How did the anthrax terrorist acts in late 2001 stimulate pandemic-related, also called emerging infectious disease research? Knowledge of the pieces related here are based on my personal experience in building that response at Virginia Tech. I will discuss important research funding programs, efforts to build out safe research facilities both large and small, and planning for pandemic stockpiles.
Following the 9-11(-2001) terrorist attacks on the World Trade Center and the Pentagon, and the subsequent anthrax scare that followed closely afterwards because a terrorist sent envelopes full of ‘weaponized’-grade anthrax spores to several media offices and two democrat senators, killing five people and infecting 17 others, the U.S. government decided that it was not spending enough on research related to infectious agents that could be used as terrorist weapons, and it needed to be better prepared for a terrorist attack involving bioweapons in the future. The experts in the new Department of Homeland Security (DHS), the Department of Health and Human Services (DHHS), including the National Institutes of Health (NIH), particularly the National Institute of Allergy and Infectious Diseases (NIAID), Center for Disease Control (CDC), and the Food and Drug Administration (FDA), the Department of Defense (DOD), the National Institute for Standards & Technology (NIST), the National Science Foundation (NSF), and the U.S. Department of Agriculture (USDA), started thinking about what was needed.
This post will cover actions resulting from recommendations for new or improved research organizations and programs since late 2001. Addressed in the next postings will be three efforts to increase preparedness for an actual bioterrorist attack or pandemic:
- Biologically secure infection disease facilities called Bio-Safety Level 3 (BSL-3) and 4 (BSL-4) for laboratory and animal research.
- Stockpiles of supplies needed in a bioterrorist attack or pandemic
- Facilities for the containment of the infected and sick
Efforts for new pandemic research organizations and programs after 9-11
Organizations were required to improve the management of research into various aspects of protecting against bioterrorist attacks or pandemics, and a number of programs were needed to not only stimulate the creation of these new organizational forms, but also to do the research to understand how the U.S. could mitigate the threat of bioterrorist attacks or pandemics. Organizations and programs were needed by the DHS, NIAID, DOD (within the Defense Advanced Research Program Agency, DARPA, Defense Threat Reduction Agency, DTRA, Joint Science and Technology Office, JSTO, and U.S. Army Medical Research Institute for Infectious Disease, USAMRIID), NSF and the USDA. Programmatic concerns included:
- Vaccines, treatments and diagnostics (i.e., tests) for bioterrorist and ’emerging infectious disease’ agents which could cause plant, animal or human pandemics (NIAID, FDA and USDA concerns)
- Technology for monitoring for potential bioterrorist events (NSF, DOD and DHS concerns)
- Pandemic prediction and modeling technology (NSF and DHS concerns)
- Tracking and attribution technology (NIH, USAMRIID, and DHS concerns)
In particular NIAID noted:
“…that developing new medical countermeasures for biodefense and emerging infectious diseases is associated with specific challenges. For example, the basic biology and pathogenesis of threat agents are often not well understood. Many target pathogens must be handled under high level biosafety conditions that require specialized facilities and training. The regulatory path to licensure for biomedical countermeasures often requires demonstrating efficacy in appropriate animal models, many of which have yet to be developed. Finally, many of the target pathogens do not pose public health risks outside of their use as weapons, especially within the United States, thus, to date, there has not been a significant commercial market for products developed to treat diseases caused by these microbes.”“NIAID Strategic Plan for Biodefense Research – 2007 Update,” September 2007, p1. https://www.niaid.nih.gov/sites/default/files/biosp2007.pdf.
These concerns, vocalized by the Blue Ribbon Panel in recommendations to NIAID resulted in specific funding opportunities and funding efforts at various academic and government contracting institutions. I was primarily involved in two of these while I was manager of program development in the Office of the Vice Provost for Research and Graduate Studies (OVPRGS) between August 2002 and August 2003, and then Director of Research Initiatives in the Virginia-Maryland Regional College of Veterinary Medicine from August 2003 to August 2008:
- The NIAID Regional Centers of Excellence in Biodefense and Emerging Infectious Diseases (discussed below)
- Bio-Safety Level 3 Animal Research Facilities (discussed in a future posting)
NIAID National Centers of Excellence in Biodefense and Emerging Infectious Diseases
In February 2002 the Blue Ribbon Panel on Bioterrorism and Its Implications for Biomedical Research mentioned above gave a number of recommendations to NIAID led at that time, as it is today by Anthony Fauci, our 2020 hero. As a result, in 2002 and 2003 NIAID began developing research programs that specifically funded research that would be useful in the development of biodefense countermeasures. The NIAID also included in these programs funding for research about pandemic countermeasures. This made sense because preparing for the spread of emerging infectious diseases, such as Severe Acute Respiratory Syndrome (SARS), which created a pandemic scare in 2002, was much the same as preparing for bioterrorist events.
The focus of this research was on three categories of agents as defined by the CDC, Category A, B and C bioterrorism agents, with A being the greatest threat for bioterrorism, B being agents representing lesser threats, while C included many emerging infectious diseases which could develop into pandemic threats. NIAID had separate research agendas for Category A agents (1) and Category B and C agents (2).
One of the recommendations of the Blue Ribbon Panel was the creation of a network of large Regional Centers of Excellence (RCE) in Biodefense and Emerging Infectious Diseases to support research of Category A, B and C agents. The announcement to fund RCEs came out in August 2002, which, for NIH, was a rapid response to 9-11 and the Anthrax bioterrorist attacks in late 2001. The value of the potential research funding was enough to stimulate most major academic medical centers around the country to pursue this opportunity.
At the time I was working in the Office of the Vice Provost for Research and Graduate Studies (OVPRGS) at Virginia Tech as a manager of [research] program development, and though my responsibilities covered supporting research programs throughout Virginia Tech, for several reasons, I found myself playing a significant role in building a response to the RCE Request for Proposal (RFP) that came out in 2002, and my efforts continued when I moved over to the VMR College of Veterinary Medicine. Firstly, I had doctoral training in biomedical research with previous experience pursuing NIH funding. Second, I was in an organization, the OVPRGS, which could work across colleges, which was required to be successful obtaining funding for this research program. Finally, I not only had experience pulling together multiple colleges into major research initiatives, including, in particular, the Food, Nutrition, and Health Cross-Cutting Initiative, but also had been successful winning funding for a multi-institution initiative that involved four Virginia universities, the Internet Technology Innovation Center. That experience was critical since Virginia Tech was not going to be the lead of a major RCE with the limited infectious disease experience it had at that point. VT was going to have to partner.
Also at that time the Virginia Bioinformatics Institute (VBI) was just starting to get off the ground having hired both a director, Bruno Sobral and a research program developer, David Sebring. With a major commitment to infectious disease bioinformatics research VBI was going to be a player in this partnership, and Gerhardt Schurig, who was leading the Infectious Disease Research Initiative at Virginia Tech would also be a key player, having developed a vaccine used internationally for Brucella prevention. I had previous relationships with both of these senior administrators.
A clear strategy for partnering was needed if we were to participate in a winning RCE proposal. Based on the RCE RFP, I reasoned that each region would have one winning RCE, so the key to winning this award would be partnering with the winning lead academic medical center. Dave Sebring indicated that one partnership was likely to win with its base either at John Hopkins University School of Public Health, or the University of Maryland (UMD) Baltimore Medical School. Through connections we got an invitation to a preliminary discussion at UMD Baltimore and eventually became partnered with them, as JHU agreed to allow UMD Baltimore to take the lead – a negotiation that I’m sure was intense between these competitors for funds from the NIAID.
This proposal became the Mid-Atlantic Regional Center of Excellence (MARCE) in Biodefense and Emerging Infectious Diseases with subordinate roles for both the Virginia Bioinformatics Institute and the VMR College of Veterinary Medicine. The MARCE proposal also included a number of other key regional institutions like the University of Pennsylvania College of Veterinary Medicine, Penn State University, John Hopkins University, and others. The award was made by NIAID to MARCE in 2003 along with seven other RCEs around the country.
Subsequent Progress on Biodefense and Pandemic Research Agenda
Since the funding in mid-2003 and the progress reports about Category A research (1) and Category B and C research (2), another progress report responding to the recommendations of the Blue Ribbon Panel of Infectious Disease Experts was published in 2006 (3). Then the NIAID published an update to the Strategic Plan for Biodefense Research – 2007 Update (4) which created a new categorization of threats:
- Traditional Agents that could cause mass casualties like Bacillus anthracis (anthrax) and Yersinia pestis (plague).
- Enhanced Agents that were modified to harm humans like multi-drug resistant plague.
- Emerging Agents that were previously unrecognized naturally occurring agents that threaten human health like Severe Acute Respiratory Syndrome (SARS) or avian influenza.
- Advanced Agents that were engineered in laboratories to bypass countermeasures like multi-drug resistant anthrax.
The 2007 update of the NIAID Biodefense strategic plan (4) stated a new understanding that:
“Responding to traditional and new types of threats will require the capability to rapidly identify unknown or poorly defined agents, quickly evaluate the efficacy of available interventions, and develop and deploy novel treatments to prevent or mitigate medical consequences and the subsequent impact on society.”“NIAID Strategic Plan for Biodefense Research – 2007 Update,” September 2007, p3. https://www.niaid.nih.gov/sites/default/files/biosp2007.pdf.
With a major research program in place including efforts like the RCEs funded, the 2007 strategic plan, focused on flexible responses using “broad spectrum” approaches (4). The idea was to develop broad spectrum diagnostics, treatments and vaccines which could mitigate threats to many biological agents. For example there was interest in development of a vaccine that could protect against Ebola, Marburg and Lassa viruses, or therapeutic agents that could reduce the ‘cytokine storms’ which, uncontrolled can result in fatalities to a broad range of infections (4).
Another interest was in the development platforms that could be used to reduce the time and cost of bringing a countermeasure to market. For example, in vitro safety testing, monoclonal antibody production, and screening systems that would speed development of new therapeutics and vaccines (4).
Pandemic and All-Hazards Preparedness Act (PAHPA)
In December 2006 Congress passed the The Pandemic and All-Hazards Preparedness Act (5) and reauthorized it with amendments in 2013 (6). This act amended the Public Health Service Act (7) to establish the Assistant Secretary for Preparedness and Response (ASPR) in the DHHS who was to submit and regularly revise a strategy for pandemic preparedness. The response to this act was a document published as the 2007, 2012, 2014, 2015, 2016, 2017-18 as the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy and Implementation Plan (SIP; 8, 9). This document details the progress and plans for pandemic-related research.
Some government-funded basic, preclinical and clinical research projects specifically mentioned in the 2017-2018 PHEMCE SIP (9), with a significant focus on Ebola and Zika virus, include:
- Developing novel vaccines and therapeutics for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) by NIAID funding of Regeneron and others, as well as DOD funding of GeneOne Life Science.
- Developing in vitro diagnostics for antimicrobial resistance with a BARDA project called “Antimicrobial Resistance Rapid, Point-of-Need Diagnistic Test Challenge” which will result in $20 M awards in 2020.
- Developing a simple blood test of patterns of gene expression to assess if patient’s respiratory response is due to bacterial or viral infection with funding going to Antibacterial Resistance Leadership Group (ARLG).
- Testing in clinics promising broad-spectrum antibacterial therapeutics by NIAID and BARDA.
- Discovering multifunctional antibodies against Ebola virus by the DTRA, JSTO and USAMRIID with controbutions by AbbVie, other biopharmas and academic institutions.
- Using systems biology, with NIH funding, to identify, quantify, model and predict molecular interaction dynamics of pathogens resistant to antibiotics to help identify therapeutic agents.
- Evaluating, with FDA approval, FilmArray NGDS Warrior Panel, a molecular diagnostic that assesses presence in blood of B. anthracis, C. bumetii, F. tularensis, Y. pestis, Ebola, and Marburg virus DNA.
- Evaluating, with FDA approval, a CDC Rickettsia Real-time PCR Assay that differentiates R. rickettsii and R. prowazekii, and a CDC variola virus Real-time PCR.
- Qualifying, with NIAID funding and FDA review, a non-human primate model of pneumonic tularemia.
- Transitioning funding from NIH to BARDA for a potential antidote for chlorine inhalation.
- Transitioning funding from BARDA to Project Bioshield for a biodosimetry program at Columbia University for measuring exposure to radiation.
- Supporting therapeutics, vaccines and diagnostic candidates for the Ebola outbreak in West Africa from 2014-2015 with some expectation some promising candidates will be transitioned from BARDA to Project Bioshield funding.
- Responding to Zika virus threat, NIAID funded basic and clinical research studying how the virus causes disease in animals and humans, and particularly has its influence on fetus, as well as developing a number of vaccine and therapeutic candidates using a Zika virus infection model in rhesus macaques with funding to Southern Research Institute.
- Developing, with NIAID and BARDA funding, and FDA encouragement, diagnostic tests for Zika virus.
- Forming an interagency group of DOD, NIAID, BARDA and FDA called the Filovirus Animal Nonclinical Group (FANG) to assay Ebola antibodies in human sera from vaccine clinical trials.
- Studying filovirus vaccines from Janssen, Profectus Biosciences and Novavax with funding from NIAID.
The above list of research projects developing vaccines, therapeutics and diagnostics for potential pandemic and bioterrorist agents, is not exhaustive of all the projects listed in the 2017-2018 PHEMCE SIP (9). These are listed here to give you an idea of how extensive current research is in this field.
Note that SARS and SARS-CoV2 were not mentioned, though MERS-CoV, a virus closely related to SARS was mentioned in item 1 above. This does not mean that research is not being done on SARS, but SARS-CoV2 was a new agent just discovered Chinese in December 2019 and sequenced by them in early January 2020. The point to recognize here is that “emerging infectious diseases” can arise at any time and we may not have much information about them except from related emerging infectious diseases like SARS (“classic”) in the case of SARS-CoV2. The idea of having an army of experts working on flexible, broad spectrum therapeutics, vaccines, and diagnostics as well as platforms for quickly creating new therapeutics, vaccines and diagnostics, is critical to the response to any emerging infectious disease (4). The funding that the Federal government and private foundations, like the Gates Foundation, have put towards doing this research has served this purpose and allowed for the training of many experts in infectious disease diagnostics, vaccines, and therapeutics.
Our biggest challenge during the COVID-19 Pandemic has not been our ability to quickly as possible respond to this crisis, but to have the stockpiles of resources like ventilators (in the hundreds of thousands) and protective masks (in the tens of millions), as well as an efficient government machine prepared to respond quickly and effectively to a pandemic. The focus in preparation for this crisis could have been more attention to how an event like this would be handled efficiently and effectively.
Following posts will look at more of the preparation efforts that have been pursued since the Anthrax terrorist attacks in late 2001.
- “NIAID Biodefense Research Agenda for CDC Category A Agents August 2003 Progress Report.” Progress Report. NIAID, August 2003. https://www.niaid.nih.gov/sites/default/files/category_a_progress_report.pdf.
- “NIAID Biodefense Research Agenda for Category B and C Priority Pathogens: Progress Report.” NIAID, June 2004. https://www.niaid.nih.gov/sites/default/files/category_bc_progress_report.pdf.
- “NIAID Biodefense Research Agenda for CDC Category A Agents, 2006 Progress Report,” n.d., 90.
- “NIAID Strategic Plan for Biodefense Research – 2007 Update,” September 2007. https://www.niaid.nih.gov/sites/default/files/biosp2007.pdf.
- “Pandemic and All Hazards Preparedness Act (PAHPA),” December 2006. https://www.phe.gov/preparedness/legal/pahpa/pages/default.aspx.
- Rogers, Mike J. “H.R.307 – 113th Congress (2013-2014): Pandemic and All-Hazards Preparedness Reauthorization Act of 2013.” Webpage, March 13, 2013. 2013/2014. https://www.congress.gov/bill/113th-congress/house-bill/307.
- “Public Health Service Act.” In Wikipedia, December 16, 2019. https://en.wikipedia.org/w/index.php?title=Public_Health_Service_Act&oldid=931080385.
- “2014 Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy and Implementation Plan,” 2014. http://www.phe.gov/Preparedness/mcm/phemce/Documents/2014-phemce-sip.pdf.
- “2017-2018 Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy and Implementation Plan,” 2017, 87.