Effectiveness of convalescent plasma therapy for COVID-19 patients infected with variants of concerns

Abstract
COVID-19 cases in Indonesia seemed to be increasing by each passing day at the time of writing this review, more positive cases discovered than the recovered ones. With the highest rank within all ASEAN countries, and also a home of many variants of COVID-19, Indonesia had become a break off destination to others. Along with the problem associated with the pandemic, which all people had to face, the purpose of this review is to elaborate the use of convalescent plasma therapy on treatment against COVID-19, especially its different variants. We overview the evidence that we obtained from several databases using specific keywords. A large amount of evidence points out that the convalescent plasma therapy has shown a promising outcome against COVID-19 infection, as it did for infectious diseases. Although in COVID-19 variants of concern, convalescent plasma therapy showed a reduction in neutralization ~ 3-fold against P.1, and 7-13 folds against B.1.351 variant, it still can be used as a treatment for COVID-19 and its variants.

Abbreviations: PPE - personal protective equipment; VoC - Variants of concern; VoI - Variants of interest; CPT - convalescent plasma therapy; RBD - receptor-binding domain; ARDS - Acute Respiratory Distress Syndrome; ICU - Intensive Care Unit; IQR - Interquartile Range; RCT - Randomized Clinical Trial; RT-PCR - Reverse Transcriptase-Polymerase Chain Reaction; NAbs - neutralizing antibodies

Key words: Convalescent plasma therapy; COVID-19, Variants of Concern

Citation: Kurniawati EM, Putri IS, Widiatmaja DM, Praba VM, Visuddho 2, Prameswari FU, Zahrani M, Putra FN, Nugraha D, Widiastara AA. Effectiveness of convalescent plasma therapy for COVID-19 patients infected with variants of concerns. Anaesth. pain intensive care 2022;26(4):535-545; DOI: 10.35975/apic.v26i4.1962
Received: July 31, 2021; Reviewed: May 17, 2022; Accepted: May 18, 2022

 
Introduction
At this time, all countries around the globe, including Indonesia have been suffered from misery of COVID-19 since March, 2020.1 As of August 7th, 2020 Indonesia surpassed People’s Republic of China with the total of 121.226 cases, 5.593 deaths, and 77.557 recovered.2 Indonesia has been and continues to struggle to overcome this pandemic, especially in the last few weeks with the variant of concern that hit Indonesia and caused the second wave. Recently, Indonesia has reached new record with total confirmed cases over 2,780,803 and 71,397 deaths which makes Indonesia become the epicenter in Asia. Notwithstanding, the government of Indonesia has initiated on using many ways and strategies to suppress the COVID-19 spread in the community since 2020. Ever since the first case was confirmed to be positive, measures taken included large scale social restrictions, strict stay-at-home orders, improvement in healthcare services, and provision of personal protective equipment (PPEs) to healthcare workers across the country.3
‘Variants of concern’ (VoCs) comprise of SARS-CoV-2 variants that meet the definition of a VoIs (variants of interest) and, through a comparative assessment, have been demonstrated to be associated with increases in transmissibility or detrimental change in COVID-19 epidemiology, increases in virulence or changes in clinical disease presentation, and/or decreases in effectiveness of public health and social measures or available diagnostics, vaccines, therapeutics at a degree of global public health significance.4 As VoCs have been suspected for the massive spread and higher mortality cases, various studies had introduced the use of convalescent plasma therapy (CPT) as an adjuvant therapy to counter against it. CPT is a passive antibody therapy administered to the patients with a main purpose to treat and possibly prevent infectious diseases.5,6 As SARS-CoV-2 VoC strains spread in human populations, the use of CPT was proposed as alternative therapy options. This provides an additional rationale for surveillance of virus strains, which is necessary to follow SARS-CoV-2 evolution, just as it is for influenza.7
A recent study showed that although the beta (B.1.351) and gamma (P.1) variants had similar mutations in their receptor-binding domain (RBD), administration of serum from recovered patients as well as recipients of mRNA vaccine showed a ~3 fold reduction in neutralization against P.1 and as much as 7-13 fold for B.1.351.8,9 Another study also stated that the plasma generated by infection with the B.1.351 variant not only effectively neutralized the B.1.351 virus, but also succeeded in cross-neutralizing the previous variant.10,11,12 We aimed to elaborate studies on how much efficacy CPT does have in order to neutralize the infection, to accelerate the recovery rate and lower the damages caused. The authors worked on descriptive research, collecting data from various published sources on CPT and also COVID-19, including its VoCs. The collected data was then compiled and describes how the CPT does work and how much it has proved effective against COVID-19 VoCs.

CPT in COVID-19 and its efficacy against VoCs
CPT has been used to prevent and possibly cure infectious diseases; this notion obviously includes SARS-CoV2 infection. Several studies evaluated the effects of therapy in COVID-19 patients, one of which looked at studies in China and one study in Korea involving a total of 27 patients with varying degrees of severity.13 – 17 They concluded that CPT in COVID-19 patients shows promise as it has improved clinical symptoms, laboratory and imaging parameters, but it is too early to be sure it is purely from transfusion due to various underlying clinical conditions, other treatments received, comorbidities and several days of transfusion treatment after the patient's hospitalization.18
An uncontrolled case series of five ARDS-complicated COVID-19 patients were on mechanical ventilation, four of whom were ≥ 50 y of age. They received 400 mL of convalescent plasma infusion each immediately after being obtained by aphaeresis from ABO-compatible donors. Following plasma transfusion, with an IgG titter > 1000 and a neutralization titter > 40, the patient’s high temperature returned to normal within 3 days and the range of their PaO2/FiO2 improved within 12 days. While it has shown and realized that the administration of convalescent plasma containing neutralizing antibody was followed by improvement in the patients’ clinical status, they were faced with several limitations such as the uncontrollable status of the case. It is not clear if these patients would have improved without transfusion of convalescent plasma since they were also administered other medications. Hence, it is difficult to determine whether the improvement observed was in fact, related to CPT or other medications.13,19
The clinical benefits of CPT reported in various studies may include reduced mortality, improved O2 saturation, reduced time for clinical improvement, reduced ventilator support requirement, increased PaO2/FiO2, improved radiologic finding, and improved respiratory distress symptoms. Plasma donor contains anti-inflammatory cytokines, neutralizing antibody, and other proteins which have immunomodulatory effects from anti-inflammatory cytokines and neutralizing antibody.20,21 Neutralizing antibody is essential to prevent SARS-CoV-2 entering lung tissues which afterward causing activation of neutrophils and macrophage in lung tissues. Pulmonary damage is associated with activation of neutrophils and macrophage.22 Beside neutralizing antibody activity, CPT also increases lymphocyte count in infected patients and reduces neutrophils and macrophage activation.23 Using CPT as adjuvant therapy has been suggested to help suppress the virus and modify the inflammatory response.24,25
Time is essential factor of antibodies production and the appropriate timing for CPT administration is crucial. Previous clinical trials have proved that CPT could be more beneficial and the efficacy reached its highest effect at early phase of disease before the patient is critically ill.26,27 The reason might be that the antibody contained in CPT might have suppressed viremia which commonly peaked in the early phase of the disease.26 Moreover, CPT could also prevent overactivity of immune system and also avert cytokine storm and lung damage.27
On the other hand, the most problematic COVID-19’s VoC right now is the delta variant (B.1617.2.1), which was first discovered in India.28 This delta variant has been designated as a ‘variant of concern’ thus it gets attention related to the risk to public health which is higher and has been mentioned if this type has shown increased transmission in the community. Some of the results showed that viruses with the B.1.617 spikes were 2.3 fold resistant to neutralization by convalescent sera and it were caused by the L452R and E484Q mutation.29 Another study stated that the effect of CPT on the Delta variant showed a significantly decreased neutralization titer by 4-6 fold when compared to the Alpha and D614G strains. This study indicated that the Delta variant showed increased resistance to neutralization by serum from unvaccinated, recovered individuals, particularly one year after the infection.30 Thus the Delta variant is declared less sensitive to the administration of CPT.

Chen et al. showed that samples taken on the third day likely reflect antibody titers from convalescent plasma donors, showing strong neutralization titers against the Alpha variant, but at the same time neutralizing antibody titers decreased abruptly from 3 days to 10 and persisted at low levels up to 19th day.31 The decrease in neutralizing antibody could be partially explained by the reduced neutralizing activity after CPT. Interestingly, the neutralizing antibody titer increased after day 19 and reached the same level as day 3 on day 33 and day 56.31 In another in-vitro study, the beta variant exhibited complete escape from therapeutically relevant monoclonal antibodies as well as neutralizing antibodies in COVID-19 convalescent plasma.32 Another study showed that most sera had high activity against the parental spike protein of the virus and the α variant to a lesser extent.33 Only 58% of serum samples could efficiently neutralize a spike protein derivative containing mutations present in the β variant.33 Besides, only 43% of non-ICU hospitalized patients had neutralizing antibody activity greater than 50 serum dilution IC50 against the spike protein with the K417N/E484K/N501Y mutation found in the β variant. The γ variant has a similar mutation profile in the RBD, and some of these non-ICU patients would be predicted to be susceptible to infection by this SARS-CoV-2 variant. Individuals whose infection had required an ICU stay generally displayed higher neutralizing antibody activity against all tested spike protein variants, although they too were less effective against the β-γ triple mutant.33
Mechanism of action
It was then understood that passive immunomodulatory properties, along with pathogen neutralization can be provided by the immune plasma. Neutralizing antibodies are considered essential, saying that titered antibodies in the convalescent plasma were associated with the efficacy of this therapy.5,18,43 It proved to decrease the viral load, cytokine response, and mortality rate.44,45,46
CPT involves collection of plasma from the recovered patients via apheresis and transfused to symptomatic patients, assuming the donor has developed antibodies against the causal agent of the disease.47,48 During apheresis, neutralizing antibodies (NAbs) and other proteins such as clotting factors, anti-inflammatory cytokines, defensins, pentraxins, natural antibodies, and other undefined proteins are collected from donors. Convalescent plasma transfusion into a COVID-19 patient is expected to have an antiviral effect from the antibodies and other immunomodulation benefits in severe inflammatory response of COVID-19.48 Here are several potential mechanism of CPT against COVID-19:

3.1. Neutralizing and suppresion of viremia
Study of CPT administration among severe COVID-19 patients was shown to be beneficial in reducing short-term mortality.49 CPT also improved clinical outcomes in severe and critically ill COVID-19 patients.13,15,49,50,51 Reduced mortality and morbidity in COVID-19 patients, who received CPT, may be explained by mechanisms involving neutralization and suppression of the viremia.13,15,49,50,51,52 Several studies have shown that CPT can increase the cycle threshold (CT) value 13,15 or decrease viral load up to being undetectable.13,5,49,50 As shown in an RCT conducted by Li et al., CPT was associated with negative conversion rate of viral PCR in 87.2% COVID-19 patients at 72 h post-infusion.51 These should be good results because viral load was associated with the disease severity and progression.53,54
NAbs have been considered as the key factor of CPT mechanism of action in restricting virus infection.15,52 NAbs was correlated with SARS-CoV-2-specific antibody, targeting on different domains of spike (S) protein including RBD, S1, and S2 that mediate virus entry into host cells via the ACE2 receptor.52,55,56 NAbs play a vital role as long-lasting humoral immune response in accelerating virus clearance and preventing entry into target cells, also critical for patient’s survival and viral control.13,15,52,55,56 It was known that NAbs titers significantly increased in COVID-19 patients after convalescent plasma transfusion and provide rapid neutralization in viremia.13,15,49,50,51 This neutralizing mechanism was one of the reasons for CPT efficacy 50 and could be a promising ability in improving survival and clinical outcomes of COVID-19 patients.

3.2. Immunomodulation
CPT immunomodulation works through multiple different mechanisms. Antibodies in CPT increase antigen presentation to T cells. Marked increases in CD8+ and CD4+ SARS-CoV-2-specific T cells were found following CPT and simultaneously produced TNF-α and IFN-γ.57 An immunoglobulin fragment, F(ab’)2, provides high neutralization titers against different strains of SARS-CoV-2. However, the efficacy of F(ab’)2 has not yet been determined against other recent mutants such as the Delta variant.58 The Fc region of IgG isotype has been associated with inhibitory effects of the immune cells and may help the modulation of immune response in COVID-19 patients. FcRn receptor is a critical regulator of IgG half-life that works by preventing degradation and clearance of IgG and shortening autoantibodies lifetime in autoimmune conditions.59,60 Some antibodies may limit the inflammatory cascade driven by pathogenic antibodies, as well as the cellular damage induced by the complement cascade (i.e., C3a and C5a) activation in excessive inflammatory environments, limiting the formation of immune complexes. IgG transferred by plasma also neutralize cytokines such as IL-1β and TNFα.60
CPT may enhance anti-inflammatory properties of dendritic cells by canceling the maturation of dendritic cells, reducing production of IL-12, enhancing production of IL-10, IL-4, IL-13, and IL-33 that expands IL-4-producing basophils and enhances Th2, activating β-catenin in an IgG-sialylation independent manner that is critical for reducing inflammation, and down regulation of HLA-II.61–66 On cell B, CPT inhibits NF-κB signaling pathway, causes reduction of CD25 and CD40 expression and reduction of IL-6 and IL-10 production by B cells and it seems to be regulated by SH2 domain–containing phosphatase 1.60 CPT also contains NAbs for B cell–activating factor (BAFF) that could cause a reduction in proliferation and increased rates of apoptosis of B cells. B-cell receptor (BCR) may also experience modulations by the interaction of BCR and CD22 resulted in a down-regulation of tyrosine phosphorylation of Lyn and the B-cell linker proteins which resulted in a sustained activation of Erk 1/2 and arrest of the cell cycle at the G/1 phase.60
CPT may also promote anti-inflammatory macrophage profile by increasing production of IL-10 cytokine and reducing IL-12/23p40. Administration of convalescent plasma in early stages of COVID-19 may prevent innate immune cells migration to lung tissues and prevent excessive cytokine production and pulmonary damage.60 A study showed a significant drop of neutrophil counts 3 days after plasma infusion.67 COVID-19 patients experienced lower eosinophil count and normal level of eosinophil count was correlated with better prognosis. However, a study found there were no significant differences in eosinophil counts in patients with CPT compared to conventional therapy, despite another case report showing a patient with eosinophilia following CPT. Therefore, the effect of CPT on eosinophil count still needs further investigation.68,69
3.3. Antibody-dependent cellular cytotoxicity
In terms of CPT mechanisms, it's worthy to note that, aside from neutralization, there are a number of additional probable direct and indirect humoral and cellular immunological processes through which convalescent plasma works against virus.70 In addition to complement-mediated inactivation of viral particles and/or their phagocytosis, one of the key direct ways is Antibody-dependent cellular cytotoxicity (ADCC), in which convalescent plasma can destroy infected cells exhibiting viral antigens on their surface.70 ADCC is a cell-mediated immune defense process in which an immune system effector cell purposefully lyses a target cell which membrane-surface antigens are bound by particular antibodies.71 In ADCC, NK cells use their FcRIII receptor, CD16, to detect and attach to Ab-opsonized (targeted) cells, resulting in perforin and cytotoxicity granzyme degranulation of infected target cells.72 ADCC is also considered to play an essential role in the body's response to COVID-19 infection which the elevated ADCC response has been linked to inflammation during viral infection.73 According to a study, of 95 people infected with SARS-CoV-2 found an increase in ADCC activity in COVID-19 patients, especially those who were hospitalized.74 This is also supported by another study that shown that the highest level of ADCC was about 2 weeks from the onset of the disease, that were early than the peak period of neutralizing antibodies (Nabs), which was around 3 weeks.75 From 6 to 12 months after infection, ADCC activity remained generally steady until the last tested point at 462 days.75 This data suggests that ADCC can be used as an infection marker instead of Nab, extending the window beyond what can be deduced from neutralizing activity.75


According to several studies show that the efficacy of a CPT should be measured not just in terms of the quantity of neutralizing antibodies (nAb) produced, but also in terms of the totality of the SARS-CoV-2-specific humoral response produced. In such studies, the possible contribution and persistence of non-neutralizing antibodies' effector mechanism should be evaluated. Given the importance and urgency of establishing a successful CPT, a more extensive and in-depth examination is certainly required to have a better understanding.72
3.4. Restoration of Coagulation Factor
COVID-19 viral infection has direct effect on the endothelium, causing endothelial injury and inflammation that may lead to profound thromboses in COVID-19 patients.76 Convalescent plasma treatment could be the solution for restoring the coagulation factor.77 In a study conducted by Klompas et al.78, low rates of thrombotic and thromboembolic events were found in COVID-19 patients, even in critically ill COVID-19 patients, who had convalescent plasma transfusion.78
Convalescent plasma provides procoagulant and antifibrinolytic factors that could restore the endothelium glycocalyx and prevent vascular leakage.77 Steric hindrance between receptor and ligand that provides by plasma and proteins in plasma have important role in fixing the endothelium glycocalyx.76 D-dimer levels, which is an important marker of thrombosis, was found decreased in following to the convalescent plasma transfusion. Convalescent plasma is a source of some plasma proteins that have important role in the hemostatic process, such as antithrombin and albumin.79
3.5. CPT on Variant of Concern
The use of CPT against VoCs will work depending on the strain-specific match between the antibody present in the donor plasma and the variant that infects the patient. For example, the Alpha variant which has changes in spike glycoprotein can be neutralized by CPT.80,81 Meanwhile, the Beta variant also shows significant neutralization when given CPT, but CPT only works effectively if patients who receive CPT also get or have SARS-CoV2 IgG antibody that is high.32,82 However, neutralization ability of CPT is reported less effective when introduced to Delta variant as much as threefold to fivefold less than wild-type D614G strain.83 Moreover, Delta sub-lineages such as Delta+N501S or variants under monitoring such as C.1.2 are largely resistant to CPT.83 Another study also reported that the effect of CPT for delta decreases compared to previous variants.84 Surprisingly, the Omicron variant has shown extensive escape from CPT and it has not shown any improvement in outcomes.85
Limitations of CPT
Even though CPT has been stated to offer promising results in treating COVID-19 and its VoCs, there are still several limitations in its use. As declared that CPT is not authorized for non-hospitalized patients with COVID-19 under the Emergency Use Authorization (EUA), and it is still not recommended during pregnancy, because the safety and efficacy have not been evaluated.86  Reported in other study, titer of neutralizing antibodies are not always high in all CPT donors and levels of these antibodies last only for short duration, estimated for weeks or months.87,88 It also still requires special consideration to determine the effective timing for giving CPT to the recipient.89 For treatment purpose, it is needed in large volumes, e.g., between 200-2400 mL of plasma.15,17,90 There are several probable adverse effects that may lead to life-threatening condition such as bronchospasm, transfusion related acute lung injury and circulatory overload in patients with cardiorespiratory disorders, renal impairment and aged individuals; also immunological reactions that could turn into serum sickness and anaphylaxis.87,91
Several studies in current recovery trials have shown contradictive results with the benefits of CPT in patients with COVID-19. In a clinical trial, the administration of high-titer CPT did not improve clinical outcome and survival of patients with severe to life-threatening COVID-19.51 A meta-analysis of 10 RCTs also revealed that treatment with CPT was not associated with any benefit for clinical outcomes or with decrease in all-cause mortality, compared to placebo or standard treatment group.92 This evidence showed that the use of CPT in COVID-19 still needs special concern and further studies to prove its clinical benefits, if any.

Conclusion
In conclusion, the effectiveness of the CPT is currently questionable in the treatment of COVID-19 and its variants of concern. It seems to have been abandoned because CPT does not work well against some variants of concern. In addition, there are still reservations about its use including not so much improvement in patient survival and other clinical outcomes.

Conflict of Interests
There is no conflict of interests declared by the authors.

Authors’ contribution
EMK: concept, literature search, proofreading

ISP: concept, literature search, manuscript editing

DMW, VMP, V, MZ, FNP, AAW: concept, manuscript editing

FUP: concept, literature search, manuscript writing, bibliography editing

DN: concept, manuscript editing, bibliography editing

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