Authored by Tim Olsen, PhD, RoosterBio Inc.
Where are we now in our therapeutic response to COVID?
As of writing this article, over 1.5 Million Americans have confirmed cases of COVID-19 and 90,000 lives have been lost.  This global biothreat has not only claimed lives and infected patients to cause comorbid diseases like acute respiratory distress syndrome (ARDS) that overwhelm the hospital infrastructure,    but it’s also crippled the U.S. economy and set record numbers for unemployment or permanent ex-employment.  More than ever, America requires a rapid response to fight the spread of the virus and treat those infected.
In an attempt to re-allocate existing drugs for off-label use, early studies with hydroxychloroquine and remdesivir have not yet conclusively demonstrated objective benefit for COVID patients as monotherapies.    Nevertheless, times of crisis can fuel interdisciplinary efforts toward rapid innovation. Over the past few months, we observed new public-private partnerships to rapidly develop, test, and deploy a variety of Medical Countermeasures (MCM) for use on the front lines by health care professionals to combat COVID.      One promising technology are human mesenchymal stromal/stem cells (hMSCs). With an excellent safety profile established over hundreds of clinical trials and tens of thousands of patients dosed, MSCs are actively being used in the clinic for indications including acute respiratory distress syndrome (ARDS), acute lung injury, pneumonia, and more. 
Promising preliminary results are already reported from the first studies in COVID patients.      Not only are MSCs being used experimentally to treat patients now, but advances in scalable manufacturing could enable the plausible option for these cellular products to be produced at an emergency response level to store in the Strategic National Stockpile (SNS),  for off-the-shelf use in future public health emergencies related to chemical, biological, radiological or nuclear (CBRN) threats.        Incidentally, BARDA recently re-opened a grant opportunity communicated via BAA-18-100-SOL-00003, updated on 24-April-2020, with application window to close on 31-Oct-2020 (formerly 31-Oct-2019).
This Broad Agency Announcement (BAA; latest Amendment here)
“…is to solicit proposals that focus on one or more of the following areas of interest as listed here and further described in Part I.
Research and Development Areas of Interest:
- CBRN Vaccines
- Antitoxins and Therapeutic Proteins
- Radiological/Nuclear Threat Medical Countermeasures
- Chemical Threat Medical Countermeasures
- Burn Medical Countermeasures
- Influenza and Emerging Infectious Diseases (IEID) Vaccines
- Influenza and Emerging Infectious Diseases (IEID) Therapeutics
- Respiratory Protective Devices
- MCM Production Platform Systems
- Modeling as an Enabling Technology for Influenza, Emerging Infectious Disease, and CBRN Threat
- Visual Analytics an Enabling Technology for Influenza, Emerging Infectious Disease, and CBRN Threats”
Although these proposal “areas of interest” in the latest BAA must now necessarily be COVID-19 focused, it’s obvious how one might employ MSCs as stockpiled countermeasures—or as therapies directed at Influenza and Emerging and Infectious Diseases (IEIDs). While Countermeasures Areas of Interest need to be at least at a Technology Readiness Level (TRL) of 4 or more (“Candidate Optimization and Non-GLP In Vivo Demonstration of Activity and Efficacy”), IEID therapeutics need to be at TRL-6 (“as evidenced by release of a final report for a Phase 1 clinical study and a US IND, unless otherwise indicated”). To see if a cellular therapeutic or countermeasure product or process fits with BAA-18-100-SOL-00003,  or a different funding vehicle, you can request to schedule a “CoronaWatch” advisory meeting with the Federal Government HERE. 
How does the United States respond to public health emergencies like COVID?
The U.S. Department of Health and Human Services began discussions of a readily deployable supply of emergency medical countermeasures in 1999. The first real deployments were during the aftermath of the September 11th attacks and the anthrax threat in 2001. A critical attribute of the mobilization of these emergency supplies is their at-scale manufacture and pre-packaging, such that these ‘push packages’ could be deployed anywhere in the United States with 12 hours’ notice. In 2002, The Strategic National Stockpile (SNS)  was officially created and codified in the Public Health Service Act to be a supplement to state and local supplies during public health emergencies.
Although full details are classified, examples of the SNS inventory include ventilators, antibiotics, antitoxins, personal protective equipment, vaccines and more. As new threats emerge, new technologies are called upon to be deployed to help combat the threat. However, oftentimes these technologies are not at commercial level manufacturing, and a gap exists to accelerate small scale manufacturing to pandemic level manufacturing; access to these innovative solutions is thus restricted during times of need. This conundrum gave rise to the U.S. Department of Health and Human Services directive to establish the Biomedical Advanced Research and Development Authority (BARDA) to protect America from CBRN threats, as well as from pandemic influenza and emerging infectious diseases. BARDA focuses on medical countermeasure development and deployment of diagnostics (biothreat detection), vaccines (biothreat prevention), and therapeutics (biothreat mitigation). By providing funding and resources, BARDA helps to bridge the gap between early stages of development and full-scale manufacturing for acquisition of approved medical countermeasures for the Strategic National Stockpile. Thus far, BARDA supported 42 FDA approvals for products for threats against National Security.
The largest deployment of MCMs from the SNS,  with support from BARDA, was for the H1N1 influenza in 2009, where 12.5M antiviral regimens, 19.6M pieces of PPE, 85.1M N95 respirators, and 2,129 regimens of Peramivir IV were distributed across the country.
Currently, the SNS has $7B of inventory.  The COVID supply  deployment, and procurement from countries around the world, promises to trump any national health emergency to date when it is all said and done as the country returns to a ‘new normal.’
Learning from COVID to prepare for the ‘next one.’
As dismal as the death toll has been for COVID-19 thus far, experts warn that the next global health emergency crisis could be even worse, and is a matter of not ‘if,’ but ‘when.’ The reality is that there are still unknowns regarding SARS-CoV-2’s persistence, its infectivity, the immunity of inoculated humans, its amenability to antiviral drug cocktails, and its sequelae of long-term damages to recovering patients. For example, mildly sick COVID patients younger than 50  are beginning to appear in hospitals, presenting with stroke at unprecedented rates.   COVID-19’s effects on other vital, non-lung related organs and physiology may be non-trivial for many.     Therefore, generalized regenerative medicine technology approaches, which aren’t pathogen, indication, or disaster specific, could be ideal candidates to be added into the National Stockpile.
In early trials with hMSCs aimed at COVID-19 indications, clinical data are consistent with what may be interpreted as the first signs of safety and efficacy, pending future validation with more higher powered studies.   Mesoblast and Pluristem have reported 83% (n=12)  and 100% (n=7)  survival rates, respectively, from their initial compassionate use studies for COVID patients experiencing acute respiratory complications.  While promising, larger studies will be required to demonstrate concomitant safety and efficacy, and multiple groups are moving quickly to do just that. Athersys has received FDA approval for initiating a pivotal Phase 2/3 clinical study of its stem cell therapy, Multistem, on 400 patients with COVID induced ARDS.  The World Health Organization has reported that ARDS is the leading cause of death in COVID infected patients, highlighting the impact of Athersys’ study.  BARDA has designated Athersys’ Cell Therapy as ‘Highly Relevant’ for COVID-19, representing another opportunity for private-public partnership.
MSCs have not only been shown to be compelling for early studies related to COVID indications, but have also been reported via preclinical data to be effective in treating a variety of model CBRN threats.    As of May, 2020, ClinicalTrials.gov has at least 16 trials listed for burns (chemical and trauma induced), 129 trials listed for infection, and 25 trials listed for inflammation and systemic inflammatory response syndrome.  Another intriguing characteristic of MSCs is their ability to be modified via genetic engineering or genome editing, setting the stage to create a “plug-and-play” MSC platform with cross-functionality to combat many emerging threats.       
When manufacturing materials for a stockpile, the transportation logistics, cold chain, and shelf-life are critical.       MSCs have been shown to be successfully banked for years under proper cryopreservation conditions. MSC-derived extracellular vesicles (MSC-EVs) have commanded significant interest over the years as a potential treatment for ARDS due to similar functionality with their parent MSCs and eased storage logistics,     since freeze drying via lyophilization can greatly extend shelf- life.  Human clinical trials are now underway involving use of MSC-EVs against severe COVID-19,  and one preliminary result from a small study via NYU’s Grossman School of Medicine  is consistent with preclinical data  that could suggest signs of benefit. Nevertheless, it is strongly advised that studies with EVs adhere to stringent standards of consistency and quality, made via material generated under current Good Manufacturing Practices (cGMP), weighing potential risks and benefits, and minimizing hazard.  RoosterBio’s most recent blogs discuss the imperative of safety pertaining to MSCs in the COVID-19 crisis,  and the complex manufacturing considerations of large scale MSC-EV dose preparation for trials directed at the pandemic’s victims. 
Rather than having to wait for months or years for trials to be initiated and completed during national health emergencies, having a readily available supply of cryopreserved MSCs and MSC-EVs to be deployed via the SNS 12-hour Push Packs can aid in front line countermeasures for patients in need. The duration from culture seeding to harvest and dose-filling of hMSCs or other regenerative cell types can last from days (under the most state of the art bioprocesses)   to weeks or months. Ability to rapid deploy a life-saving therapeutic at the “point of panic” may be critical when dealing with acute illnesses or injuries in national emergencies.
It took a pandemic to provide the fuel for scaling cell manufacturing to new heights.
Manufacturing at scales required to fulfill the needs during a pandemic is no small feat. MSCs were once written off as a viable technology because it was thought that they could not be scaled to large stirred tank bioreactor systems to meet commercially or clinically relevant lot sizes, or in this case a global pandemic response. Over the last decade, tremendous progress has been made in the scalable manufacturing of MSCs.      Several groups have achieved manufacturing runs at the 50L scale and above.   Prior to pandemic, the demand for manufacturing programs was to create batch sizes to fuel early to mid-stage clinical trials with up to a few hundred patients. Unoptimized 2D-flask based systems have been deployed for these early trials, but the industry consensus is that scalable stirred tank bioreactor systems are the future. Thus, there was no demand to scale to 500L or 2,000L systems that could produce thousands of MSC doses at a time. Not because it wasn’t feasible before in development labs, but the input costs alone (cells, media, reagents, consumables, labor) are north of $1M per run. Public-private collaborations and the associated funding will be absolutely critical to obtain the resources required to develop the infrastructure for manufacturing MSCs for the SNS.
The greater our complacency, the greater the crisis will be.
Urgency is key to deployment of patient ready therapeutics. Experts of emerging diseases have indicated that it is not a matter of ‘if’ the next pandemic comes, but rather ‘when.’ Some models estimate that up to a large fraction of the USA could be exposed or infected by COVID-19.  The current mortality rate of COVID-19 can be approximated by the number of deaths divided by the number of clinical cases (subclinical cases excluded). It is about 6% in the USA and 7% globally.  But what if the next global threat rivals the 50% mortality rate of Ebola?  A well prepared and disciplined defense is the worst enemy of any emerging health threat. Given their versatility and manufacturability, MSCs would be a valuable therapeutic asset as a broad-spectrum front-line defense for addition to the SNS as a MCM against the unknown, but certainly developing, emerging public health threats of the future.
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