Opinion | COVID Convalescent Plasma Finds a Therapeutic Role

In the dark days of the early COVID-19 pandemic, when there was no known therapy, COVID-19 convalescent plasma (CCP) brought a ray of hope. COVID-19 survivors, community organizers, clinicians, regulators, and blood bankers collaborated to quickly bring CCP to patients. First used at the end of March 2020 in the U.S., 40% of all hospitalized patients were being treated with CCP by October 2020, considerable progress for a treatment without pharmaceutical industry support.

Since those early days, CCP use has largely fallen off based on insufficient evidence of efficacy in hospitalized patients and the availability of other therapies. But growing evidence has shown benefits of CCP in a population with diminished treatment options and vaccine responses: the immunocompromised. This population encompasses about 3% of the population and their needs have been relatively neglected in treatment guidelines during the COVID-19 pandemic.

A Review of CCP History and Data

Guided by historical principles of antibody therapy dictating early use that were increasingly affirmed by contemporary data, more clinicians began to treat COVID-19 patients with CCP as rapidly as possible after hospital admission during the beginning of the pandemic. The FDA issued an Emergency Use Authorization (EUA) for inpatient CCP use in August 2020. However, several randomized controlled trials (RCTs) then reported no benefit of CCP in hospitalized COVID-19 patients. These trials, conducted mostly abroad, tested CCP in critically ill patients, some using CCP units without sufficient antibody content. Negative results from these trials were generalized to all COVID-19 patients, irrespective of their stage of disease, contributing to a precipitous decline in CCP use by early 2021. The concurrent approval and increased availability of remdesivir, which is also most effective in the early stage of COVID-19 infection, may also have contributed to diminished CCP demand.

As the pandemic progressed, further evidence showing that CCP was effective when used early and with high antibody content emerged, strengthening support for the FDA EUA in specific groups. However, with evidence of widespread benefit being considered insufficient in the broader patient population, CCP was largely branded as ineffective, collections dropped, and little or no CCP was available when Omicron surged in early 2022.

Unfortunately, Omicron defeated most monoclonal antibodies that were effective in ambulatory patients earlier in the pandemic. The loss of monoclonal antibody therapies was a serious blow to immunocompromised patients, especially those with B cell deficiencies who cannot make their own neutralizing antibody responses or respond to vaccines, which may lead COVID-19 to recur or persist in a smoldering form.

CCP in the Immunocompromised

What other therapies are available for immunocompromised patients? These patients respond well to CCP, including much later in their illness than non-immunocompromised patients. The continued needs of immunocompromised patients and the discovery that CCP obtained from vaccinated convalescent donors possess extremely high levels of antibodies that neutralize all known variants to date, including Omicron, have promoted a CCP comeback. CCP use is now recommended for immunocompromised patients by multiple major professional organizations, including the Infectious Diseases Society of America (IDSA) and the Association for the Advancement of Blood and Biotherapies (AABB).

In December 2021, the FDA expanded its CCP authorization to include ambulatory, as well as hospitalized, immunocompromised patients. CCP is polyclonal, making it more resistant to viral escape than monoclonal antibodies, which bind a single viral determinant. As such, CCP may have added value in immunocompromised patients who may harbor and/or develop viral mutants that are resistant to monoclonal antibodies or even antiviral drugs. CCP evolves with the virus such that recently collected plasma contains antibodies to circulating viral strains. Increasing population-wide immunity and vaccination makes collection of high titer CCP with activity against current variants feasible. Old CCP with inadequate titers against new variants is not necessarily thrown away since it can be used as regular plasma.

When the first SARS-CoV-2 variants emerged, the concern that CCP could select for variants was raised. This idea was fueled by case reports of the identification of antibody-resistant variants in CCP-treated patients, with the caveat that in such reports, low titer CCP was used. Over time, new variants still emerged even though CCP use ceased. This is consistent with continued viral evolution in the setting of widespread viral transmission. In fact, based on theory and accumulating evidence, high titer CCP, which binds a multitude of viral determinants, is less likely to lead to emergence of antibody-resistant variants than monoclonal antibodies, which only bind one viral determinant. Typically, recently collected convalescent plasma binds ancestral and novel variants. In keeping with this broad activity, CCP successfully eliminated resistant virus that arose in immunocompromised patients treated with monoclonal antibodies. Therefore, we believe CCP is the best option in immunocompromised patients with high viral loads who are at risk for selecting resistant variants. In this regard we note that monoclonal antibody therapies have significantly reduced activity against the newer omicron variants.

Our group works with organizations representing the needs of immunocompromised patients to provide educational materials and insure continued CCP availability. These efforts are necessary to sustain an infrastructure sufficient to identify and collect CCP units for ongoing use. As we learned during the Omicron wave when CCP was suddenly scarce, the infrastructure for CCP supply is dependent upon extraordinary efforts by a blood banking industry already stretched to the limit to meet ongoing demands for blood products. Continued CCP availability amid continued viral evolution requires an informed patient community that knows of this treatment, clinicians who know when and how to use it effectively, and an infrastructure that can support its use.

The authors comprise the leadership group on the COVID-19 Convalescent Plasma Project (CCPP19). Arturo Casadevall, MD, PhD, is a Bloomberg Distinguished Professor and chair of the Department of Molecular Microbiology and Immunology at Johns Hopkins University School of Public Health. Jeffrey P. Henderson, MD, PhD, is associate professor of medicine and molecular microbiology at Washington University School of Medicine. Brenda J. Grossman, MD, MPH, is medical director of transfusion medicine services and a professor at Washington University. Michael J. Joyner, MD, is Caywood Professor of Anesthesiology at the Mayo Clinic. Shmuel Shoham, MD, is a professor at Johns Hopkins School of Medicine. Nigel Paneth, MD, MPH, is Emeritus University Distinguished Professor of Epidemiology & Biostatistics and Pediatrics & Human Development at Michigan State University. Liise-anne Pirofski, MD, is Selma and Dr. Jacques Mitrani Chair in Biomedical Research and professor and chief of the Division of Infectious Diseases at Albert Einstein College of Medicine and Montefiore Medical Center.