Passive antibody therapy in emerging infectious diseases

Abstract

The epidemic of corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 and its variants of concern (VOCs) has been ongoing for over 3 years. Antibody therapies encompassing convalescent plasma, hyperimmunoglobulin, and neutralizing monoclonal antibodies (mAbs) applied in passive immunotherapy have yielded positive outcomes and played a crucial role in the early COVID-19 treatment. In this review, the development path, action mechanism, clinical research results, challenges, and safety profile associated with the use of COVID-19 convalescent plasma, hyperimmunoglobulin, and mAbs were summarized. In addition, the prospects of applying antibody therapy against VOCs was assessed, offering insights into the coping strategies for facing new infectious disease outbreaks.

Keywords

SARS-CoV-2 / COVID-19 / convalescent plasma / hyperimmunoglobulin / neutralizing monoclonal antibodies

1 Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded positive-sense RNA virus belonging to the genus Betacoronavirus, and it has been responsible for the COVID-19 epidemic since December 2019 [1]. As of March 29, 2023, 761 402 282 confirmed cases of COVID-19, including 6 887 000 deaths, have been reported according to the World Health Organization (WHO) [2]. COVID-19 progression involves two stages: virus replication and immune response. In the host immune response stage, some severe and critical COVID-19 cases progress to the life-threatening condition of multiorgan dysfunction, which includes intractable hypoxemia caused by acute respiratory distress syndrome [3–5]. In accordance with the natural disease progression of COVID-19, before the body’s immune response is activated, that is, under high baseline viral load, exogenous immune effectors administered to patients with COVID-19 can passively induce adaptive immune responses, resulting in therapeutic effects [6].

During the COVID-19 outbreak in 2020, obtaining vaccines or antiviral drugs in a short time was difficult [7]. On the basis of the time needed for the development of therapeutic antibody drugs, SARS-CoV-2 passive immunotherapy can be divided into three stages: COVID-19 convalescent plasma (CCP), COVID-19 hyperimmunoglobulin (COVID-HIG), and neutralizing monoclonal antibodies (mAbs). CCP therapy, as a traditional passive immunotherapy, was the easiest and most readily available strategy for COVID-19 treatment prior to the successful development of COVID-19 vaccines. CCP is obtained from the plasma of patients with protective antibodies, who have recovered from COVID-19, and viral inactivation of plasma is mainly performed with psoralen (S-59) in combination with ultraviolet A (UVA) light, riboflavin ultraviolet light, or methylene blue light [8,9]. COVID-HIG is obtained from the plasma of a definite number of patients who recovered from COVID-19 or healthy COVID-19 vaccine recipients with high-titer antibodies. In addition to the viral removal and inactivation techniques, the mixed plasma pool is separated and purified using the industrial low-temperature ethanol method or through caprylic acid precipitation [10,11]. For the development of SARS-CoV-2 neutralizing mAbs, several attractive platforms have been developed. For example, in antigen-specific single B cell sorting technology, single B cells are acquired from patients who recovered from COVID-19 or recipients of vaccines with target specific antigens (receptor binding domain (RBD) or N-terminal domain (NTD) of spike protein, or other sites of spike (S)) (Fig.1), and direct amplification of the genes encoding the VH and VL regions of single B cells and their subsequent expression in cell culture systems are performed [12,13]. In phage display technology, the B cells of recovered patients are used to construct a phage library, and high-affinity antibodies are obtained after screening [14]. In transgenic mouse technology, human antibody genes are introduced into mice by using gene editing technology, and fully humanized antibodies are obtained through conventional animal immunization and hybridoma screening technology [15]. The process of obtaining and industrial production of CCP, COVID-HIG, and COVID-19 neutralizing mAbs is illustrated in Fig.2.

2 Action mechanism of antibodies in COVID-19 treatment

CCP, COVID-HIG, and mAbs have strong anti-infection and neutralizing activities. The SARS-CoV-2 specific antibodies in CCP, COVID-HIG, or the mAbs targeting S protein, and RBD or NTD of S protein block conformational changes in S protein or bind to it to prevent receptor binding or membrane fusion of SARS-CoV-2, thereby preventing the entry of virus into host cells [16,17]. After antibodies binds to viruses, the antibody–virus aggregates enhance virus clearance [18]. Studies showed in a number of viral infection settings that antibodies eliminate infected cells displaying viral surface antigens through complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and antibody-dependent cell-mediated cytotoxicity [19]. These same mechanisms have also been shown to be functional in the case of COVID-19 [20, 21]. Antibodies induce endogenous antiviral immune responses, form immune complexes with virus particles and/or infected cells, and enhance antiviral cytotoxic T lymphocyte responses through FcγR-mediated binding to dendritic cells; they also inhibit Treg cell expansion, limit immunosuppressive activity, and induce neutrophil antiviral activity [22]. Moreover, the therapeutic effectors in CCP and COVID-HIG can activate the complement system to dissolve and kill pathogens [23], reduce inflammatory responses to S protein, and enhance nucleocapsid (N) humoral responses [24].

3 Convalescent plasma as initial COVID-19 treatment

CCP has emerged as a potentially effective drug for the treatment of COVID-19 due to its ability to inhibit viral replication and improve inflammatory responses [25]. Duan et al. and Shen et al. were the first two groups that independently reported CCP treatment in COVID-19 in the early 2020 [8, 26]. Both groups observed improvements in clinical and biological parameters and rapid decrease in the viral load of critically ill patients with COVID-19 after CCP infusion. Some controlled clinical studies showed that CCP treatment in patients with COVID-19 can help reduce mortality, decrease viral load, and improve their clinical status [27–29].

CCP’s therapeutic effect across different clinical trials may be related to the basic characteristics of participants, the specific supportive care, the combination therapy, the risk factors for disease progression, and the time of RCT implementation. Other factors, such as specific antibody titers in CCP, dose and frequency of CCP use, and clinical endpoint determination, may also affect the results of each clinical trial [30–32]. In spite of the controversies on the CCP effectiveness in the literature [30,33–35], many studies showed that in the early stage (within 72 hours after diagnosis) of COVID-19, the application of CCP containing high-titer anti-SARS-CoV-2 antibodies can improve symptoms, decrease incidences of disease progression and hospitalization, and reduce mortality rate, which indicates the importance of timely use of the CCP with high level specific antibodies against SARS-CoV-2 [36–40]. A 2023 systematic review revealed that high-dose CCP treatment within 5 days of symptom onset can offer some protection [41]. This viewpoint is supported by the results of early outpatient treatment for COVID-19 with CCP [42]. Possibly, in the late stage of COVID-19, the body has already produced high titers of antibodies against SARS-CoV-2, so using small doses (1–2 units) of CCP at this stage will not show the therapeutic effect of CCP. High-titer neutralizing antibodies are an effective therapeutic component of CCP; when the SARS-CoV-2-specific IgG titer in CCP was 1:3200 or higher, the risk of severe COVID-19 reduced by 73% in patients with COVID-19 aged ≥ 75 years. The reason for this phenomenon may rely on the weakened humoral immune function in elderly patients [36]. In a small-sample clinical study, compared with standard-titer (1:160–1:640) CCP, high-titer (> 1:640) CCP demonstrated a crucial role in improving the symptoms of COVID-19 patients [43]. A large-sample clinical study of 3082 hospitalized non-intubated patients with COVID-19 reported 30-day mortality rates of 22.3%, 27.4%, and 29.6% in patients who received high-, medium-, and low-titer CCP treatments, respectively [31]. In high-risk patients (such as pregnant women, immunocompromised children, or solid organ transplant recipients), CCP should be considered early in the course of infection (within 72 h of onset) and administered before or upon admission.

4 Treatment of convalescent plasma in patients with immunocompromised/underlying diseases

In the review of four patient groups (patients with cancer, immunosuppressed patients, patients with laboratory-determined risk for disease progression, and elderly patients with COVID-19), no therapeutic effect of CCP was observed when all cases were analyzed together [44]. However, subgroup analysis showed that the patients with cancer, who received CCP treatment, had a shorter recovery time and higher survival rates than the control group. Moreover, the patients with cancer exhibited an increased level of neutralizing antibodies (P = 0.001), indicating that CCP may improve COVID-19 outcomes in these patients who are unable to generate sufficient immune responses. The mortality rate was found to be reduced by 63% in patients with B cell lymphoid malignancies upon CCP treatment, while it is well known that these patients are not capable of generating adequate humoral immune responses to COVID-19 [45]. A 2023 meta-analysis of immunocompromised patients with COVID-19 included three randomized clinical trials (RCTs), five controlled studies, 125 case series or reports, and uncontrolled large case series enrolling 358 participants [46]. According to the stratified and merged model (i.e., RCTs and cohort studies), CCP treatment was associated with a decrease in mortality among immunocompromised patients with COVID-19 (risk ratio (RR), 0.63; 95% CI, 0.50–0.79). Complex interactions involving cytokine storms, inflammation, endothelial dysfunction, and pathological coagulation lead to increased severity of COVID-19 [47,48], and use of CCP exchange therapy may provide some benefits in such cases [49]. A systematic review and meta-analysis including six clinical studies supported that CCP exchange therapy can decrease the mortality rate of critically ill patients with COVID-19 [50].

5 Guide support for convalescent plasma use

Joyner et al. provided four viewpoints to support CCP treatment [51]. The Chinese guideline “Diagnosis and Treatment Protocol for COVID-19 (Trial Version 9)” emphasizes that CCP and COVID-HIG can be used in patients in the early stages of COVID-19 with high-risk factors, high viral loads, and rapid disease progression [52]. In August 2020, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for CCP treatment of hospitalized patients with COVID-19 [53]. Based on pooled data from 16 RCTs involving 16 236 mild, severe, and critically ill patients with COVID-19, the WHO recommends that CCP therapy can be used only for severe and critically ill groups [54]. The current EUA stipulates that CCP products with high-titer anti-SARS-CoV-2 antibodies can be used for the treatment of outpatients or inpatients with COVID-19 having immunosuppressive diseases or those receiving immunosuppressive therapy, and it has also revised the standards for high-antibody titer CCP products [55]. On the basis of two systematic reviews of RCTs evaluating the efficacy of CCP treatment from January 1, 2019, to January 26, 2022, the Clinical Practice Guidelines from the Association for the Advancement of Blood and Biotherapies provided the guidelines for CCP use and stated that high-titer CCP treatment is highly effective in the early stage of COVID-19 infection [56]. Overall, CCP treatment should be used in the early stages for patients with COVID-19 having high-risk factors or serious underlying diseases.

6 Role of COVID-hyperimmunoglobulin (HIG) in COVID-19 treatment

HIG products are commonly used to treat diseases, such as varicella-zoster virus, hepatitis B, anthrax, and cowpox [57–59]. The process of preparing COVID-HIG, a polyclonal antibody product from CCP, is highly complicated. Therefore, its clinical use was not as common as that of CCP during the COVID-19. However, many systematic reviews, meta-analyses, and clinical studies suggested the potential use of COVID-HIG for COVID-19 treatment [60,61].

Similar to CCP, conflicting results have been reported in clinical studies on the efficacy of COVID-HIG in COVID-19 treatment. A multicenter proof-of-concept interventional study revealed that COVID-HIG reduced the mortality rate of patients with COVID-19 compared with the expected mortality rate according to the national statistics. However, because of the lack of a control group and limited control of patients’ basic characteristics, further clinical trials were required to validate the findings [62]. A single-center, single-blind, phase I/II RCT in Pakistan reported that administering COVID-HIG to severe and critically ill patients with COVID-19 was safe and associated with high survival rate and reduced disease progression risk [63]. Meanwhile, a randomized, double-blind, placebo-controlled phase III trial reported that COVID-HIG did not provide any benefit, possibly because antibody therapy might be ineffective in patients who had already developed an immune response; other factors associated with progressive COVID-19 could also affect the efficacy of COVID-HIG [64]. In several clinical studies, early administration of a high dose of COVID-HIG was reported to improve the prognosis of patients with COVID-19, such as a decrease in 28-day mortality rate; this finding might be related to the COVID-HIG functions of anti-cytokine effects, the decrease in pro-inflammatory responses, the inhibition of complement activation, and the suppression of B- and T-cell functions, which could prevent organ failure and subsequent death [65–69]. Compared with CCP, COVID-HIG meets the high-titer requirements of neutralizing antibody in COVID-19 treatment. Though the number of COVID-HIG clinical studies is less in number than that of CCP clinical studies, based on the existing clinical studies and the component of the two plasma products, the use of COVID-HIG should also be recommended for patients with COVID-19 with high-risk factors or serious underlying diseases in early stages.

7 Use of mAbs for COVID-19 treatment

The use of mAbs was proven to be highly effective in treating infectious diseases, with numerous successful cases worth emulating. In 1998, the FDA approved the use of the short-acting palivizumab for the treatment of respiratory syncytial virus (RSV) [70]. In 2018, the FDA approved the mAb drug Trogarzo (ibalizumab) for HIV treatment [71]. Given the well-established manufacturing method for mAbs and the well-characterized preclinical and clinical studies, the effectiveness of multiple mAbs was extensively evaluated in COVID-19 treatment [72].

In a 2020 phase I–III clinical trial, Regeneron Pharmaceuticals reported a high efficacy of REGEN-COV cocktail therapy consisting of two mAbs (casirivimab and imdevimab) in reducing the SARS-CoV-2 viral load in non-hospitalized patients, especially those with a high baseline viral load or lacking an immune response [73]. Based on the results of a phase II/III clinical trial in 2020, Eli Lilly and Company reported that cocktail therapy comprising bamlanivimab and etesevimab, both targeting the critical RBD of the virus S protein, could yield better results in terms of the viral load reduction and clinical symptom alleviation in non-hospitalized patients with mild-to-moderate COVID-19, as compared to bamlanivimab monotherapy [74]. A phase III clinical trial conducted by VIR/GSK in 2021 reported that sotrovimab could reduce the risk of disease progression leading to hospitalization or death in non-hospitalized patients with mild-to-moderate COVID-19 but also high-risk factors, with a relative risk reduction (RRR) of 85% [75]. In a 2021 phase III clinical trial, based on 6-month follow-up data, AstraZeneca reported that a single dose of intramuscularly injected tixagevimab/cilgavimab could effectively prevent COVID-19 infection, with an RRR of 83% [76]. In a phase II/III clinical trial conducted by Brii Biosciences in 2021, the combination therapy of amubarvimab and romlusevimab could significantly reduce hospitalization or all-cause death risks in non-hospitalized COVID-19 patients, with an RRR of 81% [77]. Ample clinical evidence indicated that mAb therapies were effective in non-hospitalized patients with mild-to-moderate COVID-19 but not in hospitalized patients with severe COVID-19. This finding might be attributed to most severely ill patients who did not lack neutralizing antibodies but developed multiple-organ failure and life-threatening conditions in the later stages of the disease complicated by overactivation of the immune system and subsequent cytokine storm [78].

Owing to the efficacy of SARS-CoV-2 mAbs confirmed in clinical trials, the FDA issued emergency use authorizations (EUAs) for multiple mAb drugs. In November 2020, Eli Lilly and Company’s bamlanivimab was granted the first EUA in the world, followed by Regeneron Pharmaceuticals’ casirivimab/imdevimab combination, Eli Lilly and Company’s bamlanivimab/etesevimab combination, GSK and Vir Biotechnology’s sotrovimab, AstraZeneca’s tixagevimab/cilgavimab combination, and Eli Lilly and Company’s bebtelovimab. In December 2022, Brii Biosciences’ amubarvimab/romlusevimab combination received conditional approval for marketing from the National Medical Product Administration, China. Almost all mAbs approved for marketing are indicated for use in individuals aged ≥ 12 years with mild-to-moderate symptoms, who are at a high risk of progressing to severe disease, including hospitalization or death. The FDA authorized six mAbs targeting specific SARS-CoV-2 proteins for emergency use in COVID-19 treatment, and numerous mAbs targeting cytokines associated with severe disease progression, such as IL-6, CCR5, and granulocyte macrophage colony-stimulating factor (GM-CSF), also were under clinical stage [79–81] (Tab.1).

Currently, most mAbs used to treat COVID-19 are administered intravenously. However, this mode of administration decreases the local antibody levels in the lungs and respiratory tract of patients by 200–500 times compared with those in serum, thereby limiting their effectiveness [89]. A high intravenous dosage is generally required to achieve therapeutic neutralizing antibody concentrations in the respiratory tract, whereas nasal spray or inhalation delivers mAbs locally to the upper respiratory tract and lungs, thereby providing benefits in terms of dose saving, strengthened targeting, and increased safety. Hence, research on COVID-19 treatment and prevention focuses on delivering mAbs through nasal spray or inhalation. For instance, the mAbs (F61 and H121) developed by Lu et al., administered through the nasal route at a low dose, offered significant prophylactic protection against lethal challenges of the Delta and Omicron variants in mice [90]. In addition, a nasal immunization protection trial of F61 mAb in susceptible populations exhibited a prophylactic protective effect (ChiCTR2200066391). Researchers at the University of Texas modified the constant region of existing IgG mAbs to obtain the corresponding IgM subtype of mAbs, which was more potent than the parental IgG. Further, nasal administration of IgM-type mAbs in mice showed good preventive and therapeutic effects [91]. Researchers at Fudan University (Shanghai, China) constructed a bispecific single-domain antibody targeting two conserved epitopes on S protein. This antibody could efficiently neutralize various variants, including Omicron, when delivered to the lungs through nebulization, and demonstrated promising therapeutic effects in a mouse infection model [92]. Overall, mAbs therapies were proven to be highly effective in treating infectious diseases, including COVID-19, and thus represent a promising avenue.

8 Difference among three antibody therapies

As CCP and COVID-19-HIG are from plasma, they share several common features, such as relatively rapid manufacturing process and quick adaptation to the new VOCs, and a variety of antibody species against many different viral antigens [93]. For example, different isotype antibodies have been identified in CCP and COVID-HIG, including IgG, IgM, and IgA [94,95]. CCP and COVID-HIG contain polyclonal antibodies, with high binding affinities to the S, RBD, NTD, and nucleocapsid proteins of SARS-CoV-2, thus providing certain broad-spectrum antiviral effects against SARS-CoV-2 VOCs [10,96]. Meanwhile, some differences exist between CCP and COVID-HIG. COVID-HIG is produced by pooling numerous units of the donor plasma in a limited volume for purified high titers of SARS-CoV-2 neutralizing antibody, and the average IgG concentration of COVID-HIG may be 5.5-fold higher than that of the pooled plasma [10,97,98]. COVID-HIG is significantly superior to CCP in terms of high purity, low risk of blood-related viruses and potentially harmful clotting factors, uniform accurate antibody titer and dose, and ease of storage and transport [99,100]. However, CCP may be physiologically more effective because of the presence of other plasma factors with positive clinical effects such as pro-coagulants and anti-fibrinolytic factors [99]. CCP may carry autoantibodies, including those against immunoreactive components. Therefore, selecting donors on the basis of individual characteristics is of importance [101].

CCP and COVID-HIG therapies also pose challenges, including the heavy donor selection process, and large amounts of donated plasma from convalescent individuals with COVID-19 or COVID-19 vaccine recipients, and the strict procedures to eliminate the risk of blood-related pathogens. Compared with CCP and COVID-HIG, mAbs have the advantages of good specificity, high safety, and identified antibody titer [75,102,103]. In addition, mAbs can be used for the prevention and treatment of patients infected with SARS-CoV-2 VOCs via intranasal administration, which quickly inhibits viral invasion and replication [90,104].

9 Immune escape of SARS-CoV-2 VOCs against antibody

As for CCP and COVID-19-HIG, along with most mAbs targeting the RBDs developed during the early waves of prototype COVID-19, their neutralizing activity against Omicron has been observed to decrease in vitro [105-107]. With the continuous mutation of SARS-CoV-2, the Omicron variants were reported to contain over 15 mutation sites on RBD [108], with more mutants in the strains XBB and BQ.1.1 that are currently globally prevalent [109, 110] and possess strong immune escape ability. Yi et al. isolated and identified 93 RBD-specific antibodies from the memory B cells of convalescent patients with COVID-19 by using single B cell cloning technology. They found that K417N, E484K, L452R, F486L, N450K, F490S, and R346S mutations might lead to the occurrence of immune escape [111]. According to the cryo-electron microscopy structure of ACE2-bound SARS-CoV-2 Omicron S protein, mutation sites on the Omicron RBD are concentrated in the epitope region of most neutralizing antibodies, decreasing the binding affinity of the Fab antibody to S protein, where some mutation sites could form new interactions with ACE2 [112–114]. Owing to the immune escape of VOCs from mAbs [115], the FDA has withdrawn EUAs for all the COVID-19 mAb drugs.

Regarding the immune escape of VOCs, researchers have found that although CCP and COVID-HIG against the prototype virus cannot effectively neutralize the Omicron variants BA.1–BA.5, CCP obtained from BA.1 infection and 2020 hyperimmune anti-SARS-CoV-2 intravenous immunoglobulin (hCoV-2IG) can effectively neutralize Omicron subtypes [116,117]. However, the speed of the development of mAbs against SARS-CoV-2 VOCs seems unable to catch up with the mutation rate of SARS-CoV-2 that the existing mAbs cannot compete with the VOCs. Many researchers have thus turned their attention to developing more broad-spectrum anti-SARS-CoV-2 VOC mAbs. Peking University researchers identified mAbs from convalescents individuals who received COVID-19 inactivated vaccine previously; these mAbs can effectively recognize conserved sites in the RBD region of various SARS-CoV-2 VOCs, including all Omicron subvariants. The conserved sites are related to the core functions of the virus (ACE2 binding and glycosylation), making it difficult for the new VOCs to escape from the antibody [118]. On the basis of the S protein extracellular region, the neutralizing mAbs targeting the highly conserved S2′ cleavage site and fusion peptide region have been isolated from the PBMCs of convalescent patients. These antibodies can inhibit S2′ cleavage, block virus–host cell membrane fusion, and inhibit virus entry, thus exerting a neutralizing effect on the virus. Owing to the presence of a novel neutralizing mechanism, these antibodies exhibit extensive neutralizing activities against various VOCs [119]. Furthermore, computer-stimulated algorithm has been used in antibody design, and on the basis of the protein structure prediction and target antibody screening, new broad-spectrum antibodies are rapidly being designed. By using a large amount of data on the structure and affinity of antibody–antigen complexes, Tsinghua University team has induced mutations on the antibody complementarity-determining regions, obtained broad-spectrum high-affinity antibodies and validated them using pseudovirus-based neutralizing activity assay [120]. Computer-stimulated algorithms such as XBCR-net and high-throughput artificial intelligence have been used to identify target antibodies that can effectively neutralize different variants of the virus by predicting broad-spectrum mAbs against SARS-CoV-2 and its VOCs directly from single-cell B cell receptor sequences to rapidly design new broad-spectrum mAbs against SARS-CoV-2 [121]. Though only few approved antibody drugs can maintain neutralizing activity against the latest circulating strain XBB, they bring hope for the development of broad-spectrum mAbs.

10 Study on the possible antibody-dependent enhancement with anti-COVID-19 antibody therapies

Antibody-dependent enhancement (ADE) has been clinically or epidemiologically proven to occur in various viruses, including dengue virus (DENV), RSV, and measles virus. Studies have shown that infection with one DENV serotype increases the likelihood of infection with another serotype, and vaccinations against RSV and measles can intensify disease symptoms after infection [122–125]. In SARS and Middle East respiratory syndrome (MERS), although laboratory studies have suggested that the pre-existing antibodies to SARS-CoV and MERS-CoV may induce ADE, clinical evidence is lacking [126,127]. Studies have documented several mechanisms for ADE-mediated viral infection. Binding of SARS-CoV-2 with virus-specific antibodies (generally non-nAbs) can enhance viral infection and replication by facilitating virus entry into the macrophages expressing Fcγ receptor IIa (FcγRIIa), subsequently leading to increased inflammation and immunopathology. In addition, ADE can be induced by excessive Fc-mediated effector functions or immune complex formation, further exacerbating disease progression [128–131]. ADE may also be enhanced through the mediation of the complement component C1q [132]. The potential risk of ADE induced by CCP, COVID-HIG, and mAbs in SARS-CoV-2 infection is a major concern among researchers, primarily due to its ability to enhance infection and worsen disease caused by new SARS-CoV-2 variants. In-vitro assays have shown that 1Ba-3H can enhance the Gamma variant infection of Vero E6 cells in a dose-dependent manner [133], whereas the higher the neutralizing activity of certain mAbs against the S protein, the lower is the potential risk of ADE. A comparison of ADE potential induced by three mAbs (Cas, Imd, and Sot) has suggested that the FcR binding function of these antibodies are not necessarily the reason for ADE [134]. More interestingly, in-vitro assays have demonstrated that two types of FcγRs (FcγRIIA and FcγRIIIA) can eventually enhance the infection of SARS-CoV-2 and its VOCs in monocyte-derived macrophages, although the two FcγRs are unable to cause excess cytokine production from macrophages [135]. Besides, mAbs (S1D2-hIgG1 and STI-1499-LALA) and CCP may display a weak ability to induce ADE in human blood monocyte-derived macrophages [136].

Although the existence of ADE has been elucidated at the laboratory level, whether ADE occurs as the molecular and host immunological responses to SARS-CoV-2 and its VOC infections has not been fully clarified. Among numerous clinical trials, only two clinical studies reported higher cumulative deaths in the CCP treatment group than in the standard-of-care group, though the CCP treatment group showed more serious adverse events; however, no direct evidence pointed ADE as the cause [137,138]. No significant immune damage or ADE was observed after reinfection with SARS-CoV-2 in animal models immunized with inactivated vaccine, providing an insight into the protective effect of pre-existing antibodies in the body against SARS-CoV-2 [139–141]. The safety of CCP was investigated in a large cohort study of 5000 people, followed by a large cohort study of 20 000 people. The results indicated that no ADE effect was present in the antibody treatment strategy and supported the viewpoint that early antibody therapy in the clinical course of COVID-19 was more likely to reduce mortality [36,142]. mAbs (sotrovimab) provided real-world evidence for the effectiveness in reducing hospitalizations among outpatients with COVID-19 during the Delta variant epidemic that sotrovimab reduced hospitalizations and death instead of aggravating the disease [143]. Based on the available clinical data, in-vivo imported antibodies (CCP, COVID-HIG, and mAbs) do not produce ADE in humans.

11 Study on plasma-borne pathogens with CCP and COVID-HIG

Since 1987, no transmission of blood-borne pathogens has been reported in commercial plasma products received by hemophiliacs with multiple transfusions [144]. ABO and Rh compatibility in CCP contributor and recipients is essential because CCP and COVID-HIG present no viral transmission risk through strict development and production processes including donor screening, virus screening, virus inactivation, and virus removal [98]. Although CCP exhibits moderately increased levels of the inflammatory markers IL-6 and TNF-α, no discernible difference in ex-vivo bioactivity has been noted in comparison with control plasma [145]. Large-sample data from the US Expanded Access Program of CCP have provided evidence supporting the safety of CCP treatment in hospitalized patients with COVID-19 [146]. Only low rates of serious adverse events were observed, such as transfusion reactions and thromboembolic or thrombotic events. Moreover, most thromboembolic or thrombotic events and cardiac events were judged to be unrelated to plasma transfusion, thereby proving the safety of CCP use in hospitalized patients with COVID-19 [41,147]. Hyperimmunoglobulin has been indicated for use in various diseases, including immunodeficiency or autoimmune diseases, and it is associated with mild and temporary adverse reactions, such as headache, flushing, fever, chills, fatigue, nausea, diarrhea, changes in blood pressure and tachycardia [148,149], as confirmed in numerous clinical studies [150,151]. mAbs demonstrate good safety in clinical trials owing to their relatively pure components. Sufficient clinical evidence suggests that mAbs can be used as the first-line therapeutic option for patients with COVID-19 [147,152]. In conclusion, the benefits of antibody intervention therapy outweigh its risks.

12 Conclusions

During the initial phase of SARS-CoV-2 pandemic in 2020–2021, CCP and COVID-HIG emerged as the preferred options for COVID-19 treatment, especially in the early disease stage, and they could bring benefits to many patients with COVID-19. CCP and COVID-HIG are still required for treating patients with COVID-19 and immunosuppressive diseases as well as those receiving immunosuppressive therapy. CCP treatment strategy has been retained in the COVID-19 Treatment Guidelines of NIH and the Chinese guideline “Diagnosis and Treatment Protocol for COVID-19 (Trial Version 9)” [153]. With the emergence of new SARS-CoV-2 mutant strains and the availability of many types of antiviral drugs, the healthcare providers almost no longer provide CCP and COVID-HIG as a routine, but their clinical values against COVID-19 cannot be negated within selected settings.

The immune escape mechanism of SARS-CoV-2 VOCs is associated with great risks and challenges to approved or in-development mAbs. The origin of the convergent evolution, escape mutation profiles, and neutralization activity of mAbs isolated and screened from individuals with SARS-CoV-2 and its VOC infections should be thoroughly analyzed based on deep mutational scanning profiles. Meanwhile, convergent RBD mutations should be accurately inferred. The prediction of future mutations and possible monoclonal antibody structures relying on existing biological procedures should be explored in depth, combined with humoral immune spectrum and antibody response mechanism, to design versatile mAbs. Nasal spraying or inhalation provides a preventive effect, facilitating direct targeting of viruses in the respiratory tract and offering the convenience of self-administration. Broad-spectrum mAbs can also be injected as a post-exposure treatment.

Studies on ADE should focus on two key aspects. First is the composition of serum antibodies (the antibody spectrum) and the biological effects of the antibody spectrum in viral infection. The composition ratio distribution of antibodies against different antigens of SARS-CoV-2, such as the structural proteins S, N, E, and M and nonstructural antigens, and the antibody function during the process of SARS-CoV-2 and its VOC invasion, release, and cell-to-cell transmission should be emphasized and subject to further studies [134]. Second, the circulating immune cells and the immune molecule response to SARS-CoV-2 and its VOCs should be addressed [154]. Changes in the balance of pro-inflammatory cytokines/chemokines ultimately leading to the pathogenesis of COVID-19 after antibody-mediated invasion must be investigated.

Overall, the components, structure, and immune mechanisms of antibody drugs including CCP, COVID-HIG and neutralizing mAbs should be comprehensively studied, and their therapeutic potential should be further explored against new or mutant infectious disease viral strains.

References

[1] Singh D, Yi SV. On the origin and evolution of SARS-CoV-2. Exp Mol Med 2021; 53(4): 537–547

[2] WorldHealth Organization. WHO Coronavirus (COVID-19) Dashboard. 2023. Available at the website of WHO (accessed April 15, 2023)

[3] Sakoulas G, Geriak M, Kullar R, Greenwood KL, Habib M, Vyas A, Ghafourian M, Dintyala VNK, Haddad F. Intravenous immunoglobulin plus methylprednisolone mitigate respiratory morbidity in coronavirus disease 2019. Crit Care Explor 2020; 2(11): e0280

[4] Scialpi M, Scialpi S, Piscioli I, Battista Scalera G, Longo F. Pulmonary thromboembolism in critical ill COVID-19 patients. Int J Infect Dis 2020; 95: 361–362

[5] Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating, Research Team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382(8): 727–733

[6] Tenforde MW, Kim SS, Lindsell CJ, Billig Rose E, Shapiro NI, Files DC, Gibbs KW, Erickson HL, Steingrub JS, Smithline HA, Gong MN, Aboodi MS, Exline MC, Henning DJ, Wilson JG, Khan A, Qadir N, Brown SM, Peltan ID, Rice TW, Hager DN, Ginde AA, Stubblefield WB, Patel MM, Self WH, Feldstein LR; IVY Network Investigators; CDC COVID-19 Response Team; IVY Network Investigators. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020. MMWR Morb Mortal Wkly Rep 2020; 69(30): 993–998

[7] Khan Z, Karataş Y, Rahman H. Anti COVID-19 drugs: need for more clinical evidence and global action. Adv Ther 2020; 37(6): 2575–2579

[8] Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M, Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, Peng Y, Hu Y, Lin L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, Gong Q, Zhang W, Zheng X, Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, Zhang X, Yang X. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci USA 2020; 117(17): 9490–9496

[9] WorldHealth Organization. Guidelines on viral inactivation and removal procedures intended to assure the viral safety of human blood plasma products. 2004. Available at the website of WHO (accessed April 15, 2023)

[10] Yu D, Li YF, Liang H, Wu JZ, Hu Y, Peng Y, Li TJ, Hou JF, Huang WJ, Guan LD, Han R, Xing YT, Zhang Y, Liu J, Feng L, Li CY, Liang XL, Ding YL, Zhou ZJ, Ji DM, Wang FF, Yu JH, Deng K, Xia DM, Dong DM, Hu HR, Liu YJ, Fu DX, He YL, Zhou DB, Yang HC, Jia R, Ke CW, Du T, Xie Y, Zhou R, Li CS, Wang ML, Yang XM. Potent anti-SARS-CoV-2 efficacy of COVID-19 hyperimmune globulin from vaccine-immunized plasma. Adv Sci (Weinh) 2022; 9(14): e2104333

[11] Ali S, Uddin SM, Ali A, Anjum F, Ali R, Shalim E, Khan M, Ahmed I, Muhaymin SM, Bukhari U, Luxmi S, Khan AS, Quraishy S. Production of hyperimmune anti-SARS-CoV-2 intravenous immunoglobulin from pooled COVID-19 convalescent plasma. Immunotherapy 2021; 13(5): 397–407

[12] Jones BE, Brown-Augsburger PL, Corbett KS, Westendorf K, Davies J, Cujec TP, Wiethoff CM, Blackbourne JL, Heinz BA, Foster D, Higgs RE, Balasubramaniam D, Wang L, Zhang Y, Yang ES, Bidshahri R, Kraft L, Hwang Y, Žentelis S, Jepson KR, Goya R, Smith MA, Collins DW, Hinshaw SJ, Tycho SA, Pellacani D, Xiang P, Muthuraman K, Sobhanifar S, Piper MH, Triana FJ, Hendle J, Pustilnik A, Adams AC, Berens SJ, Baric RS, Martinez DR, Cross RW, Geisbert TW, Borisevich V, Abiona O, Belli HM, de Vries M, Mohamed A, Dittmann M, Samanovic MI, Mulligan MJ, Goldsmith JA, Hsieh CL, Johnson NV, Wrapp D, McLellan JS, Barnhart BC, Graham BS, Mascola JR, Hansen CL, Falconer E. The neutralizing antibody, LY-CoV555, protects against SARS-CoV-2 infection in nonhuman primates. Sci Transl Med 2021; 13(593): eabf1906

[13] Shi R, Shan C, Duan X, Chen Z, Liu P, Song J, Song T, Bi X, Han C, Wu L, Gao G, Hu X, Zhang Y, Tong Z, Huang W, Liu WJ, Wu G, Zhang B, Wang L, Qi J, Feng H, Wang FS, Wang Q, Gao GF, Yuan Z, Yan J. A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature 2020; 584(7819): 120–124

[14] Pan Y, Du J, Liu J, Wu H, Gui F, Zhang N, Deng X, Song G, Li Y, Lu J, Wu X, Zhan S, Jing Z, Wang J, Yang Y, Liu J, Chen Y, Chen Q, Zhang H, Hu H, Duan K, Wang M, Wang Q, Yang X. Screening of potent neutralizing antibodies against SARS-CoV-2 using convalescent patients-derived phage-display libraries. Cell Discov 2021; 7(1): 57

[15] Hansen J, Baum A, Pascal KE, Russo V, Giordano S, Wloga E, Fulton BO, Yan Y, Koon K, Patel K, Chung KM, Hermann A, Ullman E, Cruz J, Rafique A, Huang T, Fairhurst J, Libertiny C, Malbec M, Lee WY, Welsh R, Farr G, Pennington S, Deshpande D, Cheng J, Watty A, Bouffard P, Babb R, Levenkova N, Chen C, Zhang B, Romero Hernandez A, Saotome K, Zhou Y, Franklin M, Sivapalasingam S, Lye DC, Weston S, Logue J, Haupt R, Frieman M, Chen G, Olson W, Murphy AJ, Stahl N, Yancopoulos GD, Kyratsous CA. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science 2020; 369(6506): 1010–1014

[16] Noy-Porat T, Mechaly A, Levy Y, Makdasi E, Alcalay R, Gur D, Aftalion M, Falach R, Leviatan Ben-Arye S, Lazar S, Zauberman A, Epstein E, Chitlaru T, Weiss S, Achdout H, Edgeworth JD, Kikkeri R, Yu H, Chen X, Yitzhaki S, Shapira SC, Padler-Karavani V, Mazor O, Rosenfeld R. Therapeutic antibodies, targeting the SARS-CoV-2 spike N-terminal domain, protect lethally infected K18-hACE2 mice. iScience 2021; 24(5): 102479

[17] Suryadevara N, Shrihari S, Gilchuk P, VanBlargan LA, Binshtein E, Zost SJ, Nargi RS, Sutton RE, Winkler ES, Chen EC, Fouch ME, Davidson E, Doranz BJ, Chen RE, Shi PY, Carnahan RH, Thackray LB, Diamond MS, Crowe JE Jr. Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein. Cell 2021; 184(9): 2316–2331.e15

[18] Brandtzaeg P. Induction of secretory immunity and memory at mucosal surfaces. Vaccine 2007; 25(30): 5467–5484

[19] Pelegrin M, Naranjo-Gomez M, Piechaczyk M. Antiviral monoclonal antibodies: can they be more than simple neutralizing agents? Trends Microbiol 2015; 23(10): 653–665 doi:10.1016/j.tim.2015.07.005

[20] Cunningham AC, Goh HP, Koh D. Treatment of COVID-19: old tricks for new challenges. Crit Care 2020; 24(1): 91

[21] Tso FY, Lidenge SJ, Poppe LK, Peña PB, Privatt SR, Bennett SJ, Ngowi JR, Mwaiselage J, Belshan M, Siedlik JA, Raine MA, Ochoa JB, Garcia-Diaz J, Nossaman B, Buckner L, Roberts WM, Dean MJ, Ochoa AC, West JT, Wood C. Presence of antibody-dependent cellular cytotoxicity (ADCC) against SARS-CoV-2 in COVID-19 plasma. PLoS One 2021; 16(3): e0247640

[22] Nasser R, Pelegrin M, Plays M, Gros L, Piechaczyk M. Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies. Blood 2013; 121(7): 1102–1111

[23] Xi Y. Convalescent plasma therapy for COVID-19: a tried-and-true old strategy? Signal Transduct Target Ther 2020; 5(1): 203 doi:10.1038/s41392-020-00310-8

[24] Herman JD, Wang C, Burke JS, Zur Y, Compere H, Kang J, Macvicar R, Taylor S, Shin S, Frank I, Siegel D, Tebas P, Choi GH, Shaw PA, Yoon H, Pirofski LA, Julg BD, Bar KJ, Lauffenburger D, Alter G. Nucleocapsid-specific antibody function is associated with therapeutic benefits from COVID-19 convalescent plasma therapy. Cell Rep Med 2022; 3(11): 100811

[25] Rojas M, Rodríguez Y, Monsalve DM, Acosta-Ampudia Y, Camacho B, Gallo JE, Rojas-Villarraga A, Ramírez-Santana C, Díaz-Coronado JC, Manrique R, Mantilla RD, Shoenfeld Y, Anaya JM. Convalescent plasma in Covid-19: possible mechanisms of action. Autoimmun Rev 2020; 19(7): 102554

[26] Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, Wei J, Xiao H, Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, Zhang Z, Liu Y, Liu L. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 2020; 323(16): 1582–1589

[27] Shenoy AG, Hettinger AZ, Fernandez SJ, Blumenthal J, Baez V. Early mortality benefit with COVID-19 convalescent plasma: a matched control study. Br J Haematol 2021; 192(4): 706–713

[28] Zeng H, Wang D, Nie J, Liang H, Gu J, Zhao A, Xu L, Lang C, Cui X, Guo X, Zhou C, Li H, Guo B, Zhang J, Wang Q, Fang L, Liu W, Huang Y, Mao W, Chen Y, Zou Q. The efficacy assessment of convalescent plasma therapy for COVID-19 patients: a multi-center case series. Signal Transduct Target Ther 2020; 5(1): 219

[29] Sarkar S, Soni KD, Khanna P. Convalescent plasma is a clutch at straws in COVID-19 management! A systematic review and meta-analysis. J Med Virol 2021; 93(2): 1111–1118

[30] Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vázquez C, Savoy N, Giunta DH, Pérez LG, Sánchez MDL, Gamarnik AV, Ojeda DS, Santoro DM, Camino PJ, Antelo S, Rainero K, Vidiella GP, Miyazaki EA, Cornistein W, Trabadelo OA, Ross FM, Spotti M, Funtowicz G, Scordo WE, Losso MH, Ferniot I, Pardo PE, Rodriguez E, Rucci P, Pasquali J, Fuentes NA, Esperatti M, Speroni GA, Nannini EC, Matteaccio A, Michelangelo HG, Follmann D, Lane HC, Belloso WH; PlasmAr Study Group. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med 2021; 384(7): 619–629

[31] Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW, Theel ES, Wiggins CC, Bruno KA, Klompas AM, Lesser ER, Kunze KL, Sexton MA, Diaz Soto JC, Baker SE, Shepherd JRA, van Helmond N, Verdun NC, Marks P, van Buskirk CM, Winters JL, Stubbs JR, Rea RF, Hodge DO, Herasevich V, Whelan ER, Clayburn AJ, Larson KF, Ripoll JG, Andersen KJ, Buras MR, Vogt MNP, Dennis JJ, Regimbal RJ, Bauer PR, Blair JE, Paneth NS, Fairweather D, Wright RS, Casadevall A. Convalescent plasma antibody levels and the risk of death from Covid-19. N Engl J Med 2021; 384(11): 1015–1027

[32] Fish M, Rynne J, Jennings A, Lam C, Lamikanra AA, Ratcliff J, Cellone-Trevelin S, Timms E, Jiriha J, Tosi I, Pramanik R, Simmonds P, Seth S, Williams J, Gordon AC, Knight J, Smith DJ, Whalley J, Harrison D, Rowan K, Harvala H, Klenerman P, Estcourt L, Menon DK, Roberts D, Shankar-Hari M; REMAP-CAP Immunoglobulin Domain UK Investigators. Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial. Intensive Care Med 2022; 48(11): 1525–1538

[33] LiLZhangWHuYTongXZhengSYangJKongYRenLWeiQMeiHHuCTaoCYangRWangJYuYGuoYWuXXuZZengLXiongNChenLWangJManNLiuYXuHDengEZhangXLiCWangCSuSZhangLWangJWuYLiuZ. 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(5): 460–460 Erratum in: JAMA 2020; 4; 324(5): 519 doi:10.1001/jama.2020.10044

[34] RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet 2021; 397(10289): 2049–2059

[35] Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P; PLACID Trial Collaborators. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ 2020; 371: m3939

[36] Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, Esteban I, Caballero MT, Wood C, Berrueta M, Rondan A, Lescano G, Cruz P, Ritou Y, Fernández Viña V, Álvarez Paggi D, Esperante S, Ferreti A, Ofman G, Ciganda Á, Rodriguez R, Lantos J, Valentini R, Itcovici N, Hintze A, Oyarvide ML, Etchegaray C, Neira A, Name I, Alfonso J, López Castelo R, Caruso G, Rapelius S, Alvez F, Etchenique F, Dimase F, Alvarez D, Aranda SS, Sánchez Yanotti C, De Luca J, Jares Baglivo S, Laudanno S, Nowogrodzki F, Larrea R, Silveyra M, Leberzstein G, Debonis A, Molinos J, González M, Perez E, Kreplak N, Pastor Argüello S, Gibbons L, Althabe F, Bergel E, Polack FP; Fundación INFANT–COVID-19 Group. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med 2021; 384(7): 610–618

[37] JoynerMJSenefeldJWKlassenSAMillsJRJohnsonPWTheelESWigginsCCBrunoKAKlompasAMLesserERKunzeKLSextonMADiaz SotoJCBakerSEShepherdJRAvan HelmondNvan BuskirkCMWintersJLStubbsJRReaRFHodgeDOHerasevichVWhelanERClayburnAJLarsonKFRipollJGAndersenKJBurasMRVogtMNPDennisJJRegimbalRJBauerPRBlairJEPanethNSFairweatherDWrightRSCarterRECasadevallA. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. medRxiv 2020; doi:10.1101/2020.08.12.20169359

[38] Joyner MJ, Bruno KA, Klassen SA, Kunze KL, Johnson PW, Lesser ER, Wiggins CC, Senefeld JW, Klompas AM, Hodge DO, Shepherd JRA, Rea RF, Whelan ER, Clayburn AJ, Spiegel MR, Baker SE, Larson KF, Ripoll JG, Andersen KJ, Buras MR, Vogt MNP, Herasevich V, Dennis JJ, Regimbal RJ, Bauer PR, Blair JE, van Buskirk CM, Winters JL, Stubbs JR, van Helmond N, Butterfield BP, Sexton MA, Diaz Soto JC, Paneth NS, Verdun NC, Marks P, Casadevall A, Fairweather D, Carter RE, Wright RS. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clin Proc 2020; 95(9): 1888–1897

[39] Focosi D, Franchini M. COVID-19 convalescent plasma therapy: hit fast, hit hard!. Vox Sang 2021; 116(9): 935–942

[40] Focosi D, Franchini M, Pirofski LA, Burnouf T, Paneth N, Joyner MJ, Casadevall A. COVID-19 convalescent plasma and clinical trials: understanding conflicting outcomes. Clin Microbiol Rev 2022; 35(3): e0020021

[41] LevineACFukutaYHuamanMAOuJMeisenbergBRPatelBPaxtonJHHanleyDFRijndersBJGharbharanARokxCZwagingaJJAlemanyAMitjàOOuchiDMillat-MartinezPDurkalski-MauldinVKorleyFKDumontLJCallawayCWLibsterRMarcGPWappnerDEstebanIPolackFSullivanDJ. COVID-19 convalescent plasma outpatient therapy to prevent outpatient hospitalization: a meta-analysis of individual participant data from five randomized trials. medRxiv 2022; doi:10.1101/2022.12.16.22283585

[42] Sullivan DJ, Gebo KA, Shoham S, Bloch EM, Lau B, Shenoy AG, Mosnaim GS, Gniadek TJ, Fukuta Y, Patel B, Heath SL, Levine AC, Meisenberg BR, Spivak ES, Anjan S, Huaman MA, Blair JE, Currier JS, Paxton JH, Gerber JM, Petrini JR, Broderick PB, Rausch W, Cordisco ME, Hammel J, Greenblatt B, Cluzet VC, Cruser D, Oei K, Abinante M, Hammitt LL, Sutcliffe CG, Forthal DN, Zand MS, Cachay ER, Raval JS, Kassaye SG, Foster EC, Roth M, Marshall CE, Yarava A, Lane K, McBee NA, Gawad AL, Karlen N, Singh A, Ford DE, Jabs DA, Appel LJ, Shade DM, Ehrhardt S, Baksh SN, Laeyendecker O, Pekosz A, Klein SL, Casadevall A, Tobian AAR, Hanley DF. Early outpatient treatment for Covid-19 with convalescent plasma. N Engl J Med 2022; 386(18): 1700–1711

[43] Bartelt LA, Markmann AJ, Nelson B, Keys J, Root H, Henderson HI, Kuruc J, Baker C, Bhowmik DR, Hou YJ, Premkumar L, Cornaby C, Schmitz JL, Weiss S, Park Y, Baric R, de Silva AM, Lachiewicz A, Napravnik S, van Duin D, Margolis DM. Outcomes of convalescent plasma with defined high versus lower neutralizing antibody titers against SARS-CoV-2 among hospitalized patients: coronavirus inactivating plasma (CoVIP) study. MBio 2022; 13(5): e0175122

[44] Denkinger CM, Janssen M, Schäkel U, Gall J, Leo A, Stelmach P, Weber SF, Krisam J, Baumann L, Stermann J, Merle U, Weigand MA, Nusshag C, Bullinger L, Schrezenmeier JF, Bornhäuser M, Alakel N, Witzke O, Wolf T, Vehreschild MJGT, Schmiedel S, Addo MM, Herth F, Kreuter M, Tepasse PR, Hertenstein B, Hänel M, Morgner A, Kiehl M, Hopfer O, Wattad MA, Schimanski CC, Celik C, Pohle T, Ruhe M, Kern WV, Schmitt A, Lorenz HM, Souto-Carneiro M, Gaeddert M, Halama N, Meuer S, Kräusslich HG, Müller B, Schnitzler P, Parthé S, Bartenschlager R, Gronkowski M, Klemmer J, Schmitt M, Dreger P, Kriegsmann K, Schlenk RF, Müller-Tidow C. Anti-SARS-CoV-2 antibody-containing plasma improves outcome in patients with hematologic or solid cancer and severe COVID-19: a randomized clinical trial. Nat Can 2023; 4(1): 96–107

[45] Hueso T, Godron AS, Lanoy E, Pacanowski J, Levi LI, Gras E, Surgers L, Guemriche A, Meynard JL, Pirenne F, Idri S, Tiberghien P, Morel P, Besson C, Duléry R, Lamure S, Hermine O, Gagneux-Brunon A, Freymond N, Grabar S, Lacombe K. Convalescent plasma improves overall survival in patients with B-cell lymphoid malignancy and COVID-19: a longitudinal cohort and propensity score analysis. Leukemia 2022; 36(4): 1025–1034

[46] Senefeld JW, Franchini M, Mengoli C, Cruciani M, Zani M, Gorman EK, Focosi D, Casadevall A, Joyner MJ. COVID-19 convalescent plasma for the treatment of immunocompromised patients: a systematic review and meta-analysis. JAMA Netw Open 2023; 6(1): e2250647

[47] Zhai P, Ding Y, Wu X, Long J, Zhong Y, Li Y. The epidemiology, diagnosis and treatment of COVID-19. Int J Antimicrob Agents 2020; 55(5): 105955

[48] Tahmasebi S, Khosh E, Esmaeilzadeh A. The outlook for diagnostic purposes of the 2019-novel coronavirus disease. J Cell Physiol 2020; 235(12): 9211–9229

[49] Keith P, Day M, Perkins L, Moyer L, Hewitt K, Wells A. A novel treatment approach to the novel coronavirus: an argument for the use of therapeutic plasma exchange for fulminant COVID-19. Crit Care 2020; 24(1): 128

[50] Qin J, Wang G, Han D. Benefits of plasma exchange on mortality in patients with COVID-19: a systematic review and meta-analysis. Int J Infect Dis 2022; 122: 332–336

[51] Joyner MJ, Paneth N, Casadevall A. Use of convalescent plasma in the treatment of COVID-19. Nat Rev Nephrol 2023; 19(4): 271–271

[52] NationalHealth Commission & National Administration of Traditional Chinese Medicine. Diagnosis and Treatment Protocol for COVID-9 (Trial Version 9). 2022. Available at the website of National Health Commission (accessed April 15, 2023)

[53] FoodAdministrationDrug. Clinical memorandum for the emergency use authorization of COVID-19 convalescent plasma. 2020. Available at the website of FDA (accessed April 15, 2023)

[54] WorldHealth Organization. WHO recommends against the use of convalescent plasma to treat COVID-19. 2021. Available at the website of WHO (accessed April 15, 2023)

[55] FoodAdministrationDrug. Fact sheet for health care providers: Emergency Use Authorization (EUA) of COVID-19 convalescent plasma for treatment of coronavirus disease 2019 (COVID-19). 2021. Available at the website of FDA (accessed April 18, 2023)

[56] Estcourt LJ, Cohn CS, Pagano MB, Iannizzi C, Kreuzberger N, Skoetz N, Allen ES, Bloch EM, Beaudoin G, Casadevall A, Devine DV, Foroutan F, Gniadek TJ, Goel R, Gorlin J, Grossman BJ, Joyner MJ, Metcalf RA, Raval JS, Rice TW, Shaz BH, Vassallo RR, Winters JL, Tobian AAR. Clinical practice guidelines from the Association for the Advancement of Blood and Biotherapies (AABB): COVID-19 convalescent plasma. Ann Intern Med 2022; 175(9): 1310–1321

[57] Levin MJ, Duchon JM, Swamy GK, Gershon AA. Varicella zoster immune globulin (VARIZIG) administration up to 10 days after varicella exposure in pregnant women, immunocompromised participants, and infants: varicella outcomes and safety results from a large, open-label, expanded-access program. PLoS One 2019; 14(7): e0217749

[58] Zubkova I, Zhao Y, Cui Q, Kachko A, Gimie Y, Chabot S, Murphy T, Schillie S, Major M. Assessing the impact of hepatitis B immune globulin (HBIG) on responses to hepatitis B vaccine during co-administration. Vaccine 2023; 41(4): 955–964

[59] FoodAdministrationDrug. Products approved for anthrax. Available at the website of FDA (accessed April 15, 2023)

[60] Iannizzi C, Chai KL, Piechotta V, Valk SJ, Kimber C, Monsef I, Wood EM, Lamikanra AA, Roberts DJ, McQuilten Z, So-Osman C, Jindal A, Cryns N, Estcourt LJ, Kreuzberger N, Skoetz N. Convalescent plasma for people with COVID-19: a living systematic review. Cochrane Database Syst Rev 2023; 5(5): CD013600

[61] Focosi D, Tuccori M, Franchini M. The road towards polyclonal anti-SARS-CoV-2 immunoglobulins (hyperimmune serum) for passive immunization in COVID-19. Life (Basel) 2021; 11(2): 144

[62] Perotti C, Baldanti F, Bruno R, Del Fante C, Seminari E, Casari S, Percivalle E, Glingani C, Musella V, Belliato M, Garuti M, Meloni F, Frigato M, Di Sabatino A, Klersy C, De Donno G, Franchini M; Covid-Plasma Task Force. Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma. A proof of concept single arm multicenter trial. Haematologica 2020; 105(12): 2834–2840

[63] Ali S, Uddin SM, Shalim E, Sayeed MA, Anjum F, Saleem F, Muhaymin SM, Ali A, Ali MR, Ahmed I, Mushtaq T, Khan S, Shahab F, Luxmi S, Kumar S, Arain H, Khan M, Khan AS, Mehmood H, Rasheed A, Jahangeer A, Baig S, Quraishy S. Hyperimmune anti-COVID-19 IVIG (C-IVIG) treatment in severe and critical COVID-19 patients: a phase I/II randomized control trial. EClinicalMedicine 2021; 36: 100926

[64] ITAC (INSIGHT 013) Study Group. Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial. Lancet 2022; 399(10324): 530–540

[65] Shao Z, Feng Y, Zhong L, Xie Q, Lei M, Liu Z, Wang C, Ji J, Liu H, Gu Z, Hu Z, Su L, Wu M, Liu Z. Clinical efficacy of intravenous immunoglobulin therapy in critical ill patients with COVID-19: a multicenter retrospective cohort study. Clin Transl Immunology 2020; 9(10): e1192

[66] Bonam SR, Kaveri SV, Sakuntabhai A, Gilardin L, Bayry J. Adjunct immunotherapies for the management of severely ill COVID-19 patients. Cell Rep Med 2020; 1(2): 100016

[67] Xie Y, Cao S, Dong H, Li Q, Chen E, Zhang W, Yang L, Fu S, Wang R. Effect of regular intravenous immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19. J Infect 2020; 81(2): 318–356

[68] SrivastavaRRamakrishnaCCantinE. Anti-inflammatory activity of intravenous immunoglobulins protects against West Nile virus encephalitis. J Gen Virol 2015; 96(Pt 6): 1347–1357 doi:10.1099/vir.0.000079

[69] Chan KR, Zhang SL, Tan HC, Chan YK, Chow A, Lim AP, Vasudevan SG, Hanson BJ, Ooi EE. Ligation of Fc gamma receptor IIB inhibits antibody-dependent enhancement of dengue virus infection. Proc Natl Acad Sci USA 2011; 108(30): 12479–12484

[70] Wittenauer R, Pecenka C, Baral R. Cost of childhood RSV management and cost-effectiveness of RSV interventions: a systematic review from a low- and middle-income country perspective. BMC Med 2023; 21(1): 121

[71] Blair HA. Ibalizumab: a review in multidrug-resistant HIV-1 infection. Drugs 2020; 80(2): 189–196

[72] Chen P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J, Huhn G, Cardona J, Mocherla B, Stosor V, Shawa I, Adams AC, Van Naarden J, Custer KL, Shen L, Durante M, Oakley G, Schade AE, Sabo J, Patel DR, Klekotka P, Skovronsky DM; BLAZE-1 Investigators. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med 2021; 384(3): 229–237

[73] Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, Musser BJ, Soo Y, Rofail D, Im J, Perry C, Pan C, Hosain R, Mahmood A, Davis JD, Turner KC, Hooper AT, Hamilton JD, Baum A, Kyratsous CA, Kim Y, Cook A, Kampman W, Kohli A, Sachdeva Y, Graber X, Kowal B, DiCioccio T, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD; Trial Investigators. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med 2021; 384(3): 238–251

[74] Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J, Huhn G, Cardona J, Mocherla B, Stosor V, Shawa I, Kumar P, Adams AC, Van Naarden J, Custer KL, Durante M, Oakley G, Schade AE, Holzer TR, Ebert PJ, Higgs RE, Kallewaard NL, Sabo J, Patel DR, Klekotka P, Shen L, Skovronsky DM. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA 2021; 325(7): 632–644

[75] Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Moya J, Falci DR, Sarkis E, Solis J, Zheng H, Scott N, Cathcart AL, Hebner CM, Sager J, Mogalian E, Tipple C, Peppercorn A, Alexander E, Pang PS, Free A, Brinson C, Aldinger M, Shapiro AE; COMET-ICE Investigators. Early treatment for Covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab. N Engl J Med 2021; 385(21): 1941–1950

[76] Levin MJ, Ustianowski A, De Wit S, Launay O, Avila M, Templeton A, Yuan Y, Seegobin S, Ellery A, Levinson DJ, Ambery P, Arends RH, Beavon R, Dey K, Garbes P, Kelly EJ, Koh GCKW, Near KA, Padilla KW, Psachoulia K, Sharbaugh A, Streicher K, Pangalos MN, Esser MT; PROVENT Study Group. Intramuscular AZD7442 (tixagevimab-cilgavimab) for prevention of Covid-19. N Engl J Med 2022; 386(23): 2188–2200

[77] Hoy SM. Amubarvimab/romlusevimab: first approval. Drugs 2022; 82(12): 1327–1331

[78] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497–506

[79] Gaylis NB, Ritter A, Kelly SA, Pourhassan NZ, Tiwary M, Sacha JB, Hansen SG, Recknor C, Yang OO. Reduced cell surface levels of C-C chemokine receptor 5 and immunosuppression in long coronavirus disease 2019 syndrome. Clin Infect Dis 2022; 75(7): 1232–1234

[80] Canziani LM, Trovati S, Brunetta E, Testa A, De Santis M, Bombardieri E, Guidelli G, Albano G, Folci M, Squadroni M, Beretta GD, Ciccarelli M, Castoldi M, Lleo A, Aghemo A, Vernile L, Malesci A, Omodei P, Angelini C, Badalamenti S, Cecconi M, Cremonesi A, Selmi C; Humanitas, Gavazzeni/Castelli COVID-19 Task Forces. Interleukin-6 receptor blocking with intravenous tocilizumab in COVID-19 severe acute respiratory distress syndrome: a retrospective case-control survival analysis of 128 patients. J Autoimmun 2020; 114: 102511

[81] Temesgen Z, Kelley CF, Cerasoli F, Kilcoyne A, Chappell D, Durrant C, Ahmed O, Chappell G, Catterson V, Polk C, Badley A, Marconi VC. C reactive protein utilisation, a biomarker for early COVID-19 treatment, improves lenzilumab efficacy: results from the randomised phase 3 ‘LIVE-AIR’ trial. Thorax 2023; 78(6): 606–616

[82] FoodAdministrationDrug. Coronavirus (COVID-19) update: FDA revokes emergency use authorization for monoclonal antibody bamlanivimab. 2020. Available at the website of FDA (accessed April 15, 2023)

[83] Deeks ED. Casirivimab/imdevimab: first approval. Drugs 2021; 81(17): 2047–2055

[84] FoodAdministrationDrug. FDA authorizes bamlanivimab and etesevimab monoclonal antibody therapy for post-exposure prophylaxis (prevention) for COVID-19. 2021. Available at the website of FDA (accessed April 15, 2023)

[85] Heo YA. Sotrovimab: first approval. Drugs 2022; 82(4): 477–484

[86] Keam SJ. Tixagevimab + cilgavimab: first approval. Drugs 2022; 82(9): 1001–1010

[87] FoodAdministrationDrug. FDA updates on bebtelovimab. 2023. Available at the website of FDA (accessed April 15, 2023)

[88] Syed YY. Regdanvimab: first approval. Drugs 2021; 81(18): 2133–2137

[89] DeFrancesco L. COVID-19 antibodies on trial. Nat Biotechnol 2020; 38(11): 1242–1252

[90] Lu J, Yin Q, Pei R, Zhang Q, Qu Y, Pan Y, Sun L, Gao D, Liang C, Yang J, Wu W, Li J, Cui Z, Wang Z, Li X, Li D, Wang S, Duan K, Guan W, Liang M, Yang X. Nasal delivery of broadly neutralizing antibodies protects mice from lethal challenge with SARS-CoV-2 delta and omicron variants. Virol Sin 2022; 37(2): 238–247

[91] Ku Z, Xie X, Hinton PR, Liu X, Ye X, Muruato AE, Ng DC, Biswas S, Zou J, Liu Y, Pandya D, Menachery VD, Rahman S, Cao YA, Deng H, Xiong W, Carlin KB, Liu J, Su H, Haanes EJ, Keyt BA, Zhang N, Carroll SF, Shi PY, An Z. Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants. Nature 2021; 595(7869): 718–723

[92] Li C, Zhan W, Yang Z, Tu C, Hu G, Zhang X, Song W, Du S, Zhu Y, Huang K, Kong Y, Zhang M, Mao Q, Gu X, Zhang Y, Xie Y, Deng Q, Song Y, Chen Z, Lu L, Jiang S, Wu Y, Sun L, Ying T. Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody. Cell 2022; 185(8): 1389–1401.e18

[93] Sheridan C. Convalescent serum lines up as first-choice treatment for coronavirus. Nat Biotechnol 2020; 38(6): 655–658

[94] Klingler J, Weiss S, Itri V, Liu X, Oguntuyo KY, Stevens C, Ikegame S, Hung CT, Enyindah-Asonye G, Amanat F, Baine I, Arinsburg S, Bandres JC, Kojic EM, Stoever J, Jurczyszak D, Bermudez-Gonzalez M, Nádas A, Liu S, Lee B, Zolla-Pazner S, Hioe CE. Role of immunoglobulin M and A antibodies in the neutralization of severe acute respiratory syndrome coronavirus 2. J Infect Dis 2021; 223(6): 957–970

[95] Misbah SA, Chapel HM. Adverse effects of intravenous immunoglobulin. Drug Saf 1993; 9(4): 254–262

[96] Zhou D, Duyvesteyn HME, Chen CP, Huang CG, Chen TH, Shih SR, Lin YC, Cheng CY, Cheng SH, Huang YC, Lin TY, Ma C, Huo J, Carrique L, Malinauskas T, Ruza RR, Shah PNM, Tan TK, Rijal P, Donat RF, Godwin K, Buttigieg KR, Tree JA, Radecke J, Paterson NG, Supasa P, Mongkolsapaya J, Screaton GR, Carroll MW, Gilbert-Jaramillo J, Knight ML, James W, Owens RJ, Naismith JH, Townsend AR, Fry EE, Zhao Y, Ren J, Stuart DI, Huang KA. Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient. Nat Struct Mol Biol 2020; 27(10): 950–958

[97] Vandeberg P, Cruz M, Diez JM, Merritt WK, Santos B, Trukawinski S, Wellhouse A, Jose M, Willis T. Production of anti-SARS-CoV-2 hyperimmune globulin from convalescent plasma. Transfusion 2021; 61(6): 1705–1709

[98] Burnouf T, Gathof B, Bloch EM, Bazin R, de Angelis V, Patidar GK, Rastvorceva RMG, Oreh A, Goel R, Rahimi-Levene N, Hindawi S, Al-Riyami AZ, So-Osman C; ISBT COVID-19 Convalescent Plasma Working Group. Production and quality assurance of human polyclonal hyperimmune immunoglobulins against SARS-CoV-2. Transfus Med Rev 2022; 36(3): 125–132

[99] Wolberg AS, Aleman MM, Leiderman K, Machlus KR. Procoagulant activity in hemostasis and thrombosis: Virchow’s triad revisited. Anesth Analg 2012; 114(2): 275–285

[100] Hung IFN, To KKW, Lee CK, Lee KL, Yan WW, Chan K, Chan WM, Ngai CW, Law KI, Chow FL, Liu R, Lai KY, Lau CCY, Liu SH, Chan KH, Lin CK, Yuen KY. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest 2013; 144(2): 464–473

[101] Khamsi R. Rogue antibodies could be driving severe COVID-19. Nature 2021; 590(7844): 29–31

[102] Gaudinski MR, Coates EE, Novik L, Widge A, Houser KV, Burch E, Holman LA, Gordon IJ, Chen GL, Carter C, Nason M, Sitar S, Yamshchikov G, Berkowitz N, Andrews C, Vazquez S, Laurencot C, Misasi J, Arnold F, Carlton K, Lawlor H, Gall J, Bailer RT, McDermott A, Capparelli E, Koup RA, Mascola JR, Graham BS, Sullivan NJ, Ledgerwood JE; VRC 608 Study team. Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study. Lancet 2019; 393(10174): 889–898

[103] Domachowske JB, Khan AA, Esser MT, Jensen K, Takas T, Villafana T, Dubovsky F, Griffin MP. Safety, tolerability and pharmacokinetics of MEDI8897, an extended half-life single-dose respiratory syncytial virus prefusion f-targeting monoclonal antibody administered as a single dose to healthy preterm infants. Pediatr Infect Dis J 2018; 37(9): 886–892

[104] Song R, Zeng G, Yu J, Meng X, Chen X, Li J, Xie X, Lian X, Zhang Z, Cao Y, Yin W, Jin R. Post-exposure prophylaxis with SA58 (anti-SARS-CoV-2 monoclonal antibody) nasal spray for the prevention of symptomatic COVID-19 in healthy adult workers: a randomized, single-blind, placebo-controlled clinical study. Emerg Microbes Infect 2023; 12(1): 2212806

[105] Focosi D, Franchini M. Passive immunotherapies for COVID-19: the subtle line between standard and hyperimmune immunoglobulins is getting invisible. Rev Med Virol 2022; 32(4): e2341

[106] Takashita E, Kinoshita N, Yamayoshi S, Sakai-Tagawa Y, Fujisaki S, Ito M, Iwatsuki-Horimoto K, Chiba S, Halfmann P, Nagai H, Saito M, Adachi E, Sullivan D, Pekosz A, Watanabe S, Maeda K, Imai M, Yotsuyanagi H, Mitsuya H, Ohmagari N, Takeda M, Hasegawa H, Kawaoka Y. Efficacy of antibodies and antiviral drugs against Covid-19 Omicron variant. N Engl J Med 2022; 386(10): 995–998

[107] Schubert M, Bertoglio F, Steinke S, Heine PA, Ynga-Durand MA, Maass H, Sammartino JC, Cassaniti I, Zuo F, Du L, Korn J, Milošević M, Wenzel EV, Krstanović F, Polten S, Pribanić-Matešić M, Brizić I, Baldanti F, Hammarström L, Dübel S, Šustić A, Marcotte H, Strengert M, Protić A, Piralla A, Pan-Hammarström Q, Čičin-Šain L, Hust M. Human serum from SARS-CoV-2-vaccinated and COVID-19 patients shows reduced binding to the RBD of SARS-CoV-2 Omicron variant. BMC Med 2022; 20(1): 102

[108] Andreano E, Piccini G, Licastro D, Casalino L, Johnson NV, Paciello I, Dal Monego S, Pantano E, Manganaro N, Manenti A, Manna R, Casa E, Hyseni I, Benincasa L, Montomoli E, Amaro RE, McLellan JS, Rappuoli R. SARS-CoV-2 escape from a highly neutralizing COVID-19 convalescent plasma. Proc Natl Acad Sci USA 2021; 118(36): e2103154118

[109] Wang Q, Iketani S, Li Z, Liu L, Guo Y, Huang Y, Bowen AD, Liu M, Wang M, Yu J, Valdez R, Lauring AS, Sheng Z, Wang HH, Gordon A, Liu L, Ho DD. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell 2023; 186(2): 279–286.e8

[110] Yi C, Sun X, Lin Y, Gu C, Ding L, Lu X, Yang Z, Zhang Y, Ma L, Gu W, Qu A, Zhou X, Li X, Xu J, Ling Z, Xie Y, Lu H, Sun B. Comprehensive mapping of binding hot spots of SARS-CoV-2 RBD-specific neutralizing antibodies for tracking immune escape variants. Genome Med 2021; 13(1): 164

[111] Wu L, Zhou L, Mo M, Liu T, Wu C, Gong C, Lu K, Gong L, Zhu W, Xu Z. SARS-CoV-2 Omicron RBD shows weaker binding affinity than the currently dominant Delta variant to human ACE2. Signal Transduct Target Ther 2022; 7(1): 8

[112] Guo H, Gao Y, Li T, Li T, Lu Y, Zheng L, Liu Y, Yang T, Luo F, Song S, Wang W, Yang X, Nguyen HC, Zhang H, Huang A, Jin A, Yang H, Rao Z, Ji X. Structures of Omicron spike complexes and implications for neutralizing antibody development. Cell Rep 2022; 39(5): 110770

[113] Mannar D, Saville JW, Zhu X, Srivastava SS, Berezuk AM, Tuttle KS, Marquez AC, Sekirov I, Subramaniam S. SARS-CoV-2 Omicron variant: antibody evasion and cryo-EM structure of spike protein-ACE2 complex. Science 2022; 375(6582): 760–764

[114] Yue C, Song W, Wang L, Jian F, Chen X, Gao F, Shen Z, Wang Y, Wang X, Cao Y. ACE2 binding and antibody evasion in enhanced transmissibility of XBB.1.5. Lancet Infect Dis 2023; 23(3): 278–280

[115] QianWZhitengLYichengGIanAMShoIMichaelLJianYRiccardoVAdamSLZizhangSAubreeGLihongLDavidDH. Evolving antibody evasion and receptor affinity of the Omicron BA.2.75 sublineage of SARS-CoV-2. bioRxiv 2023; doi:10.1101/2023.03.22.533805

[116] Awasthi M, Golding H, Khurana S. Severe acute respiratory syndrome coronavirus 2 hyperimmune intravenous human immunoglobulins neutralizes Omicron subvariants BA.1, BA.2, BA.2.12.1, BA.3, and BA.4/BA.5 for treatment of coronavirus disease 2019. Clin Infect Dis 2023; 76(3): e503–e506

[117] Focosi D, Joyner MJ, Casadevall A. Recent hybrid plasma better neutralizes Omicron sublineages than old hyperimmune serum. Clin Infect Dis 2023; 76(3): 554

[118] Cao Y, Jian F, Zhang Z, Yisimayi A, Hao X, Bao L, Yuan F, Yu Y, Du S, Wang J, Xiao T, Song W, Zhang Y, Liu P, An R, Wang P, Wang Y, Yang S, Niu X, Zhang Y, Gu Q, Shao F, Hu Y, Yin W, Zheng A, Wang Y, Qin C, Jin R, Xiao J, Xie XS. Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents. Cell Rep 2022; 41(12): 111845

[119] Sun X, Yi C, Zhu Y, Ding L, Xia S, Chen X, Liu M, Gu C, Lu X, Fu Y, Chen S, Zhang T, Zhang Y, Yang Z, Ma L, Gu W, Hu G, Du S, Yan R, Fu W, Yuan S, Qiu C, Zhao C, Zhang X, He Y, Qu A, Zhou X, Li X, Wong G, Deng Q, Zhou Q, Lu H, Ling Z, Ding J, Lu L, Xu J, Xie Y, Sun B. Neutralization mechanism of a human antibody with pan-coronavirus reactivity including SARS-CoV-2. Nat Microbiol 2022; 7(7): 1063–1074

[120] Shan S, Luo S, Yang Z, Hong J, Su Y, Ding F, Fu L, Li C, Chen P, Ma J, Shi X, Zhang Q, Berger B, Zhang L, Peng J. Deep learning guided optimization of human antibody against SARS-CoV-2 variants with broad neutralization. Proc Natl Acad Sci USA 2022; 119(11): e2122954119

[121] Lou H, Zheng J, Fang XL, Liang Z, Zhang M, Chen Y, Wang C, Cao X. Deep learning-based rapid generation of broadly reactive antibodies against SARS-CoV-2 and its Omicron variant. Cell Res 2023; 33(1): 80–82

[122] Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, Parrott RH. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol 1969; 89(4): 422–434

[123] Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am J Epidemiol 1969; 89(4): 405–421

[124] Rauh LW, Schmidt R. Measles immunization with killed virus vaccine. Serum antibody titers and experience with exposure to measles epidemic. 1965. Bull World Health Organ 2000; 78(2): 226–231

[125] Iankov ID, Pandey M, Harvey M, Griesmann GE, Federspiel MJ, Russell SJ. Immunoglobulin antibody-mediated enhancement of measles virus infection can bypass the protective antiviral immune response. J Virol 2006; 80(17): 8530–8540

[126] Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, He L, Chen Y, Wu J, Shi Z, Zhou Y, Du L, Li F. Molecular mechanism for antibody-dependent enhancement of coronavirus entry. J Virol 2020; 94(5): e02015–19

[127] Wang SF, Tseng SP, Yen CH, Yang JY, Tsao CH, Shen CW, Chen KH, Liu FT, Liu WT, Chen YM, Huang JC. Antibody-dependent SARS coronavirus infection is mediated by antibodies against spike proteins. Biochem Biophys Res Commun 2014; 451(2): 208–214

[128] Lee WS, Wheatley AK, Kent SJ, DeKosky BJ. Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies. Nat Microbiol 2020; 5(10): 1185–1191

[129] Arvin AM, Fink K, Schmid MA, Cathcart A, Spreafico R, Havenar-Daughton C, Lanzavecchia A, Corti D, Virgin HW. A perspective on potential antibody-dependent enhancement of SARS-CoV-2. Nature 2020; 584(7821): 353–363

[130] Bournazos S, Gupta A, Ravetch JV. The role of IgG Fc receptors in antibody-dependent enhancement. Nat Rev Immunol 2020; 20(10): 633–643

[131] de Alwis R, Chen S, Gan ES, Ooi EE. Impact of immune enhancement on Covid-19 polyclonal hyperimmune globulin therapy and vaccine development. EBioMedicine 2020; 55: 102768

[132] Okuya K, Hattori T, Saito T, Takadate Y, Sasaki M, Furuyama W, Marzi A, Ohiro Y, Konno S, Hattori T, Takada A. Multiple routes of antibody-dependent enhancement of SARS-CoV-2 infection. Microbiol Spectr 2022; 10(2): e0155321

[133] Lai GC, Chao TL, Lin SY, Kao HC, Tsai YM, Lu DC, Chiang YW, Chang SY, Chang SC. Neutralization or enhancement of SARS-CoV-2 infection by a monoclonal antibody targeting a specific epitope in the spike receptor-binding domain. Antiviral Res 2022; 200: 105290

[134] Shimizu J, Sasaki T, Koketsu R, Morita R, Yoshimura Y, Murakami A, Saito Y, Kusunoki T, Samune Y, Nakayama EE, Miyazaki K, Shioda T. Reevaluation of antibody-dependent enhancement of infection in anti-SARS-CoV-2 therapeutic antibodies and mRNA-vaccine antisera using FcR- and ACE2-positive cells. Sci Rep 2022; 12(1): 15612

[135] Maemura T, Kuroda M, Armbrust T, Yamayoshi S, Halfmann PJ, Kawaoka Y. Antibody-dependent enhancement of SARS-CoV-2 infection is mediated by the IgG receptors FcγRIIA and FcγRIIIA but does not contribute to aberrant cytokine production by macrophages. MBio 2021; 12(5): e0198721

[136] Wang YT, Allen RD 3rd, Kim K, Shafee N, Gonzalez AJ, Nguyen MN, Valentine KM, Cao X, Lu L, Pai CI, Johnson S, Kerwin L, Zhou H, Zhang Y, Shresta S. SARS-CoV-2 monoclonal antibodies with therapeutic potential: broad neutralizing activity and no evidence of antibody-dependent enhancement. Antiviral Res 2021; 195: 105185

[137] Writing Committee for the REMAP-CAP Investigators; Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D, Arabi YM, Arnold DM, Beane A, Bégin P, van Bentum-Puijk W, Berry LR, Bhimani Z, Birchall JE, Bonten MJM, Bradbury CA, Brunkhorst FM, Buxton M, Callum JL, Chassé M, Cheng AC, Cove ME, Daly J, Derde L, Detry MA, De Jong M, Evans A, Fergusson DA, Fish M, Fitzgerald M, Foley C, Goossens H, Gordon AC, Gosbell IB, Green C, Haniffa R, Harvala H, Higgins AM, Hills TE, Hoad VC, Horvat C, Huang DT, Hudson CL, Ichihara N, Laing E, Lamikanra AA, Lamontagne F, Lawler PR, Linstrum K, Litton E, Lorenzi E, MacLennan S, Marshall J, McAuley DF, McDyer JF, McGlothlin A, McGuinness S, Miflin G, Montgomery S, Mouncey PR, Murthy S, Nichol A, Parke R, Parker JC, Priddee N, Purcell DFJ, Reyes LF, Richardson P, Robitaille N, Rowan KM, Rynne J, Saito H, Santos M, Saunders CT, Serpa Neto A, Seymour CW, Silversides JA, Tinmouth AA, Triulzi DJ, Turner AM, van de Veerdonk F, Walsh TS, Wood EM, Berry S, Lewis RJ, Menon DK, McArthur C, Zarychanski R, Angus DC, Webb SA, Roberts DJ, Shankar-Hari M. Effect of convalescent plasma on organ support-free days in critically ill patients with COVID-19: a randomized clinical trial. JAMA 2021; 326(17): 1690–1702

[138] Bégin P, Callum J, Jamula E, Cook R, Heddle NM, Tinmouth A, Zeller MP, Beaudoin-Bussières G, Amorim L, Bazin R, Loftsgard KC, Carl R, Chassé M, Cushing MM, Daneman N, Devine DV, Dumaresq J, Fergusson DA, Gabe C, Glesby MJ, Li N, Liu Y, McGeer A, Robitaille N, Sachais BS, Scales DC, Schwartz L, Shehata N, Turgeon AF, Wood H, Zarychanski R, Finzi A; CONCOR-1 Study Group; Arnold DM. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial. Nat Med 2021; 27(11): 2012–2024

[139] Wang H, Zhang Y, Huang B, Deng W, Quan Y, Wang W, Xu W, Zhao Y, Li N, Zhang J, Liang H, Bao L, Xu Y, Ding L, Zhou W, Gao H, Liu J, Niu P, Zhao L, Zhen W, Fu H, Yu S, Zhang Z, Xu G, Li C, Lou Z, Xu M, Qin C, Wu G, Gao GF, Tan W, Yang X. Development of an inactivated vaccine candidate, BBIBP-CorV, with potent protection against SARS-CoV-2. Cell 2020; 182(3): 713–721.e9

[140] Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M, Li Y, Zhu L, Wang N, Lv Z, Gao H, Ge X, Kan B, Hu Y, Liu J, Cai F, Jiang D, Yin Y, Qin C, Li J, Gong X, Lou X, Shi W, Wu D, Zhang H, Zhu L, Deng W, Li Y, Lu J, Li C, Wang X, Yin W, Zhang Y, Qin C. Development of an inactivated vaccine candidate for SARS-CoV-2. Science 2020; 369(6499): 77–81

[141] Yadav PD, Ella R, Kumar S, Patil DR, Mohandas S, Shete AM, Vadrevu KM, Bhati G, Sapkal G, Kaushal H, Patil S, Jain R, Deshpande G, Gupta N, Agarwal K, Gokhale M, Mathapati B, Metkari S, Mote C, Nyayanit D, Patil DY, Sai Prasad BS, Suryawanshi A, Kadam M, Kumar A, Daigude S, Gopale S, Majumdar T, Mali D, Sarkale P, Baradkar S, Gawande P, Joshi Y, Fulari S, Dighe H, Sharma S, Gunjikar R, Kumar A, Kalele K, Srinivas VK, Gangakhedkar RR, Ella KM, Abraham P, Panda S, Bhargava B. Immunogenicity and protective efficacy of inactivated SARS-CoV-2 vaccine candidate, BBV152 in rhesus macaques. Nat Commun 2021; 12(1): 1386

[142] Farag YMK. Limitations of safety update on convalescent plasma transfusion in COVID-19 patients. Mayo Clin Proc 2020; 95(12): 2801–2802

[143] Aggarwal NR, Beaty LE, Bennett TD, Carlson NE, Davis CB, Kwan BM, Mayer DA, Ong TC, Russell S, Steele J, Wogu AF, Wynia MK, Zane RD, Ginde AA. Real-world evidence of the neutralizing monoclonal antibody sotrovimab for preventing hospitalization and mortality in COVID-19 outpatients. J Infect Dis 2022; 226(12): 2129–2136

[144] Di Minno G, Navarro D, Perno CF, Canaro M, Gürtler L, Ironside JW, Eichler H, Tiede A. Pathogen reduction/inactivation of products for the treatment of bleeding disorders: what are the processes and what should we say to patients? Ann Hematol 2017; 96(8): 1253–1270 doi:10.1007/s00277-017-3028-4

[145] Cognasse F, Hamzeh-Cognasse H, Rosa M, Corseaux D, Bonneaudeau B, Pierre C, Huet J, Arthaud CA, Eyraud MA, Prier A, Duchez AC, Ebermeyer T, Heestermans M, Audoux-Caire E, Philippot Q, Le Voyer T, Hequet O, Fillet AM, Chavarin P, Legrand D, Richard P, Pirenne F, Gallian P, Casanova JL, Susen S, Morel P, Lacombe K, Bastard P, Tiberghien P. Inflammatory markers and auto-Abs to type I IFNs in COVID-19 convalescent plasma cohort study. EBioMedicine 2023; 87: 104414

[146] Senefeld JW, Johnson PW, Kunze KL, Bloch EM, van Helmond N, Golafshar MA, Klassen SA, Klompas AM, Sexton MA, Diaz Soto JC, Grossman BJ, Tobian AAR, Goel R, Wiggins CC, Bruno KA, van Buskirk CM, Stubbs JR, Winters JL, Casadevall A, Paneth NS, Shaz BH, Petersen MM, Sachais BS, Buras MR, Wieczorek MA, Russoniello B, Dumont LJ, Baker SE, Vassallo RR, Shepherd JRA, Young PP, Verdun NC, Marks P, Haley NR, Rea RF, Katz L, Herasevich V, Waxman DA, Whelan ER, Bergman A, Clayburn AJ, Grabowski MK, Larson KF, Ripoll JG, Andersen KJ, Vogt MNP, Dennis JJ, Regimbal RJ, Bauer PR, Blair JE, Buchholtz ZA, Pletsch MC, Wright K, Greenshields JT, Joyner MJ, Wright RS, Carter RE, Fairweather D. Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: a national registry study. PLoS Med 2021; 18(12): e1003872

[147] Mak G, Dassner AM, Hammer BM, Hanisch BR. Safety and tolerability of monoclonal antibody therapies for treatment of COVID-19 in pediatric patients. Pediatr Infect Dis J 2021; 40(12): e507–e509

[148] Katz U, Achiron A, Sherer Y, Shoenfeld Y. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun Rev 2007; 6(4): 257–259

[149] Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol 2005; 29(3): 173–184

[150] Liu STH, Mirceta M, Lin G, Anderson DM, Broomes T, Jen A, Abid A, Reich D, Hall C, Aberg JA. Safety, tolerability, and pharmacokinetics of anti-SARS-CoV-2 immunoglobulin intravenous (human) investigational product (COVID-HIGIV) in healthy adults: a randomized, controlled, double-blinded, phase 1 study. Antimicrob Agents Chemother 2023; 67(3): e0151422

[151] Ali S, Shalim E, Farhan F, Anjum F, Ali A, Uddin SM, Shahab F, Haider M, Ahmed I, Ali MR, Khan S, Rao S, Guriro K, Elahi S, Ali M, Mushtaq T, Sayeed MA, Muhaymin SM, Luxmi S, Saifullah S. Phase II/III trial of hyperimmune anti-COVID-19 intravenous immunoglobulin (C-IVIG) therapy in severe COVID-19 patients: study protocol for a randomized controlled trial. Trials 2022; 23(1): 932

[152] Taylor PC, Adams AC, Hufford MM, de la Torre I, Winthrop K, Gottlieb RL. Neutralizing monoclonal antibodies for treatment of COVID-19. Nat Rev Immunol 2021; 21(6): 382–393

[153] NationalInstitutes of Health. COVID-19 treatment guidelines. 2023. Available at the website of National Institutes of Health (accessed April 15, 2023)

[154] Ricke DO. Two different antibody-dependent enhancement (ADE) risks for SARS-CoV-2 antibodies. Front Immunol 2021; 12: 640093

RIGHTS & PERMISSIONS

Higher Education Press