Data from rigorously controlled clinical trials of convalescent plasma are few, underscoring the need to evaluate its use objectively for a range of indications (e.g., prevention vs treatment) and patient populations (e.g., age, comorbid disease).
An overview of convalescent plasma, from evidence of benefit, regulatory considerations, logistical work flow and proposed clinical trials have been recently published by USA research groups coordinated by John Hopkins University.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), has spurred a global health crisis. To date, there are no proven options for prophylaxis for those who have been exposed to SARS-CoV-2, nor therapy for those who develop COVID-19.
Immune (i.e. “convalescent”) plasma refers to plasma that is collected from individuals, following resolution of infection and development of antibodies. Passive antibody administration through transfusion of convalescent plasma may offer the only short-term strategy to confer immediate immunity to susceptible individuals.
There are numerous examples, where convalescent plasma has been used
successfully as post-exposure prophylaxis and/or treatment of infectious diseases, including other outbreaks of coronaviruses (e.g., SARS-1, Middle East Respiratory Syndrome [MERS]).
Convalescent plasma has also been used in the COVID-19 pandemic; limited data from China suggest clinical benefit, including radiological resolution, reduction in viral loads and improved survival.
Globally, blood centers have robust infrastructure to undertake collections and construct inventories of convalescent plasma to meet the growing demand.
Nonetheless, there are nuanced challenges, both regulatory and logistical, spanning donor eligibility, donor recruitment, collections and transfusion itself. Data from rigorously controlled clinical trials of convalescent plasma are also few, underscoring the need to evaluate its use objectively for a range of indications (e.g., prevention vs treatment) and patient populations (e.g., age, comorbid disease).
Why to use convalescent plasma in Covid-19
The antibodies present in immune (i.e. “convalescent”) plasma mediate their therapeutic effect through a variety of mechanisms.
- Antibody can bind to a given pathogen (e.g. virus), thereby neutralizing its infectivity directly,
- direct inhibition of NETs (Neutrophil Extracellular Traps), of other neutrophil serine proteases with plasma SLPI, Serpin1 and alfa1antitrypsin and other cytokines-mediated pathways may also contribute to its therapeutic effect.
- Non-neutralizing antibodies that bind to the pathogen —but do
not interfere with its ability to replicate in in vitro systems — may also contribute to prophylaxis and/or enhance recovery.
- Importantly, passive antibody administration offers the only short-term strategy to confer immediate immunity to susceptible individuals. This is particularly the case in the setting of a novel, emerging infectious disease such as SARSCoV-2/COVID-19.
- While fractionated plasma products (e.g. hyperimmune globulin, monoclonal antibodies) and/or vaccination may offer durable therapeutic options, human anti-SARS-CoV-2 plasma is the only therapeutic strategy that is immediately available for use to prevent and treat COVID-19.
When to use convalescent plasma in Covid-19
Few controlled trials have been performed to evaluate the efficacy of convalescent plasma, in large part due to its emergency application in times of epidemics.
At least five clinical trials have been proposed to evaluate human anti-SARS-CoV-2 plasma for the prevention and treatment of COVID-19.
First, is the use of human anti-SARS-CoV-2 plasma as post-exposure prophylaxis: a randomized, blinded Phase 2 trialwill be undertaken to compare the efficacy and safety of human anti-SARS-CoV-2 plasma vs. control (SARS-CoV-2 nonimmune plasma) among adults (age ≥18yrs) who have had close contact exposure to COVID-19, but have not yet
manifested symptoms. For US Centers for Disease Control and Prevention (CDC), close contact exposure refers to being within approximately 6 feet (2 meters) of a patient with COVID-19 for a prolonged period of time (without personal protective equipment (PPE). Close contact may occur while caring for, living with, visiting, or sharing a healthcare waiting area or room with a COVID-19 case, or having direct contact with infectious secretions of a COVID-19 infected individual (e.g., being coughed on) without PPE. If found to be safe and effective, post-exposure prophylaxis would offer an intervention for vulnerable populations (e.g. health care workers, immunocompromised patients, individuals with cardiovascular and respiratory disease, nursing home residents) following exposure. Prevention would confer direct clinical benefit for those at risk. Moreover, societal benefits would be wide-ranging, including the protection of frontline workers in the COVID-19 pandemic.
The second trial will evaluate whether human anti-SARS-CoV-2 plasma can help patients initially presenting with mild disease. The target population would comprise symptomatic individuals with confirmed SARS-CoV-2. The endpoints would be resolution of symptoms, prevention of hypoxemia on room air or progression to severe disease, reflecting an interest in averting complications (and required hospitalization).
Third, the effect of human anti-SARS-CoV-2 plasma for moderately ill patients would be studied. The target population is hospitalized patients with COVID-19 who manifest symptoms—albeit—not of sufficient acuity to warrant ICU admission (and specifically mechanical ventilation). Staving off progression to critical illness could avoid overburdening of critical care resources, currently in shortage, such as mechanical ventilators.
A fourth trial will evaluate human anti-SARS-CoV-2 plasma treatment as a rescue intervention in patients who require mechanical ventilation due to COVID-19. This target group is important; however, it is also a group for which data are most difficult to interpret given the likely presence of confounding variables including other putative therapies for COVID-19.
Finally, a fifth trial will examine safety and pharmacokinetics convalescent plasma in high-risk pediatric patients. Children of all ages are susceptible to COVID-19 infection; while comparatively rare, severe disease and even deaths have been described in children, underscoring the need to address risk to children.