2.1. Advances in SARS‐CoV‐2‐targeting blood‐derived products

The COVID‐19 pandemic required rapid evaluation and development of blood‐derived products at an unprecedented speed (Figure 1B). COVID‐19 CP neutralizes the virus and is beneficial; furthermore, CP may be the fastest treatment strategy for acute infectious diseases that also ensures the safety of patients. ²⁹ Since SARS‐CoV‐2 was found to be highly contagious, China has focused on the safety and efficacy of COVID‐19 CP. ^{30 , 31} In January 2020, the National Health Commission of the People's Republic of China (NHC) published the Diagnosis and Treatment Protocol for COVID‐19 (Trial Version 4), recommending COVID‐19 CP for severely or critically ill patients with COVID‐19. ³⁰ The Emergency Use Authorization (EUA) of COVID‐19 CP was issued by the U.S. Food and Drug Administration (U.S. FDA) in August 2020 for hospitalized patients with COVID‐19. ³² In December 2021, the U.S. FDA revised these guidelines, suggesting the use of COVID‐19 CP for patients with immunosuppressive diseases or those receiving immunosuppressive treatment, with a preference for CP with high neutralizing antibody (nAb) titers. ^{12 , 32} In June 2022, the NHC also recommended using COVID‐19 CP for the antiviral treatment of patients with rapid disease progression, high viral loads, and high‐risk factors during the early course of COVID‐19. ³³ Two other SARS‐CoV‐2‐targeting blood‐derived products were approved for treatment following COVID‐19 CP approval, as the drug registration processes or production required more time than those of CP.

In April 2021, the NHC recommended the use of COVID‐HIG to treat patients with mild or severe COVID‐19 showing rapid disease progression. ³⁴ COVID‐HIG can be prepared from COVID‐19 CP, COVID‐19 vaccine immune plasma (VP), and COVID‐19 hyperimmune animal plasma (serum). ^{35 , 36 , 37} COVID‐HIG is prepared primarily using commercial IVIG production methods, ^{35 , 36} and the NHC exclusively recommends the use of COVID‐HIG derived from human immune plasma. ³⁴ Anti‐SARS‐CoV‐2 neutralizing IgG (recombinant) can also be derived from the peripheral blood mononuclear cells (PBMCs) of convalescent patients or SARS‐CoV‐2‐vaccinated donors, ^{38 , 39} and the U.S. FDA first issued the EUA for neutralizing IgG (recombinant) derived from PBMCs of convalescent patients with COVID‐19 in November 2020. ¹²

Both COVID‐HIG and neutralizing IgG (recombinant) can be derived from blood products after vaccination, and may have broad and potent anti‐SARS‐CoV‐2 efficacy. ³⁸ From this perspective, the protection provided by vaccines is not only limited to the prevention of SARS‐CoV‐2 infection, but also aids in the treatment of COVID‐19. COVID‐19 vaccines that have received marketing approval or been approved for EUA can be classified into mRNA, inactivated COVID‐19, nonreplicating adenovirus vector, and recombinant S protein subunit vaccines. ⁴⁰ Fully approved COVID‐19 vaccines were designed to protect against the original SARS‐CoV‐2 strain; however, they cannot provide effective protection against Omicron and its variants. Therefore, to reduce the losses caused by the global spread of Omicron variants, updated mRNA vaccines including a monovalent component (XBB.1.5) were granted EUA by the U.S. FDA. ⁴¹ In China, the trivalent recombinant S protein subunit vaccine protects against both the Delta and Omicron (XBB.1.5 + BA.5 + Delta) variants and was approved for EUA. ⁴²

Of particular concern is the likelihood that more virulent or contagious SARS‐CoV‐2 variants will emerge, and the U.S. FDA anticipates that COVID‐19 vaccine ingredients may require to be updated annually, similar to those of seasonal influenza vaccines. ⁴¹ Thus, more promising vaccines against SARS‐CoV‐2 variants have been explored to provide a greater level of protection. ^{43 , 44}

2.2. Advances in non‐SARS‐CoV‐2‐targeting blood‐derived products

Since March 2020, the NHC has recommended the use of IVIG to treat severely and critically ill children. ⁴⁵ In July 2020, the American College of Rheumatology (ACR) recommended IVIG and glucocorticoids as first‐tier agents for pediatric COVID‐19 in their clinical guidance for treating multisystem inflammatory syndrome in children (MIS‐C). ¹¹ MIS‐C is a rare condition associated with SARS‐CoV‐2 that usually occurs 2−6 weeks post‐infection and can cause inflammation of different internal and external body parts, which can be serious or even fatal. ⁴⁶ In April 2021, the NHC revised the guidelines, recommending that IVIG be used for MIS‐C treatment. ³⁴ Regarding another non‐SARS‐CoV‐2‐targeting blood‐derived product, the Surviving Sepsis Campaign (SSC) suggested the use of albumin combined with large volumes of crystalloids over the use of standalone crystalloids for adult patients with septic shock or sepsis. ⁴⁷ Although septic shock may also occur in critically ill patients with COVID‐19, considering the cost and limited availability of albumin, the SSC does not recommend routine treatment with albumin during the acute resuscitation of adult patients with COVID‐19. ^{48 , 49}

3.1. Protective and pathological functions of Fc‐dependent SARS‐CoV‐2 antibodies effector functions in SARS‐CoV‐2 infection

After infection with SARS‐CoV‐2, the host mounts antibody‐mediated responses to eliminate the virus. The B cells of the germinal centers are stimulated by the antigens of SARS‐CoV‐2 to differentiate into mature plasma cells, secreting virus‐specific IgG, IgM, and IgA antibodies to control the infection. Several structural SARS‐CoV‐2 proteins, including the S, membrane, and nucleocapsid (N) proteins, elicit a strong humoral immune response by the host. ⁶⁸ Among them, the receptor‐binding domain (RBD), N‐terminal domain, and stem helix and fusion peptide of the S protein facilitate viral infection ⁶⁹ ; therefore, the S‐specific antibodies produced by the host are considered nAbs.

Host cell‐secreted IgG, IgM, or IgA antibodies are primarily directed against the S and N proteins of SARS‐CoV‐2, and extensive research is underway to identify these antibodies against specific epitopes on these proteins. ^{70 , 71 , 72} The median time for seroconversion for SARS‐CoV‐2‐specific IgA antibodies is approximately 1 week after symptom onset, ^{73 , 74} slightly earlier than that for IgG and IgM antibodies (approximately 2 weeks after symptom onset). ^{68 , 75} However, the duration of virus‐specific IgM and IgA antibodies is shorter than that of IgG antibodies, and the levels of the IgA and IgM antibodies decrease more rapidly than those of IgG antibodies. ⁷⁶ Furthermore, the persistence of IgG antibodies targeting different viral epitopes differs. Our previous study revealed that even 24 months after recovery, approximately 75% of recovered patients continued to exhibit detectable IgG antibodies against RBD (RBD‐IgG), whereas only approximately 25% exhibited IgG antibodies against the N protein (NP‐IgG). ⁷¹ This may be because a longer duration of nAb responses helps protect the host against reinfection.

SARS‐CoV‐2 may be blocked by nAbs prior to the invasion of healthy host cells. However, when nAbs fail to block viral entry, the S and N proteins on the surface of infected host cells could be recognized by antibodies binding to SARS‐CoV‐2. Although these antibodies fail to block virus‐infected cells, they can exert antiviral effects via Fc‐mediated effector functions ⁷⁷ (Figure 2A, left). Both nAbs and non‐nAbs bind to SARS‐CoV‐2 to form an immune complex, which is bound by complement proteins or recognized by Fc receptors (FcRs) on the surface of host immune cells. ⁷⁸ Subsequently, the virus is cleared by complement‐dependent or cell‐mediated cytotoxic activity (Figure 2A, left).

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FIGURE 2

Blood‐derived products targeting pathophysiological factors in COVID‐19. (A) Dysregulated SARS‐CoV‐2 specificity and/or autoantigen antibodies, reservoirs of SARS‐CoV‐2, and herpesvirus reactivation contribute to the pathogenesis of exacerbated disease in patients with SARS‐CoV‐2 infection or long COVID. (B) SARS‐CoV‐2‐targeting blood‐derived products block viral infection of cells or simultaneously recognize and eliminate infected cells via Fc‐mediated effector functions. (C) Metabolic regulation of SARS‐CoV‐2 specificity and autoantigen antibodies by IVIG and anti‐inflammatory and immunomodulatory properties of IVIG among patients with SARS‐CoV‐2 infection or long COVID. (D) Albumin exhibits antioxidant properties against antioxidative stress and maintains plasma osmotic pressure and an anti‐hypercoagulation state. COVID‐19, coronavirus disease 2019; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; nAbs, neutralizing antibodies; non‐nAbs, non‐neutralizing antibodies that do not impede the infectivity of SARS‐CoV‐2 but are capable of binding to SARS‐CoV‐2; ACE2, angiotensin‐converting enzyme 2; TMPRSS2, transmembrane serine protease 2; PRF, perforin; GzmB, granzyme B; FcRn, neonatal Fc receptor; FcγR, Fc receptor for IgG; ROS, reactive oxygen species; COVID‐HIG, COVID‐19 hyperimmune globulin; IVIG, intravenous immunoglobulin; Auto‐IgG, autoimmune IgG; Treg, regulatory T cell; BCR, B cell receptor; FcγRIIB, Fcγ receptor IIB; CD22, cluster of differentiation‐22; EBV, Epstein–Barr virus.

IgG antibodies are the predominant antibody isotype in human serum. ⁷⁹ Human FcRs for IgG (FcγRs) comprise activating and inhibitory receptors that transmit signals via intracellular immunoreceptor tyrosine‐based activation and inhibitory motifs, respectively. ⁸⁰ The humoral immune responses of patients with COVID‐19 play key roles in suppressing SARS‐CoV‐2 infection. However, critically ill patients often exhibit high nAb titers, wheras most recovered patients produce relatively low levels of nAbs, ⁸¹ raising speculation regarding the pathogenic consequences of antibody responses. ^{70 , 82}

Following infection with SARS‐CoV‐2, antibodies mediate immune functions via Fc‐dependent effectors, showing both protective and pathogenic outcomes, and the reasons for these contradictory results are complex. The Fc‐mediated effector functions of antibodies after infection may contribute to increased inflammation levels and pathological damage, ultimately exacerbating the disease. ⁸³ Children with MIS display persistent and increased levels of SARS‐CoV‐2‐specific IgG antibodies, and high inflammatory monocyte‐activation activity. ⁸⁴ Nonspecific activation of B cells occurs in MIS‐C, resulting in increased autoantigen responses that trigger self‐attack. ⁸⁵ Furthermore, SARS‐CoV‐2 uses the property of antibodies binding to FcγR to invade macrophages or monocytes; although infected macrophages and monocytes undergo pyroptosis to terminate the infection, they also secrete interleukin‐1β and interleukin‐18, triggering systemic inflammation ⁸⁶ (Figure 2A, left). In patients with high disease severity, SARS‐CoV‐2‐specific antibodies contribute to extensive complement deposition in multiple organs, associated with high systemic inflammation and pathological damage ⁸⁷ (Figure 2A, left). Elevated neutrophil activation increases the release of neutrophil extracellular traps (NETs), referred to as NETosis, and reactive oxygen species (ROS), with NETs persisting longer in critically ill patients. ⁸⁸ However, adverse clinical outcomes after respiratory viral infection are also commonly associated with high levels of NETs. ^{89 , 90} NETs cause endothelial injury and thrombosis, whereas ROS can structurally damage albumin, impairing its ability to bind nutrient ligands and leading to the dysfunction of the red blood cells and lungs ^{78 , 91 , 92} (Figure 2A, left).

3.2. Possible mechanisms underlying long COVID

Long COVID has a series of different symptoms, and the corresponding mechanisms may also be diverse, including the long‐term adverse effects of autoAbs. Patients with COVID‐19 exhibit enhanced antibody responses against self‐antigens, indicated by autoAbs against immunomodulatory proteins (type I interferons, cytokines, and chemokines), members of the exoproteome (extracellular and secreted proteins), and phospholipids. ^{93 , 94} Moreover, these autoAbs persist after recovery during long COVID. ⁹⁵ Some SARS‐CoV‐2‐specific antibodies bind to the virus and cross‐react with self‐antigens. ⁹⁶ This phenomenon possibly intensifies the disease risk of patients with COVID‐19. Viral infection induces various autoimmune diseases by initiating immunodeficiency in patients with COVID‐19, thereby disrupting their ability to maintain self‐tolerance and causing the immune system to recognize self‐antigens. In long COVID, the autoAbs may lead to conditions such as MIS‐C, systemic lupus erythematosus, immune thrombocytopenia, cardiovascular disorders (an elevated heart rate, myocarditis, vasculitis, and thrombosis), neurological symptoms (small‐fiber polyneuropathy and autoimmune encephalitis), gastrointestinal symptoms (abdominal pain and loss of appetite), cutaneous involvement (maculopapular eruptions, urticarial lesions, and chilblains), autoimmune thyroid diseases, and arthritis ^{97 , 98 , 99} (Figure 2A, right).

Furthermore, the persistent reservoirs of SARS‐CoV‐2 in tissues (circulating SARS‐CoV‐2 RNA fragments and SARS‐CoV‐2 superantigens) and herpesvirus reactivation are factors potentially involved in the development of long COVID ^{8 , 54 , 100} (Figure 2A, right). Clinical monitoring for SARS‐CoV‐2 is usually carried out in the respiratory or gastrointestinal tract, and the virus is no longer detectable after a short period. ¹⁰¹ However, the virus replicates in multiple organ systems, and SARS‐CoV‐2 RNA fragments and antigens can persist for long period in some patients. ¹⁰² This prolonged existence may explain why long COVID symptoms affect different organ systems, including the cardiovascular, nervous, respiratory, and digestive tracts. ¹⁰³ Herpes viruses are more likely to be reactivated following SARS‐CoV‐2 infection, and the reactivation of Epstein–Barr virus (EBV) is correlated with the progression of long COVID. ⁵⁴

4.1. SARS‐CoV‐2‐targeting blood‐derived products in COVID‐19

Treatment with COVID‐19 CP, COVID‐HIG, or neutralizing IgG (recombinant) provides passively transferred SARS‐CoV‐2 antibodies to susceptible recipients. Due to the high number of patients with COVID‐19, COVID‐19 CP is easily obtained and one of the earliest therapeutic strategies available. ^{124 , 125} Additionally, the cost of COVID‐19 CP is lower than that of COVID‐HIG and neutralizing IgG (recombinant), hence it is used globally. ¹²⁶ More than 100 clinical trials have been initiated to evaluate the effectiveness of COVID‐19 CP for the prevention and treatment of COVID‐19. Clinical setting scenarios include, but are not limited to, exploring patients with different disease severity, different disease progression stages when starting dosing, different age groups of patients, patients with different immune status or functions, inpatients or outpatients, and whether combined antiviral drugs are used. ¹²⁷ However, after more than 3 years of research, the safety of COVID‐19 CP has been generally recognized, yet consensus regarding its effectiveness has not been achieved.

COVID‐HIG is prepared from COVID‐19 hyperimmune plasma; several clinical studies on COVID‐HIG have been published. ^{16 , 37 , 128 , 129} The clinically used dose range of COVID‐19 CP‐derived COVID‐HIG is 0.15−0.4 g/kg; the dose of COVID‐HIG derived from COVID‐19 hyperimmune animal plasma is lower, 4 mg/kg (two doses). The common denominator is that the use of COVID‐HIG is safe and no concerning antibody‐dependent enhancement effects have been observed. ¹³⁰ Among the VP‐derived COVID‐HIGs, only the VP obtained after inactivated vaccination has been used to produce COVID‐HIG; however, the results of clinical studies have not been published. ³⁶ In theory, the efficacy and safety of VP‐derived COVID‐HIG could be well predicted based on the efficacy of the vaccine against SARS‐CoV‐2.

In COVID‐19 CP, the IgG antibody levels far exceed those of IgM or IgA antibodies and play a decisive role in the therapeutic effect. ¹³¹ Furthermore, COVID‐HIG primarily consists of IgG with only trace amounts of IgM or IgA. ^{35 , 36} Hence, the antibody type of recombinant, commercial nAbs, or those being investigated for treating COVID‐19 should be IgG. ^{12 , 72} Various neutralizing IgG (recombinant) targeting S protein demonstrated effectiveness in preventing and treating COVID‐19, and have therefore been granted EUA by the U.S. FDA. ^{132 , 133}

5.1. Non‐SARS‐CoV‐2‐targeting blood‐derived products in SARS‐CoV‐2 infection

Clinical trial subgroup analyses based on time to IVIG initiation showed that patients who received IVIG earlier after symptom onset showed benefits, ^{160 , 161 , 163} whereas those who received IVIG treatment at a later stage did not obtain benefits. ^{159 , 164} Nonetheless, the total dose of IVIG administered was inconsistent among different clinical centers, resulting in a wide range of doses and treatment cycles. The recommended administration dosage is 0.1−1.5 g/kg per day with a treatment cycle of 3−15 days (Table 2). However, the treatment seems effective only when the dosage exceeds 0.2 g/kg per day, as dosages below this threshold were ineffective in different clinical trials. ^{161 , 162} A dosage of 0.2−0.5 g/kg per day requires injection for 5 consecutive days, while 1.5 g/kg per day for 3 days has shown benefits for patients. Furthermore, the proportion of IgM in IVIG affected clinical trial outcomes. IgM‐enriched IVIG (IGAM) is more immunomodulatory than traditional IVIG. ¹⁷² Treatment with IGAM has shown beneficial effects, with no safety concerns, in critically ill patients not yet requiring mechanical ventilation and/or within the first 14 days following symptom onset, when administered for 3 or more days. ¹⁶⁵ However, the significant costs and general scarcity of IGAM hinder its widespread use.

Albumin can improve the function of the respiratory, cardiovascular, and central nervous systems in critically ill patients with hypoalbuminemia. ¹⁷³ Patients with COVID‐19 exhibiting low serum albumin levels generally have a poor prognosis ^{50 , 51} ; therefore, albumin administration may benefit patients with COVID‐19 and hypoalbuminemia. ¹⁷⁴ Clinical research has revealed that continuous albumin supplementation for 3 or more consecutive days inhibits the hypercoagulable state of patients with COVID‐19 and improves the prognosis of patients with COVID‐19 and hypoalbuminemia (Table 2).

6.1. Quality of evidence for blood‐derived product therapies

Based on the evidence‐based medicine approach of the Oxford Center, we assessed the quality of the evidence, and the levels of evidence were rated as 1a, 1b, 1c, 2a, 2b, 2c, 3a, 3b, 4, or 5. ¹⁸⁹ Table 3 lists all blood‐derived products, the type of studies demonstrating effectiveness, and the highest degree of evidence achieved for their effectiveness. The levels of evidence can provide references to formulate clinical recommendations, but low‐level evidence should not be ignored. ²⁰⁰ Considering the lack of therapeutic strategies for COVID‐19, high‐quality controlled clinical studies remain necessary.

6.2. SARS‐CoV‐2‐targeting blood‐derived product therapies for SARS‐CoV‐2 infection

SARS‐CoV‐2‐targeting blood‐derived products (antiviral therapy) should be administered during periods of rapid viral proliferation, including SARS‐CoV‐2 incubation, stage I, and stage II. Most patients with COVID‐19 produce endogenous anti‐viral antibodies on day 10 post symptom onset, ²⁰¹ and patients also enter the aviremic stage at this time. ^{202 , 203} Therefore, early administration of antiviral therapy effectively suppresses viral replication and prevents disease progression (Figure 4B).

The source of COVID‐19 CP is crucial. COVID‐HIG can be derived from COVID‐19 CP, and therefore consideration must be given to the choice of CP as it affects the efficacy of the two aforementioned passive immunotherapies. The high nAb titers of COVID‐19 CP have better treatment efficacy than low titers; thus, obtaining safe COVID‐19 CP with high titers for administration is particularly important. The nAb titers of COVID‐19 CP are affected by several factors, including the time since CP collection from recovered patients, the disease severity of donor patients, and the subtype of SARS‐CoV‐2 strains that the recovered patients were infected with.

The severity of the disease is correlated with nAb titers. Patients with severe and critical infections have higher levels of autoantibodies than those with mild or moderate infections. To ensure safety, CP collected from recovered patients with mild‐to‐moderate disease and high nAb titers are ideal treatment options. A peak in nAb titers is typically observed at 4−5 weeks after the onset of symptoms in recovered patients, ²⁰⁴ which is the optimal time window for CP collection. Moreover, the antibody profiles of CP collected from recovered patients infected with different mutants may vary; therefore, gathering comprehensive information on recovered patients when collecting CP is essential. COVID‐19 plasma collected close in time and location to patients would be more beneficial. ²⁰³

COVID‐HIG can also be derived from the plasma of healthy donors after COVID‐19 vaccination as it only requires consideration of nAb titers because antibodies produced after receiving the COVID‐19 vaccine are safe. ²⁰⁵ More importantly, the impact of immune escape by mutant strains is critical for the efficacy of SARS‐CoV‐2‐targeting blood‐derived products, including neutralizing IgG (recombinant) preparations; the immune escape of the globally circulating SARS‐CoV‐2 mutants should continue to be investigated.

Although patient prognosis and recovery should be optimal if viral replication is suppressed during the early stages of infection, in immunocompromised patients, including organ transplant recipients, patients with human immunodeficiency virus infection, and patients with hematologic malignancies, the use of SARS‐CoV‐2‐targeting blood‐derived products should be recommended at all disease progression stages because SARS‐CoV‐2 may be detectable in such patients for 7−8 months or even longer. ²⁰⁶ The seroconversion rate of immunocompromised patients after receiving the vaccine remains relatively low, ²⁰⁷ and hence SARS‐CoV‐2‐targeting blood‐derived product therapies can be used as a treatment option that does not rely on the humoral immune response.

The authors thank Prof. Dong Liu from Chengdu Rongsheng Pharmaceuticals Co., Ltd., and Dr. Xuanxuan Nian from the Wuhan Institute of Biological Products Co., Ltd., for their helpful discussions regarding the manuscript. The authors also thank the Clinical Operation Department of the Tiantan Biological R&D Center for their support. This work was funded by the China Ministry of Science and Technology grant titled “Preparation of specific plasma and specific globulin from patients with a recovery period of COVID‐19 infection” (grant number 2020YFC0841800).