**5. Adverse effects**

Previous studies did not find any adverse effects associated with CP immunotherapy during historical influenza A (H1N1), SARS-CoV, or MERS-CoV epidemics [18, 26, 43]. In case of Ebola, it was associated with mild adverse effects such as fever, nausea, skin erythema, and no other significant adverse events were found [44]. A self-limited facial erythema occurred in 2 out of 10 SARS-CoV-2 infected patients with no major adverse events found during the transfusion study [28]. The therapy was well tolerated in most of the patients while some reported only mild adverse effects. Several studies of SARS-CoV-2 have shown that CP immunotherapy is safe and not associated with any significant adverse effects.

## **6. Limitations**

The risk of Hepatitis B virus, Hepatitis C virus and HIV disease transmission through the donated plasma should be thoroughly investigated before CP transfusion. The nucleic acid test for this viruses is strictly mandatory to ensure the safety of SARS-CoV-2 infected CP recipients [45].

Vaccine development should consider ADE phenomenon in COVID-19 patients as ADE may promote intensity of infection and administration of CP in those coronaviruses endemic areas should be carried out with caution since ADE appears to be harmful to actively infected patients [46].

All the recovered patients received not only the CP transfusion but also other standard care like antiviral treatment. As a consequence, these antiviral agents may also lead to the subsequent recovery of patients, or may synergize with the therapeutic effect of CP, which cannot be ruled out.

Taken together, these studies suggested that convalescent plasma from recently recovered patients with high neutralizing antibody titers against SARS-CoV-2 would be more effective for CP immunotherapy. A warranted random clinical trial in larger groups is required for dose optimization and to overcome possible adverse side effects of CP immunotherapy.

Furthermore, the kinetics of nAbs titers against SARS-CoV-2 need to be critically evaluated because of neutralizing antibodies represented short term humoral immune response.
