The FDA’s withdrawal of its authorization for Evusheld, a monoclonal antibody therapy used to prevent and treat Covid-19, leaves no monoclonals available for this purpose. Another monoclonal, bebtelovimab, used to treat Covid-19, was withdrawn late last November. The FDA pulled its approval for these therapies because they were no longer effective against the newer SARS-CoV-2 variants circulating in the United States.
But an underused antibody alternative exists: Covid convalescent plasma (CCP). This is plasma rich in anti-Covid-19 antibodies that can be harvested from donors who have recently recovered from an infection. When used properly, it remains highly effective at reducing hospitalizations and death in people with Covid-19, and prevention studies in uninfected immunocompromised patients are being planned.
Unlike monoclonal antibodies, which can be defeated by new SARS-CoV-2 variants, CCP collected from vaccinated donors after recent breakthrough infections (VaxCCP) evolves with the variants and retains the ability to neutralize them. What makes CCP an even more promising therapy is that there are now many potential donors available in the U.S. who have been vaccinated and had recent breakthrough infections.
As with the once-effective monoclonal antibodies, CCP given to high-risk Covid-19-positive outpatients dramatically reduces the risk of hospitalization. Since studies supporting this use were conducted before the availability of VaxCCP, we believe that this more potent second-generation form of CCP will be even more effective than first generation used in 2020 and 2021.
Covid convalescent plasma given early in the course of hospitalization to less severely ill patients helps prevent deaths, something that was never demonstrated with monoclonal antibodies. We stress again that these observations were made with first-generation CCP, making it reasonable to imagine that the more potent second-generation will be at least as effective — or may be more effective — than first-generation CCP.
Immunocompromised people are especially vulnerable to SARS-CoV-2 infection. Many are unable to mount an antibody response to vaccination or infection. As a result, they are at high risk for poor outcomes, including death. Some immunocompromised people develop smoldering cases of Covid-19 that last for months or years. While their immune suppression apparently limits the risk of life-threatening pneumonia and acute respiratory distress syndrome, these lingering infections make these individuals veritable variant generators.
An array of data, including randomized controlled trials and careful retrospective studies, show a clear survival benefit when CCP is given to immunocompromised individuals who test positive for SARS-CoV-2. There are also impressive case reports and case series showing that Covid convalescent plasma, especially VaxCCP, is effective in patients with smoldering Covid-19.
So why isn’t CCP being more widely used? While the data on its effectiveness and appropriate use case is now clear three years into the pandemic, the path to clarity was long and twisted. Four important challenges emerged.
First, use of CCP at scale early in the pandemic was unexpected, as the Expanded Access Program designed to explore it grew beyond what anyone imagined when it started in April 2020. Even though data from the program showed a clear association between antibody dose, time to treatment, and survival, critics and evidence based medicine purists could always ask, “But where is data from the randomized controlled trial?” This concern was likely amplified by the rollout of data from the Expanded Access Program, including some confusion about the reduction in mortality communicated by then-FDA Commissioner Stephen Hahn at an August 2020 White House event immediately before the Republican National Convention, which politicized the therapy.
Second, the early “major” RCTs that tested the efficacy of CCP on survival in hospitalized patients tested the wrong use case. These studies treated patients who were too sick for too long to benefit from antibody therapy. But the major “negative” trials all showed evidence of effectiveness among people who received CCP earlier, who were not already desperately ill, who were immunocompromised, or who received the most antibodies. Unfortunately, these positive signals, which were consistent with impressive real-world data on Covid-19 and CCP, were buried under the top-line results.
Third, therapy is dominated by well-characterized small-molecule compounds with known pharmacologic characteristics that are given at fixed doses. They are embedded in treatment algorithms and decision trees. By contrast, blood products are far more variable than drugs and are typically titrated for each patient to some combination of physiological and biomarker-based endpoints. This variability, plus the limitations of the early trial results, may have limited enthusiasm for Covid convalescent plasma by some physicians, and also made it harder to incorporate into guidelines issued by professional societies and governmental agencies.
Such guidelines now dominate clinical practice in many large, consolidated health systems. Unfortunately, guidelines can be many months behind state-of-the-art data. For example, the WHO advised against using Covid convalescent plasma in December 2021 relying on data from the previous summer and has yet to update its guidance. These issues are especially acute during a fast-moving pandemic in an era when scientific communication has been accelerated via tools like preprints. Advocates for immunocompromised people believe that the lack of a full throated endorsement for CCP by the NIH Covid-19 guidelines panel has blunted enthusiasm and access to a potentially lifesaving therapy for them.
A fourth and final challenge has been the supply of Covid convalescent plasma in light of the confusion we have enumerated. The U.S. blood collection and banking system is a remarkable network of not-for-profit organizations. Early in the pandemic, the financial risk they took to collect and distribute CCP at scale was buffered by funding from the federal government. This funding was discontinued in 2021 and as a result, the collection and distribution of CCP declined rapidly during 2021.
With the loss of the remaining monoclonals from the anti-Covid armamentarium, immunocompromised people have no prophylactic options and will continue to need antibodies should they contract Covid-19. In this context, VaxCCP sufficient to treat between 500 and 1,000 immunocompromised people per week in the U.S. should be collected and distributed. (For context, through the Expanded Access Program and subsequent emergency use authorization, more than 500,000 units of Covid convalescent plasma were collected and delivered to hospitals large and small across the country.) Because the cost of CCP is modest compared to other treatment options — hundreds of dollars per unit of CCP compared to thousands per dose for monoclonals, even when purchased in bulk by the U.S. government — this would require only moderate subsidies to the U.S. blood collection and banking system. To standardize how CCP is used, guideline-making groups, including the National Institutes of Health, should partner with content experts to educate patients, physicians, and health systems about how to order and obtain VaxCCP. A prevention trial of VaxCCP in immunocompromised patients should also be initiated.
As the U.S. and the world enter the fourth year of the pandemic, Covid convalescent plasma is the “Little Engine That Could” of antibody therapy. With coordination and planning, we believe it should be poised to play a key role in the treatment of Covid-19 well into the future.
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. Nigel Paneth is a professor emeritus of pediatrics and epidemiology at Michigan State University. Arturo Casadevall is chair of the Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health and chair of the National Covid-19 Convalescent Plasma Project. The views expressed here are those of the authors alone.
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