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Pages 64-99

The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
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From page 64...
... population at risk of severe adverse events from replicating smallpox vaccine. Public Health Nursing 34(3)
From page 65...
... 2024b. Product classification: Variola virus nucleic acid-based detection assay.
From page 66...
... 2023. mRNA vaccines encoding fusion proteins of monkeypox virus antigens protect mice from vaccinia virus challenge.
From page 67...
... Presentation at Meeting 2 of the Committee on Current State of Research, Development, and Stockpiling of Smallpox MCMs of the National Academies. December 1.
From page 68...
... 2015. Safety and immunogenicity of modified vaccinia Ankara-Bavarian Nordic smallpox vaccine in vaccinia-naive and experienced human immu nodeficiency virus-infected individuals: An open-label, controlled clinical phase II trial.
From page 69...
... State of Alaska Epidemiology Bulletin, February 9. https://epi.alaska.gov/bul letins/docs/b2024_02.pdf (accessed February 22, 2024)
From page 70...
... 2013. Unintentional transfer of vaccinia virus associated with smallpox vaccines: ACAM2000® compared with Dryvax®.
From page 71...
... 2015. Cardiac safety of modified vaccinia Ankara for vaccination against smallpox in a young, healthy study population.
From page 73...
... The effectiveness of smallpox MCMs (whether diagnostics, vaccines, or therapeutics) as agents of risk reduction rests on numerous factors, from a working knowledge of smallpox biology and epidemiology to the risks and benefits of emerging science and technology to myriad operational planning decisions.
From page 74...
... EVOLVING BIOTHREAT LANDSCAPE As noted by the World Health Organization (WHO) Advisory Committee on Variola Virus Research (ACVVR)
From page 75...
... . It has long been known that accidental or deliberate outbreaks remain possible due to existing and allowed viral collections, and even natural outbreaks are at least theoretically possible if there is viable virus in, for example, thawing permafrost, but recent advances in synthetic biology technology now mean that the variola virus or another microbe that could cause smallpox-like illness could be recreated in a laboratory even if all known collections of variola virus were to be verifiably destroyed (Jaschke et al., 2019; Levrier et al., 2023; Noyce et al., 2018; Reardon, 2014, Thi Nhu Thao et al., 2020; WHO, 2015)
From page 76...
... . Vaccinia, the prototype poxvirus and basis of modern smallpox vaccines, is also a member of the orthopoxvirus genus and has occasionally caused disease in humans following vaccination.
From page 77...
... However, the committee recognizes the theoretical potential for spillover of other poxviruses to occur from animal reservoirs and cause disease in humans. The orthopoxvirus genus comprises many of the mammalian viruses and consists of 13 species, including variola virus -- which is unique in its
From page 78...
... Orthopoxvirus Pathogenesis in Humans Variety across the orthopoxvirus genus, the adaptation of variola virus to a single host (i.e., humans) , and its exceptional virulence together imply the presence of a complex set of mechanisms of pathogenesis as well as a complex relationship between host and pathogen which is poorly understood.
From page 79...
... Understanding Immune Evasion and Species Tropism Understanding immune evasion and species tropism allows for a better understanding of viral pathogenesis and might lead to the development of additional therapeutic options. Knowledge of the features of human tropism of variola virus might also produce insights into the potential for "natural" (or unnatural)
From page 80...
... . Early mRNAs encode many immunoregulatory proteins, intermediate transcription factors, and DNA replication enzymes/factors.
From page 81...
... , which targets a protein that is vital for MV envelopment into EV and required for cell-to-cell spreading. Antiviral agents developed to date work by interrupting viral DNA replication (cidofovir and brincidofovir)
From page 82...
... For instance, science has not identified the receptors used for poxvirus entry, and it is possible that poxviruses use an unconventional entry mechanism. In addition, there are many outstanding questions regarding DNA replication, transcription, virion assembly, envelope morphogenesis, and egress.
From page 83...
... Yet, considerable gaps remain in understanding variola virus to inform improved MCM development as well as in current understanding of other orthopoxviruses with one or more mammalian reservoir hosts that can infect humans (Moss and Smith, 2021)
From page 84...
... Basic poxvirus research is beneficial to smallpox MCM development and contributes to readiness against other known and potential novel orthopoxviruses affecting hu mans. General advances in developing orthopoxviruses as vaccine vectors, gene delivery, and oncolytic virotherapy can have multiple benefits, includ ing enhancing smallpox MCMs.
From page 85...
... and entry mechanisms, DNA replication mechanism, virion assembly, and egress. • High-resolution imagery of virion structures and structures at various stages of viral replication.
From page 86...
... The exact extent of the risk entailed by keeping live virus and the effectiveness of various efforts to mitigate these risks are challenging to assess, while the potential benefits of research using live virus at the current time are easier to quantify. Potential Risks of Technological Advancements on MCM Readiness Synthetic Biology and Gene Editing Advancements in the fields of synthetic biology and reverse genomics have shown that infectious viruses (e.g., horsepox virus and SARS-CoV-2)
From page 87...
... criminal code has stated ever since that it is "unlawful for any person to knowingly produce, engineer, synthesize, acquire, transfer directly or indirectly, receive, possess, import, export, or use, or possess and threaten to use, variola virus" (with an exception for work conducted "by, or under the authority of" the HHS secretary) .2 The law goes on to define variola virus as the virus itself or any derivative that contains more than 85 percent of the gene sequence of the variola major or variola minor virus.
From page 88...
... However, the impacts of AI-based tools on pox virus research and planning may be limited by the number of available poxvirus genome
From page 89...
... Such possibilities seem likely to become more material throughout the 2020s, emphasizing that now is the time to develop robust, resilient, and agile approaches for protecting against malicious or inadvertent future smallpox outbreaks. Genome Sequencing Advances in genomic sequencing and computational molecular biology have afforded an improved understanding of the genetic relatedness and evolutionary history of orthopox viruses, though gaps remain.
From page 90...
... The COVID-19 pandemic and the mpox outbreak spurred significant research and development efforts for vaccines, biologics, therapeutics, and diagnostic tools. Lessons learned from these experiences can inform the evaluation of smallpox MCMs and illustrate the potential value of investing in innovative technologies.
From page 91...
... The potential exists to synthesize the complete or partial variola virus genome and to manufacture infectious viral particles based on published genomes. Targeted modifications to the genome are also possible, which could alter functional components of the virus that could affect transmissi bility or virulence.
From page 92...
... Strategic National Stockpile (SNS) , these products have never been deployed in response to an actual smallpox outbreak so it is unknown how well the system will perform, to what extent smallpox MCMs will reach intended end users, and how frontline responders and laboratories will manage the influx of smallpox cases.
From page 93...
... Advances in the use of poxviruses as vaccine vectors, for gene delivery, and as oncolytic virotherapy might also bring benefits for enhancing smallpox MCMs, and these might also attract commercial resources and therefore enhance the smallpox response capability. In 2012, HHS established the Centers for Innovation in Advanced Development and Manufacturing (CIADM)
From page 94...
... Understanding the dynamic interplay between vaccine and treatment access and acceptance will be important for modeling uptake scenarios for smallpox MCMs. While the nature and amounts of MCMs procured and stockpiled influence national infectious disease preparedness, comprehensive readiness necessitates a whole-of-society approach.
From page 95...
... One study assessed health care provider willingness in 2002 to receive pre-event smallpox vaccination; 73 percent were willing, and the most common reason cited for those who did not want the vaccine was concern over adverse events (Everett et al., 2003)
From page 96...
... . Variables that might affect uptake will include individual- and populationlevel willingness to receive vaccine; the level of risk messaged to the public; whether the vaccine is being administered pre- or post-exposure; the level of tolerance for vaccine side effects (especially because there are known severe adverse events of replicating smallpox vaccine)
From page 97...
... . The wealth of studies on these dynamics can inform smallpox planning efforts and improve understanding about the: • root causes of MCM hesitancy and how to evaluate and implement strategies to address hesitancy and how vaccine hesitancy relates to therapeutic hesitancy, • role of transparency and science literacy in building trust in advance, • role of avoiding or mitigating financial conflicts of interest in re search on MCM development and production (IOM, 2009a)
From page 98...
... . Clinical guidance for smallpox MCMs would need to be communicated to frontline providers.
From page 99...
... . This guidance should be updated to reflect new data on smallpox vaccines -- especially data about use for prevention of mpox and its efficacy -- and clinical guidelines for indications and use of smallpox therapeutics should be developed.


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