Convalescent plasma therapy for coronavirus infection: experience from MERS and application in COVID-19

ABSTRACT

The emergence of the COVID-19 pandemic has resulted in a very large number of infections and high number of mortality. There is no specific therapeutic options that are approved for clinical use. Administration of convalescent plasma as a possible therapy was used in the case of viral pneumonia including SARS and influenza. There have been multiple studies of COVID-19 patients utilizing convalescent plasma. These studies employed different dosage levels and different regiments, were observational and lacked control arms, and had variable outcomes. Two of these studies used plasma with anti-SARS-CoV-2 titers of >1:640 to >1:1000. A recent randomized controlled clinical trial showed no benefit of convalescent plasma in patients with severe diseases. However, the study was terminated early and thus further clinical trials are needed to show efficacy in patients with COVID-19 infection.

KEYWORDS:

• Convalescent plasma
• SARS-CoV-2
• COVID-19
• MERS-CoV
• SARS

Introduction

In the last 20 years, the world had witnessed the emergence of three coronaviruses with significant impacts. These viruses are Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and the SARS-CoV-2 (the causative agent of COVID-19). The SARS-CoV initially emerged in 2002 in the Guangdong Province in China.^1,2 SARS resulted in 8096 cases and the death of 774 (9.6%) from late 2002 to early 2003.³ In addition, SARS cases were reported from Vietnam, Hong Kong, Canada, United Sates, Ireland, Vietnam, and Singapore.^1,4-11 The initial cases were linked to a single patient who stayed in hotel M in Hong Kong.¹²

In 2012, ten years later, a new coronavirus was isolated from a patient in Saudi Arabia.^13,14 The virus was subsequently named MERS-CoV.¹⁵ One of the characteristics of MERS-CoV is healthcare-associated infection between patients and from patients to healthcare workers.^16–36 MERS-CoV carries a high case fatality rate in patients with comorbidities and the rate is lower in patients with mild symptoms.³⁷ The overall case fatality rate was 28.6–63.6%.³⁸ Despite the high case fatality rate, there has been no approved therapeutic option for MERS-CoV.

The newest novel coronavirus was first identified in Wuhan city, China and was officially reported to WHO in Dec 2019. The first cases were among a cluster of pneumonia related to a seafood market.³⁹ The virus was subsequently named SARS-CoV-2 and the disease was named COVID-19. COVID-19 had become a global pandemic.⁴⁰ The recently emerged SARS-CoV-2 had caused a world-wide pandemic with a significant number of cases worldwide. Currently, there is no specific approved therapy for the treatment of COVID-19 patients. There are multiple therapeutics that had been tried and include: antiviral drugs, corticosteroids, and immune modulating agents. However, one possible therapy is the use of convalescent plasma. Here, we review currently available data on the use of convalescent plasma as a therapy for COVID-19 patients.

Mechanism of action of convalescent plasma

The use of convalescent plasma relies on the concept of passive immunization where the recipients receive antibody-rich plasma from those individuals who had recovered from an illness. In sharp contrast to active immunization that is usually designed to prevent infection, convalescent plasma might be used for prevention. However, the main aim of convalescent plasma is treatment of patients with severe disease. There are multiple proposed mechanisms by which convalescent plasma act as a therapeutic option. Convalescent plasma contains IgM and IgG antibodies that may bind to a specific pathogen (SARS, MERS-CoV, SARS-CoV-2) and act as neutralizing antibodies and thus inhibit these viruses.⁴¹ In the case of SARS, the binding sites for these neutralizing antibodies are the spike1-receptor binding protein (S1-RBD), S1-N-terminal domain and S2.⁴² The levels of anti-SARS-CoV-2–specific antibody were found in the range of 1800 and 16200 and neutralizing antibodies titers were of 80–480.⁴³ These neutralizing antibodies peak 10–15 days after COVID-19 onset.⁴⁴ In two studies of convalescent plasma in COVID-19, neutralizing antibody titer was ≥40 in one study⁴³ and ≥640 in a second study.⁴⁵

Other mechanisms of action of convalescent plasma include: complement activation, antibody-dependent cellular cytotoxicity, and phagocytosis by macrophages through opsonization.⁴⁶

Convalescent plasma therapy in influenza

Convalescent plasma had been used previously to treat viral pneumonia. Observational studies had suggested possible reduction in mortality in patients with severe SARS-CoV and influenza.^47–50 There were multiple studies utilizing convalescent plasma in the treatment of the 2009 pandemic H1N1.⁴⁷ In one prospective cohort study, patients who were treated with convalescent plasma containing a neutralizing antibody titer of ≥ 1:160 showed a reduction of the relative risk of mortality compared to patients who declined participation (odds ratio 0 · 20 [95% CI 0 · 06–0 · 69], p = 0 · 01).⁴⁷ A systematic review of multiple studies, which were predominantly observational, demonstrated reductions in viral load and improvement in fever, oxygenation, and radiographic images.⁵¹ However, the main drawback of these studies is the fact that these were observational in nature. A single double-blind randomized controlled trial demonstrated that hyperimmune intravenous immunoglobulin treatment resulted in a lower viral load and reduced mortality in a subgroup who received treatment within 5 days of symptom onset of H1N1 infection.⁵² The use of hyperimmune immunoglobulin in a double-blind, randomized, placebo-controlled trial resulted in no difference in the primary outcome measured by a 6-point ordinal scale of clinical status on Day 7, although there were favorable antiviral and clinical responses in the subgroup of patients with influenza B.⁵³ A third study of severe influenza, high-titer anti-influenza plasma transfusion did not result in a significant benefit in comparison with nonimmune plasma.⁵⁴ Two meta-analysis of convalescent plasma in patients with viral pneumonia revealed reduction in mortality.^48,51 The second meta-analysis included 1703 patients with pneumonia secondary to the 1918 influenza and showed 21% absolute reduction of the crude mortality rate.⁴⁸

Advantage and disadvantage of convalescent plasma

The transfusion of convalescent plasma has certain advantages and disadvantages. Convalescent plasma transfusion is potentially associate with a short-lived immunity and provide a fast and immediate therapy. Theoretically, convalescent plasma would work especially in moderately or severe infection when given early. Potential risks of convalescent plasma transfusion include: risks of the transfusion of infectious agents, transfusion-associated circulatory overload (TACO), transfusion-associated acute lung injury (TRALI) which is of particular concern in SARS, SARS-CoV-2 and MERS-CoV patients, and antibody-dependent enhancement (ADE). ADE is a possible concern that leads to worse immune-mediated tissue damage due to the presence of non-neutralizing antibodies and even in the presence of neutralizing SARS-CoV antibodies.⁵⁵ In Rhesus macaques model of infection, vaccination with SARS-CoV spike protein and the development of neutralizing antispike antibodies before inoculation with SARS-CoV had resulted in severe lung disease despite develop lower viral loads.⁵⁶

Convalescent plasma in the SARS and MERS-CoV Era

During SARS-CoV infection, it was thought that convalescent plasma improve the outcome of infected patients.⁵⁷ Previous studies including a meta-analysis of 27 studies of patients with SARS-CoV infection⁵¹ suggest that convalescent plasma may be used for patients with SARS as convalescent plasma showed improvements in survival and resulted in a shorter hospital stay.^58,59 However, most of the studies were of low or very low quality, lacked control groups, and had risk of bias.⁵¹ The analysis included 6 case studies, 20 case series, 2 case-comparison studies, and 1 prospective cohort study.⁵¹

A protocol for the use of convalescent plasma as a therapeutic option for MERS was suggested.⁶⁰ Plasma donors were identified as those with anti-MERS-CoV indirect immunofluorescence assay (IFA) antibodies (titer of ≥1:160) with no evidence of active MERS-CoV infection.⁶⁰ However, of 443 tested samples for MERS-CoV antibodies, only 12 (2.7%) had a reactive ELISA, and 9 of the 12 had reactive indirect fluorescent antibody and microneutralization assay titers. The study proved that clinical trial using such interventions is challenging due to the small pool of potential donors with sufficient high antibody titers.⁶¹ In nine confirmed survivors of MERS-CoV infection, 55%, 33%, and 22% of them had positive MERS antibodies by IFA at 3, 10, and 18 months, respectively.⁶² The two patients who had long lasting antibodies as tested by ELISA and IFA had severe disease; however, the actual titer of the antibodies was not reported in the study.⁶² In a larger study, MERS-CoV neutralizing antibodies were produced at low levels and were short-lived after mild or subclinical infection.^63,64 Further studies of the kinetics of the MERS-CoV antibodies showed that all surviving patients and 50% of fatal cases produced IgG and neutralizing antibodies during the first 2 weeks after diagnosis.⁶⁵ However, these antibodies did not eliminate the virus from lower respiratory tract.⁶⁵ In 12 patients from South Korea, nine (75%) patients had PRNT50 titers >1:320 by day 21 and two had titers >1:320 by day 28.⁶⁶

Convalescent plasma in COVID-19 therapy

The FDA recently approved convalescent plasma for the use in patients with COVID-19 as a new investigational drug on an emergency basis.⁶⁷ The use of convalescent plasma is contingent upon the presence of an adequate level of neutralizing antibodies in the donor plasma before transfusion.^68–70 At the present time, limited data are available about the efficacy of convalescent plasma for COVID-19 patients. The presence of IgM antibodies were weakly detected by ELISA and high IgG titers were observed in five samples.⁷¹ A summary of the use of convalescent plasma in COVID-19 patients is shown in Table 1. Subsequently, one patient received convalescent plasma and the patient did not require mechanical ventilation.⁷¹ In a single study of 4 patients, convalescent plasma (without determination of the level of neutralizing antibodies in donor plasma) resulted in negative SARS-CoV-2 by RT-PCR on days 3–22 after convalescent plasma.⁷² Two patients with COVID-19 were initially treated with lopinavir-ritonavir and hydroxychloroquine with persistent fever and progressive bilateral infiltrations.⁷³ Then, they received convalescent plasma without determination of the level of neutralizing antibodies in donor plasma and those patients had improvements and reduction in the viral loads.⁷³ One patient had myelodysplastic syndrome and disseminated tuberculosis developed COVID-19 and was successfully treated with convalescent plasma.⁷⁴ Another patient received two doses of convalescent plasma and subsequently had negative SARS-CoV-2 by PCR.⁷⁵ A study of 25 severe COVID-19 patients showed that 14 days post-transfusion, 76% had at least a 1-point improvement in clinical status and 44% were discharged.⁷⁷

Table 1. A summary of the different studies utilizing convalescent plasma for the treatment of COVID-19 patients

Number of Cases	Convalescent Plasma Dose	Titer	Administration Day	Other antiviral therapies	Disease Severity	Viral load after therapy	Reference
5	400 ml × 2 doses	>1:1000	10–20 days after admission	Interferon alfa‐1b, Lopinavir/ritonavir, favipiravir, arbidol, darunavir (in different combination)	Mechanical ventilation	Negative within 12 days	^Citation45
10	200 ml × 1 dose	>1:640	Mean of 16.5 days from onset	Arbidolol, remdesivir	Intensive care admission	Undetectable in 7 patients	^Citation43
4	Variable	-	12–19 after admission	Arbidolol, lopinavir‐ritonavir, interferon alpha, interferon alpha‐2b	Mechanical ventilation	Negative within 18–46 days	^Citation72
2	500 ml in 2 doses	-	6–10 days after admission	Hydroxychloroquine, lopinavir/ritonavir	Mechanical ventilation	Negative 20–26 days later	^Citation73
1	200 ml × 2 doses	IgG semiquantitative titer of 6.6	-	Favipiravir, tocilizumab	Severe disease	-	^Citation74
1	200 ml × 2 doses	S-RBD-specific IgG titer of > 1:640	5 days after hospitalization	None	Moderately severe	Negative viral load at day 12 of hospitalization	^Citation75
6	Variable	-	33–50 days after admission	Arbidolol	Moderate disease	Negative in 4 patients	^Citation76
25	300 ml × 1 dose (1 patient received 2 doses)	RDB titer 50–1350	Median time from symptom to transfusion: 10 days [IQR, 7.5–12.5], and from hospitalization to transfusion: 2 days [IQR, 2–4]	Majority of patients received tocilizumab and steroids. Most received hydroxychloroquine and azithromycin, ribavirin, and/or lopinavir/ritonavir, and two patients received remdesivir	Severe and/or life-threatening	14 days posttransfusion, 76% had at least a 1-point improvement in clinical status and 44% were discharged	^Citation77
52	4–13 mL/kg of recipient body weight.	S-RBD–specific IgG titer of at least 1:640	Time between symptom onset and randomization, median (IQR), d 27 (22–39) [n = 49]	Other treatments included antiviral medications, antibacterial medications, steroids, human immunoglobulin, Chinese herbal medicines, and other medications	23 with severe disease; 29 with life-threatening disease	22/26 (84.6%) negative at 72 hours	^Citation78
5000	-	-	-	-	Hospitalized adults with severe or life-threatening COVID-19	Assessed adverse events	^Citation79

In a case series of 5 patients with ARDS and severe pneumonia with rapid progression of disease and continuously high SARS-CoV-2 viral load despite antiviral treatment received convalescent plasma (SARS-CoV-2-specific IgG antibody binding titer > 1:1000 by enzyme-linked immunosorbent assay [ELISA]) and a neutralization titer > 40).⁴³ In those patients, temperature normalized within 3 days in 4 patients, the SOFA score decreased, and Pao2/Fio2 increased within 12 days, viral tests became negative within 12 days, and 3 patients were discharged.⁴³ This study is limited by absence of control group and a small number of cases. In addition, it is not clear if the improvement is due to the convalescent plasma or due to other therapies. The patients received the transfusion between day 10 and 22 after admission and thus there was late administration of convalescent plasma with different timing.⁴³

In a study of six patients, they received ABO-compatible convalescent plasma and five patients had resolution of ground glass opacities and consolidation.⁷⁶ In a prospective study of 10 patients with severe COVID-19 infection, patients received one dose of 200 mL of convalescent plasma from recently recovered donors (neutralizing antibody titers > 1:640).⁴⁵ In those patients, the median time from onset of disease to transfusion of convalescent plasma was 16.5 days. There was radiological improvements within 7 days and viremia was undetectable in seven (70%) patients.⁴⁵ However, the recovery was faster in those receiving convalescent plasma before 14 days after onset of illness compared to those who received the therapy after that time.⁴⁵ In a systematic review, five studies were included with 27 patients and all studies were with associated with a high risk of bias, and were nonrandomized with confounders, poor methodology, different dosage, and variable duration of therapy.⁸⁰

Currently, convalescent plasma is being considered in clinical trial. It is worth noting that in a study of convalescent plasma for the therapy of Ebola, post hoc analysis showed that convalescent plasma with neutralizing antibodies might have been associated with improvement. However, convalescent plasma with unknown levels of neutralizing antibodies in confirmed Ebola therapy was not associated with a significant improvement in survival.⁴¹ More than 50 planned or ongoing cohort studies and randomized controlled trial are on the horizon utilizing convalescent plasma in COVID-19 patients (such as NCT04345523, NCT04345991, NCT04347681,as listed on https://clinicaltrials.gov/). The US National COVID-19 Convalescent Plasma Project is evaluating three trials in relation to the activity and safety in exposed patients with high risk of developing severe COVID-19 (NCT04323800), in hospitalized patients with acute respiratory symptoms (NCT04325672), and in mechanically ventilated COVID-19 patients. Other current therapeutic trials utilize convalescent plasma for post-exposure prophylaxis in a randomized, blinded Phase 2 trial, in patients with mild, moderate or severe clinical disease. Thus, the endpoint of each study is dependent on the severity of the disease and includes clinical improvement, the rate of SARS-CoV-2 clearance, impact of donor need for extracorporeal membrane oxygenation or renal replacement therapy, length of hospital length of stay and other clinical endpoints.⁸¹ In addition, the protocols of these studies are variable and not all studies have a control arm. However, few studies have standard plasma as the control arm.⁸¹ There is also a variation in the doses being considered and this might be weight-based similar to immunoglobulin.⁸⁰

A recent open-label, multicenter, randomized clinical trial of the use of convalescent plasma was terminated early and showed no clinical improvement within 28 days.⁷⁸ Clinical improvement occurred in 51.9% of the 52 convalescent plasma group vs 43.1% in the 51 control group (p = .26).⁷⁸ In a large study of 5000 patients, adverse reactions were <1%.⁷⁹ The study design did not allow evaluation of efficacy but the reported mortality was 14.9% compared to historical data of 10–20%.⁷⁹

In conclusion, the use of convalescent plasma is a promising therapy. However, it is not known if recovered COVID-19 patients would have adequate antibody levels and if there is a good serologic test to confirm the presence of a significant level of antibodies that would lead to therapeutic effect. This therapeutic option is based on the availability of donors who had recovered and had adequate antibodies. The use of hyperimmune globulin where anti-SARS-CoV-2 antibodies from multiple donors are pooled is another possible therapeutic option.

Disclosure of potential conflicts of interest

All authors have no conflicts of interest