August 2025
INTRODUCTION —
Convalescent plasma and/or hyperimmune globulin have been used to provide passive immunity in several notable viral outbreaks.
This topic discusses practical aspects of how convalescent plasma for coronavirus disease 2019 (COVID-19) was obtained and administered, especially during the early years of the pandemic.
Separate topic reviews discuss COVID-19 management and general information about plasma administration:
●COVID-19 – (See "COVID-19: Evaluation and management of adults with acute infection in the outpatient setting" and "COVID-19: Management in hospitalized adults" and "COVID-19: Management of the intubated adult".)
●Plasma – (See "Clinical use of plasma components" and "Pathogen inactivation of blood products".)
GENERAL CONCEPTS
History of collection and use during the pandemic
●Collection – Early in the COVID-19 pandemic, convalescent plasma was collected by major blood centers in the United States and was reimbursed through a government-funded mechanism.
●Waning demand and resource allocation – The advent of effective vaccines and vaccine coverage, coupled with acquisition of herd immunity through natural exposure and/or vaccination, resulted in waning demand for the product, and blood centers subsequently reduced or stopped collection.
Other factors that contributed to the reduced demand included the growing body of evidence that COVID-19 convalescent plasma was not effective in late-stage disease. Some evidence supported use in some severely ill individuals, but this magnitude of disease severity became less common as the pandemic subsided [1]. (See "COVID-19: Management in hospitalized adults", section on 'Limited role for antibody-based therapies (monoclonal antibodies and convalescent plasma)'.)
Further, there were unprecedented blood shortages in the early years of the pandemic, and use of personnel to collect convalescent plasma competed for critical frontline staff.
●Narrowing indications – As successive viral variants emerged, some blood centers intermittently continued collections, albeit not in quantities that matched the scale of the early phase of the pandemic (during 2020 and the early part of 2021). By 2024, most conventional plasma units contained antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, indicating high rates of herd immunity from exposure to the virus and/or vaccination; antibody levels in conventional plasma became similar to levels in convalescent plasma [2].
By 2025, use of COVID-19 convalescent plasma became very limited and largely confined to immunocompromised patients, such as those who are unable to mount effective humoral immune responses against the causative virus or from vaccination, typically due to primary or acquired B cell deficiency [3].
In 2025, a blood center obtained formal US Food and Drug Administration (FDA) approval for use of COVID-19 convalescent plasma to treat immunocompromised patients with SARS-CoV-2 infection [4]. (See 'Access to therapy' below and "COVID-19: Considerations in patients with cancer", section on 'Management of COVID-19' and "COVID-19: Evaluation and management of adults with acute infection in the outpatient setting", section on 'Persistent infection in immunocompromised patients'.)
The global experience during the pandemic provided invaluable insights into how to mobilize plasma collection to support clinical and research use, and this experience will be important for future outbreaks and pandemics [5-8].
●Mechanisms for access
•April 2020 (EAP) – In April 2020, the FDA provided an Expanded Access Program (EAP) to institutions and an emergency investigational new drug (eIND) pathway for individuals to obtain convalescent plasma. The EAP was the major mechanism for obtaining convalescent plasma in the United States. At the time of the EAP termination in late August 2020 (due to implementation of the EUA mechanism), over 94,000 patients with severe or life-threatening COVID-19 had been transfused with convalescent plasma through the program. The Mayo Clinic was the data coordinating center for the EAP [9,10].
•August 2020 (EUA) – In late August of 2020, the FDA granted Emergency Use Authorization (EUA) for COVID-19 convalescent plasma for individuals hospitalized with COVID-19 based on the findings that it is safe and may be effective [11,12]. This authorization was extended [13].
The EUA replaced the EAP as the primary mechanism for obtaining convalescent plasma outside of a clinical trial. Originally, it specified antibody levels that qualified for high-titer and low-titer classification of units, understanding that the optimal titer remained unknown. Subsequently, the EUA was revised to specify the exclusive use of "high-titer" units. (See 'Antibody measurements and definition of "high titer"' below and 'Optimal timing and titer (or antibody level)' below.)
Other differences from the EAP included greater ease of access and reduced administrative burden (no institutional review board [IRB] required) with no specific reporting requirements [14]. A grace period was allowed through February 2021, during which institutions could use existing inventories of convalescent plasma obtained before the EUA [15]; in February 2021 this was extended to June 1, 2021, with early transition to exclusively high-titer inventories encouraged. (See 'Optimal timing and titer (or antibody level)' below.)
•January 2025 (BLA) – In 2025, a biologics licensing application (BLA) was obtained successfully for use of COVID-19 convalescent plasma for immunocompromised patients [4]. This leaves some uncertainty about the continuation of the EUA for COVID-19 convalescent plasma in light of formal approval under BLA. It was previously stated that the EUA will be revoked once there are "adequate, available, approved alternatives to the COVID-19 convalescent plasma provided through emergency use" [4].
Overview of products — Convalescent plasma and hyperimmune globulin are obtained from individuals who have recovered from an infection and have generated an immune response against the infecting pathogen. Neutralizing antibodies are thought to be the main active component; other immune mediators may also contribute.
Until herd immunity has been attained (through mass vaccination and/or natural infection), these products have the potential to provide passive antibody-based immunity to previously unexposed individuals to reduce the risk of disease or to lessen its clinical impact if already infected. (See 'Mechanism of action' below.)
●Convalescent plasma – Convalescent plasma (also called immune plasma or hyperimmune plasma) is similar to standard Fresh Frozen Plasma (FFP) or Plasma Frozen Within 24 Hours After Phlebotomy (PF24). (See "Clinical use of plasma components", section on 'Plasma products'.)
The major difference from other plasma products is that convalescent plasma is obtained from donors who have recovered from a specific infection (or, in principle, those who have been vaccinated, although in the United States convalescent plasma based on vaccination alone [vax-plasma] was not approved). (See 'Donation after COVID-19 vaccination (vax-plasma)' below.)
Ideally, it contains polyclonal antibodies to the pathogen at sufficient titer and biologic activity to provide passive immunity to the recipient. (See 'Plasma donation' below.)
Convalescent plasma is typically obtained by apheresis in a blood center, although it can also be obtained from whole blood units. The plasmapheresis collection takes approximately one to two hours. Plasma proteins are replenished rapidly in the donor, and according to the US Food and Drug Administration (FDA), individuals can donate plasma by apheresis as frequently as twice in a seven-day period (at least two days apart), as long as the health of the donor is preserved [16]. (See 'Apheresis versus whole blood collection' below.)
Convalescent plasma is administered as a standard plasma transfusion; typically, one or two units are given. Typically, it will come from a blood center frozen and is thawed prior to use. (See 'Optimal dose and frequency' below.)
During the COVID-19 pandemic, COVID-19 convalescent plasma became routinely available in the United States, under an Emergency Use Authorization (EUA) by the FDA; over 500,000 units of convalescent plasma were administered either as part of an EAP, EUA, or clinical trial [17]. (See 'Access to therapy' below.)
Historically, although convalescent plasma had been made available for other pathogens at times of disease epidemics or pandemics, its usage had not been as widespread as during the COVID-19 pandemic, nor had its efficacy been studied in as much detail.
Once an epidemic has subsided, convalescent plasma is likely to become unavailable unless a process has been put in place to bank plasma for future use; plasma has an expiration date of one year from collection. (See 'Maintaining the supply' below.)
Optimal characteristics of convalescent plasma include [18,19]:
•Sufficient titer of the relevant antibodies (see 'Optimal timing and titer (or antibody level)' below)
•Lack of infectious particles (see 'Infectious disease screening and pathogen inactivation' below)
•Demonstrated safety and efficacy when used for the specific condition (see "COVID-19: Management in hospitalized adults", section on 'Limited role for antibody-based therapies (monoclonal antibodies and convalescent plasma)' and 'Safety' below)
●Hyperimmune globulin – During the COVID-19 pandemic, manufacture of hyperimmune globulin was pursued in parallel with investigation of convalescent plasma [18]. Hyperimmune globulin is a licensed product manufactured from convalescent plasma from thousands of donors and is subject to pathogen reduction technologies and other standardization [20]. It consists of a concentrated polyclonal immune globulin fraction with well-defined properties. (See 'Hyperimmune globulin' below.)
●Monoclonal antibodies – Monoclonal antibodies (mAbs) with neutralizing potential are another approach to providing passive immunity [21]. Each mAb recognizes a single antigen. Use in COVID-19 is discussed separately. (See "Overview of therapeutic monoclonal antibodies", section on 'Target is an infectious organism' and "COVID-19: Evaluation and management of adults with acute infection in the outpatient setting", section on 'Therapies with limited role or uncertain benefit'.)
Mechanism of action — Convalescent plasma can provide passive immunity in the form of neutralizing antibodies (and/or possibly other immune mediators) against the infectious pathogen. Various immunoglobulin (Ig) subclasses including IgG, IgM, and IgA may be useful.
The mechanism of action is not well understood.
●Antibodies that bind to a virus can potentially decrease viral entry into cells and enhance viral clearance via antibody-dependent phagocytosis or antibody-dependent cellular toxicity; the mechanism for viral clearance of the virus that causes COVID-19 may include proteolysis of the spike protein [22-24].
●Antibody factors other than antibody titer (notably, epitope specificity) may predict functionality of convalescent plasma [25].
●Proinflammatory interleukin 6 (IL-6) may contribute [26].
For individuals who have not previously been exposed to or vaccinated against the pathogen, it can take as long as two to three weeks to mount an antibody response [27]. Providing antibodies has the potential to prevent illness or shorten the duration or severity of illness sufficiently to prevent serious or life-threatening complications [19,28]. (See "The adaptive humoral immune response", section on 'Passive humoral immunity'.)
Once infection has progressed to the point that organ damage or other consequences of massive inflammation have occurred, convalescent plasma has not been shown to provide benefit. This is the rationale for providing plasma early in the disease course [28-32]. (See 'Optimal timing and titer (or antibody level)' below.)
SARS-CoV-2 has four major structural proteins, two of which appear to be the main antigenic targets [33-35]:
●Spike protein – The spike protein (S) is a transmembrane surface glycoprotein that binds to the angiotensin-converting enzyme 2 (ACE2) receptor on respiratory epithelial cells and gastrointestinal cells and mediates viral entry [36]. In principle, anti-S, especially antibodies targeting its receptor-binding domain (RBD), might block viral entry into respiratory epithelium, which could reduce the severity or duration of infection [28]. Many variants of concern cause amino acid substitutions that affect the spike protein. Studies of the mechanism of action are ongoing. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Viral evolution and variants of concern'.)
●Nucleocapsid protein – The nucleocapsid protein (N) interacts with the viral nucleic acid (RNA) and contributes to the assembly of functional virions [37]. Antibodies to N generally develop along with anti-S, but their role in recovery from infection is less well understood.
Assays that rely on antibody binding, such as enzyme-linked immunosorbent assay (ELISA)-type assays, have been developed for antibodies against both S and N. Testing of individuals recovering from COVID-19 suggest that in the majority, IgM anti-S and anti-N begin to appear within approximately one week and continue to increase over two weeks, while IgG appears a few days later (typically, by the third week), with faster class switching in non-intensive care unit (ICU) patients than in ICU patients [33]. ELISA-type immunoassays and biologic (functional) assays for antiviral activity of convalescent plasma are in use, as discussed below. (See 'Antibody measurements and definition of "high titer"' below.)
Comparison with other antibody-based therapies — Other antibody therapies include monoclonal antibodies and hyperimmune globulin. (See 'Overview of products' above.)
There are several differences among these therapies, and none have been compared with each other in randomized trials, making it challenging to assess relative efficacy.
●Advantages and disadvantages of purified antibody products
•Advantages include greater standardization and avoidance of exposure to plasma, which can cause transfusion reactions.
•Disadvantages include reduced efficacy when viral antigenic drift occurs, high cost, and time required for manufacture (measured in months to years), contributing to lack of availability [38-40].
●Advantages and disadvantages of convalescent plasma
•Advantages include ease and rapidity of collection, potential for greater likelihood of matching antibody specificity to currently circulating viral variants, polyclonality, lower cost, and potentially greater availability [41]. The first monoclonal antibody against SARS-CoV-2 took nearly a year to become available, whereas production of COVID-19 convalescent plasma began much earlier in the pandemic (by January 2020, within weeks of the first cases).
Experience with other viruses — Prior to the COVID-19 pandemic, convalescent plasma had been applied to diverse pathogens with mixed success.
●Junin virus – The best evidence for the efficacy of convalescent plasma in other viral infections comes from a randomized trial in patients with Argentine hemorrhagic fever (caused by Junin virus, an arenavirus), in which 217 patients were assigned to receive 500 mL of convalescent plasma or control plasma within eight days of symptom onset [42]. Mortality was lower in the convalescent plasma group (1 versus 16.5 percent). In comparison, patients treated after nine or more days from symptom onset did not have a survival benefit.
●Other coronaviruses and influenza viruses – A 2015 meta-analysis identified several observational studies that suggested reduced mortality and other clinical benefits when convalescent plasma was used for other coronaviruses (such as severe acute respiratory syndrome virus [SARS]) and influenza viruses [43]. The reviewed studies were generally considered of low quality due to high risk of bias and lack of control groups.
PLASMA DONATION
Who can donate — Blood centers may suspend or restart collection of convalescent plasma depending on society recommendations and demand. (See 'Maintaining the supply' below.)
The need for convalescent plasma donation for COVID-19 has declined, with massive collection and use during the first year, reduction in use by late 2021, intermittent collection in 2022, and collection by only three or four centers in 2023. (See 'History of collection and use during the pandemic' above.)
As of 2025, demand for COVID-19 convalescent plasma decreased due to limited indications, and only a few centers are collecting convalescent plasma.
Approaches to donor recruitment during the early phases of the pandemic varied depending on the region of the world, type of health care system, local disease prevalence, and evolution of the pandemic. Initial strategies relied on donor self-identification, social media campaigns, and clinician referrals. Plasma donors must meet standard criteria for blood donation and must have fully recovered from COVID-19 for 10 days following complete resolution of symptoms (previously, the interval was two weeks). Historically, receipt of an investigational (non-licensed) vaccine has required a 12-month deferral period, but this policy was modified for COVID-19 to allow for convalescent plasma donation, with the proviso that the individual must meet all other convalescent plasma donation criteria including prior COVID-19 diagnosis or evidence of SARS-CoV-2 antibodies from natural infection. (See "Blood donor screening: Medical history and deferral criteria".)
The length of time that donors continue to produce high titers of antibodies to SARS-CoV-2 (and hence the period they can continue to donate convalescent plasma) is variable.
●One study suggested that many individuals had persistent antibodies for at least four months [44].
●Another serial testing study suggested that the optimal time for high antibody levels is between four to eight weeks [45].
●In a cohort of nearly 300 recovered individuals, anti-RBD antibody levels were stable over 10 weeks but declined over the course of several donations [46]. Some donors may continue to produce high levels of antibodies outside this range.
US Food and Drug Administration (FDA) recommendations state that the donation should be within six months of diagnosis. Only plasma from donors who qualify at the time of donation will be used.
Information from clinical trials suggests that many individuals who have recovered from COVID-19 did not have sufficient antibody titers to provide benefit, emphasizing the importance of testing the antibody level or titer prior to transfusing the plasma. (See 'Antibody measurements and definition of "high titer"' below.)
Advanced age, male sex, and severity of illness were associated with high-titer antibody responses [47]. However, titer cannot be inferred from clinical criteria alone.
●A study that evaluated 126 potential COVID-19 convalescent plasma donors at a median of 43 days after an initial positive test for infection found that males had higher antibody levels than females, older individuals had higher levels than younger individuals, and those who were hospitalized had higher levels than outpatients [47]. Having been hospitalized was the strongest predictor of high antibody levels.
●A study that evaluated immune responses in 175 individuals recovering from mild COVID-19 reported neutralizing antibodies, assayed by pseudovirus neutralization, in most individuals within 10 to 15 days [23]. Up to 30 percent had very low-titer neutralizing antibodies; in approximately 6 percent, the antibodies were below the limits of detection. Titers of neutralizing and spike-binding antibodies were higher in individuals who were older (60 to 85 years) and middle-aged (40 to 59 years). There was a trend toward higher neutralizing antibody titers in males versus females and a positive correlation with C-reactive protein (CRP) levels. (See "Acute phase reactants".)
●A study that compared immune responses in 37 asymptomatic individuals with confirmed SARS-CoV-2 infection and 37 symptomatic individuals found that the symptomatic individuals had slightly higher levels of virus-specific IgG and slightly longer antibody persistence during the first eight weeks after hospital discharge [48].
Maintaining the supply — Supply and demand of convalescent plasma varied over the course of the pandemic. Challenges to maintaining a supply occur after an outbreak starts to resolve, as the number of recently affected, highly motivated individuals may decline, and the infrastructure and resources for collecting and/or storing convalescent plasma may no longer exist. Demand may also wane as other therapies are developed. (See "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy'.)
General approaches for maintaining the supply for future outbreaks or a second wave of an outbreak might include:
●Banking units for future use.
●Immunizing selected individuals to generate high-titer units.
●Immunizing animals, as is done with rabies immune globulin from horses.
●Generating immortalized lymphocytes to produce monoclonal or polyclonal antibodies. (See 'Hyperimmune globulin' below.)
PREPARATION
Apheresis versus whole blood collection — Plasma can be obtained via apheresis or separated from whole blood collected as a standard blood donation.
Apheresis collection is strongly preferred [19]:
●Greater yield – A single apheresis donation can provide two to four units of convalescent plasma, versus one unit of plasma from one unit of donated whole blood.
●More frequent donation – Apheresis donations can be performed from the same person as often as twice in a seven-day period, according to guidance from the US Food and Drug Administration (FDA) [49]. In practical terms, repeated apheresis plasma donation, if indicated, would likely be performed at approximately two- to four-week intervals. Donations of whole blood (from which plasma is separated) require a longer recovery (at least 56 days; varies by center). (See "Blood donor screening: Overview of recipient and donor protections", section on 'Donation frequency'.)
●Greater donor safety – Since apheresis only removes plasma and not red blood cells (RBCs), individuals are not made transiently anemic. General complications of apheresis plasma donation are presented separately. (See "Blood donor screening: Overview of recipient and donor protections", section on 'Complications of apheresis'.)
Apheresis has been the major mode of collection in high-income countries. However, the higher technical complexity and associated costs may limit its use in low- and middle-income countries [50]. (See 'Resource-limited settings' below.)
Donation after COVID-19 vaccination (vax-plasma) — COVID-19 vaccination is not a contraindication to donating convalescent plasma, but, in the United States, vaccination in the absence of SARS-CoV-2 infection does not qualify an individual to donate. This is the case even though plasma from vaccinated individuals ("vax-plasma") elicits high-titer antibody response with demonstrated efficacy against the original virus and subsequent variants of concern [51].
●One study that tested plasma pre- and post-vaccination found increases in neutralizing activity of several logs and against multiple variants [52].
●Other studies demonstrated that vaccination following COVID-19 led to further increases in antibody levels [53,54].
Individuals who have been vaccinated for COVID-19 can donate regular plasma, platelets, and RBCs, provided standard donation criteria are met. (See "Blood donor screening: Medical history and deferral criteria".)
Antibody measurements and definition of "high titer" — Antibodies are typically measured using either a functional assay for neutralizing activity against the virus or a pseudovirus. This is done by making serial dilutions of the plasma sample to derive a quantitative titer of neutralizing antibody or in a serologic assay that measures antibody binding to specific viral epitopes. (See 'Types of assays' below.)
Efficacy is believed to depend on sufficient antibody levels; optimal antibody thresholds were uncertain early in the pandemic.
Under the revised Emergency Use Authorization (EUA) recommendations from the FDA, nine assays were approved to qualify units of COVID-19 convalescent plasma for clinical use in hospitalized patients and to be labeled as high titer [55]. Each assay had its own criteria for determination of the high-titer designation. This classification was consistent with guidance from the Association for the Advancement of Blood and Biotherapies [17,29]. (See 'History of collection and use during the pandemic' above.)
Unlike hyperimmune globulins and monoclonal antibodies, plasma cannot be concentrated as a means of raising the titer or antibody level.
Donor characteristics that may correlate with antibody titer are discussed above. (See 'Who can donate' above.)
Types of assays — Antibodies can be measured functionally or serologically:
●Bioassays – Bioassays are functional assays that assess the effect of the plasma on virus viability (also called viral neutralization) and are reported as a titer (often referred to as a plaque reduction neutralizing titer [PRNT]). These bioassays are not as commonly used as serologic assays because they require propagation of live virus and require specialized expertise to avoid infection of laboratory or other personnel. They are also difficult to standardize across different laboratories and are logistically complex and have slow turnaround times.
As an alternative, viral components may be expressed in a vector to create a "pseudovirus" that can be used in a neutralization assay [23,56]. In these assays, individual viral proteins (but not live virus) can be expressed in cell culture, and their ability to infect cells can be assayed in the presence and absence of plasma. These assays also have the problem of standardization across different laboratories.
●Serologic binding assays – Many programs use a serologic assay that measures antibody binding to a target antigen in an enzyme-linked immunosorbent assay (ELISA)-type assay or a chemiluminescence assay. Measurements using serologic assays are generally qualitative (ie, positive/reactive versus negative/nonreactive) but can be semiquantitative when reported in terms of signal-to-cutoff (S/C) ratio. Technically speaking, this is not a titer.
Bioassays are more representative of clinical effectiveness, but serologic binding assays are easier to perform, automate, and scale. Correlations between a titer obtained from a live virus or pseudovirus neutralization assay and an S/C ratio reported in a serologic assay may be challenging to infer and will be specific to a given manufacturer's assay. Many studies evaluated the performance characteristics of different assays [23,34,57,58].
Which to assay (donor or unit) — Antibodies (neutralization titer or serologic binding assay) can be measured on a sample collected from the donor or on the plasma unit.
Several approaches were used for qualification of units of convalescent plasma. Early studies collected plasma first and measured the antibody titer on the plasma unit, as this was considered more efficient when serologic assays were not widely available. As testing became more widely available, testing the donor during a pre-donation visit was used.
Infectious disease screening and pathogen inactivation — Convalescent plasma donations undergo the same infectious disease screening as all blood donations. (See "Blood donor screening: Medical history and deferral criteria" and "Blood donor screening: Laboratory testing", section on 'Infectious disease screening and surveillance'.)
Plasma is not routinely tested for the virus that causes COVID-19. The FDA does not recommend testing donated blood for the virus, as respiratory viruses are not known to be transmitted by transfusion [59]. (See "Blood donor screening: Laboratory testing", section on 'Emerging infectious disease agents'.)
Pathogen inactivation may be used to further decrease infectious risk. (See "Pathogen inactivation of blood products".)
Screening for antibodies that mediate hemolysis and TRALI — Other screening for plasma includes:
●Blood type – ABO and RhD type are determined so that ABO-compatible plasma can be transfused. (See 'ABO compatibility' below.)
●Anti-HLA – For previously pregnant female donors, testing for antibodies against human leukocyte antigens (anti-HLA) is recommended to reduce the risk of transfusion-related acute lung injury (TRALI). Ideally, this is undertaken during pre-donation qualification, given that a third of parous females are expected to have anti-HLA antibodies [60]. Units (and donors) with anti-HLA antibodies should not be used for plasma transfusion. (See "Transfusion-related acute lung injury (TRALI)", section on 'Prevention'.)
ADMINISTRATION
Overview of therapeutic considerations — Convalescent plasma may be most appropriate for immunocompromised individuals at risk of severe disease when alternative therapies (direct antiviral agents or monoclonal antibodies) are not available [3]. It may be combined with other disease-specific and supportive care interventions. The plasma should ideally be collected from donors who have recovered from a contemporary or recently circulated variant [61]. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Viral evolution and variants of concern'.)
Recommendations for appropriate use have evolved as new data accrue and are listed separately. (See "Society guideline links: COVID-19 – Transfusion (including convalescent plasma)".)
A 2023 meta-analysis reported that COVID-19 convalescent plasma was associated with a decrease in mortality (risk ratio [RR] 0.63, 95% CI 0.50-0.79) [62].
In the COVIC-19 trial, which randomly assigned 120 immunocompromised individuals with mild COVID-19 to standard of care with or without COVID-19 convalescent plasma, death or hospitalization for COVID-19 occurred in none of the participants in the convalescent plasma arm and in five (9 percent) in the control arm (p = 0.027) [63].
Indications for COVID-19 convalescent plasma are presented separately:
●Selected inpatients with immunocompromising conditions. (See "COVID-19: Management in hospitalized adults", section on 'Limited role for antibody-based therapies (monoclonal antibodies and convalescent plasma)'.)
●Patients with hematologic malignancies. (See "COVID-19: Considerations in patients with cancer", section on 'Management of COVID-19'.)
Available evidence suggests that the greatest likelihood of efficacy will occur when plasma is administered earlier relative to disease onset and with a higher antibody level (or titer) [17]. Trials showing a benefit have used high-titer convalescent plasma early in the disease course, especially in the outpatient setting. (See 'Optimal timing and titer (or antibody level)' below.)
There are challenges in establishing an outpatient convalescent plasma transfusion service, including infrastructure, staffing, infection control, communications, and transport [5].
Optimal timing and titer (or antibody level) — Convalescent plasma was primarily used to improve the clinical course of disease in individuals who were already ill. Limited evidence suggested it was not effective as postexposure prophylaxis [64].
●Timing – Treatment in late disease was not beneficial, consistent with the perceived mechanism of action [65]. (See 'Mechanism of action' above.)
The major trial in outpatients found that administration within nine days of symptom onset provided clinically significant benefit [30].
●Antibody level – The level of antibodies is believed to be an important determinant of efficacy, although the optimal antibody level or titer was not determined. (See 'Mechanism of action' above.)
The clinician who requests the plasma does not specify the titer needed or the assay used. By June 2021, all COVID-19 convalescent plasma transfused under the EUA was required to be "high titer" [66]. (See 'Antibody measurements and definition of "high titer"' above.)
●Early administration, good titer – Randomized trials using convalescent plasma early in the course of disease showed improved survival.
•Outpatients – A 2023 meta-analysis of five randomized trials in 2693 outpatients reported that convalescent plasma reduced the rate of hospitalization (12.2 percent in controls versus 8.5 percent treated with convalescent plasma, relative risk reduction [RRR] 30 percent, 95% CI 12-44 percent; absolute risk reduction 3.7 percent, 95% CI 1.3-6 percent) [67].
•Inpatients – A Cochrane review of randomized trials concluded that convalescent plasma was not effective when given in late-stage disease [65]. A small randomized trial from Spain involving 81 hospitalized individuals within a median of eight days of disease onset found that survival and likelihood of progression was better in the convalescent plasma group (mortality at 15 and 29 days, 0 percent with convalescent plasma and 9 percent in controls) [68]. The trial reached less than 30 percent of the planned target enrollment and as a result lacked statistical power.
●Early administration, insufficient titer – A randomized trial from India in 464 hospitalized individuals with moderate disease did not show a benefit in a composite outcome of survival (85 versus 86 percent) or disease improvement/stabilization at 28 days [69].
●Late administration – There are two reasons that late administration is less likely to be effective:
•Most individuals will have begun to mount their own antibody response by 8 to 10 days after initial infection, and donor plasma may not boost antibody levels above the endogenous response. (See 'Mechanism of action' above.)
•As the disease progresses, severe manifestations may be more strongly associated with the host inflammatory response rather than the virus itself. (See "COVID-19: Clinical features", section on 'Acute course and complications'.)
Randomized trials from Argentina and China found no statistically significant survival benefit with convalescent plasma [70-72]. A randomized trial in the Netherlands in individuals who had been symptomatic for 10 days was stopped when most participants were found to have existing anti-SARS-CoV-2 antibodies [73].
SARS-CoV-2 variants — Convalescent plasma, which has polyclonal antibodies, may be more robust than monoclonal antibodies, although preliminary data suggest that convalescent plasma may be less effective against certain SARS-CoV-2 variants than against the original SARS-CoV-2 virus [74,75]. Despite a possible reduction in efficacy, infection with later-arising variants is not a reason to avoid using convalescent plasma if it is otherwise appropriate.
Convalescent plasma may confer passive immunity to some variants for which monoclonal antibodies are ineffective, since some of the antibodies may recognize altered versions of the spike protein. A study from 2022 found that some units of convalescent plasma were able to neutralize the omicron variant [76]. (See 'Mechanism of action' above.)
Optimal dose and frequency — The optimal dose of convalescent plasma is unknown; institutional or clinical trial protocols for dosing should be followed. Clinical trials have generally used one or two units in adults (approximately 200 to 250 mL per unit). Pediatric dosing is based on body weight.
Several cases reports have used multiple units and repeated dosing in immunocompromised patients, but there are limited data to support this practice and there is no consensus regarding optimal dosing frequency.
●Multiple doses were used in some patients with immunocompromise, but increased efficacy was not established [77,78].
●In a systematic review of immunocompromised individuals, the median dose was 2 units (range 1 to 11 units) [62].
The risk of transfusion-associated circulatory overload (TACO) should be considered if administered over short periods; however, most patients are likely to tolerate doses higher than 200 mL [10].
ABO compatibility — Patients are ABO typed prior to transfusion, and ABO-compatible plasma is typically transfused [5]. Some institutions allow out-of-group plasma transfusion in selected cases (eg, group A units might be used in group B patients, if determined to have a low titer of anti-B). Institutional policy and regulatory guidelines should be followed. (See "Clinical use of plasma components", section on 'ABO matching'.)
Premedications (typically not indicated) — Administration of convalescent plasma is no different from standard plasma transfusion, and the same cautionary measures apply. (See "Clinical use of plasma components".)
Some institutions or clinicians routinely premedicate with an antihistamine and/or acetaminophen. There is little objective evidence that this is effective, and premedications are typically not required before transfusion of convalescent plasma. Further, widespread use of premedications can have adverse effects. However, patients with a history of certain immunologic reactions may benefit from premedication. (See "Immunologic transfusion reactions", section on 'Prevention of FNHTR'.)
Monitoring — There are no established guidelines to specify what clinical and laboratory monitoring is indicated in recipients of convalescent plasma [3]. General aspects of monitoring (oxygenation, hemodynamic status) are discussed separately. (See "COVID-19: Management of the intubated adult", section on 'Monitoring for complications'.)
Access to therapy
United States — As of 2025, at least one blood manufacturer has obtained formal FDA approval for COVID-19 convalescent plasma through the Biologics Licensing Application (BLA) mechanism [4]. (See 'History of collection and use during the pandemic' above.)
Patients who receive convalescent plasma outside of this mechanism or as part of a clinical trial may need to be informed that it remains an investigational therapy (depending on the source and indication for the transfusions); this information can be included in the consent for blood product administration.
During the early years of the pandemic, various mechanisms were made available to provide (or increase) access to convalescent plasma for individuals without access to a clinical trial. (See 'History of collection and use during the pandemic' above.)
Resource-limited settings — Collecting and administering convalescent plasma in low- and middle-income countries may require additional considerations such as the following [50]:
●Documentation of infection and recovery by laboratory criteria (viral nucleic acid or serologic evidence of prior infection) are ideal, although self-report of infection may be considered sufficient in some cases. Most countries consider resolution of symptoms to be sufficient evidence of viral clearance; persistent positivity for viral RNA does not always correlate with active infection or infectivity.
●Standard eligibility criteria for blood donation should be enforced to prevent transfusion-transmitted infections.
●If apheresis equipment is not available, convalescent plasma can be prepared from whole blood donation. (See 'Apheresis versus whole blood collection' above.)
●Mobilization of donors may be challenging. Fixed-location collection sites are likely to provide greater safety (lower risk of infection) to collection personnel than mobile collection sites. Measures to reduce infection should be followed. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)
SAFETY
Transfusion reactions — Convalescent plasma is a human blood product that can cause various transfusion reactions, including allergic and anaphylactic reactions, hemolysis, transfusion-associated circulatory overload (TACO), and transfusion-related acute lung injury (TRALI). (See "Clinical use of plasma components", section on 'Risks'.)
However, plasma has generally been well-tolerated, with rare transfusion reactions that can generally be controlled with supportive measures. The incidence of transfusion reactions with convalescent plasma appears to be comparable with that of standard plasma when applied to a patient population of similar acuity of illness.
Observational studies have found complication rates to be low [79,80]. As an example, in an update from the COVID-19 Convalescent Plasma Project (CCPP) covering nearly 22,000 recipients of convalescent plasma, complication rates included the following [79]:
●Transfusion reactions in 89 (<1 percent)
●Thromboembolic complications in 87 (<1 percent)
●Cardiac events in 680 (approximately 3 percent)
The majority of thromboembolic and cardiac events were judged to be unrelated to the plasma.
Overall mortality at seven days was approximately 8.6 percent [81]. This was noted to be lower than the mortality with the first 5000 patients, for whom the mortality rate was 12 percent [82]. However, comparisons with other cohorts are challenging, since care may be improving over time, and the patient population treated with convalescent plasma has shifted to a less critically ill group.
Antibody-dependent enhancement — Antibody-dependent enhancement (ADE) was a theoretical risk of COVID-19 convalescent plasma early in the pandemic, but it has not been reported in individuals with COVID-19 (or many other viral infections), despite administration of thousands of doses [22,79,80,82].
ADE is a phenomenon by which antibodies to an infecting pathogen can paradoxically increase viral uptake by cells and exacerbate disease severity. It was observed when a specific vaccine for dengue virus led to disease worsening in a subset of individuals who had not previously been infected and received the vaccine. Monitoring is challenging, as ADE is a clinical phenomenon without specific laboratory findings, and some individuals may experience clinical deterioration unrelated to ADE [79,82]. (See "Dengue virus infection: Pathogenesis", section on 'Immune response and viral clearance' and "Dengue virus infection: Prevention and treatment".)
HYPERIMMUNE GLOBULIN —
Hyperimmune globulin is another investigational approach to providing passive immunity to individuals exposed to SARS-CoV-2 or those early in the disease course [20]. (See 'General concepts' above and "Intravenous plasma derivatives and recombinant DNA-produced coagulation factors", section on 'Hyperimmune globulins'.)
A randomized trial of hyperimmune globulin in patients hospitalized with COVID-19 did not demonstrate benefit [83].
●Advantages – Potential advantages of hyperimmune globulin include:
•Pathogen reduction steps are standard during manufacture (cold ethanol fractionation, chromatography, nanofiltration, solvent/detergent treatment, and heat treatment)
•Lower volume
•More concentrated (high titer of antibodies)
•Lower (but not eliminated) risk for transfusion reactions and other adverse events
•Potential for intramuscular administration
•Ease of storage and shipping, allowing transfer to regions of active outbreaks
●Disadvantages – Disadvantages include the cost of preparation, the large number of plasma units required for manufacture, and the time it takes to prepare the products.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition – Convalescent plasma is obtained from individuals who have recovered from an infection (or vaccination) and have generated an immune response. During the coronavirus disease 2019 (COVID-19) pandemic, over 500,000 units were administered to patients in the United States via an expanded access program, emergency use authorizations, and clinical trials. (See 'General concepts' above.)
●Criteria for donation – Most blood donation centers are no longer collecting convalescent plasma. Donation criteria are the same as other blood product donations; the individual must have fully recovered from COVID-19 for at least 10 days. Having been vaccinated for COVID-19 by itself is not sufficient for convalescent plasma donation, but vaccinated individuals can donate if they meet other criteria. (See 'Plasma donation' above.)
●Plasma collection – High-titer plasma is generally collected by apheresis. The titer or level of the relevant antibody can be determined on the donor or the plasma unit using a functional virus neutralization assay or a serologic binding assay. Standard infectious disease screening and ABO and RhD typing are performed. Testing for anti-human leukocyte antigen (HLA) antibodies (and exclusion if positive) is used in parous female donors to reduce the risk of transfusion-related acute lung injury (TRALI). The Emergency Use Authorization (EUA) from the FDA specifies that all units should be "high titer"; criteria for making this determination are discussed above. (See 'Preparation' above.)
●Indications for use – There may be benefit in immunocompromised patients; indications are discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'Limited role for antibody-based therapies (monoclonal antibodies and convalescent plasma)' and "COVID-19: Considerations in patients with cancer", section on 'Management of COVID-19'.)
●Administration – If used, convalescent plasma is most likely to be effective if given within nine days of symptom onset in outpatients or within three days of hospitalization. Typically, a single dose of one to two units is transfused without premedication. (See 'Overview of therapeutic considerations' above and 'Optimal timing and titer (or antibody level)' above and 'Optimal dose and frequency' above and 'Premedications (typically not indicated)' above and 'Monitoring' above.)
●Safety – Transfusion reactions may occur. Antibody-dependent enhancement (ADE) has not been noted. Convalescent plasma might interfere with vaccine efficacy, but this question has not been addressed clinically. (See 'Safety' above.)
●Hyperimmune globulin – Hyperimmune globulin is a concentrated product manufactured from thousands of units of convalescent plasma. Efficacy was not demonstrated in a randomized trial. (See 'Hyperimmune globulin' above.)
ACKNOWLEDGMENT —
Dr. Bloch is a member of the US Food and Drug Administration (FDA) Blood Products Advisory Committee. The views expressed in this topic are those of the author(s) and do not reflect the official views of the Blood Products Advisory Committee or the formal position of the FDA and also do not bind or otherwise obligate or commit either the Advisory Committee or the FDA to the views expressed.
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