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10
Conclusions and Recommendations
T
hirty years have passed since WHO declared smallpox eradicated.
Since then, programs for universal vaccination against smallpox
have ceased worldwide, yielding a growing population of immuno-
logically naïve individuals; U.S. and international regulatory requirements
for licensure of antiviral drugs and vaccines have become better defined;
and technological advances in molecular biology have generated sophisti-
cated tools for research and development, many of which have been applied
to improving knowledge about variola virus. Given that an accidental or
deliberate release of variola virus could have devastating results worldwide,
current global public health preparedness efforts address the potential
threat of a smallpox outbreak. WHO considers any confirmed case of
smallpox to be a public health emergency of international concern, and the
U.S. government classifies this pathogen as a select agent.
This committee was not asked to consider whether live variola virus
stocks should be retained or destroyed or to address the potential for a
smallpox outbreak. Nevertheless, these issues underlie global deliberations
about smallpox, and the development and availability of adequate medical
countermeasures against one of the most virulent and dangerous pathogens
remains a strategic international goal.
Variola is a unique and highly adapted pathogen that has established
a close and obligate relationship with the human species, its only natural
host. While not immediately essential, research that advances understand-
ing of the biology of the human species and its responses to life-threatening
microbial challenges could be highly beneficial. Such research could provide
fundamental insights into human physiology and immunology that would
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LIVE VARIOLA VIRUS
be relevant for biomedical research, leading to new therapies and preven-
tive measures.
Capabilities in DNA synthesis, sequence error correction, and assembly
of custom-designed long DNA molecules have grown exponentially over
the past decade. It is now technically feasible to chemically synthesize and
assemble a complete variola genome in the laboratory, although the subse-
quent steps necessary for production of intact, replication-competent virions
are likely to be challenging. It is uncertain that variola virions generated
from synthetic variola genomes would be virulent for humans, and if so to
what degree. However, fully virulent synthetic variola virus is a distinct pos-
sibility. This disconcerting reality should be acknowledged because it has
major implications for the risks associated with unregulated possession and
genetic manipulation of variola virus. These advances also offer potential
benefits for the future development of variola countermeasures.
In this contemporary context, some research with live variola virus
remains essential for public health preparedness, some would be useful for
this purpose, and some would have significant scientific merit as biomedical
research without an immediate connection to preparedness. All research
with live variola virus requires rigorous scientific evaluation before being
undertaken, proper laboratory safeguards to protect those working with
the virus and the public, and a significant investment in public health
infrastructure and research capacity. Research to develop and improve
diagnostics and preventive and therapeutic countermeasures against small-
pox must also be undertaken with specific attention to regulatory concerns.
While the scientific pathway for development of these diagnostics and
countermeasures may offer a spectrum of options, from ideal to practical,
the absence of human infection presents special challenges for regulatory
approval. Regulatory agencies must evaluate new interventions that are of
potential but unproven value for the prevention and treatment of smallpox
and establish appropriate contingency protocols for their use in the event of
an accidental or intentional release. These interventions may also warrant
evaluation against nonvariola poxvirus infections, such as disseminated
vaccinia or monkeypox disease, under conditions that make standard clini-
cal trials difficult or impossible to accomplish.
CONCLUSIONS
This committee, like its predecessor in 1999, did not consider the risk
assessment or financial resources required to undertake necessary or useful
research, as these issues were beyond its scope. In addition, since decision
making can be based only on information in hand, the committee recog-
nizes that future technological advances or policy considerations based
on assessment of the risk of an accidental or intentional release of variola
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CONCLUSIONS AND RECOMMENDATIONS
virus could alter the scientific landscape. With these caveats, the committee
offers the following conclusions, which are based on its evaluation of cur-
rent scientific capabilities and are meant to address the question of whether
live variola virus would be needed should the recommended research be
undertaken.
Development of Therapeutics
The discovery of antiviral drugs and alternative therapeutic agents
effective against smallpox and their advanced development through licen-
sure and postlicensure is vital. Such agents are needed for the medical man-
agement of variola infection, a critical element in preparedness for a rapid
response to an outbreak. Antiviral agents with good oral bioavailability
that are effective for prophylaxis as well as treatment are important for
containing the spread of smallpox in an immunologically naïve population.
Having more than one licensed therapeutic utilizing multiple mechanisms
of action is desirable because of the potential for the emergence of drug
resistance and unanticipated adverse effects. Even if multiple licensed drugs
were available, there would be gaps in information regarding their safety in
special populations, such as children or pregnant women. If an appropri-
ate clinical context is available, such as a monkeypox outbreak or cases of
eczema vaccinatum, candidate drugs should be assessed in these groups.
The development of licensed therapeutics is a long-term effort. Over
the last decade, substantial progress has been made in the development of
antiviral drugs with potential efficacy against smallpox using surrogate
orthopoxviruses. Live variola virus has been used to measure the activity of
lead candidate drugs in vitro and in nonhuman primate models. Additional
studies are needed to develop useful drugs and immunobiologics through
discovery efforts aimed at identifying variola-specific targets. This under-
taking will require a better understanding of variola-specific proteins and
their functions in cultured cells and of how these gene products contribute
to the pathogenesis of smallpox disease in suitable animal models.
The committee concludes that, for both scientific and regulatory
reasons, the final developmental stages leading to licensure of small-
pox therapeutics cannot occur without the use of live variola virus.
Furthermore, although the regulatory environment may change,
the scientific reasons will remain. Therapeutic agents need to be
evaluated against a representative panel of variola strains to reduce
the possibility that some strains might be naturally resistant.
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LIVE VARIOLA VIRUS
Development of Vaccines
The availability and strategic deployment of an effective vaccine enabled
the eradication of smallpox. Despite the occurrence of adverse reactions,
enough people worldwide were vaccinated and developed immunity suffi-
cient to interrupt transmission. Today, the majority of the world’s popula-
tion is unvaccinated, placing them at risk of life-threatening disease in the
case of a smallpox outbreak. Should an outbreak of smallpox occur, scaling
up immunization programs with the traditional vaccines could be expected
to be effective again. However, vaccine safety would be of particular con-
cern for the substantial number of immunocompromised individuals and
other vulnerable populations.
Since the 1999 IOM report was issued, traditional vaccines such as
Dryvax and the Lister/Elstree vaccine, which were manufactured by being
grown in animals, have been augmented by the production and licensure
of second-generation vaccines using modern tissue culture techniques. For
first- and second-generation vaccines, successful vaccination is manifested
by a “take”—formation of a lesion at the site of inoculation. This method
cannot be used for evaluation of third-generation vaccines, and immuno-
logic correlates of protection cannot be defined in the absence of circulating
variola virus. Evidence that would support likely efficacy can be obtained
only in animal model studies using variola virus. It should be emphasized
that populations for whom the use of first- and second-generation vaccines
would be contraindicated would need to rely on safer third-generation vac-
cines in the event of an outbreak. Some consideration should be given to
methods that could accelerate the pathway to licensure (or at least approved
use) in these populations.
The committee concludes that the current development and licen-
sure pathway for first- and second-generation vaccinia vaccines
that produce a “take” does not require use of the live variola virus.
Use of the live virus will be necessary, however, for the develop-
ment and licensure of any vaccine that does not manifest such a
cutaneous lesion at the site of inoculation.
Development of Methods for Detection and Diagnosis
Contemporary nucleic acid-based methods for viral detection have been
shown to identify variola virus genes directly, and multiplex PCR assays
differentiate variola from other poxviruses and unrelated viruses, such as
varicella-zoster virus, that may cause similar clinical signs. Since tissues
contain inhibitors that may reduce the sensitivity and specificity of nucleic
acid-based methods, the development of these assays is enhanced by the
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CONCLUSIONS AND RECOMMENDATIONS
availability of stored clinical materials and specimens from nonhuman pri-
mates infected with variola virus, but these materials and specimens are not
essential. Whether these methods have been tested with a representative set
of phylogenetically and genetically diverse smallpox isolates is an important
question, but further testing, if needed, does not require the growth of the
live virus from existing stocks.
Protein-based assays have not been pursued as extensively as PCR
methods; however, these methods can be tested using variola proteins made
in expression vectors. Limited information has been published about the
performance of any methods for environmental sampling to detect variola,
but again such assessments do not require live variola virus. Licensing of
these methods can also proceed without experiments using live virus. The
primary barrier to development of these methods is a lack of development
incentives and of a market for products that would allow rapid field detec-
tion and diagnosis.
The committee concludes that live variola virus is not required
for further development of detection and diagnostic methods.
Virus materials such as DNA and proteins would suffice for this
purpose.
genomic Analysis
The past decade has seen advances in genome sequencing and functional
genomics capabilities. As a result, significant progress has been made in
acquiring new variola genome sequence data and in furthering understand-
ing of the evolution of variola. This work has revealed significant sequence
variability among variola strains, some of which is likely to be associated
with virulence. The observed genetic differences between variola and other
orthopoxviruses must be responsible for the specificity of variola virus for
the human host. Variola genomic sequence data may enhance efforts to
develop therapeutics and vaccines that are predicted to be active against
the breadth of available variola strains. Despite the progress in sequencing
variola strains, much remains to be learned about the extent of variola’s
genetic variability. In addition, the biological consequences of sequence dif-
ferences for replication in particular cell types important to pathogenesis
and to host range specificity and virulence are unknown. Today, sequenc-
ing of the genomes of all remaining variola strains to completion would be
relatively straightforward and inexpensive.
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LIVE VARIOLA VIRUS
The committee concludes that live variola virus is not needed for
variola genome sequence analysis, as long as specimens contain-
ing viral DNA of adequate quantity and quality are available.
Live variola virus would be needed for functional genomics-based
experimental approaches.
Discovery Research
Variola virus can be useful for understanding human physiology and
immunology because it has the capacity to overwhelm the host in a way
that few viral pathogens do. Through studies in nonhuman primates, some
progress has been made in understanding how variola virus modulates
the functions of host cells for its benefit and how infection with the virus
progresses in the host. However, current methods for studying variola in
vitro and in vivo are inadequate or have not been fully exploited for the
expeditious discovery of novel interventions, both for smallpox and for
other diseases, that might result from a better understanding of how this
pathogen takes over human cells and subverts the immune response. Further
research is needed to develop improved animal models that can recapitulate
key aspects of the human disease and to understand virus–cell interactions
in human target cells relevant to pathogenesis and immune response.
The committee concludes that discovery research to gain greater
understanding of human physiology and immunology, while not
essential, would require use of the live variola virus and might
ultimately support efforts to discover and evaluate therapeutics and
vaccines. Further, research with live variola virus and research with
variola proteins could lead to discoveries with broader implications
for human health.
RECOMMENDATIONS
Gaps remain in understanding of variola virus and its interaction with
its human host that could be critical in identifying potential targets for the
discovery of therapeutics and vaccines. In particular, better understanding
of the diversity and variability of variola strains would result in more effec-
tive therapeutics and vaccines, as well as more refined diagnostics. Genome
sequencing could close existing knowledge gaps by illuminating differences
among strains in molecular mechanisms of infection and response.
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CONCLUSIONS AND RECOMMENDATIONS
The committee recommends that WHO authorize the complete
genome sequencing of all remaining variola strains, with the aim
of understanding the patterns and extent of sequence variation and
the relationships of these patterns to disease severity. This activity
would be carried out at CDC, and ideally at VECTOR as well.
Similarly, a better understanding of variola pathogenesis would enhance
the development of therapeutics and vaccines. Because smallpox is no longer
naturally occurring, the closest approximation to human infection would
involve a nonhuman primate. A more precise nonhuman primate model
is essential for correct characterization of the efficacy of new therapeutics
and vaccines. It is important to optimize approaches to infecting nonhuman
primates so as to best recapitulate variola pathogenesis as it occurs in the
human host, for example, by testing aerosol or intratracheal delivery as well
as intravenous inoculation.
The committee recommends that a comprehensive evaluation of
the work done to date on the nonhuman primate model of variola
pathogenesis be undertaken by CDC, in conjunction with an expert
panel knowledgeable about poxviruses and animal models of viral
infection. The objective would be to identify ways in which the
predictive value of the model for testing therapeutics and vaccines
might be improved.
Finally, functional genomics tools, which are used to evaluate interac-
tions between a replicating virus and the host cell, should be applied using
a few representative variola strains in a number of representative differenti-
ated human cell types. The purpose of this research would be to identify
novel targets for therapeutics and to design third-generation vaccines.
The committee recommends that WHO explore the use of func-
tional genomics approaches to improve understanding of variola
pathogenesis and advance the development of novel strategies for
therapeutic intervention.
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