The global medical community encountered a highly contagious aerosolized pathogen with no known treatment when the SARS-CoV 2-virus triggered the Covid-19 global pandemic nearly five years ago. Fortunately, Covid responded to treatment with convalescent plasma while other therapies and vaccinations were under development.
Today, the H5N1 avian flu virus, currently lurking in birds and cows, is perhaps only a few mutations away from a potentially similar widespread and deadly outbreak in humans. It might not happen, but eventually, some global or regional pandemic will occur — whether it’s bird flu or a yet unidentified “disease X” pathogen. When that happens, convalescent plasma (CP) will almost certainly be used as an early therapeutic option. To make the most of CP “next time,” it is essential to outline and apply the lessons learned and relearned about CP, a therapy that saved tens of thousands of lives and could have saved even more during the Covid-19 pandemic had it been deployed optimally.
CP is generated by harvesting plasma from a donor who has recently recovered from the disease of concern. Such plasma is rich in disease-fighting antibodies and potentially other immune modulators and can be administered to an infected patient to treat the disease and reduce mortality. The idea is that the transfer of antibodies will neutralize the infectious agent and speed recovery from it. CP, animal-derived antibody therapies, and humanized monoclonal antibody preparations are forms of passive immunity, where antibodies made in one host are transferred to another to treat or prevent disease. Convalescent blood products have been used successfully before, such as in the 1918 Spanish flu pandemic.
For CP and other forms of passive immunity therapies to be effective, a few key principles must be followed. Importantly, the product must contain plenty of specific antibodies against the infectious agent of concern and it works best if given as soon as possible early in the course of disease. These are old principles that were well established before World War II and learned again during the Covid-19 pandemic. We also learned that CP can work anytime in immunocompromised patients who can’t make their own antibodies.
Covid offers a few lessons for preparing to optimize the use of CP before the next outbreak.
During Covid-19 the Food and Drug Administration first used the expanded access regulatory pathway to allow CP to be given at scale during the spring and summer of 2020. This was followed by emergency use authorization. The expanded access mechanism reduced the administrative burden for CP administration by both clinicians and regulators. It also permitted essential outcomes data to be collected as part of the U.S. Convalescent Plasma Study (USCPS). Other key administrative features included use of a single institutional review board, digital and web-based enrollment, consent and data collection methods, and remote support of community-based clinicians and hospitals.
There was also a public-private partnership between the FDA and the research team that facilitated near real-time data analysis and safety monitoring. Additionally, to facilitate the safe, timely and effective collection and distribution of CP at scale for the U.S., the Biomedical Advanced Research and Development Authority worked with and funded the national not-for-profit blood collection and banking system to collect and distribute CP to the approximately 2,000 sites participating in the USCPS. This system already had distribution networks that were then leveraged to deliver CP all over the United States and treat more than 500,000 patients. Donor recruitment was also aided by community partners using a number of techniques including social media, radio and TV public service announcements, and celebrity endorsements.
However, the earliest iterations of the expanded access program had limitations. For instance, it focused on hospitalized patients instead of taking a broader outlook. Furthermore, patients received only one unit (approximately 200 milliliters) of CP, and because there were no assays, the amount of antibody in the CP was unknown.
In preparation for “next time” we recommend use of prepared “fill in the blank” templates for regulatory documents, site initiation, and data collection. Use of pre-existing IRB reliance agreements, as is common today in multi-center clinical trials, will facilitate the addition of hospitals and physician investigators rapidly across the U.S.
To improve upon our experiences in the Covid-19 pandemic, we suggest development of easily adaptable antibody assay systems and diagnostic tests for families of pathogens. This will allow high titer units of plasma to be identified and patients to be diagnosed early in the course of disease. In the early days of such an emergency, when there is unlikely to be sufficient testing of units, physicians can give two CP units to increase the likelihood that patients will receive sufficient antibodies. Skeleton versions of online training, data collection, and analysis systems should also be developed. Steps to ensure that adequate supplies of the disposables needed to collect CP using plasma apheresis techniques are available should be taken.
The good news is that most of what needs to happen can simply leverage and build on the experience and approaches that evolved in 2020.
However, the best opportunity for doing it better next time is to plan for outpatient administration of high titer CP at scale to patients diagnosed in the earliest stages of disease. Hospitals are ideal for blood product administration, but during a major flu or disease X outbreak, they may be stressed to the breaking point with patients who need to be admitted, including the critically ill, and thus be unwilling to allow less sick patients to enter for passive immunity therapy administration as a safeguard against disease transmission for staff, other patients undergoing medical treatment for non-pandemic illnesses, or as a matter of workflow management. Thus, public health officials must identify spaces where CP can be transfused to outpatients who are at high risk for progression and death since this therapy is most effective when given early. In this regard, CP for Covid-19 was as effective as monoclonal antibody therapies in preventing hospitalization when given within five days of symptom onset.
Outpatient administration at scale will require creativity depending on local factors including geography and the availability of things like tents or convention centers for pop-up administration facilities. Mobile diagnostic capabilities and blood typing might also be needed. Outpatient administration might also require the repurposing personnel like paramedics to start IV catheters and help administer the CP. Digital tools could guide symptomatic individuals to the best location for them. Local solutions with coordinated teamwork across the health care and non-health care communities are paramount, as is regulatory flexibility.
The planning required to generate what we have outlined above can start as soon as modest resources are available to reestablish the academic, government, and nonprofit network from Covid. Once that network is reestablished, it can go beyond the informal conversations and communications that are happening now. By engaging in the needed inventory taking and planning required to optimize the use of CP for pandemic flu or a disease X outbreak, such a team will be able to save as many lives as possible next time.
Michael J. Joyner is a professor in the Department of Anesthesiology and Perioperative Medicine at the Mayo Clinic and led the U.S. Expanded Access Program for Convalescent Plasma. R. Scott Wright is a professor of medicine at the Mayo Clinic, serves as chair of its IRB and Human Research Protection program, and worked as a co-leader with Dr. Joyner in the USCPS. Arturo Casadevall is chair of the Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health and a board-certified infectious disease specialist. He chaired the National Covid-19 Convalescent Plasma Project. The views expressed here are those of the authors alone.