Source: https://b-ok.org/book/1198420/21595e
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Document Index: 33106420

Matched Legal Cases: ['art 73', 'art 121', '§ 72', 'art 732', 'art 331', 'art 121', 'arts 72', 'art\n331', 'art 121']

Protecting the Frontline in Biodefense Research: The Special Immunizations Program | Committee on Special Immunizations Program for Laboratory Personnel Engaged in Research on Countermeasures for Select Agents and National Research Council | download
Main Protecting the Frontline in Biodefense Research: The Special Immunizations Program
Committee on Special Immunizations Program for Laboratory Personnel Engaged in Research on Countermeasures for Select Agents and National Research Council
ISBN 10: 0309209242
ISBN 13: 9780309209243
PROTECTING THE FRONTLINE IN
Committee on Special Immunizations Program for Laboratory Personnel
Engaged in Research on Countermeasures for Select Agents
THE NATIONAL ACADEMIES PRESSâ•† 500 Fifth Street NWâ•† Washington, DC 20001
This project was supported by Contract HHSP23320042509XI (Task Order
HHSP23337007T) between the National Academy of Sciences and the Department of
Health and Human Services. The content of this publication does not necessarily reflect
the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the
Fifth Street NW, Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 3343313 (in the Washington metropolitan area); Internet, http://www.nap.edu.
COMMITTEE ON SPECIAL IMMUNIZATIONS PROGRAM
FOR LABORATORY PERSONNEL ENGAGED IN RESEARCH
ON COUNTERMEASURES FOR SELECT AGENTS
DONALD S. BURKE (Chair), Dean, Graduate School of Public Health;
UPMC-Jonas Salk Chair in Global Health; Associate Vice Chancellor for
Global Health; and Director, Center for Vaccine Research, University of
W. EMMETT BARKLEY, President, Proven Practices, Bethesda, Maryland
GERARDO CHOWELL, Assistant Professor, School of Human Evolution
and Social Change, Arizona State University; Research Associate, Fogarty
International Center, U.S. National Institutes of Health, Tempe, Arizona
ALAN S. CROSS, Professor of Medicine, Center for Vaccine Development,
STEPHEN W. DREW, President, Drew Solutions LLC, Summit, New Jersey
Vanderbilt Vaccine Research Program, Vanderbilt University, Nashville,
ROBERT J. HAWLEY, Independent Consultant, Biological Safety,
Biosecurity and Biosurety Issues, Frederick, Maryland1
THOMAS G. KSIAZEK, Professor, Department of Pathology and
Department of Microbiology and Immunology; Director, National
Biodefense Training Center; Senior Staff Scientist and Director,
High Containment Operations Core, Galveston National Laboratory,
THOMAS P. MONATH, Partner, Pandemic and Biodefense Fund, Kleiner
Perkins Caufield and Byers; Adjunct Professor, Harvard School of Public
Health, Cambridge, Massachusetts
Group, Inc., Bethesda, Maryland
HOLLY A. TAYLOR, Assistant Professor, Department of Health Policy and
Management, Bloomberg School of Public Health; Core Faculty, Berman
Institute of Bioethics, Johns Hopkins University, Baltimore, Maryland
THOMAS E. WALTON, Former Associate and Acting Deputy
Administrator for Veterinary Services, Animal and Plant Health
Inspection Service, U.S. Department of Agriculture (retired), Eloy,
1â†œSenior
Advisor, Science, Midwest Research Institute, Frederick, Maryland, until April 2011
ADAM FAGEN, Study Director and Senior Program Officer (until June
KEITH R. YAMAMOTO (Chair), University of California, San Francisco,
SEAN EDDY, Howard Hughes Medical Institute, Janelia Farm Research
Campus, Ashburn, Virginia
DONALD E. GANEM, University of California, San Francisco, California
that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of objectivity,
process. We thank the following individuals for their review of this report:
Arturo Casadevall, Albert Einstein College of Medicine of Yeshiva
release. The review of this report was overseen by Adel Mahmoud, Princeton
University. Appointed by the National Research Council, he was responsible
1.1 The Current Context of Pathogen Research, 9
1.2	Categorization of Pathogens and Management of Pathogen
Research, 10
1.3 Charge to the Committee, 15
1.4 Organization of the Report, 19
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, 21
2.2	The History of Vaccine Production for the Special Immunizations
Program, 23
2.3	The Role of Immunization in Research with Hazardous Pathogens
and Lessons Learned, 27
2.4	Lessons Learned from the Fort Detrick Occupational Health and
2.5 Findings on Laboratory Infections, 41
The U.S. Medical Countermeasures Enterprise and Recent Reviews
and Current Operation of the Special Immunizations Program
3.1 The U.S. Medical Countermeasures Enterprise, 43
3.2 National Biodefense and Medical Countermeasures Priorities, 46
3.3	Review of Previous Reports Relevant to Biodefense Medical
Countermeasures, 48
3.4	Recent Developments Regarding the Special Immunizations Program
(2000–2010), 53
3.5 The Current Special Immunizations Program, 58
3.6	Findings and Conclusions on the Medical Countermeasures
Enterprise and the Current Special Immunizations Program, 73
Regulations and Other Guidance Pertaining to the Development and
Use of Vaccines in the Special Immunization Program
4.1 Overall Regulatory Framework for Vaccines, 78
4.2 Options for U.S. Licensure, 79
4.3	Administration of SIP Vaccines Under an Investigational New Drug
Application, 84
4.4	Other Regulations and Guidance Offering Potential Incentives to the
Developers of SIP Vaccines, 88
4.5 Regulatory Considerations: Looking Toward the Future, 89
4.6	Findings and Conclusions on Regulatory Pathways Applicable to the
SIP, 94
New Vaccine Development and the Future Needs of the Special
5.1 The Process of Vaccine Development, 95
5.2	New Vaccine Development and the Future Needs of the Special
Immunizations Program, 96
5.3	The International Context of the Special Immunizations
Program, 108
5.4 Cooperation with the Veterinary Community, 113
5.5	Findings and Conclusions Related to Future Vaccine Needs in the
Special Immunizations Program, 113
Potential Options for the Special Immunizations Program and for
Personnel Immunization
6.1	Options for the Future of the SIP, 116
6.2	Conclusion on Potential Options for the SIP, 128
7.1 The Role of Vaccines in Protecting Research Workers, 129
7.2	For Which Pathogens Would It Be Highly Desirable to Have a
Vaccine, and Which Pathogens Should Receive Priority
Attention?, 131
7.3	Advantages and Disadvantages of the Use of Investigational Vaccines
as They Have Been Used in the Special Immunizations Program, 132
7.4	Vaccine Development and Supply Within and Beyond the Existing
Special Immunizations Program, 133
7.5	General Observations Regarding the Role of Immunizations in the
Context of Research with Hazardous Pathogens, 134
Medical Research and Materiel Command (USAMRMC). The SIP provides immunizations to laboratory personnel who are at risk of exposure to hazardous
The SIP is designed to augment the protection provided by other components of laboratory biosafety, including best practices, engineering controls,
fever, and tularemia, and licensed vaccines for protection against anthrax, hepatitis B, Japanese encephalitis, rabies, smallpox, and yellow fever.
HSC PCC recommendations regarding the expansion of the SIP, and to consider the larger context of vaccination for researchers who work with potentially
available in the United States or other countries might be considered for inclusion in the SIP. Finally, the committee considered other factors that might
and corresponding recommendations about the SIP and the general role of immunization in the context of hazardous pathogen research in the United States.
The SIP has played a significant historical role in offering additional protection to laboratory workers involved in U.S. biodefense research. The lessons
vaccines, such as those currently offered in the SIP, remain an important component of an overall biosafety program for laboratory workers at risk of exposure to hazardous pathogens.
at-risk laboratory workers and other occupationally exposed personnel working with hazardous pathogens. USAMRMC has the history, personnel, clinic
facilities, protocols, standard operating procedures, and regulatory infrastructure needed to successfully administer, monitor, and document immunizations
priority attention for inclusion in the SIP, a strategic review and systematic assessment on a pathogen-by-pathogen basis should be undertaken
1â†œBiosafety
The IND vaccines currently used in the SIP were developed and manufactured largely in the 1970s and 1980s under standards that would likely be
products that have not been produced for many years, the safety and immunogenicity profiles of some of the vaccines are less than optimal, and immunization under the required Phase II clinical trial protocols places substantial
for whom the benefits of immunization outweigh the risks (as judged by appropriately conducted risk assessments).
and older or outdated products for similar applications should be considered for removal. Products currently licensed for use in other countries,
The committee found that vaccines in the SIP typically have no or extremely limited commercial value, and therefore do not attract the interest of
Recommendation 6: The Food and Drug Administration and other relevant regulatory authorities should explore new administrative and regulatory pathways to facilitate the development and licensure of SIP vaccines.
Europe). U.S. government (HHS, DOD) vaccine production and procurement plans should be designed to take full advantage of the SIP program
The SIP appears to lack a governance structure that enables regular strategic review of the investigational and licensed vaccines included in the program
The committee identified several obstacles faced by civilian biodefense research workers that prevented ready access to SIP vaccines. Paramount among
should consider covering the cost of immunizing at-risk research workers, so that this cost is not borne solely by the institutions working on
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 ensure the safety and well-being of participants through continuous
To collect vaccine safety and immunogenicity data to further medical
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
1â†œAs
discussed in more detail in Chapters 3 and 4, the IND immunizations administered through
the SIP are part of Phase II clinical trials that provide safety and immunogenicity data.
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
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
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
1.1â•‡ 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
2â†œEdward
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
3â†œFor 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).
4â†œIn 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.
1.2â•‡ 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
5â†œUnder
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.
6â†œFurther 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
7â†œSelect
Agents are defined in Title 42, Code of Federal Regulations (CFR) Part 73 for CDC and
9 CFR Part 121 for USDA.
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
[2002]) 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
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
8â†œA few Select Agents that affect both humans and animals are considered overlap agents and
appear on both CDC and APHIS lists.
9â†œPathogens most often considered as posing the greatest human health threats include Bacillus
anthracis (anthrax), Clostridium botulinum toxin, Francisella tularensis (tularemia), Yersinia pestis
(plague), and variola virus (smallpox).
TABLE 1.1â•‡ Select Agents and Toxins
Botulinum neurotoxin–producing species of
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)
(formerly known as Russian spring and
summer encephalitis)
Burkholderia mallei (formerly Pseudomonas
mallei)
Burkholderia pseudomallei (formerly Pseudomonas
Malignant catarrhal fever virus (Alcelaphine
herpesvirus type 1)
Mycoplasma capricolum subspecies
capripneumoniae (contagious caprine
small colony (MmmSC) (contagious bovine
Vesicular stomatitis virus (exotic): Indiana
subtypes VSV-IN2, VSV-IN3
TABLE 1.1â•‡ Continued
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.
1.3â•‡ 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 1.2â•‡ NIAID Category A, B, and C Priority Pathogens
Variola major (smallpox) and
—lymphocytic
(LCM) virus, Junin
virus, Machupo virus,
—Lassa fever virus
—Hantaviruses
—Rift Valley fever virus
—Dengue viruses
—Ebola virus
—Marburg virus
Pathogenic Vibrio spp. (e.g., cholerae)
—Viruses (Caliciviruses, hepatitis A)
—Protozoa
—West Nile
—California encephalitis
—Venezuelan equine encephalitis
—Eastern equine encephalitis
—Western equine encephalitis
—Japanese encephalitis
—Kyasanur Forest disease
TABLE 1.2â•‡ Continued
Emerging infectious disease threats, such as Nipah virus and additional hantaviruses
NIAID priority areas:
—Crimean–Congo hemorrhagic fever viruses
Other Rickettsia species
Severe acute respiratory syndrome–associated coronavirus (SARS-CoV)
Antimicrobial resistance, excluding research on sexually transmitted organisms a
—Research on mechanisms of antimicrobial resistance
—Studies of the emergence and/or spread of antimicrobial resistance genes within pathogen
—Studies of the emergence and/or spread of antimicrobial-resistant pathogens in human
—Research on therapeutic approaches that target resistance mechanisms
—Modification of existing antimicrobials to overcome emergent resistance
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)
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
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:
 hat should the general role of vaccines be in protecting laboratory workers
from effects caused by the materials they work with?
•	Are there specific pathogens that researchers are working with now for which
it would be highly desirable to have a vaccine?
• Which pathogens should receive priority attention?
•	In an expanded program, what would be the advantages and disadvantages
of continuing to use investigational vaccines as they have been used in the
DOD Special Immunizations Program?
•	If expansion of an immunization program is recommended, the committee
should also consider issues of vaccine development and supply within and
beyond the existing SIP.
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.
1.4â•‡ 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.
History of the Special Immunizations
Program and Lessons Learned
from Occupational Immunization
Against Hazardous Pathogens
2.1â•‡ HISTORICAL PATHOGEN AND COUNTERMEASURES
RESEARCH AND THE ORIGINS OF THE
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
1â†œIn 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).
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 involving 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 research 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 defensive research program continued.
The Special Immunizations Program (SIP) at Fort Detrick began as an
immunization program to provide an additional measure of protection of laboratory workers against occupational infections. A Special Procedures Section
performed medical examinations on personnel assigned to work in the biowarfare sections, saved blood samples—which also allowed the detection of
asymptomatic infections, and maintained records. In 1962, the Special Procedures 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 investigational 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 procedures were implemented to support the biological safety (biosafety) goals. Annual 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 seroconversion. Every infection was treated as laboratory-acquired until proved otherwise. 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-
2â†œUse 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 necessary 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).
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 laboratory 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 investigational 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 discontinued 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).
2.2â•‡ THE HISTORY OF VACCINE PRODUCTION FOR
2.2.1â•‡ Origin and Evolution of the Salk Institute’s
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
3â†œThe 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).
4â†œAn 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).
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.
2.2.2â•‡ Relationship of the U.S. Army with the Salk Institute
A 1991 report from the General Accounting Office (GAO; now the Government Accountability Office) examined details of the Army’s relationship
with the Salk Institute (GAO 1991). The U.S. Army issued a request for proposal 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 facility capable of making vaccines that were not commercially available and had
received similar Army contracts since 1960, the Army decided that the proposed 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 separate 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
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 produced 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 cGMPcompliant 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 quantities of attenuated virus vaccines to meet Army requirements (GAO 1991).
TABLE 2.1â•‡ Dates of Manufacture of Vaccines in Storage at the Salk Institute
Q fever, phase 1, inactivated
Q fever, chloroform and methanol residue, inactivated
Chikungunya, live, attenuated
Junin candidate I, live, attenuated
Rift Valley fever, live, attenuated
Smallpox (TSI vaccinia strain)
Rift Valley fever, inactivated
Venezuelan equine encephalitis, TC83, live, attenuated
Eastern equine encephalitis, inactivated
Western equine encephalitis, inactivated
Venezuelan equine encephalitis, C84, inactivated
1962, 1964, and 1985
1978, 1979, and 1989
1968, 1970, 1971, and 1972
1969, 1970, and 1989
SOURCE: GAO 1991.
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 Department 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).
2.2.3â•‡ Closing of the Salk Institute Government Services Division
In the late 1990s, the Salk Institute GSD ceased operations at its Swiftwater, 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 maintain 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
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
TABLE 2.2â•‡ Milestones in the History of the SIP, 1940s–1990s
Opening of biological warfare laboratories at Fort Detrick
Establishment of Fort Detrick industrial health and safety program
Operation of Special Procedures Section
Continuation of offensive and defensive bioweapons research
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
Swiftwater facility donated to Salk Institute
Salk Institute GSD in Swiftwater produces vaccines under Army contract
DOD–FDA MOU allowing exempt use of investigational vaccines ends
SIP vaccination at external sites ends
Salk contract with Army ends
Salk GSD closes
Army vaccine contract established with DynPort
2.3â•‡ THE ROLE OF IMMUNIZATION IN RESEARCH WITH
HAZARDOUS PATHOGENS AND LESSONS LEARNED
2.3.1â•‡ 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 laboratory will most likely occur through direct routes, such as accidental percutaneous 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
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
2.3.2â•‡ 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 materials. 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 2.3â•‡ Sources of Exposure for 3,921
Laboratory-Associated Infections from the End
of the 19th Century Through 1974, Listed by
Worked with agent
Unknown or not indicated
Animal and ectoparasite
SOURCE: Adapted from Pike 1976.
TABLE 2.4â•‡ Laboratory-Associated Infections
Resulting from Various Types of Accidents
from the End of the 19th Century Through
Needle or syringe exposure
Spill or spray exposure
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 associated 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 conducting 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
Hazards peculiar to the animal species.
Increased susceptibility by gender.
Availability and use of specific therapy or effective vaccines.
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 microorganisms 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 foundation 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 performance of those practices have also become important elements of the risk
assessment paradigm (CDC/NIH 2009).
2.3.3â•‡ 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 undertaken 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 occurred 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
continued at an average of 3.4 cases per year and 1.9 cases per year, respectively.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 sufficiently 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 research continued to be conducted (Rusnak et al. 2004a). During this period, 234
individuals were evaluated for potential exposures to 289 pathogens; five infections 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 reportedly 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 conducted 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
5â†œData
on yearly rates of infection with C. burnetii and VEE viruses were not available for the
period before BSCs were introduced in 1950.
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 tularemia decreased from 5.7 cases to 0.27 cases per 1000 at-risk employees
with the introduction of NDBR 101 live, attenuated tularemia vaccine
C. burnetii: “From 1943 to 1965, Q fever was the third most frequent
disease seen (55 cases diagnosed between 1950–1965). Only 1 confirmed case of Q fever has been diagnosed since use of the vaccine in
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” information. 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 outside 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-
TABLE 2.5â•‡ Fort Detrick Experience in Immunizing Workers with
Investigational Vaccines Against High-Risk Pathogens and Toxins, 1943–1969
Anthrax whole-cell vaccine
Limited to no protection; changes in practices
Brucella early vaccine
Cell-free anthrax antigen
BSCsb were available in 1950; practices
and BSCs provided protection; vaccination
recommended for protocols with high potential
for aerosolization
Phenolized tularemia vaccine
(Foshay vaccine)
Ameliorated symptoms of disease; did not
prevent infection after exposure; cases continued
to occur after introduction of BSCs in 1950c
Live tularemia vaccine
Immediate decrease in infections; use of BSCs
provided limited protection, perhaps related to
work with lyophilized culturesc
Vaccination prevented infections; BSCs provided
limited protection from 1950 to 1965c
Early VEE vaccine candidates
No protective benefits
Live VEE TC-83 vaccine
Provided potential protection; BSCs provided
limited protectionc
Bivalent botulinum AB
Provided potential protection
Pentavalent botulinum
ABCDE toxoid
SOURCES: Wedum 1996; Rusnak et al. 2004b.
aMeasures such as decreases in observed numbers of LAIs are taken as indicative of potential
bâ†œBSCs 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
tee examined the reports of several recent incidents of pathogen exposures in
As referenced above, a laboratory worker at USAMRIID became infected in 2000 with Burkholderia mallei and contracted glanders; a
vaccine against B. mallei is not available. The case investigation noted
TABLE 2.6â•‡ Laboratory-Associated Infections with Pathogens Now Classified
as Select Agents
Period of LAI Report
1930–19781,2,3
1979–20044
2005–20095
Far Eastern encephalitis
Coccidioides speciesa
SOURCES: 1Pike 1978; 2Pike 1979; 3Leifer et al. 1970; 4Harding and Byers 2006; CDC, unpublished material, Nov. 2010; 6Paweska et al. 2008.
aCoccidioides immitis and Coccidioides posadasii were only recently defined as separate species
based on genomic analysis.
6â†œAs
that the worker did not consistently follow appropriate biosafety and
laboratory procedures and was likely exposed while handling laboratory equipment without gloves (CDC 2000).
In 2002, an unvaccinated laboratory worker in Texas contracted cutaneous 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 tularensis, 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 procedure 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 unidentified isolates on open benchtops (CDC 2008a). The CDC reported 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 handling 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 Connecticut, 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 infection 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
judged by failure of a lesion to form at the vaccination site (CDC 2008b).
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 contracted 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 Yersinia 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 release 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 2.7â•‡ Select Agent and Toxin Potential Loss and
Release Reports in the United States, 2003–2009
No. Loss Reports
No. Release Reports
SOURCE: CDC, unpublished material, Nov. 2010.
TABLE 2.8â•‡ Type and Number of Pathogens and Toxins
Noted in Reports of Potential Loss and Release, 2003–2009
No. Reports of
Total agents (reports)
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 2.9â•‡ Activity Resulting in Potential Loss Events,
No. Potential Loss
Sample lost or discarded
Shipment or transportation issue
Total loss events
TABLE 2.10â•‡ Activity Resulting in Potential Release Events,
No. Potential Release
Equipment mechanical failure
Personal protective equipment failure
Total release events
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 highcontainment 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 expansion 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 an