The global medical community was confronted with a highly contagious aerosolized pathogen with no known treatment when the SARS-CoV 2 virus caused 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 avian flu virus H5N1, which currently lurks in birds and cows, may only be present a few changes later of a possibly similar widespread and deadly outbreak in humans. It may not happen, but eventually a global or regional pandemic will occur – whether it is 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 essential to use the lessons learned and relearned about CP, a therapy that tens of thousands of lives saved and could have saved even more during the Covid-19 pandemic if it had been used optimally.
CP is generated by collecting plasma from a donor who has recently recovered from the disease of concern. Such plasma is rich in disease-fighting antibodies and possibly 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 up its recovery. CP, animal-derived antibody therapies, and humanized monoclonal antibody preparations are forms of passive immunityin which antibodies made in one host are transferred to another to treat or prevent disease. There have been convalescent blood products used successfully before, such as during the Spanish flu pandemic of 1918.
For CP and other forms of passive immunity therapies to be effective, a some core principles must be followed. Importantly, the product must contain sufficient specific antibodies against the infectious agent in question and it works best if it is administered as soon as possible in the early stages of the disease. These are old principles that were well established before World War II and were relearned 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 a few lessons to prepare for optimizing CP use before the next outbreak.
During Covid-19, the Food and Drug Administration used the expanded access regulatory process to deliver CP on a large scale in 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 physicians and supervisors. It also allowed essential outcome data to be collected as part of the American convalescent plasma research (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 from community-based physicians and hospitals.
There was also a public-private partnership between the FDA and the research team that allowed for near real-time data analysis and safety monitoring. In addition, 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 has collaborated with and been funded by the national nonprofit blood collection and banking system to collect and distribute CP distribute to the approximately 2,000 locations participating in the USCPS. This system already had distribution networks in place that were then deployed to deliver CP throughout the United States and handle more than that 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, early versions of the expanded access program had limitations. For example, it focused on hospitalized patients rather than taking a broader view. In addition, patients received only one unit (about 200 milliliters) of CP, and because there were no tests, the amount of antibody in the CP was unknown.
To prepare for “next time,” we recommend using prepared “fill in the blank” templates for regulatory documents, site initiation, and data collection. The use of pre-existing IRB reliance agreements, as is common in multicenter clinical trials today, will quickly facilitate the addition of hospitals and physician investigators in the US.
To improve our experiences with the Covid-19 pandemic, we propose the development of easily adaptable antibody test systems and diagnostic tests for families of pathogens. This allows high titer plasma units to be identified and patients to be diagnosed early in the disease course. In the early days of such an emergency, when it is unlikely that enough units will be tested, physicians may give two units of CP to increase the likelihood that patients will receive treatment. sufficient antibodies. Skeletal versions of online training, data collection, and analysis systems also need to be developed. Steps should be taken to ensure that adequate supplies of the disposable items required for CP collection using plasma apheresis techniques are available.
The good news is that most of what needs to be done can simply build on the experiences and approaches developed in 2020.
However, the best opportunity to do better next time is to plan outpatient administration of high-titer CP on a large scale to patients diagnosed in the earliest stages of the disease. Hospitals are ideal for administering blood products, but during a major flu or disease to let. for the administration of 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 should identify areas where CP can be transfused to outpatients who are at high risk for progression and death, as this therapy is most effective when given early. In this respect, CP for Covid-19 was as effective as monoclonal antibody therapies in preventing hospital admission when administered within five days of the onset of symptoms.
Ambulatory administration on a large scale requires 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 may also be necessary. Outpatient administration may also require repurposing personnel, such as paramedics, to initiate IV catheters and assist in administering the CP. Digital tools can direct symptomatic individuals to the best location for them. Local solutions with coordinated teamwork across the healthcare and non-healthcare communities are paramount, as is regulatory flexibility.
The planning required to generate what we have outlined above can begin once modest resources are available to rebuild the academic, government, and nonprofit network from Covid. Once that network is re-established, it can go beyond the informal conversations and communications that are happening now. By participating 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 led the US Expanded Access Program for Convalescent Plasma. R. Scott Wright is a professor of medicine at the Mayo Clinic, chairs the IRB and Human Research Protection Program, and worked with Dr. Joyner as co-leader at the USCPS. Arturo Casadevall is chairman 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.