State-of-the-art therapeutic medical countermeasures for viral threat agents

In recent years, there has been an increase in the perceived threat of biological agents being used against civilian populations. This has prompted an urgent need for the development and procurement of medical countermeasures (MCMs) against highly pathogenic viruses that can prevent morbidity and mortality from infections caused by these agents. To date, antiviral drug development has been largely focused on clinically prevalent chronic infections due to their commercial viability. This has left a huge gap in the drug development path for acute infections of biodefense importance. In this review, we discuss the antiviral research and development initiatives focusing specifically on poxviruses, filoviruses, and equine encephalitis viruses (EEV). We discuss the benefits and technical challenges in the current development strategies and the hurdles in the licensure path for MCMs against these highly pathogenic viruses under the FDA Animal Rule, and we provide recommendations for the path forward.     

Biological threat characterization research: a critical component of national biodefense

Biological warfare (BW) threat assessments identify and prioritize BW threats to civilian and military populations. In an ideal world, they provide policymakers with clear and compelling guidance to prioritize biodefense research, development, testing, evaluation, and acquisition of countermeasures. Unfortunately, the biodefense community does not exist in an ideal world. National security professionals responsible for crafting BW threat assessments often are challenged by factors that limit the clarity and/or timeliness of those assessments. Moreover, the potential for life science advances to enhance threats enabled by state programs and the possibility that non-state actors may pursue crude but effective BW methodologies will drastically expand the scope of the perceived threat. Appropriate investment of federal biodefense funds will require some mechanism for validating and prioritizing present and future threats. Ideally, such a mechanism will incorporate empirical data targeted to elucidate actual hazards. In this regard, the Department of Homeland Security's creation of a Biological Threat Characterization Program for the technical validation of threat agents will be a valuable addition to the nation's overall biodefense strategy. This article articulates the need for a coordinated national biological threat characterization program, discusses some of the principal challenges associated with such research, and suggests a few options for their resolution.     

U.S. medical countermeasure development since 2001: a long way yet to go

The U.S. government has taken significant steps toward developing and acquiring vaccines, drugs, and other medical countermeasures (MCMs) to protect and treat the population after a biological attack. In contrast to 2001, there is now a procedure for the Department of Health and Human Services (HHS) to develop, license, and stockpile MCMs for civilian use. Another major accomplishment is smallpox preparedness: There is now an adequate supply of vaccine for every person in the U.S., and there is an alternative vaccine meant for immunocompromised people and those with close contact with them. In spite of these and other accomplishments, the U.S. government MCM effort has been criticized by federal advisory committees, National Academy of Sciences reports, a congressional commission, and outside analysts who state that the efforts lack central leadership and accountability and that the pace of progress has been slow. A clear operational strategy for using MCMs, which would guide their development and acquisition, is also lacking. In this article, we review key areas of progress made since 2001 to develop and acquire MCMs, and we summarize what we judge to be the most critical and often mentioned areas where improvements are needed.     

Antibodies for biodefense

Potential bioweapons are biological agents (bacteria, viruses, and toxins) at risk of intentional dissemination. Biodefense, defined as development of therapeutics and vaccines against these agents, has seen an increase, particularly in the US following the 2001 anthrax attack. This review focuses on recombinant antibodies and polyclonal antibodies for biodefense that have been accepted for clinical use. These antibodies aim to protect against primary potential bioweapons, or category A agents as defined by the Centers for Disease Control and Prevention (Bacillus anthracis, Yersinia pestis, Francisella tularensis, botulinum neurotoxins, smallpox virus, and certain others causing viral hemorrhagic fevers) and certain category B agents. Potential for prophylactic use is presented, as well as frequent use of oligoclonal antibodies or synergistic effect with other molecules. Capacities and limitations of antibodies for use in biodefense are discussed, and are generally applicable to the field of infectious diseases.     

Antibodies for biodefense

Potential bioweapons are biological agents (bacteria, viruses and toxins) at risk of intentional dissemination. Biodefense, defined as development of therapeutics and vaccines against these agents, has seen an increase, particularly in the US, following the 2001 anthrax attack. This review focuses on recombinant antibodies and polyclonal antibodies for biodefense that have been accepted for clinical use. These antibodies aim to protect against primary potential bioweapons or category A agents as defined by the Centers for Disease Control and Prevention (Bacillus anthracis, Yersinia pestis, Francisella tularensis, botulinum neurotoxins, smallpox virus and certain others causing viral hemorrhagic fevers) and certain category B agents. Potential for prophylactic use is presented, as well as frequent use of oligoclonal antibodies or synergistic effect with other molecules. Capacities and limitations of antibodies for use in biodefense are discussed, and are generally applicable to the field of infectious diseases.Key words: antibody, anthrax, plague, smallpox, botulism, tularemia, brucellosis, hemorrhagic, ricin, SEB     

Evaluation of perceived threat differences posed by filovirus variants

In the United States, filoviruses (ebolaviruses and marburgviruses) are listed as National Institute of Allergy and Infectious Diseases (NIAID) Category A Priority Pathogens, Select Agents, and Centers for Disease Control and Prevention (CDC) Category A Bioterrorism Agents. In recent months, U.S. biodefense professionals and policy experts have initiated discussions on how to optimize filovirus research in regard to medical countermeasure (ie, diagnostics, antiviral, and vaccine) development. Standardized procedures and reagents could accelerate the independent verification of research results across government agencies and establish baselines for the development of animal models acceptable to regulatory entities, such as the Food and Drug Administration (FDA), while being fiscally responsible. At the root of standardization lies the question of which filovirus strains, variants, or isolates ought to be the prototypes for product development, evaluation, and validation. Here we discuss a rationale for their selection. We conclude that, based on currently available data, filovirus biodefense research ought to focus on the classical taxonomic filovirus prototypes: Marburg virus Musoke in the case of marburgviruses and Ebola virus Mayinga in the case of Zaire ebolaviruses. Arguments have been made in various committees in favor of other variants, such as Marburg virus Angola, Ci67 or Popp, or Ebola virus Kikwit, but these rationales seem to be largely based on anecdotal or unpublished and unverified data, or they may reflect a lack of awareness of important facts about the variants' isolation history and genomic properties.     

Federal Agency biodefense funding, FY2011-FY2012

Since 2001, the United States government has spent substantial resources on preparing the nation against a bioterrorist attack. Earlier articles in this series have analyzed civilian biodefense funding by the federal government for fiscal years (FY) 2001 through proposed funding for FY2011. This article updates those figures with budgeted amounts for FY2012, specifically analyzing the budgets and allocations for biodefense at the Departments of Health and Human Services, Defense, Homeland Security, Agriculture, Commerce, and State; the Environmental Protection Agency; and the National Science Foundation. This article also includes an updated assessment of the proportion of biodefense funding provided for programs that address multiple scientific, public health, healthcare, national security, and international security issues in addition to biodefense. The FY2012 federal budget for civilian biodefense totals $6.42 billion. Of that total, $5.78 billion (90%) is budgeted for programs that have both biodefense and nonbiodefense goals and applications, and $637.6 million (10%) is budgeted for programs that have objectives solely related to biodefense.     

The development of broad-spectrum antiviral medical countermeasures to treat viral hemorrhagic fevers caused by natural or weaponized virus infections

The Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) began development of a broad-spectrum antiviral countermeasure against deliberate use of high-consequence viral hemorrhagic fevers (VHFs) in 2016. The effort featured comprehensive preclinical research, including laboratory testing and rapid advancement of lead molecules into nonhuman primate (NHP) models of Ebola virus disease (EVD). Remdesivir (GS-5734, Veklury, Gilead Sciences) was the first small molecule therapeutic to successfully emerge from this effort. Remdesivir is an inhibitor of RNA-dependent RNA polymerase, a viral enzyme that is essential for viral replication. Its robust potency and broad-spectrum antiviral activity against certain RNA viruses including Ebola virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to its clinical evaluation in randomized, controlled trials (RCTs) in human patients during the 2018 EVD outbreak in the Democratic Republic of the Congo (DRC) and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic today. Remdesivir was recently approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19 requiring hospitalization. Substantial gaps remain in improving the outcomes of acute viral infections for patients afflicted with both EVD and COVID-19, including how to increase therapeutic breadth and strategies for the prevention and treatment of severe disease. Combination therapy that joins therapeutics with complimentary mechanisms of action appear promising, both preclinically and in RCTs. Importantly, significant programmatic challenges endure pertaining to a clear drug and biological product development pathway for therapeutics targeting biodefense and emerging pathogens when human efficacy studies are not ethical or feasible. For example, remdesivir’s clinical development was facilitated by outbreaks of Ebola and SARS-CoV-2; as such, the development pathway employed for remdesivir is likely to be the exception rather than the rule.The current regulatory licensure pathway for therapeutics targeting rare, weaponizable VHF agents is likely to require use of FDA’s established Animal Rule (21 CFR 314.600–650 for drugs; 21 CFR 601.90–95 for biologics). The FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is safe and likely to produce clinical benefit in humans. In practical terms, this is anticipated to include a series of rigorous, well-documented, animal challenge studies, to include aerosol challenge, combined with human safety data. While small clinical studies against naturally occurring, high-consequence pathogens are typically performed where possible, approval for the therapeutics currently under development against biodefense pathogens will likely require the Animal Rule pathway utilizing studies in NHPs. We review the development of remdesivir as illustrative of the effort that will be needed to field future therapeutics against highly lethal, infectious agents.     

Federal agency biodefense funding, FY2012-FY2013

Since 2001, the United States government has spent substantial resources on preparing the nation against a bioterrorist attack. Earlier articles in this series have analyzed civilian biodefense funding by the federal government for fiscal years (FY) 2001 through proposed funding for FY2012. This article updates those figures with budgeted amounts for FY2013, specifically analyzing the budgets and allocations for civilian biodefense at the Departments of Health and Human Services, Defense, Homeland Security, Agriculture, Commerce, and State; the Environmental Protection Agency; and the National Science Foundation. As in previous years, our analysis indicates that the majority (>90%) of the "biodefense" programs included in the FY2013 budget have both biodefense and non-biodefense goals and applications-that is, programs to improve infectious disease research, public health and hospital preparedness, and disaster response more broadly. Programs that focus solely on biodefense represent a small proportion (<10%) of our analysis, as the federal agencies continue to prioritize all-hazards preparedness. For FY2013, the federal budget for programs focused solely on civilian biodefense totals $574.2 million, and the budget for programs with multiple goals and applications, including biodefense, is $4.96 billion, for an overall total of $5.54 billion.     

Billions for biodefense: federal agency biodefense funding, FY2001-FY2005

Over the past several years, the United States government has spent substantial resources on preparing the nation against a bioterrorist attack. This article analyzes the civilian biodefense funding by the federal government from fiscal years 2001 through 2005, specifically analyzing the budgets and allocations for biodefense at the Department of Health and Human Services, the Department of Homeland Security, the Department of Defense, the Department of Agriculture, the Environmental Protection Agency, the National Science Foundation, and the Department of State. In total, approximately $14.5 billion has been funded for civilian biodefense through FY2004, with an additional $7.6 billion in the President's budget request for FY2005.     

Billions for biodefense: Federal Agency biodefense funding, FY2006-FY2007

Since 2001, the United States government has spent substantial resources on preparing the nation against a bioterrorist attack. Earlier articles in this series analyzed the civilian biodefense funding by the federal government from fiscal years 2001 through 2006. This article updates those figures with budgeted amounts for fiscal year 2007, specifically analyzing the budgets and allocations for biodefense at the Department of Health and Human Services, the Department of Homeland Security, the Department of Agriculture, the Environmental Protection Agency, the Department of State, and the National Science Foundation.     

Billions for biodefense: federal agency biodefense funding, FY2008-FY2009

Since 2001, the United States government has spent substantial resources on preparing the nation against a bioterrorist attack. Earlier articles in this series analyzed civilian biodefense funding by the federal government from fiscal years 2001 through 2008. This article updates those figures with budgeted amounts for fiscal year 2009, specifically analyzing the budgets and allocations for biodefense at the Departments of Health and Human Services, Homeland Security, Defense, Agriculture, and State and the Environmental Protection Agency and the National Science Foundation.     

Billions for biodefense: federal agency biodefense funding, FY2007-FY2008

Since 2001, the U.S. government has spent substantial resources on preparing the nation against a bioterrorist attack. Earlier articles in this series analyzed civilian biodefense funding by the federal government from fiscal years 2001 through 2007. This article updates those figures with budgeted amounts for fiscal year 2008, specifically analyzing the budgets and allocations for biodefense at the Department of Health and Human Services, the Department of Homeland Security, the Department of Defense, the Department of Agriculture, the Environmental Protection Agency, the Department of State, and the National Science Foundation.     

Reliability and accuracy of handheld stopwatches compared with electronic timing in measuring sprint performance

This study assessed reliability of split times obtained by handheld stopwatches (HHSs) compared with electronic timing (ET) during a 200-m sprint. Two HHS timing methods were compared with ET: single-split timers (SST) and multiple-split timers (MST). Twenty-six timers without previous experience were given instruction and completed practice trials until good agreement was achieved between ET and HHS. Trained runners (8 males, 10 females) were timed for each 25-m interval on a standard 200-m course. Repeated-measures analysis of variance and intraclass correlation models were used to determine reliability. A total of 248 split times were analyzed. No significant differences were found between the three timing methods (p > 0.99), and calculated intraclass correlation values were high (0.988). Mean error between SST, MST, and ET (-0.04 +/- 0.24 and -0.05 +/- 0.24 seconds, respectively) indicated faster HHS times, though not significantly. However, absolute errors were considerably larger (0.15 +/- 0.20 and 0.16 +/- 0.19 between SST, MST, and ET, respectively). The HHS-recorded splits were faster than ET in 67.3% of splits and slower in 29.4%. The distribution of errors made the development of a reliable correction factor to convert HHS to ET impossible. It was concluded that on the basis of the small mean error and high intraclass correlations, the use of HHSs may be a viable alternative to ET in collecting group data. However, on the basis of the absolute error between HHS and ET, when high degrees of precision are required, ET should be used, and reliable correction of HHS to ET values is not possible. It was further concluded that HHS times should be reported without attempting correction and interpreted in light of the shortcomings of the HHS method.     

Use of recombinant adenovirus vectored consensus IFN-α to avert severe arenavirus infection

Several arenaviruses can cause viral hemorrhagic fever, a severe disease with case-fatality rates in hospitalized individuals ranging from 15-30%. Because of limited prophylaxis and treatment options, new medical countermeasures are needed for these viruses classified by the National Institutes of Allergy and Infectious Diseases (NIAID) as top priority biodefense Category A pathogens. Recombinant consensus interferon alpha (cIFN-α) is a licensed protein with broad clinical appeal. However, while cIFN-α has great therapeutic value, its utility for biodefense applications is hindered by its short in vivo half-life, mode and frequency of administration, and costly production. To address these limitations, we describe the use of DEF201, a replication-deficient adenovirus vector that drives the expression of cIFN-α, for pre- and post-exposure prophylaxis of acute arenaviral infection modeled in hamsters. Intranasal administration of DEF201 24 h prior to challenge with Pichindé virus (PICV) was highly effective at protecting animals from mortality and preventing viral replication and liver-associated disease. A significant protective effect was still observed with a single dosing of DEF201 given two weeks prior to PICV challenge. DEF201 was also efficacious when administered as a treatment 24 to 48 h post-virus exposure. The protective effect of DEF201 was largely attributed to the expression of cIFN-α, as dosing with a control empty vector adenovirus did not protect hamsters from lethal PICV challenge. Effective countermeasures that are highly stable, easily administered, and elicit long lasting protective immunity are much needed for arena and other viral infections. The DEF201 technology has the potential to address all of these issues and may serve as a broad-spectrum antiviral to enhance host defense against a number of viral pathogens.     

Billions for biodefense: federal agency biodefense budgeting, FY2005-FY2006

Since 2001, the United States government has spent substantial resources on preparing the nation against a bioterrorist attack. An earlier article analyzed the civilian biodefense funding by the federal government from fiscal years 2001 through 2005. This article updates those figures with budgeted amounts for fiscal year 2006, specifically analyzing the budgets and allocations for biodefense at the Department of Health and Human Services, the Department of Homeland Security, the Department of Agriculture, the Environmental Protection Agency, the National Science Foundation, and the Department of State.     

Casting a wider net for countermeasure R&D funding decisions

Among potential bioweapons attacks, endemic infectious diseases (that is, those naturally occurring diseases that afflict us every year), and a potential influenza pandemic, how should we apportion funding and resources for basic research and countermeasure development? To address this question, I argue for a "combined risk assessment" that considers bioweapons attacks with natural pandemics and endemic infectious disease. At present, risk assessments for bioweapons attacks are carried out separately from the assessments long carried out for endemic infectious diseases to make public health and medical care decisions. One result of this separation is that funding decisions may be unduly influenced by an overblown fear of a big bioweapons attack and by political whim. The result of the simplified combined risk assessment presented here argues for more funding and resources for endemic infectious disease and for placing biodefense against anthrax and other bioweapons in a place lower in the risk hierarchy. Since the assessment here considers only fatalities to make the point that our priorities are skewed, the conclusions are only a "first word" on the subject, far from the last. Furthermore, the impact of other issues on priorities, such as national and international policy, is not considered. It is a call for a debate on the public stage of the policy and other rationale and the quantitative risk assessment arguments that now place bioweapons attacks at the top of our risk ranking.     

具有重大历史意义的苏州会议

40年前于1979年,在苏州召开的中国古生物学会第三届全国会员代表大会暨第12次学术年会盛况空前,在中国古生物学发展史上具有非常重要的意义。它标志着中国古生物学研究步入发展的新阶段,优秀成果大量涌现、学术交流频繁;此后的数年里学会活动空前活跃、会员人数大幅增加,从此学会活动正规化;中国古生物学界重新回到国际大家庭,对外交流频繁。