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1
Introduction
T
hroughout history, humankind has been plagued by a number of
deadly diseases. Smallpox, perhaps the most devastating of these,
has always been greatly feared (Morens et al., 2008). The earliest
description of smallpox as a distinct clinical syndrome emerged in fourth-
century CE China, but earlier records hint at its presence in Europe before
then (Damon, 2006). Its causative agent, variola virus, has adapted in
unique ways to its only known host species—humans.
After centuries of recurring smallpox epidemics that swept through
human populations worldwide, impacted the course of history, and killed
more than 500 million people, Edward Jenner reported in 1798 that inocu-
lation with related viruses, obtained from either cows or horses, conferred
immunity to smallpox (Jenner, 1798). More than 150 years later, with
this critical tool in hand, the World Health Organization (WHO) in 1959
embarked on an ambitious plan to control and eventually eradicate the
disease. In 1977, the last known naturally occurring case of smallpox was
recorded in Somalia, and the following year an accidental laboratory-
associated infection became the last known case of the disease. In 1979, a
commission of health experts certified that natural transmission of smallpox
had ceased, and WHO endorsed the declaration a year later in 1980. This
final eradication of smallpox represents a monumental event in the history
of medicine and public health, and smallpox remains the only intentionally
eradicated disease of humankind (Fenner et al., 1998; Tucker, 2001).
Since the eradication of smallpox, the global public health community,
acting through the World Health Assembly (WHA), has debated the issue
of whether stocks of the live variola virus should be retained. In 1983, the
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0 LIVE VARIOLA VIRUS
number of centers authorized to house and perform research with the live
virus was limited to two—the Centers for Disease Control and Prevention
(CDC) in the United States and the Research Institute for Viral Prepara-
tions in Moscow, Russia. In 1994, the Russian stocks were transferred to
the State Centre for Research of Virology and Biotechnology (VECTOR)
in Novosibirsk (Fenner et al., 1998; Tucker, 2001).
In 1996, the WHO ad hoc Committee on Orthopoxvirus Infections
recommended final destruction of the live variola virus stocks at both
research centers, and WHA subsequently set the termination date for 1999.
However, the decision to destroy the virus was postponed that year in light
of increasing public health and biosecurity concerns, and was ultimately
deferred by WHA to assess the potential for continued scientific needs
for the live virus (Smallpox Preservation Advisable, 1999; WHO, 1999).
In that same year, the Institute of Medicine (IOM) released a consensus
report identifying key areas for further scientific research that required the
use of live variola virus (IOM, 1999). The conclusions from that report are
presented in Box 1-1.
Ten years have passed since the 1999 IOM report was issued, and
much has since transpired that is relevant to the question of the utility
of research using live variola virus. These developments include advances
in science and biotechnology, incidents involving bioterrorism, increased
investment in research and development on countermeasures, changes in
the regulatory approval process, and the reinstitution of smallpox vaccina-
tion among civilian and military populations in the United States. Since
1999, WHO has convened a standing Advisory Committee on Variola
Virus Research, which has met annually since 1999 and which monitors
the state of research in key areas at the two WHO Collaborating Centers
for Smallpox and Other Poxviruses. (The reports of the committee’s meet-
ings are available through the WHO website.) This committee reports its
findings at the annual meetings of WHA, which is the ultimate decision-
making body of WHO; these meetings are attended by delegations from all
of the WHO member states. WHA has agreed to revisit the issue of variola
virus destruction in 2010. In this context, it is important to re-assess the
conclusions of the 1999 IOM report and to review the progress that has
been made over the last decade.
OVERVIEW OF SCIENTIFIC NEEDS FOR LIVE VARIOLA VIRUS
Despite the successful eradication of smallpox 30 years ago, concerns
remain about the potential for its reemergence. While a natural outbreak
appears unlikely, the threat of intentional reintroduction or accidental
release exists. In addition, the emergence of human disease due to monkey-
pox (another member of the Orthopoxvirus genus), including its 2003
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INTRODUCTION
BOX 1-1
Conclusions from the 1999 Institute of Medicine Report
In 1998–1999, the IOM convened a committee to evaluate the scientific needs
for continued retention of live variola virus. The committee identified one short-
term need and six long-term needs. Specifically, the committee drew the following
conclusions:
• Genomic sequencing and limited study of variola surface proteins derived from
geographically dispersed specimens is an essential foundation for important
future work. Such research could be carried out now, and could require a delay
in the destruction of known stocks, but would not necessitate their indefinite
retention.
• The most compelling reason for long-term retention of live variola virus stocks
is their essential role in the identification and development of antiviral agents
for use in anticipation of a large outbreak of smallpox. It must be emphasized
that if the search for antiviral agents with activity against live variola virus were
to be continued, additional public resources would be needed.
• Adequate stocks of smallpox vaccine must be maintained if research is to be
conducted on variola virus or if maintenance of a smallpox vaccination program
is required. Live variola virus would be necessary if certain approaches to the
development of novel types of smallpox vaccine were pursued.
• If further development of procedures for the environmental detection of variola
virus or for diagnostic purposes were to be pursued, more extensive knowl-
edge of the genome variability, predicted protein sequences, virion surface
structure, and functionality of variola virus from widely dispersed geographic
sources would be needed.
• The existence of animal models would greatly assist the development and test-
ing of antiviral agents and vaccines, as well as studies of variola pathogenesis.
Such a program could be carried out only with live variola virus.
• Live or replication-defective variola virus would be needed if studies of variola
pathogenesis were to be undertaken to provide information about the response
of the human immune system.
• Variola virus proteins have potential as reagents in studies of human immunol-
ogy. Live variola virus would be needed for this purpose only until sufficient
variola isolates had been cloned and sequenced.
SOURCE: IOM, 1999, pp. 82–85.
introduction into the western hemisphere, highlights the importance of
research into prevention of orthopoxvirus infection and disease (Reed et al.,
2004; Sale et al., 2006; Rimoin et al., 2007; Dubois and Slifka, 2008).
At the same time, tools to control potential smallpox outbreaks remain
imperfect. While smallpox vaccines based on cross-protection provided by
vaccinia-induced immunity are available and are known to be effective from
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LIVE VARIOLA VIRUS
extensive historical experience, there are still concerns regarding their safety.
An estimated 40 percent of those vaccinated with the original and newer,
second-generation vaccinia vaccines experience mild to severe adverse reac-
tions (McCurdy et al., 2004). The development of third-generation vaccines
with the potential to have a much improved safety profile is currently under
way. Additionally, no U.S. Food and Drug Administration (FDA)-approved
therapeutics or validated, rapid, point-of-care diagnostics for smallpox are
available. The lack of these tools would be an obstacle in the event of a
future outbreak of smallpox or other orthopox.
Advances made in the fields of molecular biology and genetics in the
past 10 years could provide important tools to improve understanding
of the structure of variola virus and the functions of its gene products.
Additionally, given variola’s specificity for the human species, studying live
variola virus in cultured human cells in vitro—including both cells that are
targets for initial infection and spread and specialized cells that mediate
the immune response—holds the potential to yield new insights into the
antiviral mechanisms of host cells and the biology of the human immune
system. These findings could provide valuable information not only in the
context of controlling DNA viruses, but also as a means of understanding
basic inflammatory pathways that can protect or damage the host. Such
observations could be extended in appropriate animal models of variola
pathogenesis. Complete chemical resynthesis of the variola genome and
subsequent production of viable intact virions is now scientifically plausible
and technically feasible. This newly emerging and rapidly evolving capabil-
ity has profound implications for both the future threat posed by smallpox
and the future development of smallpox countermeasures.
Box 1-2 summarizes features of the contemporary context in which the
scientific needs for live variola virus must be assessed.
CURRENT STATUS OF VARIOLA VIRUS AND MATERIALS
Because of the biohazard posed by live variola virus, rigorous precau-
tionary measures are essential, including strict regulation of the type of
facility that is approved for storing and conducting experiments with the
virus. Research with live variola virus must be conducted in laboratories
with the highest safety and security rating, designated biosafety level 4
(BSL-4) containment facilities. Although other BSL-4 facilities exist, only
the two noted above in the United States and Russia are authorized by
WHO to perform research with live variola virus under international agree-
ment (WHO, 2008).
WHO oversees all scientific research with live variola virus, and to
ensure the safety of researchers and the security of the virus stocks, periodi-
cally conducts inspections of the authorized research facilities. In addition
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INTRODUCTION
BOX 1-2
Contemporary Context for Assessment of the
Scientific Needs for Live Variola Virus
Smallpox as a bioweapon. Smallpox’s virulence makes it an obvious candidate
for use as a bioweapon. Historical anecdotes, while not confirmed, suggest that
contaminated materials could be used to spread smallpox in target populations.
Both the United States and the Soviet Union have engaged in research aimed at
weaponizing smallpox.
Monkeypox outbreaks. First recognized in humans in 1970, monkeypox is
e
ndemic in central Africa. Periodic outbreaks have occurred in the Democratic
Republic of Congo, with a case fatality rate of 1–10 percent. In addition, the intro-
duction of monkeypox in the United States in 2003 demonstrated the continuing
threat of orthopoxvirus outbreaks.
Immunologically naïve populations. Routine smallpox vaccination ceased in
1980, and earlier in some countries. Almost half the world’s population is currently
immunologically naïve to the disease. At the same time, the rise of diseases such
as HIV/AIDS that weaken the immune system, as well as the prevalence of atopic
dermatitis, would make resumption of routine vaccination difficult.
Lack of proper countermeasures. There are today no licensed therapeutics for
the treatment of smallpox, and currently licensed vaccines, while effective, are
contraindicated for immunocompromised individuals.
Resynthesis of the variola genome. Technological advances have led to new
breakthroughs, including the complete sequencing of multiple strains of variola
virus. The ability to resynthesize viral genomes is well established and may be
possible for variola virus.
to handling of the live virus, work with the genomic components of the
virus is tightly regulated by WHO. Specifically, laboratories other than
CDC and VECTOR cannot possess more than 20 percent of the variola
genome at any time (WHO, 1994).
From its most recent (November 2008) meeting, the WHO Advi-
sory Committee on Variola Virus Research reports that access to the
BSL-4 laboratories at CDC and VECTOR remains highly controlled and
regulated; security procedures are reviewed by WHO, and in the United
States by the U.S. Select Agent Program. CDC has also reported on an
expansion of its BSL-4 facilities, with another laboratory scheduled to be
operational in 2009. Since November 2006, the long-term inventory of
variola virus materials at CDC has remained at 451, and genomes from
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LIVE VARIOLA VIRUS
45 of the 70 working stock isolates have been sequenced. Withdrawals
have been made to support WHO-approved projects. Since 2007, a total
of 200 nonviable or duplicate working stocks at VECTOR have been
destroyed, reducing its collection of variola stocks to 691 registered vials
(WHO, 2008).
REgULATIONS AND OTHER gUIDANCE PERTAININg
TO COUNTERMEASURES FOR SMALLPOX
Since the IOM’s 1999 report was issued, a number of regulations and
other guidance have been promulgated in the United States to guide and
facilitate the development and licensure of additional countermeasures for
the diagnosis, prevention, and therapy of bioterrorism threats, including
smallpox. The most important and directly relevant of these are summa-
rized below:
• Approval of Biological Products When Human Efficacy Studies
Are Not Ethical or Feasible (21 CFR 601 Subpart H, as well as
21 CFR 314 Subpart I for New Drugs). This rule, known as “the
Animal Rule,” was designed to permit approval of drugs and
biologics intended to reduce or prevent serious or life-threatening
conditions caused by exposure to biological, chemical, radiological,
or nuclear substances when human efficacy studies are not ethical
and field trials are not feasible (FDA, 2002a).
• FDA Guidance for Industry—Smallpox (Variola) Infection: Devel-
oping Drugs for Treatment or Prevention (November 2007). This
guidance (FDA, 2007a) outlines the unique challenges of develop-
ing safe and effective antiviral agents for the treatment and/or pro-
phylaxis of smallpox. These challenges include the exceptionally
narrow host range of variola virus, the lack of a previously recog-
nized effective therapeutic agent, and the lack of human diseases
that can be considered closely analogous to smallpox.
• The Project BioShield Act of 00 (Public Law 108–276). This
act establishes a comprehensive Emergency Use Authorization
(EUA) program that enables the emergency use of medical products
against biological, chemical, radiological, and nuclear attacks, real
or potential, for both civilian and military personnel. Under this
program, the FDA Commissioner can approve the emergency use
of drugs, vaccines, medical devices, and diagnostics not previously
approved for a particular purpose (FDA, 2007b).
• The Public Readiness and Emergency Preparedness Act of 00
(Public Law 109–148) provides immunity from liability claims aris-
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INTRODUCTION
ing from the administration and use of countermeasures covered
under EUA.
• The Public Health Security and Bioterrorism Preparedness and
Response Act of 00 (the “Bioterrorism Act,” June 12, 2002)
(FDA, 2002b). This act states that the “prompt approval of safe and
effective new drugs and other therapies is critical to the improve-
ment of the public health.”
The European Union—primarily through the European Medicines
Agency (EMEA), which is responsible for the scientific evaluation of appli-
cations for European marketing authorization (licensure) of medicinal
products in the European Community—has also focused on the threat
of bioterrorism in accordance with Article 57(q) of Regulation (EC) No.
726/2004. This article states that the EMEA shall, with a view to protection
of the public health, compile “scientific information concerning pathogenic
agents which might be used in biological warfare, including the existence of
vaccines and other medicinal products available to prevent, or to treat, the
effects of such agents.” EMEA produced a guidance document in 2002 on
the use of available medicinal products for the treatment and prophylaxis of
biological agents that might be used as weapons of bioterrorism (European
Agency for the Evaluation of Medicinal Products, 2002a). Note for Guid-
ance on the Development of Vaccinia-Based Vaccines Against Smallpox
applies to the development and manufacture of second-generation vaccinia
vaccines produced in embryonated eggs or tissue culture (European Agency
for the Evaluation of Medicinal Products, 2002b).
Finally, in 2003 WHO updated its Recommendations [formerly known
as Requirements] for the Production and Quality Control of Smallpox Vac-
cine, which had last been revised in 1965 (WHO, 2004). The document
acknowledges that global resumption of the production of smallpox vaccine
would benefit from modern approaches to production and control, and that
present-day regulatory expectations should be met in the licensing process.
In addition, the document encourages the development of contemporary
international reference materials as guidance for determining the potency of
new vaccines and their immunogenicity in vaccinated individuals.
STUDy CHARgE AND APPROACH
In anticipation of the WHA meeting in 2010, CDC requested that the
IOM convene a committee to conduct a study on the continued use of live
variola virus stocks for research and public health purposes. The charge to
the committee is presented in Box 1-3.
To address this charge, the IOM convened a committee of experts from
both the United States and abroad. Experts in the field of orthopoxvirology
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LIVE VARIOLA VIRUS
BOX 1-3
Charge to the Committee
An ad hoc committee of the Institute of Medicine shall conduct a study on the
continued use of live variola virus stocks for research and public health purposes.
In follow-on to the IOM’s 1999 report, Assessment of Future Scientific Needs for
Live Variola Virus, an IOM committee will perform a comprehensive evaluation of
the research and development work recommended in that report and completed to
date, and consider what unmet needs still exist that require the use of live variola
virus. The conclusions and recommendations will inform policy discussions in
the United States and within the world community regarding the continued need
to retain the official stocks of live variola virus for research purposes, and would
provide a major review of completed, ongoing and planned research activities that
should be undertaken.
The committee shall specifically consider and offer recommendations perti-
nent to the utility of live variola virus in addressing potential unmet requirements
including:
• Advanced development through licensure and post-licensure of antivirals for
use in treatment of variola virus infections.
• Advanced development through licensure and post-licensure of new, safe and
effective vaccine(s).
• Development through licensure and post-licensure of less-reactogenic
vaccines.
• Development of approved protein-based diagnostics which can be used in
field situations or diagnostics which have sources of error distinct from those
of nucleic acid-based diagnostics.
• Improved pathogenesis data to drive therapeutic discovery.
were consulted, as well as those with expertise in vaccine, antiviral, and
diagnostic development; public health; biosecurity; federal government
regulation; and bioethics. The committee held two open workshops to
gather information from experts and researchers in the salient fields. A
comprehensive search of the scientific literature published on variola and
other poxviruses was undertaken, and key literature was assessed. The
committee also made inquiries to WHO, CDC, and VECTOR regarding
research undertaken outside of the United States that might not be readily
accessible in the scientific literature.
It is important to note that the committee was charged with assessing
scientific needs that require live variola virus. In evaluating unmet needs,
the committee recognized the risks of such research and the critical impor-
tance of providing independent oversight and essential resources, including
BSL-4 facilities when research with live variola virus is undertaken. Com-
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INTRODUCTION
menting on retention or destruction of the live variola virus stocks was not
within its scope.
ORgANIzATION OF THE REPORT
The first four chapters of this report provide context for the question
of the scientific needs for live variola virus. Following this introductory
chapter, Chapter 2 presents an overview of smallpox and its surveillance
and control. Chapter 3 examines variola virus in the context of poxvirology
and variola’s similarities with and differences from other orthopoxviruses.
Chapter 4 reviews the state of the art with regard to animal models of the
pathogenesis and immunobiology of variola and other poxviruses.
Chapters 5 through 9 review variola-related research completed since
the 1999 IOM report was issued, with emphasis on the role of the live
virus in advancing scientific breakthroughs. These chapters also address
any unmet or future needs in applications of the research, in terms of both
medical countermeasures and any additional knowledge that could poten-
tially be gleaned from studying live variola virus. Research in the following
areas is examined in turn: genomic analysis (Chapter 5), development of
therapeutics (Chapter 6), development of vaccines (Chapter 7), detection
of variola and diagnosis of smallpox (Chapter 8), and scientific discovery
(Chapter 9). The final chapter presents the committee’s conclusions and
recommendations.
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