In this Perspective, published on Cell Reports Medicine, the role of the different immunotherapeutic approaches, including convalescent plasma, is analysed.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has infected 5,85 millions, with more than 361,000 fatal cases as of May 29, 2020.

Currently, there are no specific COVID-19 therapies. Most patients depend on mechanical ventilation. Current COVID-19 data clearly highlight that cytokine storm and activated neutrophils migration to the lungs characterize the early immune response to COVID-19 that causes severe lung damage and development of acute respiratory distress syndrome.

In view of uncertainty associated with immunosuppressive treatments, such as corticosteroids and their possible secondary effects, including risks of secondary infections, immunotherapies can be suggested as an adjunct therapy in severe COVID-19 cases.

Such immunotherapies based on inflammatory cytokine neutralization, immunomodulation and passive viral neutralization not only reduce inflammation, inflammation-associated lung damage or viral load but could also prevent intensive care unit hospitalization and dependency on mechanical ventilation, both of which are limited resources.

Passive immunization of SARSCoV-2 by using convalescent plasma, intravenous hyperimmune globulin (containing high concentrations of neutralizing antibodies obtained from the pooled plasma of large number of recovered patients), or neutralizing monoclonal antibodies represent another potential therapeutic option.
A meta-analysis reported a significantly reduced mortality rate in SARS-CoV-infected patients following infusion of convalescent plasma. These patients recorded a rapid decline in their virus load.

Although not conclusive, a report with MERS-CoV also suggested that the use of convalescent plasma could be an option for COVID-19. Similarly, a meta-analysis of patients with Spanish influenza pneumonia concluded that influenza convalescent human blood products reduced the death risk.
Hyperimmune globulin treatment in severe H1N1 influenza within 5 days of symptoms also reduced viral load and mortality in patients.
Development of neutralizing monoclonal antibodies in cases of SARS-CoV and MERS-CoV focused mainly on spike (S) protein as a target. Several monoclonal antibodies have demonstrated efficacy in experimental models. Either antibody libraries consisting of entire VH and VL genes of B cells or antigen-specific antibodies isolated from the memory B cells of convalescent COVID-19 patients could be used to obtain potent
neutralizing monoclonal antibodies to SARS-CoV-2.

It is important to validate the neutralizing activity of plasma preparations before using with COVID-19 patients, particularly in the case of convalescent plasma, as neutralizing activity might significantly differ in mildly versus severely ill patients.

A preliminary report from China suggested that convalescent plasma therapy leads to improvement in 91 of 245 COVID-19 patients treated. An uncontrolled trial on transfusion of 400 mL of convalescent plasma (with viral neutralizing titers more than 1:40) in five patients critically ill with COVID-19 led to resolution of pulmonary lesions and reduction in the severity of the disease and viral loads. Similarly, treatment of ten severely ill COVID-19 patients with 200 mL of convalescent plasma containing viral neutralizing antibody titers more than 1:640 led to reduced CRP levels, undetectable viremia, and improved clinical symptoms.

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