COVID-19 convalescent plasma: mechanisms of action and rationale for use: a narrative review

Introduction

In December 2019, the World Health Organization (WHO) was informed of cases of pneumonia of unknown etiology associated with exposures in a local seafood market in Wuhan city (1). The novel causative virus, later named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was found to be a strain of the Coronaviridae family, which also includes severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) (2). The virus shares a 79.6% sequence identity to SARS-CoV and 96% identity to a bat coronavirus at the whole genome level (3). Compared to SARS and MERS, SARS-CoV-2 has an efficient human-to-human transmission and hence a higher pandemic potential (4,5). The coronavirus disease 2019 (COVID-19) pandemic has become within months a global health crisis, despite global public health responses aimed at containing the disease. As of 15^th of November 2020, the WHO has been informed of 54,558,120 confirmed cases of COVID-19, with 1,320,148 deaths documented worldwide (6). Although most patients infected with SARS-CoV-2 experience mild to moderate symptoms that resolve in 6–10 days, almost 15–20% of patients develop severe illness characterized by an interstitial pneumonia and acute respiratory distress syndrome (ARDS) (7). The estimated overall rates of mortality per confirmed case in early reports from China were 4.5–12% (8,9). Although the estimated mortality rate of COVID-19 is lower than SARS and MERS, the number of deaths associated with COVID-19 has already surpassed those of SARS and MERS owing to the extremely high transmissibility of SARS-CoV-2 coronavirus (4).

As the pandemic continued to spread across the globe and given the historical use of convalescent plasma (CP) in other viral outbreaks and pandemics, COVID-19 CP (CCP) was quickly deployed in treating infected patients as an easily accessible source of anti-viral antibodies. Different organizations have released their recommendations on the collection and use of CCP. However, it is notable to mention that these guidance documents and recommendations were developed on an emergent basis based on the historical experience of convalescent sera and before any information is available on the safety and efficacy of CCP (10). The WHO recognizes CCP as an experimental therapy that needs to be evaluated in clinical studies to determine effectiveness and safety (11). The literature about CCP use is rapidly growing. This narrative review aims to summarize the published literature, and to provide an overview of the current knowledge on the potential mechanisms of action of CCP, the rationale for its use, and the donor and product factors that can implicate the recipient’s response. We present the following article in accordance with the narrative review reporting checklist (available at http://dx.doi.org/10.21037/aob-2020-cp-01).

Methods

A native review of the literature was conducted using PubMed/MEDLINE, Google Scholar, and Cochrane Database. The literature was searched for published articles on the mechanisms of action of CCP and rationale for use, using a combination of the following keywords; “Convalescent plasma”, “mechanism of action”, “rationale for use”, “Neutralizing antibodies”, “ACE2 receptor”, “SARS-CoV-2” or “Severe acute respiratory syndrome coronavirus 2”, “COVID-19” or “coronavirus disease 2019”, and “ABO blood group” from January through October 2020. Articles that specifically addressed the topic of interest were pulled and screened. After the first search, we included additional articles retrieved from a manual search of cited references. Relevant cited references therein were reviewed. The exclusion criteria included articles with no full text available and articles published in non-English-language.

Discussion

SARS-CoV-2 infection and COVID-19

The human-to-human transmission of SARS-CoV-2 is primarily mediated by respiratory droplets or aerosols. Structural and functional analysis of SARS-CoV-2 revealed that it uses the human angiotensin-converting enzyme 2 (ACE2) receptor to bind to human alveolar epithelial cells (12-14). This receptor is distributed across multiple organs and tissues, most notably the oral and nasal mucosa, nasopharynx, respiratory system, gastrointestinal tract, lymph nodes, thymus, bone marrow, heart, spleen, liver, kidney, bladder, and brain (15-17). In the early stages of the infection, SARS-CoV-2 entry is facilitated by high expression of ACE2 receptors on the mucosa of the oral cavity, including the epithelial cells of the tongue and nose (18,19). Virus replication takes place in the throat, and the incubation period lasts for 4–7 days (20). Peak viremia occurs within 2–5 days of symptom onset and pharyngeal virus shedding remains very high during the first week of symptoms (21). The expression of the ACE2 receptor on many cells, including alveolar epithelial cells and vascular endothelium, results in a profound immune response during COVID-19 infection (22).

SARS-CoV-2 has four major structural proteins: the spike protein (S), small envelope protein (E), matrix protein (M), and nucleocapsid protein (N) (23). Coronavirus entry into host cells is mediated by a transmembrane S protein that initiates cell fusion via attachment to the target receptor on the host cell surface. This is followed by the delivery of the viral nucleocapsid inside the target cell for subsequent replication (24). The S protein is comprised of two units that are responsible for binding to the host cell receptor (S₁ subunit), and fusion of the viral and cellular membrane (S₂ unit) (12). The receptor-binding domain (RBD) within the S₁ subunit directly interacts with host receptors and contributes to the stabilization of the prefusion state of the membrane-anchored S₂ subunit (12,25,26). Further studies identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which are highly conserved or share similar side chain properties with those in the SARS-CoV RBD (27). However, SARS-CoV-2 RBD was also found to harbor a single mutation that significantly enhances its ACE2 binding affinity, suggesting an increased ability to infect and spread among humans (14). Some researchers reported this binding to be at a ~10–20-fold higher affinity than ACE2 binding to SARS-CoV S subunit (13,28,29). The higher binding affinity correlates with the higher potential of human-to-human disease transmission, disease severity, and overall viral replication (14). After attachment to ACE2, the transmembrane protease serine 2 (TMPRSS2) cleaves and primes the receptor-bound S protein to mediate fusion of the viral envelope with the membrane of the target cell in the host (30,31). This priming of the S protein allows the virus to enter the host cell through endocytosis or via direct fusion of the viral envelope with the host membrane (32).

During SARS-CoV-2 infection, it is hypothesized that the virus first attacks the organs that express ACE2 receptors. In a subset of patients, the viral infection progresses down the trachea to the lung targeting the epithelial lining of the lower airways owing to the substantial expression of ACE2 (33,34). As part of viral replication, the apoptotic response leads to epithelial cell death, diffuse alveolar damage, vascular leakage, edema, alveolar hemorrhage, local inflammation, and interstitial atypical pneumonia (35,36). It has been reported that ACE2 expression is sharply down-regulated shortly after virus entry, because of endocytosis of the receptor together with the virus, which leads to an increase in angiotensin II in lung tissue, and simulation of the type I angiotensin receptor (ATR1) (37,38). This mediates angiotensin II-induced vascular permeability and is hypothesized to contribute to organ injury in COVID-19 (39).

Viral entry to the cell promotes its proliferation and cell death, thereby incurring local and systemic inflammatory responses. The interaction between SARS-CoV-2 and the host induces the production of interferons, activation of natural killer (NK) cells, dendritic cells, macrophages, and neutrophils among other immune responses as reviewed elsewhere (40). During this phase, 20–30% of patients rapidly progress to ARDS with severe hypoxia and multi-organ failure. This stage is accompanied by a cytokine release syndrome (the ‘cytokine storm’) characterized by elevated levels of interleukins (IL) (including IL-6, IL-1β, IL-2, IL-10), granulocyte colony-stimulating factor (G-CSF), interferon-gamma (INF-γ), tumor necrosis factor (TNF-α), inducible protein 10 (IP-10, also known as CXCL10), and monocyte chemokines (CCL2, CCL7, CCL12) (41-44). Different reports estimated up to 10% fatality rates at this stage (45,46).

Growing evidence suggests that loss of vessel integrity during COVID-19 infection contributes to the initiation and propagation of ARDS by mediating diffuse endothelial inflammation, inflammatory cell recruitment, pulmonary infiltration, and endothelial cell death (47,48). This was evident from the histologic assessment of pulmonary vessels of patients with COVID-19, which showed widespread thrombosis and microangiopathy (47). After infecting pulmonary endothelial cells, endothelitis develops at least in a subset of critically ill patients, hence leading to diffuse endothelial inflammation and alteration in vascular hemostasis (48). Moreover, there is a widespread complement activation, especially in patients with severe COVID-19 as a major contributor to the acute phase response to eliminate the invading pathogen (49). Such complement activation adds to the endothelial cell injury and death with subsequent activation of the clotting cascade, resulting in microvascular thrombosis, pulmonary intravascular coagulopathy, and pulmonary hypertension (50). This is further aggravated by the pro-inflammatory cells, cytokines, and chemokines amplifying the vicious cycle of vessel coagulation and thrombosis. The expression of tissue factor (TF) by activated monocytes further stimulates the coagulation cascade and subsequent generation of thrombin (51). Therapeutic interventions that target the host hyper-immune response, complement activation, and systemic thrombosis are hypothesized to be promising in treating severe COVID-19 disease.

Several publications suggested that the ABO blood group may contribute to an increased susceptibility to acquire SARS-COV-2 infection among group A individuals compared to group O individuals (52-57). In addition, some of these observational studies suggested a higher risk of developing severe disease and need of hospitalization among group A individuals (52,53). However, conflicting findings were reported from other publications, which may be ascribed to different patient populations among other confounders (58,59). This can be related to the inclusion of randomly selected blood donors as controls for which there is an inherent risk of blood group O enrichment. A genome-wide association analysis performed in Spanish and Italian centers on patients with severe COVID-19 disease with respiratory failure compared to population-derived controls detected cross-replicating association with two loci including rs67152 at chromosome 9q34.2, which coincided with the ABO blood group locus (60). This suggests that in addition to disease acquisition, the ABO blood group could also affect disease severity. A blood group specific analysis, corrected for age and sex, showed a higher risk of severe disease in blood group A and a protective effect in blood group O than in other blood groups. Group O Rh+ individuals significantly correlated with lower mortality in a meta-regression analysis including 8.9 million COVID-19 cases and 465,000 deaths of 101 different nations using their known blood group distribution (61).

The potential mechanism of the protective effect in group O individuals could be the possible interference of naturally-occurring anti-A isoagglutinins with the interaction of the virus S spike protein with the ACE2 receptor, hence preventing its entry into the lung endothelium, as previously studied in SARS-CoV infection (62,63). This is expected to be the case particularly given the similarity in the nucleic acid sequence and the ACE2 binding similarity between SARS-CoV and SARS-CoV-2 (14,27,32,64). Severe outcomes in group A individuals can also be explained by the higher levels of von Willebrand factor and factor VIII levels in individuals with blood group A, with a predisposition to cardiovascular complications (65). Another potential mechanism can be related to complement levels, as an association between COVID-19 prevalence and C3 and ACEI polymorphisms were previously described (66). There is a need for more studies to ascertain the association between the ABO blood group system and the risk of acquiring COVID-19 and disease severity in different patient populations.

CP—a historical perspective

The use of convalescent sera has been of particular interest in the last decades in the management and prevention of emerging viruses as a strategy of passive immunization (67). The introduction of the first serum therapies, initially extracted from animals after they had been rendered immune to the disease in question, was for the treatment of diphtheria and tetanus in the 1890s (68,69). Since then, plasma has been used emergently in epidemics where there is insufficient time or resources to generate immunoglobulin preparations. Historical data has reported the safety and efficacy of convalescent sera for use in other viral outbreaks and pandemics (67). This includes poliomyelitis (70), measles (71,72), mumps (73), and influenza (74). The Spanish influenza A (H1N1) of 1918 was the first viral pandemic for which convalescent blood products were reported to be potentially effective (75-79). A meta-analysis of 8 studies from 1918 to 1925 on the use of CP in a total of 1,703 patients with Spanish influenza A (H1N1) virus pandemic reported reduced mortality in patients who received CP (16% treated patients vs. 37% control) and lower mortality rates in patients treated early; namely within four days of pneumonia (80). However, the included studies were small and had many methodological limitations, and were variable in volume and dose of CP used. It is also noteworthy that historically, convalescent sera were developed in many cases without a mean to measure antibody titers.

Several decades later, CP treatment was deployed during the influenza A (H1N1) 2009 flu pandemic (81-83). In a prospective study by Hung et al., 20 out of 93 patients with severe influenza A (H1N1) pdm09 infection were offered treatment with CP harvested by apheresis from patients recovering from the infection (81). Neutralizing antibody titers were measured, and a cut-off of ≥1:160 was used. Clinical outcome was compared between treated and untreated controls. Mortality in the treatment group was significantly lower than in the non-treatment group (20.0% vs. 54.8%; P=0.01). Multivariate analysis showed that plasma treatment reduced mortality (odds ratio, 0.20; 95% confidence interval, 0.06–0.69; P=0.011). Subgroup analysis of 44 patients demonstrated that CP treatment was associated with significantly lower viral load at days 3, 5, and 7, and lower IL-6, IL-10, and TNF-α compared with the control group (P<0.05). A multicenter prospective double-blinded randomized control trial (RCT) of using hyperimmune IV immunoglobulin fractionated from the collected CP versus intravenous immunoglobulin (IVIG) in the control arm was associated with significantly lower viral load and mortality within 5 days of symptom onset (84). However, several limitations concerning CP donation were reported, including donor failure to meet blood donation eligibility criteria, inability to make the apheresis appointment, failed laboratory tests, and insufficient neutralizing antibody titers (85).

Different studies assessed the use of CP during the SARS-CoV outbreak in 2003 (86-89). In a non-randomized study, 40 patients with progressive SARS-CoV disease refractory to ribavirin and methylprednisolone received either CP (n=19) or a further dose of methylprednisolone (n=21) (87). Assessed outcomes revealed lower mortality (0% vs. 24%, P=0.049) and high day-22 discharge rate (73% vs. 19%, P=0.001) in the group that received CP compared to pulsed methylprednisolone. The authors reported poor clinical response in patients receiving CP after day 16. The largest study published included 80 patients with SARS in Hong Kong and reported that early treatment with CP with an antibody titer of 1:160 or more before day14 had improved outcomes for treated patients (86). The study revealed a higher day-22 discharge rate among patients who received CP before day 14 of illness (86). However, other investigators reported challenges with this approach and recommended a lower threshold of neutralizing antibodies of 1:80 or more, or selecting donors from patients who recovered from a severe illness (90).

A subsequent systematic review and meta-analysis of 32 studies assessed the effectiveness of CP for the treatment of severe acute respiratory infections, including Spanish influenza A (H1N1), influenza A (H1N1) pdm09, SARS-CoV, and avian influenza A (H5N1) (91). Although the data showed a reduction in the rates of mortality with no reports of serious adverse events or complications, it was evident that there are limited literature and a lack of high-quality studies to draw definitive conclusions. Moreover, although a subgroup analysis of viral load reduction has revealed significantly lower levels 3, 5, and 7 days after intensive care unit (ICU) admission, the confounding effects of concomitant treatments, including oseltamivir, zanamivir, and corticosteroids could not be excluded.

The WHO issued a guidance for the use of CP during the West African Ebola epidemic [2013–2016] due to the highly infectious nature of the virus, high associated case-fatality rate, and lack of proven therapies (92). A meta-analysis of clinical studies, including studies that utilized CP during the Ebola outbreak reported major limitations with the methodological design of existing studies and lack of randomization (93). The largest study was a non-randomized comparative study of 84 patients versus controls that reported a non-significant 7% decrease in mortality following two consecutive transfusions of 200–250 mL of ABO-compatible CP, albeit with unknown neutralizing antibody titers (94). No serious adverse events were reported in the patients who received CP. However, the investigators found that treatment with CP was feasible and acceptable to donors, patients, families, and health care providers. There are few reports on the use of CP in the MERS-CoV outbreak (86,89,90,95,96). A recent systematic review and meta-analysis of studies that reported outcomes for patients infected with SARS-CoV, H1N1 pdm09, H5N1, H1N1, avian influenza A (H7N9), Ebola virus, and SARS-CoV-2 show that CP treatment could reduce the risk of mortality, with a low incidence of adverse events (97).

CP—rational for use

The immediate availability of CCP offered use as an emergency intervention in several pandemics while specific treatments and vaccines are not yet available or under evaluation. The use of CCP was deployed for treating patients with SARS-CoV-2 infection in the early phases of the COVID-19 pandemic. CCP can be used for either treatment of patients with an active infection to reduce symptoms and mortality (98), or for prophylaxis for high-risk individuals; such as vulnerable individuals with underlying risk factors, healthcare providers, and those with a history of exposure to confirmed cases with COVID-19 infection. Such plasma may also be pooled and fractionated into hyperimmune immunoglobulin, which was used with success to treat other viral infections such as severe influenza A (H1N1) (84).

The ease of access to CP from recovered donors makes it an attractive therapeutic option, especially in the early stages of any pandemic. Moreover, considering the size of the pandemic, this therapeutic and preventive option could be rapidly made available when there is a sufficient number of potential donors who have recovered from COVID-19 and can donate CCP. It can also be deployed in different settings, including low and middle-income countries, which are most susceptible to being affected by devastating epidemics, although implementation can be limited by major organizational and technological challenges (10,99,100). CCP is obtained by apheresis or whole blood donation from a patient who has survived a previous infection and developed humoral immunity against the pathogen responsible for the disease of question. Apheresis is the preferred mode of the collection as it offers a larger volume collected per session and the absence of a decline in the hemoglobin level in the donor allowing for repeat collections. The WHO recommends that CCP should be used in RCTs to determine its safety and efficacy. In settings where the randomization of patients is not feasible, observational studies should be conducted with data on the characteristics of treated patients and pre-defined patient outcomes (11).

The use of CCP offers quick access as an empirical therapy when specific therapies are not available, especially that the development of neutralizing antibody-based therapies and vaccines is a lengthy process (101). Moreover, the development of immunoglobulins has high costs of production, storage, and administration which could be prohibitive in some countries. Given the spectrum of pathogenic mechanisms involved in the development of severe COVID-19, ranging from immune hyperactivation to thromboembolic complications, it is unlikely that a single individual treatment will be effective. The multifactorial pathogenic nature of the disease indicates that multiple avenues of treatment might be required, and major effort should therefore be invested to determine the optimal timing and combinations in which these drugs should be administered to maximize their efficacy in severely ill patients with COVID-19. There is a need for high-quality clinical trials to assess the efficiency and safety of CCP use for therapeutic and prophylactic purposes.

CP—mechanisms of action

The precise mechanism of action of CCP is not fully understood. There are different mechanisms whereby CCP may offer a benefit in COVID-19. These can be immune and non-immune (102). The use of CCP offers means for the provision of passive and immediate antibody-mediated immunity (AMI) involving the administration of the neutralizing antibodies against the SARS-CoV-2 virus (98). AMI is classically associated with opsonization, toxin and viral neutralization, antibody-dependent cellular cytotoxicity (ADCC), complement activation, phagocytosis, and direct antimicrobial actions through the generation of oxidants (98,101,103). B cell antibodies can be immunomodulators; bridging the innate, acquired, cellular, and humoral immune responses (101). In addition, CCP contains other constitutes that can benefit the recipient. There is a need for further research to study the role of these mechanisms in viral clearance in COVID-19.

Immune mechanisms

Neutralization and suppression of viremia

Neutralizing antibodies provide an important immune defense against viral infections, through binding against a given virus and thereby neutralizing its infectivity directly (104). The presence of neutralizing antibodies in the plasma is proposed to reduce the viral infectivity by binding to the surface of the virus particles (virions), blocking viral attachment and entry to the infected cell (105). Neutralization is defined as a reduction in viral infectivity by the binding of antibodies to the surface of the viral virions, thereby blocking a step in the viral replication cycle (106). Neutralization assays measure the ability of sera to neutralize the infectivity of the virus in cell culture.

Neutralizing antibodies can be induced in convalescent patients and can provide an important specific immune defense against SARS-CoV infection (104,107). Experience from prior SARS-CoV coronavirus pandemic shows that convalescent sera contain neutralizing antibodies to the relevant virus (108). In COVID-19 infection, high levels of neutralizing antibodies are detected at about 10 days in both mild and severely ill patients, and remain stable thereafter (109). It was also shown that the levels of neutralizing antibodies were higher in the severe group (110). Considering that the coronavirus S protein mediates entry into host cells; it is the primary inducer and target for neutralizing antibodies upon infection. Particularly, RBD within S1 unit is the most crucial target. The antibody responses that target the immunodominant SARS-CoV-2 S protein, specifically those that target the RBD, are thought to be highly associated with virus neutralization by blocking the interaction between RBD and AEC2 receptor (111,112).

Early studies on CCP during the current pandemic demonstrated the presence of neutralizing antibodies in the plasma of recovered patients from COVID-19 (21). Studies have confirmed that up to 80% of recipients of CCP show a significant increase in antibody levels after transfusion (113). It has also been demonstrated that the administration of CCP containing these neutralizing antibodies to individuals with severe COVID-19 results in a rapid viral clearance by neutralizing the SARS-CoV-2 virus (114). The passive transfusion of anti-A blood group natural isoagglutinin, is another potential benefit, especially among elderly males who are known to experience reduction of isoagglutinin titers (115).

Antibody-dependent cellular cytotoxicity

Besides the neutralizing effect, non-neutralizing antibodies present in CCP may contribute to enhanced recovery (98). Non-neutralizing antibodies, such as immunoglobulin G (IgG) and immunoglobin M (IgM) can play an important role in prophylaxis and/or recovery through other antibody-dependent mechanisms (116). It is known that antibodies consist of two structural regions; a variable fragment (Fab) that mediates antigen binding, and a constant fragment (Fc) that mediates the biological properties of the immunoglobulin molecule, such as serum half-life, interaction with cellular Fc receptors, and the ability to activate complement, and its downstream effector functions (101).

The Fc mediated antibody effect has been described in the Ebola virus and respiratory syncytial virus infection as a mean of antibody-mediated protection against viral infections (117,118). The interaction with Fc-receptors can lead to the killing of virus-infected cells through a variety of mechanisms, including ADCC and antibody-dependent cellular phagocytosis (ADCP) (98). ADCC is induced when the Fc domain of antibodies that are bound to viral proteins on the surface of virus-infected cells engage the Fc gamma receptors (FcγRs) on the innate effector cells. This interaction induces the release of cytotoxic granules resulting in the killing of infected cells (117). ADCP is the uptake of virus-antibody complexes or antibody-coated virus-infected cells by phagocytic cells, resulting in the clearance of the immune complexes from the infected host (117). The interaction with Fc-receptors can also lead to complement activation and complement-dependent cytotoxicity (CDC) (117).

Nonimmune mechanisms

Modification of inflammatory response and cytokine storm

In addition to neutralizing antibodies, collected CCP contains other proteins such as anti-inflammatory cytokines, natural antibodies, defensins, and other proteins that are obtained from the donor (119). As a result, it is hypothesized that the transfusion of CCP may provide further benefits such as immunomodulation via amelioration of the severe inflammatory response induced by the disease, which can reduce host damage (120). This is particularly the case with the over-activation of the immune system during COVID-19 and the development of the cytokine storm. It is hypothesized that CCP inhibits the formation of the inflammatory cytokine storm. Therefore, it is believed that it is most effective when administered prophylactically or used early after the onset of symptoms.

Complement activation largely contributes to the systematic inflammation and migration of the neutrophils to the lungs (121). There are several anti-inflammatory mechanisms by which IgG antibodies in IVIG reduce complement activation or interfere with the action of pro-inflammatory proteins, hence limiting the formation of complement complexes and the inflammatory effect (122). This potentially can be the case with CCP transfusion.

Restoration of coagulation factors and immunomodulation of the hypercoagulable state

Other constituents in CCP may also exert beneficial effects. It has been suggested that plasma components can provide other beneficial actions such as, restoration of the coagulation factors (123). It is possible that CCP provides procoagulant and antifibrinolytic factors that restore the endothelium glycocalyx and prevent excess vascular leakage. Moreover, it has been hypothesized that CCP might offer neutralization of autoantibodies in the recipient, similar to the effect of anti-idiotypic antibodies present in IVIG.

CP—factors impacting response

One important characteristic of antibody-based therapies is that their effectiveness decrease as the duration of infection increases, which can limit the application of such a therapeutic strategy to conditions where an early diagnosis can be made (124). When used for therapy, antibodies are most effective when administered shortly after symptom onset, as antibodies modify the initial inflammatory response. The reason for the temporal variation in efficacy could reflect that passive antibody works by neutralizing the initial inoculum, which is likely to be much smaller than that of established disease (125). As was shown when used in SARS-CoV disease, administration of CCP early in the disease would theoretically be more effective (86).

Considering that viremia peaks in the first week in most viral illnesses and seroconversion for most viruses occurs between 10 to 14 days, which is followed by the clearance of the virus, CCP is theoretically more effective if administered in the early stages of the disease, between 10–14 days, before the development of the cytokine storm (86,100). Data on COVID-19 patients indicate that seroconversion occurs after 7 days in 50% of patients, and by day 14 in all patients (21). Another study has shown that <40% of patients with COVID-19 had detectable antibodies (by enzyme-linked immunosorbent assay) within the first week of infection, increasing to 94% for IgM and 80% for IgG by day 15 after the onset of the disease (126). Some have recommended infusing CCP within the first 5 days of infection (111). Others proposed no later than 14 days post-infection or during the viremic and seroconversion stage (86). Many opted for collection after day 28 (11,127,128).

However, to achieve the desired effect, and for passive antibody therapy to be effective, a sufficient amount of antibodies must be administered (98). The efficacy of CCP therapy relies on a robust antibody response in CCP donors. The presence of an anti-SARS-CoV-2-neutralizing antibody at an adequate titer in the collected plasma is an important prerequisite. The challenge in using convalescent sera is that some CCP donors may not have high titers of neutralizing antibodies (90). Timing of donation relative to the resolution of symptoms and severity of illness could impact the antibody titer level in the donor at the time of donation (129). The titers in convalescent patients with H1N1 and MERS-CoV patients were found to correlate with viral load and severity of the viral illness (130,131). In COVID-19, male gender (reported to be at a greater risk for more severe COVID-19) (132), older age (113,133), and history of hospitalization (113) were found to be associated with increased antibody responses, and hence it has been suggested to use high antibody titer as a surrogate marker for worse clinical prognosis (126), and in the criteria of donor selection. At this time, the minimal cut-off of neutralizing antibodies and CCP doses to be effective is yet to be defined (100). A large study of 285 patients reported detectable IgG antibodies, using a magnetic chemiluminescence enzyme immunoassay (MCLIA) for virus-specific antibody detection, 17–19 days after symptom onset, while both IgG and IgM antibody titers were increasing during the first 3 weeks of symptom onset (134). Similar to other studies, IgG and IgM antibody titers were higher in the severe group when compared with the non-severe group.

Another challenge that can be encountered is that CCP donor may show no detectable antibodies with specificity toward RBD and S protein viral epitopes (133). Seroconversion studies in SARS-CoV infection have shown that there are temporal changes in S-specific and N-specific neutralizing antibody response and these may differ in patients who have either recovered or died. Patients who recovered had a higher and sustained increase in serum neutralizing antibody titers with anti-N protein-specific and anti-S glycoprotein-specific responses (135). A study assessing levels of antibodies among potential CCP donors using EUROIMMUN enzyme-linked immunosorbent assay that recognizes either IgG or IgA against the S1 domain reported a considerable heterogeneity in the antibody responses among the donors (136). Therefore, the specificity of the target of these antibodies is another factor to consider. If the correlation with outcomes in group O and B recipients is confirmed, titers of anti-A isoagglutinin would be another factor to impact response (137). Studies are ongoing to evaluate the correlation between isoagglutinin titers and outcomes in blood group O and B recipients of CCP (138).

CP—safety and efficacy

CCP was adopted quickly and widely during the pandemic without any strong evidence on safety or efficacy (100). None of the previous studies on CP use in other SARS viral infections did report a serious adverse event, although minor complications may be underreported in the literature (91). In a large study from the Mayo clinic, CCP has demonstrated safety with a low incidence of all serious adverse events within the first four hours of transfusion (139,140). The largest report on safety included data on 20,000 patients and reported transfusion reactions in 89 recipients of CCP (<1%). The 7-day mortality rate was 8.6%, including transfusion-associated circulatory overload (0.18%), severe allergic transfusion reaction (0.13%) and transfusion-related acute lung injury (0.10%) (139). The rate of thromboembolic/thrombotic events and cardiac events was also low (<1% and ~3% respectively), while the vast majority of these were judged to be unrelated to the CCP transfusion per se. The estimated 7-day mortality rate was higher among more critically ill mechanically ventilated patients, in patients admitted to the ICU, and in patients with septic shock or multiple organ dysfunction/failure (139).

As for efficacy, the initial case series reported effectiveness in treating critically ill patients with clinical improvement, reduced inflammation, and viral load (141-143). This was followed by the initiation of numerous studies and clinical trials worldwide for assessing the efficacy of therapeutic and prophylactic use of CCP. Two Cochrane reviews of these studies concluded that it remains very uncertain that CCP is effective or beneficial for admitted COVID-19 patients (144,145). The most recent Cochrane review included results from 1 RCT, 3 controlled non‐randomized studies of interventions (NRSIs), and 10 non‐controlled NRSIs with 5,443 participants, of whom 5,211 received CCP (145). The authors concluded that certainty remains unknown whether CCP has any effect on all‐cause mortality at hospital discharge, has any effect on the improvement of clinical symptoms at seven days, or prolongs time to death. Moreover, there was limited information regarding adverse events, the majority of which were allergic or respiratory events. The review identified 98 ongoing studies evaluating CCP and hyperimmune immunoglobulin, of which 50 are RCTs, projecting the upcoming wealth of information expected from the emerging literature.

Prophylaxis trials on the use of CCP in non-infected, but at-risk subjects including these with a history of exposure, are also being designed (146,147). The first trial is a randomized controlled double-blinded phase II trial that includes adult participants (18 years of age and older) with high-risk exposure within 96 hours as defined by the US Center of Disease Control. This trial aims to assess the efficacy of treatment at day 28 defined as development of SARS-CoV-2 infection (symptoms compatible with infection and/or positive molecular testing) regardless of disease severity and cumulative incidence of grade 3 & 4 and serious adverse events up to day 28 (146). The second trial includes children between 1 month and 18 years of age, determined to be at high risk for severe SARS-CoV-2 disease, including infants ≤1 year of age, immunocompromised kids, children with hemodynamically significant cardiac disease (e.g., congenital heart disease), or kids with underlying lung disease with chronic respiratory failure and with high-risk exposure. Susceptible children are defined as those with a history of exposure to a household member or in a day-care center to a person with a confirmed SARS-CoV-2 infection or with a clinically compatible disease, and randomization takes place within 96 hours of exposure (147).

CP—questions to be answered

To date, little is known about the effectiveness of CCP in treating COVID-19 patients. It is important to assess the effectiveness of CCP, considering the potential factors that determine efficacy. There is a need to determine which viral antigen epitopes elicit protective antibodies, and to estimate the required amount of antibody to use for therapy (101). It is also essential to understand the antibody characteristics and titers that can impact the response to the CCP. Results from longitudinal studies evaluating large numbers of serum samples from COVID-19 patients with a broad spectrum of clinical symptoms will be very informative to further assess the time for seroconversion and its correlation with disease severity and antibody titers. There is a need for more data to understand the dose-response effect of CCP transfusion among COVID-19 patients.

There are many identified gaps in knowledge around CCP use including patient eligibility criteria to receive CCP, best CCP dose, frequency of administration and timing, measures for assessment of response and outcomes, and application in pediatrics, neonates, and less resource countries (148). There is a need to develop international programs to facilitate access to CCP for patients in countries with limited resources. Moreover, many ethical considerations are required when establishing a CCP program including how to meet the demand with insufficient CCP supply, and when different competing needs are present, including compassionate use. It is worthwhile to mention that several neutralizing human monoclonal antibodies have been developed, and some are undergoing phase I clinical trials (112,149-154). These would avoid the limitations that are present with the use of CCP.

Conclusions

In conclusion, there are different potential mechanisms of actions for CCP in treating COVID-19. As SARS-CoV-2 spread worldwide, the deployment of different therapeutic and prophylactic strategies continues. The availability of therapeutic neutralizing antibodies against SARS-CoV-2 will offer benefits for the control of the current pandemic and the possible re-emergence of the virus in the future, and their development, therefore, remains a high priority. Until this is made available, CCP offers a therapeutic and prophylactic option. Based on the number of existing trials on the use of CCP, data from thousands of patients will be available in the near future. Time is of the essence to set up protocols for collection, preparation, and administration of CP to allow guidance for use in future emerging viral pandemics. Additional data on pathogenesis and immune response will aid in the further deployment of CCP in future viral threats.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Massimo Franchini and Cesare Perotti) for the series “Convalescent Plasma” published in Annals of Blood. The article has undergone external peer review.

Reporting Checklist: The author has completed the narrative review reporting checklist. Available at http://dx.doi.org/10.21037/aob-2020-cp-01

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aob-2020-cp-01). The series “Convalescent Plasma” was commissioned by the editorial office without any funding or sponsorship. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Coronavirus disease (COVID-19) outbreak: World Health Organization; 2020. Available online: https://www.who.int/westernpacific/emergencies/covid-19
2. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727-33. [Crossref] [PubMed]
3. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3. [Crossref] [PubMed]
4. Lee PI, Hsueh PR. Emerging threats from zoonotic coronaviruses-from SARS and MERS to 2019-nCoV. J Microbiol Immunol Infect 2020;53:365-7. [Crossref] [PubMed]
5. de Wit E, Van Doremalen N, Falzarano D, et al. SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol 2016;14:523. [Crossref] [PubMed]
6. WHO Coronavirus Disease (COVID-19) Dashboard. World Health Organization; 2020.
7. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-20. [Crossref] [PubMed]
8. Wu JT, Leung K, Bushman M, et al. Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China. Nat Med 2020;26:506-10. [Crossref] [PubMed]
9. Mizumoto K, Chowell G. Estimating Risk for Death from Coronavirus Disease, China, January–February 2020. Emerg Infect Dis 2020;26:1251. [Crossref] [PubMed]
10. Burnouf T, Seghatchian J. Ebola virus convalescent blood products: where we are now and where we may need to go. Transfus Apher Sci 2014;51:120-5. [Crossref] [PubMed]
11. World Health Organization. Guidance on maintaining a safe and adequate blood supply during the coronavirus disease 2019 (COVID-19) pandemic and on the collection of COVID-19 convalescent plasma. 2 ed; 2020.
12. Walls AC, Park YJ, Tortorici MA, et al. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020;181:281-292.e6. [Crossref] [PubMed]
13. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020;367:1260-3. [Crossref] [PubMed]
14. Wan Y, Shang J, Graham R, et al. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol 2020;94:e00127-20. [Crossref] [PubMed]
15. Hamming I, Timens W, Bulthuis M, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004;203:631-7. [Crossref] [PubMed]
16. Zou X, Chen K, Zou J, et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med 2020;14:185-92. [Crossref] [PubMed]
17. Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-4. [Crossref] [PubMed]
18. Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci 2020;12:8. [Crossref] [PubMed]
19. Sungnak W, Huang N, Bécavin C, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med 2020;26:681-7. [Crossref] [PubMed]
20. Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020;382:1199-207. [Crossref] [PubMed]
21. Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020;581:465-9. [Crossref] [PubMed]
22. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020;135:2033-40. [Crossref] [PubMed]
23. Wu A, Peng Y, Huang B, et al. Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China. Cell Host Microbe 2020;27:325-8. [Crossref] [PubMed]
24. Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virol J 2019;16:69. [Crossref] [PubMed]
25. Li F. Evidence for a common evolutionary origin of coronavirus spike protein receptor-binding subunits. J Virol 2012;86:2856-8. [Crossref] [PubMed]
26. Wong SK, Li W, Moore MJ, et al. A 193-amino acid fragment of the SARS coronavirus S protein efficiently binds angiotensin-converting enzyme 2. J Biol Chem 2004;279:3197-201. [Crossref] [PubMed]
27. Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020;581:215-20. [Crossref] [PubMed]
28. Yan R, Zhang Y, Li Y, et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444-8. [Crossref] [PubMed]
29. Wang Q, Zhang Y, Wu L, et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 2020;181:894-904.e9. [Crossref] [PubMed]
30. Matsuyama S, Nagata N, Shirato K, et al. Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2. J Virol 2010;84:12658-64. [Crossref] [PubMed]
31. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-280.e8. [Crossref] [PubMed]
32. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-80.e8. [Crossref] [PubMed]
33. Zhao Y, Zhao Z, Wang Y, et al. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. Am J Respir Crit Care Med 2020;202:756-9. [Crossref] [PubMed]
34. Zhang H, Penninger JM, Li Y, et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 2020;46:586-90. [Crossref] [PubMed]
35. Aguiar D, Lobrinus JA, Schibler M, et al. Inside the lungs of COVID-19 disease. Int J Legal Med 2020;134:1271-4. [Crossref] [PubMed]
36. Pernazza A, Mancini M, Rullo E, et al. Early histologic findings of pulmonary SARS-CoV-2 infection detected in a surgical specimen. Virchows Arch 2020;477:743-8. [Crossref] [PubMed]
37. Vaduganathan M, Vardeny O, Michel T, et al. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med 2020;382:1653-9. [Crossref] [PubMed]
38. Glowacka I, Bertram S, Herzog P, et al. Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63. J Virol 2010;84:1198-205. [Crossref] [PubMed]
39. Tikellis C, Thomas M. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int J Pept 2012;2012:256294 [Crossref] [PubMed]
40. Lega S, Naviglio S, Volpi S, et al. Recent Insight into SARS-CoV2 Immunopathology and Rationale for Potential Treatment and Preventive Strategies in COVID-19. Vaccines 2020;8:224. [Crossref] [PubMed]
41. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033. [Crossref] [PubMed]
42. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. [Crossref] [PubMed]
43. Sinha P, Matthay MA, Calfee CS. Is a “cytokine storm” relevant to COVID-19? JAMA Intern Med 2020;180:1152-4. [Crossref] [PubMed]
44. Tang Y, Liu J, Zhang D, et al. Cytokine storm in COVID-19: the current evidence and treatment strategies. Front Immunol 2020;11:1708. [Crossref] [PubMed]
45. Gattinoni L, Chiumello D, Rossi S. COVID-19 pneumonia: ARDS or not? Crit Care 2020;24:154. [Crossref] [PubMed]
46. Perico L, Benigni A, Casiraghi F, et al. Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat Rev Nephrol 2021;17:46-64. [Crossref] [PubMed]
47. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020;383:120-8. [Crossref] [PubMed]
48. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417-8. [Crossref] [PubMed]
49. Shen B, Yi X, Sun Y, Bi X, et al. Proteomic and metabolomic characterization of COVID-19 patient sera. Cell 2020;182:59-72.e15. [Crossref] [PubMed]
50. McGonagle D, O'Donnell JS, Sharif K, et al. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatol 2020;2:e437-e445. [Crossref] [PubMed]
51. Levi M, van der Poll T. Coagulation and sepsis. Thromb Res 2017;149:38-44. [Crossref] [PubMed]
52. Zhao J, Yang Y, Huang HP, et al. Relationship between the ABO Blood Group and the COVID-19 Susceptibility. Clin Infect Dis 2020; [Crossref] [PubMed]
53. Li J, Wang X, Chen J, et al. Association between ABO blood groups and risk of SARS-CoV-2 pneumonia. Br J Haematol 2020;190:24-27. [Crossref] [PubMed]
54. ZengXFanHLuDAssociation between ABO blood groups and clinical outcome of coronavirus disease 2019: Evidence from two cohorts.medRxiv 2020. Available online: https://www.medrxiv.org/content/10.1101/2020.04.15.20063107v1
55. Wu Y, Feng Z, Li P, et al. Relationship between ABO blood group distribution and clinical characteristics in patients with COVID-19. Clin Chim Acta 2020;509:220-3. [Crossref] [PubMed]
56. Leaf RK, Al‐Samkari H, Brenner SK, et al. ABO phenotype and death in critically ill patients with COVID-19. Br J Haematol 2020;190:e204-e208. [Crossref] [PubMed]
57. Göker H, Karakulak EA, Demiroğlu H, et al. The effects of blood group types on the risk of COVID-19 infection and its clinical outcome. Turk J Med Sci 2020;50:679-83. [Crossref] [PubMed]
58. Latz CA, DeCarlo C, Boitano L, et al. Blood type and outcomes in patients with COVID-19. Ann Hematol 2020;99:2113-8. [Crossref] [PubMed]
59. Abdollahi A, Mahmoudi-Aliabadi M, Mehrtash V, et al. The Novel Coronavirus SARS-CoV-2 Vulnerability Association with ABO/Rh Blood Types. Iran J Pathol 2020;15:156-60. [Crossref] [PubMed]
60. Severe Covid-19 GWAS Group, Ellinghaus D, Degenhardt F, et al. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med 2020;383:1522-34.
61. Takagi H. Down the Rabbit‐Hole of blood groups and COVID‐19. Br J Haematol 2020;190:e268-e270. [Crossref] [PubMed]
62. Gérard C, Maggipinto G, Minon JM. COVID-19 and ABO blood group: another viewpoint. Br J Haematol 2020;190:e93-e94. [Crossref] [PubMed]
63. Guillon P, Clément M, Sébille V, et al. Inhibition of the interaction between the SARS-CoV spike protein and its cellular receptor by anti-histo-blood group antibodies. Glycobiology 2008;18:1085-93. [Crossref] [PubMed]
64. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020;395:565-74. [Crossref] [PubMed]
65. Dentali F, Sironi AP, Ageno W, et al. ABO blood group and vascular disease: an update. Semin Thromb Hemost 2014;40:49-59. [PubMed]
66. Delanghe JR, De Buyzere ML, Speeckaert MM. C3 and ACE1 polymorphisms are more important confounders in the spread and outcome of COVID-19 in comparison with ABO polymorphism. Eur J Prev Cardiol 2020;27:1331-2. [Crossref] [PubMed]
67. Marano G, Vaglio S, Pupella S, et al. Convalescent plasma: new evidence for an old therapeutic tool? Blood Transfus 2016;14:152. [PubMed]
68. Simon J. Emil Behring's medical culture: from disinfection to serotherapy. Med Hist 2007;51:201-18. [Crossref] [PubMed]
69. Behring Ev. Ueber das zustandekommen der diphtherie-immunität und der tetanus-immunität bei thieren. 1890.
70. Park WH. Therapeutic use of antipoliomyelitis serum in preparalytic cases of poliomyelitis. J Am Med Assoc 1932;99:1050-3. [Crossref]
71. Park WH, Freeman RG. The prophylactic use of measles convalescent serum. J Am Med Assoc 1926;87:556-8. [Crossref]
72. Gallagher JR. Use of convalescent measles serum to control measles in a preparatory school. Am J Public Health Nations Health 1935;25:595-8. [Crossref] [PubMed]
73. Rambar AC. Mumps: use of convalescent serum in the treatment and prophylaxis of orchitis. Am J Dis Child 1946;71:1-13. [Crossref] [PubMed]
74. Luke TC, Casadevall A, Watowich SJ, et al. Hark back: passive immunotherapy for influenza and other serious infections. Crit Care Med 2010;38:e66-e73. [Crossref] [PubMed]
75. Francis F, Hall M, Gaines A. Early use of convalescent serum in influenza. Mil Surg 1920;47:177-9.
76. Lakartidnin S. Treatment of influenza pneumonia with serum from convalescents. 1920.
77. Lesne E, Brodin P, Saint-Girons F. Plasma therapy in influenza. Presse Med 1919;27:181-2.
78. Miller O, McConnell W. Report of influenza treated with serum from recovered cases. Ky Med J 1919;17:218-9.
79. Redden WR. Treatment of influenza-pneumonia by use of convalescent human serum. Boston Med Surg J 1919;181:688-91. [Crossref]
80. Luke TC, Kilbane EM, Jackson JL, et al. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med 2006;145:599-609. [Crossref] [PubMed]
81. Hung IF, To KK, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis 2011;52:447-56. [Crossref] [PubMed]
82. Ortiz JR, Rudd KE, Clark DV, et al. Clinical research during a public health emergency: a systematic review of severe pandemic influenza management. Crit Care Med 2013;41:1345-52. [Crossref] [PubMed]
83. Sang L, Zhuang PF, Fang F. Retrospective study on collecting convalescent donors’s plasma in treatment of patients with pandemic influenza A (H1N1) virus infection. Chin J Nosocomiology 2011;21:4684-6.
84. Hung IF, To KK, Lee CK, et al. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A (H1N1) infection. Chest 2013;144:464-73. [Crossref] [PubMed]
85. Wong HK, Lee CK, Hung IF, et al. Practical limitations of convalescent plasma collection: a case scenario in pandemic preparation for influenza A (H1N1) infection. Transfusion 2010;50:1967-71. [Crossref] [PubMed]
86. Cheng Y, Wong R, Soo Y, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis 2005;24:44-6. [Crossref] [PubMed]
87. Soo YO, Cheng Y, Wong R, et al. Retrospective comparison of convalescent plasma with continuing high‐dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect 2004;10:676-8. [Crossref] [PubMed]
88. Wong VW, Dai D, Wu A, et al. Treatment of severe acute respiratory syndrome with convalescent plasma. Hong Kong Med J 2003;9:199-201. [PubMed]
89. Yeh KM, Chiueh TS, Siu L, et al. Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital. J Antimicrob Chemother 2005;56:919-22. [Crossref] [PubMed]
90. Ko JH, Seok H, Cho SY, et al. Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience. Antivir Ther 2018;23:617-22. [Crossref] [PubMed]
91. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis 2015;211:80-90. [Crossref] [PubMed]
92. Use of Convalescent Whole Blood or Plasma Collected from Patients Recovered from Ebola Virus Disease for Transfusion, as an Empirical Treatment during Outbreaks. World Health Organization; 2014.
93. Dodd LE, Follmann D, Proschan M, et al. A meta-analysis of clinical studies conducted during the West Africa Ebola virus disease outbreak confirms the need for randomized control groups. Sci Transl Med 2019;11:eaaw1049 [Crossref] [PubMed]
94. van Griensven J, Edwards T, de Lamballerie X, et al. Evaluation of convalescent plasma for Ebola virus disease in Guinea. N Engl J Med 2016;374:33-42. [Crossref] [PubMed]
95. Arabi Y, Balkhy H, Hajeer AH, et al. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus 2015;4:709. [Crossref] [PubMed]
96. Momattin H, Mohammed K, Zumla A, et al. Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV)-possible lessons from a systematic review of SARS-CoV therapy. Int J Infect Dis 2013;17:e792-8. [Crossref] [PubMed]
97. Sun M, Xu Y, He H, et al. A potentially effective treatment for COVID-19: A systematic review and meta-analysis of convalescent plasma therapy in treating severe infectious disease. Int J Infect Dis 2020;98:334-46. [Crossref] [PubMed]
98. Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. J Clin Invest 2020;130:1545-8. [Crossref] [PubMed]
99. Bloch EM, Goel R, Wendel S, et al. Guidance for the procurement of COVID-19 convalescent plasma: differences between high- and low-middle-income countries. Vox Sang 2021;116:18-35. [Crossref] [PubMed]
100. Al‐Riyami AZ, Schäfer R, van den Berg K, et al. Clinical use of Convalescent Plasma in the COVID‐19 pandemic: a transfusion‐focussed gap analysis with recommendations for future research priorities. Vox Sang 2021;116:88-98. [Crossref] [PubMed]
101. Casadevall A, Dadachova E, Pirofski LA. Passive antibody therapy for infectious diseases. Nat Rev Microbiol 2004;2:695-703. [Crossref] [PubMed]
102. Psaltopoulou T, Sergentanis TN, Pappa V, et al. The Emerging Role of Convalescent Plasma in the Treatment of COVID-19. HemaSphere 2020;4:e409 [Crossref] [PubMed]
103. Casadevall A, Pirofski LA. Antibody-mediated regulation of cellular immunity and the inflammatory response. Trends Immunol 2003;24:474-8. [Crossref] [PubMed]
104. Nie Y, Wang G, Shi X, et al. Neutralizing antibodies in patients with severe acute respiratory syndrome-associated coronavirus infection. J Infect Dis 2004;190:1119. [Crossref] [PubMed]
105. Klasse PJ. Neutralization of virus infectivity by antibodies: old problems in new perspectives. Adv Biol 2014;2014:157895 [Crossref] [PubMed]
106. Klasse PJ, Sattentau Q. Occupancy and mechanism in antibody-mediated neutralization of animal viruses. J Gen Virol 2002;83:2091-108. [Crossref] [PubMed]
107. Zhang MY, Choudhry V, Xiao X, et al. Human monoclonal antibodies to the S glycoprotein and related proteins as potential therapeutics for SARS. Curr Opin Mol Ther 2005;7:151-6. [PubMed]
108. Zhang JS, Chen JT, Liu YX, et al. A serological survey on neutralizing antibody titer of SARS convalescent sera. J Med Virol 2005;77:147-50. [Crossref] [PubMed]
109. Wang Y, Zhang L, Sang L, et al. Kinetics of viral load and antibody response in relation to COVID-19 severity. J Clin Invest 2020;130:5235-44. [Crossref] [PubMed]
110. Choe PG, Kang CK, Suh HJ, et al. Antibody responses to SARS-CoV-2 at 8 weeks postinfection in asymptomatic patients. Emerg Infect Dis 2020;26:2484. [Crossref] [PubMed]
111. Tiberghien P, de Lamballerie X, Morel P, et al. Collecting and evaluating convalescent plasma for COVID-19 treatment: why and how? Vox Sang 2020;115:488-94. [Crossref] [PubMed]
112. Zost SJ, Gilchuk P, Case JB, et al. Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature 2020;584:443-9. [Crossref] [PubMed]
113. Madariaga MLL, Guthmiller JJ, Schrantz S, et al. Clinical predictors of donor antibody titre and correlation with recipient antibody response in a COVID-19 convalescent plasma clinical trial. J Intern Med 2021;289:559-73. [Crossref] [PubMed]
114. Li L, Zhang W, Hu Y, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA 2020;324:460-70. [Crossref] [PubMed]
115. Tendulkar AA, Jain PA, Velaye S. Antibody titers in Group O platelet donors. Asian J Transfus Sci 2017;11:22. [Crossref] [PubMed]
116. Rojas M, Rodríguez Y, Monsalve DM, et al. Convalescent plasma in Covid-19: Possible mechanisms of action. Autoimmun Rev 2020;19:102554 [Crossref] [PubMed]
117. van Erp EA, Luytjes W, Ferwerda G, et al. Fc-mediated antibody effector functions during respiratory syncytial virus infection and disease. Front Immunol 2019;10:548. [Crossref] [PubMed]
118. Gunn BM, Yu WH, Karim MM, et al. A role for Fc function in therapeutic monoclonal antibody-mediated protection against Ebola virus. Cell Host Microbe 2018;24:221-33.e5. [Crossref] [PubMed]
119. Choi JY. Convalescent plasma therapy for coronavirus disease 2019. Infect Chemother 2020;52:307. [Crossref] [PubMed]
120. Garraud O, Heshmati F, Pozzetto B, et al. Plasma therapy against infectious pathogens, as of yesterday, today and tomorrow. Transfus Clin Biol 2016;23:39-44. [Crossref] [PubMed]
121. Gralinski LE, Sheahan TP, Morrison TE, et al. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. mBio 2018;9:e01753-18. [Crossref] [PubMed]
122. Lutz HU, Späth PJ. Anti-inflammatory effect of intravenous immunoglobulin mediated through modulation of complement activation. Clin Rev Allergy Immunol 2005;29:207-12. [Crossref] [PubMed]
123. Roback JD, Guarner J. Convalescent plasma to treat COVID-19: possibilities and challenges. JAMA 2020;323:1561-2. [Crossref] [PubMed]
124. Buchwald UK, Pirofski LA. Immune therapy for infectious diseases at the dawn of the 21st century: the past, present and future role of antibody therapy, therapeutic vaccination and biological response modifiers. Curr Pharm Des 2003;9:945-68. [Crossref] [PubMed]
125. Robbins JB, Schneerson R, Szu SC. Perspective: hypothesis: serum IgG antibody is sufficient to confer protection against infectious diseases by inactivating the inoculum. J Infect Dis 1995;171:1387-98. [Crossref] [PubMed]
126. Zhao J, Yuan Q, Wang H, et al. Antibody Responses to SARS-CoV-2 in Patients With Novel Coronavirus Disease 2019. Clin Infect Dis 2020;71:2027-34. [Crossref] [PubMed]
127. An EU programme of COVID-19 convalescent plasma collection and transfusion. Guidance on collection, testing, processing, storage, distribution and monitored use. 1.0 ed. Brussels European Commission; Directorate-General for Health and Food Safety; 2020:7.
128. Investigational COVID-19 convalescent plasma, Guidance for Industry. FDA; September 2020.
129. Barone P, DeSimone RA. Convalescent plasma to treat coronavirus disease 2019 (COVID-19): considerations for clinical trial design. Transfusion 2020;60:1123-7. [Crossref] [PubMed]
130. Hung IF, To KK, Lee CK, et al. Effect of clinical and virological parameters on the level of neutralizing antibody against pandemic influenza A virus H1N1 2009. Clin Infect Dis 2010;51:274-9. [Crossref] [PubMed]
131. Ko JH, Müller MA, Seok H, et al. Serologic responses of 42 MERS-coronavirus-infected patients according to the disease severity. Diagn Microbiol Infect Dis 2017;89:106-11. [Crossref] [PubMed]
132. Scully EP, Haverfield J, Ursin RL, et al. Considering how biological sex impacts immune responses and COVID-19 outcomes. Nat Rev Immunol 2020;20:442-7. [Crossref] [PubMed]
133. WuFWangALiuMNeutralizing Antibody Responses to SARS-CoV-2 in a COVID-19 Recovered Patient Cohort and Their Implications. Lancet2020. Available at SSRN: https://ssrn.com/abstract=3566211 or 10.2139/ssrn.3566211
134. Long QX, Liu BZ, Deng HJ, et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med 2020;26:845-8. [Crossref] [PubMed]
135. Zhang L, Zhang F, Yu W, et al. Antibody responses against SARS coronavirus are correlated with disease outcome of infected individuals. J Med Virol 2006;78:1-8. [Crossref] [PubMed]
136. Klein SL, Pekosz A, Park HS, et al. Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population. J Clin Invest 2020;130:6141-50. [Crossref] [PubMed]
137. Focosi D, Tang J, Anderson A, et al. Convalescent plasma therapy for COVID-19: State of the Art. Clin Microbiol Rev 2020;33:e00072-20. [Crossref] [PubMed]
138. Focosi D. Anti-A isohaemagglutinin titres and SARS-CoV-2 neutralization: implications for children and convalescent plasma selection. Br J Haematol 2020;190:e148-e150. [Crossref] [PubMed]
139. Joyner MJ, Bruno KA, Klassen SA, et al. editors. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clinic Proceedings; 2020: Elsevier.
140. JoynerMJWrightRSFairweatherDEarly safety indicators of COVID-19 convalescent plasma in 5,000 patients.medRxiv 2020. doi: .10.1101/2020.05.12.20099879
141. DuanKLiuBLiCThe feasibility of convalescent plasma therapy in severe COVID-19 patients: a pilot study.medRxiv 2020. Available online: https://www.medrxiv.org/content/10.1101/2020.03.16.20036145v1 10.1101/2020.03.16.20036145
142. Shen C, Wang Z, Zhao F, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 2020;323:1582-9. [Crossref] [PubMed]
143. Zhang B, Liu S, Tan T, et al. Treatment with convalescent plasma for critically ill patients with Severe Acute Respiratory Syndrome Coronavirus 2 Infection. Chest 2020;158:e9-e13. [Crossref] [PubMed]
144. Valk SJ, Piechotta V, Chai KL, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review. Cochrane Database Syst Rev 2020;5:CD013600 [PubMed]
145. Chai KL, Valk SJ, Piechotta V, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev 2020;10:CD013600 [PubMed]
146. Efficacy and Safety Human Coronavirus Immune Plasma (HCIP) vs. Control (SARS-CoV-2 Non-immune Plasma) Among Adults Exposed to COVID-19 (CSSC-001) 2020. Available online: https://clinicaltrials.gov/ct2/show/NCT04323800?term=john+hopkins&cond=convalescent+plasma&draw=2&rank=4
147. National COVID-19 Convalescent Plasma Project; Protocols for pediatrics 2020. Available online: https://ccpp19.org/healthcare_providers/component_3/protocols_for_pediatrics.html
148. Alsayegh F, Mousa SA. Challenges in the Management of Sickle Cell Disease During SARS-CoV-2 Pandemic. Clin Appl Thromb Hemost 2020;26:1076029620955240 [Crossref] [PubMed]
149. Chi X, Yan R, Zhang J, et al. A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science 2020;369:650-5. [Crossref] [PubMed]
150. Wec AZ, Wrapp D, Herbert AS, et al. Broad neutralization of SARS-related viruses by human monoclonal antibodies. Science 2020;369:731-6. [Crossref] [PubMed]
151. Hansen J, Baum A, Pascal KE, et al. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science 2020;369:1010-4. [Crossref] [PubMed]
152. Ju B, Zhang Q, Ge J, Wang R, et al. Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature 2020;584:115-9. [Crossref] [PubMed]
153. Pinto D, Park YJ, Beltramello M, et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature 2020;583:290-295. [Crossref] [PubMed]
154. Wang C, Li W, Drabek D, Okba NM, et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat Commun 2020;11:1-6. [Crossref]