Vaccination is recommended for all personnel (ABCDE) working in direct contact with cultures of botulinum neurotoxin-producing Clostridium species or toxoid IND stock solutions of botulinum neurotoxin; IND (Investigational vaccine is available through CDC New Drug) vaccine Eastern equine IND vaccines may Use of these IND vaccines should be carefully encephalitis, Venezuelan be available in considered and based on risk assessment; equine encephalitis, limited quantities Reference is made to the possible availability and Western equine for each of these from the SIP at USAMRIID encephalitis viruses viruses Not available at this timea Rift Valley fever virus Two vaccines under development Central European Vaccine is Use of this vaccine should be carefully availablec tickborne encephalitis considered if it is available and use is based virusesb on risk assessment; the efficacy of this vaccine against Russian spring–summer encephalitis virusb infections has not been established, but is probable based on published data Q fever Q fever vaccine Use of the Q fever vaccine should be restricted to laboratory workers who are at high risk of exposure and who have no demonstrated sensitivity to Q fever antigen. Reference is made to the possible availability from the SIP at USAMRIIDd Other infectious agents Licensed vaccines Commercial vaccines should be made available to workers to provide protection against the risk posed by occupational exposure to an infectious agent they will handlee SOURCE: CDC/NIH 2009. aOne vaccine (live, attenuated) is available in the SIP IND program; the other is in clinical trial (National Institutes of Health Clinical Trials, ClinicalTrialsFeeds.org at http://clinicaltrialsfeeds. org/clinical-trials/show/NCT00869713). bA group of closely related tickborne viruses reclassified from BSL-4 containment to BSL-3 containment, provided that workers are immunized. The reclassified viruses include Absettarov, Hanzalova, Hypr, and Kumlinge. Russian spring and summer encephalitis virus is now known as Far Eastern tick-borne encephalitis virus. cNot currently available in the United States. dA skin test is administered prior to Q fever vaccination to assess reaction to the Q fever antigen and to reduce adverse event. Use of Q fever vaccine is currently limited by skin test availability. eLicensed vaccines against smallpox and yellow fever are available; the committee noted that research involving these pathogens should be performed only by vaccinated individuals.

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41 HISTORY OF SPECIAL IMMUNIZATIONS CDC and NIH have incorporated concepts learned from the Fort Detrick experience and risk assessment paradigm in the writing of all five editions of Biosafety in Microbiological and Biomedical Laboratories (BMBL), which was first published in 1984. The BMBL 5th edition, published in December 2009, emphasizes evaluating the technical proficiency of laboratory workers in per- forming laboratory protocols as a major issue in conducting a risk assessment. Table 2.11 includes the specific recommendations found in the BMBL 5th edi- tion for the use of investigational vaccines for the immunization of laboratory workers who handle high-risk pathogens and toxins (CDC/NIH 2009). 2.5 FINDINGS ON LABORATORY INFECTIONS From its review of the early history of the SIP and data on experience with laboratory infections caused by hazardous pathogens, the committee found the following: • Finding 1: The Special Immunizations Program has played an impor- tant role in offering additional protection to laboratory workers who are involved in U.S. biodefense research. The lessons that have been learned through the program have advanced the practice of biosafety. • Finding 2: Despite advances in other components of biosafety, immu- nization remains an integral component of an occupational health and safety program for people who work with highly hazardous pathogens.

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