The global medical community encountered a highly infectious aerosolized pathogen with no known treatment when the SARS-CoV 2 virus triggered the global Covid-19 pandemic nearly five years ago. Fortunately, Covid responded to treatment with convalescent plasma while other therapies and vaccinations were in development.
Today, the bird flu virus H5N1, currently lurking in birds and cows, may just be a few mutations away from a potentially similar widespread and deadly outbreak in humans. It may not happen, but eventually some global or regional pandemic will occur – whether it’s bird flu or an as-yet-unidentified “disease X” pathogen. When that happens, convalescent plasma (CP) will almost certainly be used as an early therapeutic option. To get the most out of CP ‘next time’, it is important to describe 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 if it had been optimally implemented.
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 immunomodulators 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-based antibody therapies, and humanized monoclonal antibody preparations are forms of passive immunitywhere antibodies made in one host are transferred to another to treat or prevent disease. Convalescent blood products have been used successfully earlier, as in the 1918 Spanish flu pandemic.
For CP and other forms of passive immunity therapies to be effective, a some key principles must be followed. Importantly, the product must contain very specific antibodies against the infectious substance and it works best if it is given as soon as possible early in the course of the disease. These are old principles that were well established before WWII and learned again during the covid-19 pandemic. We also learned that CP can work at any time in immunocompromised patients who cannot make their own antibodies.
Covid offers some lessons for preparing to optimize the use of CP for the next outbreak.
During Covid-19, the Food and Drug Administration used first extended access regulatory pathway to allow CP to be given on a large scale in the spring and summer of 2020. This was followed by emergency permit for use. The expanded access mechanism reduced the administrative burden of CP administration by both clinicians and regulators. It also allowed essential performance data to be collected as part of the US Convalescent Plasma Study (USCPS). Other important administrative features included the use of a single institutional review board, digital and web-based registration, consent and data collection methods, and remote support by community-based physicians 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, rapid, and efficient large-scale collection and distribution of CP for the United States, the Biomedical Advanced Research and Development Authority worked with and funded the National Non-Profit Blood Collection and Banking System to collect and distribute CP to the approximately 2,000 locations participating in USCPS. This system already had distribution networks that were then leveraged to deliver CP across the US and process more than 500,000 patients. Donor recruitment was also helped by community partners using a number of techniques including social mediaradio and TV public service announcements and celebrity endorsements.
However, the earliest iterations of the expanded access program had limitations. For example, it focused on inpatients instead of taking a broader view. In addition, the patients received only one unit (approximately 200 milliliters) of CP, and since there were no assays, the amount of antibody in the CP was unknown.
In preparation for “next time”, we recommend using prepared “fill-in-the-blank” templates for regulatory documents, website initiation and data collection. Use of pre-existing IRB agreements, common today in multicenter clinical trials, will facilitate the rapid recruitment of hospitals and physician investigators across the United States
To improve our experience with the Covid-19 pandemic, we propose the development of easily adaptable antibody assay systems and diagnostic tests for families of pathogens. This will make it possible to identify high-titer plasma units and to diagnose patients early in the course of the disease. In the early days of such an emergency, when it is unlikely that sufficient testing of devices will be sufficient, doctors may give two CP devices to increase the likelihood that patients will receive enough antibodies. Skeleton versions of online training, data collection and analysis systems should also be developed. Measures to ensure that sufficient supplies of disposables needed to collect CP using plasma apheresis techniques are available should be taken.
The good news is that most things that need to happen can simply be leveraged and built upon experiences and approaches developed in 2020.
However, the best opportunity to do better next time is to plan for large-scale outpatient administration of high-titer CP to patients diagnosed in the earliest stages of the disease. Hospitals are ideal for administering blood products, but during a major influenza 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 reluctant to admit less sick patients to administer passive immunity therapy as protection against disease transmission for staff, other patients undergoing medical treatment for non-pandemic diseases, or as a matter of workflow management. Thus, public health officials need to identify spaces where CP can be transfused to outpatients at high risk for progression and death because this therapy is most effective when given early. In this regard, CP was for Covid-19 as effective as monoclonal antibody therapies to prevent hospitalization when given within five days of symptom onset.
Open-air administration on a large scale will require creativity depending on local factors, including geography and the availability of things like tents or convention centers for pop-up administration. Mobile diagnostic capabilities and blood typing may also be needed. Ambulatory administration may also require reusing staff, such as paramedics, to start IV catheters and help administer CP. Digital tools can guide symptomatic individuals to the best place for them. Local solutions with coordinated teamwork between health care communities are paramount, as is regulatory flexibility.
The planning required to generate what we have described above can start as soon as modest resources are available to rebuild the academic, governmental and non-profit network from Covid. Once that network is re-established, it can go beyond the informal conversations and communications that happen now. By engaging in the necessary inventory and planning required to optimize the use of CP for pandemic influenza 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 directed the US 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 served as a co-leader with Dr. Joyner at 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 solely those of the authors.
