Future State of Smallpox Medical Countermeasures (2024) / Chapter Skim
Currently Skimming:
3 Factors Influencing Smallpox Readiness and Response
3 Factors Influencing Smallpox Readiness and Response
Pages 73-116
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
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... ...
. Only two viral species of poxviruses are obligate human pathogens: variola virus (orthopoxvirus genus)
|
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... ...
These knowledge gaps present barriers to the further development of specific and novel antivirals, to the improvement of vaccines, and to reducing complications associated with vaccines and therapies. Orthopoxvirus Evolution and Implications for MCM Utility Orthopoxvirus evolution appears to have been influenced over time by gene loss, fragmentation, and duplication, with subsequent impacts on such features as virus host range and virulence (IOM, 2009b)
|
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... ...
issued guidance in 2010 recommending baseline standards for the gene synthesis industry to ensure compliance with Select Agent Regulations, Export Administration Regulations, and, in general, 1 Federal Select Agent List, https://www.selectagents.gov/sat/list.htm (accessed February 5, 2024)
|
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... ...
hold the promise of significant human benefit, these technologies might also pose potential risks to biosecurity and could increase the likelihood of unsanctioned research to re-create smallpox or a virus resembling smallpox (Kuiken, 2023; White House, 2023)
|
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... ...
Vaccine Hesitancy and Risk Communications While it is outside the scope of the committee's charge to fully deliberate on the sociopolitical and economic factors that might influence stockpile decisions, the committee would like to highlight a few key dynamics that federal and state planners should consider in their decisions about smallpox readiness planning as they relate to downstream operational challenges. Vaccine hesitancy is not a new phenomenon, but the national experience with COVID-19 and mpox demonstrated what vaccine hesitancy can mean for outbreak or pandemic response and how politics, policies, and misinformation can influence vaccine uptake.
|
From page 96... ...
, and learning from previous smallpox vaccine campaigns (IOM, 2005) , could be critical to an effective risk communication response.
|
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 could result in low testing capacity at the beginning of a smallpox outbreak, not unlike the testing experiences at the start of COVID-19 and mpox in the United States. Smallpox is designated as a biosafety level 4 agent, so only a select number of laboratories could safely and securely process smallpox assays during the beginning of an outbreak.
|
From page 100... ...
100 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES BOX 3-3 Opportunities to Strengthen National Laboratory Systems for Smallpox Biosafety • Collaborating with commercial laboratories for specimen transport during public health emergencies.a Test Development • Providing redundancy in the initial test development process using advanced public health laboratories.a Test Manufacturing • Proactively developing government contracts with test manufacturers for supplies.a Stockpiling • Robustly stocking the Strategic National Stockpile with testing kits, test com ponents, and other related supplies.b Testing Capacity • Updating current LRN assays by multiplexing and adapting to high throughput.* • Establishing guidelines to ensure consistency and predictability among tradi tional and nontraditional health care testing settings.b • Striving toward immediate access to validated methods, the ability to rapidly develop methods, and a trained testing workforce.b • Securing federal testing capacity by designating laboratories, medical centers and test manufacturers to respond during outbreaks.c • Establishing emergency funding mechanisms before outbreaks can greatly impact mobilization efforts and testing readiness.c Data Management • Developing a minimum dataset for the test request process and case definition.a • Standardizing laboratory information management systems to ensure data can be shared within the national laboratory system.b Regulatory • Collaborating with FDA to develop a portfolio of pre-vetted test protocols to speed regulatory test approval in an emerging biological crisis.a • Aspiring toward nationwide mandatory reporting requirements to coordinate mitigation efforts.b • Need for federal testing guidelines with enforcement and guidance structures.b • Creating and updating test protocols that are pre-reviewed by FDA could speed regulatory test approvals during public health emergencies.c
|
From page 101... ...
Regulatory Readiness As noted in Chapter 1, access to smallpox MCMs in both domestic and global stockpiles depends considerably on the regulatory status of existing and new MCMs as well as on risk–benefit calculations that must be carried out with incomplete information. As such, these regulatory decisions reflect important scientific, legal, and ethical considerations.
|
From page 102... ...
For instance, novel smallpox MCMs cannot be tested in humans with smallpox because the disease has been eradicated, but the use of MCMs developed for smallpox in the mpox outbreaks provided valuable proxy data indicating that they might have pan-orthopoxvirus applications (Dalton et al., 2023)
|
From page 103... ...
permit to use these in a different way. Such regulatory mechanisms could also enable the use of other products such as the Aventis Pasteur smallpox vaccine (see Chapter 2)
|
From page 104... ...
Relevant Ethical Questions for Smallpox MCMs Basic science research on smallpox may fit the definition of dual use research of concern and therefore receives additional ethical scrutiny (NASEM, 2017)
|
From page 105... ...
But experience with COVID-19 and mpox demonstrated that effective risk communication has been a challenge, especially considering vaccine hesitancy and the politicization of vaccination, and misinformation and disinformation. These same chal lenges could occur in a smallpox outbreak.
|
From page 106... ...
OVERARCHING CONCLUSIONS Based on the evidence and findings on the ongoing utility of orthopoxvirus research more broadly for smallpox readiness and response, on the implications of scientific and technological advancements on available smallpox MCMs, and on operational considerations affecting SNS planning, the committee drew the following overarching conclusions: In addition to smallpox readiness, research should continue to be used to enhance readiness and response for other orthopoxviruses, this includes supporting the validation, approval and licensure, and commercializa tion of existing and next-generation MCMs for use in the management of non-variola orthopoxviruses as an efficient way to expand readi ness more broadly by enabling vendor-managed inventory approaches to stockpiling. A comprehensive and ongoing risk–benefit analysis is needed for smallpox MCMs research using emerging technologies as well as ongoing careful oversight to mitigate the risks of this research and ensure the risk–benefit balance is maintained.
|
From page 107... ...
2023. Strategic National Stockpile smallpox medical countermeasures overview.
|
From page 108... ...
2023. Current state of research, development, and stockpiling of smallpox MCMs.
|
From page 109... ...
https://www.fda.gov/ regulatory-information/search-fda-guidance-documents/emergency-use-investigational-drug or-biologic (accessed February 7, 2024)
|
From page 110... ...
Presentation at Meeting 3 of the Committee on Current State of Research, Development, and Stockpiling of Smallpox MCMs of the National Academies. December 14.
|
From page 111... ...
https://www.nationalacademies.org/ event/41411_12-2023_meeting-3-of-the-committee-on-the-current-state-of-research-develop ment-and-stockpiling-of-smallpox-medical-countermeasures (accessed February 18, 2024)
|
From page 112... ...
2021. Ensuring an effective public health emergency medical countermeasures enterprise.
|
From page 113... ...
Presentation at Meeting 3 of the Committee on Current State of Re search, Development, and Stockpiling of Smallpox MCMs of the National Academies. December 14.
|
From page 114... ...
https://www.who. int/publications/i/item/the-independent-advisory-group-on-public-health-implications-of-syn thetic-biology-technology-related-to-smallpox (accessed February 15, 2024)
|
From page 115... ...
FACTORS INFLUENCING SMALLPOX READINESS AND RESPONSE 115 Yuan, S., H
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.