Highly Neutralizing COVID-19 Convalescent Plasmas Potently Block SARS-CoV-2 Replication and Pneumonia in Syrian Hamsters

Abstract

Despite various attempts to treat SARS-CoV-2-infected patients with COVID-19-convalescent plasmas, neither appropriate approach nor clinical utility has been established. We examined the efficacy of administration of highly-neutralizing COVID-19-convalescent plasma ( hn -plasmas) and such plasma-derived IgG administration using the Syrian hamster COVID-19 model. Two hn -plasmas, which were in the best 1% of 340 neutralizing-activity-determined convalescent plasma samples, were intraperitoneally administered to SARS-CoV-2-infected hamsters, resulting in significant reduction of viral titers in lungs by up to 32-fold as compared to the viral titers in hamsters receiving control non-neutralizing plasma, while with two moderately neutralizing plasmas ( mn -plasmas) administered, viral titer reduction was by up to 6-fold. IgG fractions purified from the two hn -plasmas also reduced viral titers in lungs than those from the two mn -plasmas. The severity of lung lesions seen in hamsters receiving hn -plasmas was minimal to moderate as assessed using micro-computerized tomography, which histological examination confirmed. Western blotting revealed that all four COVID-19-convalescent-plasmas variably contained antibodies against SARS-CoV-2 components including the receptor-binding domain and S1 domain. The present data strongly suggest that administering potent-neutralizing-activity-confirmed COVID-19-convalescent plasmas would be efficacious in treating patients with COVID-19. Importance Convalescent plasmas obtained from patients, who recovered from a specific infection, have been used as agents to treat other patients infected with the very pathogen. To treat using convalescent plasmas, despite that more than 10 randomized-controlled-clinical-trials have been conducted and more than 100 studies are currently ongoing, the effects of convalescent plasma against COVID-19 remained uncertain. On the other hand, certain COVID-19 vaccines have been shown to reduce the clinical COVID-19 onset by 94-95%, for which the elicited SARS-CoV-2-neutralizing antibodies are apparently directly responsible. Here, we demonstrate that highly-neutralizing-effect-confirmed convalescent plasmas significantly reduce the viral titers in the lung of SARS-CoV-2-infected Syrian hamsters and block the development of virally-induced lung lesions. The present data provide a proof-of-concept that the presence of highly-neutralizing antibody in COVID-19-convalescent plasmas is directly responsible for the reduction of viral replication and support the use of highly-neutralizing antibody-containing plasmas in COVID-19 therapy with convalescent plasmas.

A Multi-Center, Open-Label, Randomized Controlled Trial to Evaluate the Efficacy of Convalescent Plasma Therapy for Coronavirus Disease 2019: A Trial Protocol (COVIPLA-RCT)

“…At a high concentration, it can completely inhibit SARS-CoV-2 infection at the single-cell level [ 18 ]. In a hamster model representing an in vivo cell infection system, the administration of convalescent plasma inhibited viral replication in the lung [ 31 ]. However, several RCTs of convalescent plasma therapy have already been conducted in countries outside Japan, but no conclusion has been reached with respect to the efficacy of convalescent plasma therapy, which is likely in part because of the heterogeneity of the types of target patients, interventions, and endpoints among trials [ 32 ].…”

Early post-infection treatment of SARS-CoV-2 infected macaques with human convalescent plasma with high neutralizing activity had no antiviral effects but moderately reduced lung inflammation

“…In the current study, we demonstrate that administration of a pooled human CCP with high titer of neutralizing and spike-binding antibodies, administered one day after virus inoculation, conferred therapeutic benefits to SARS-CoV-2 infected macaques in terms of moderately reduced interstitial pneumonia, despite limited effects on markers of virus replication. Therapeutic effects of CCP with high titers of neutralizing antibodies were recently also described in Syrian hamsters [ 36 ].…”

Advances in Oncology in US and Japan: Focusing on Cancer and Infectious Diseases

“…Mitsuya and his group have demonstrated that, in SARS-CoV-2-infected hamster model, COVID-19-convalescent plasmas significantly reduce SARS-CoV-2 titers in the lung of Syrian hamsters and prevent pneumonia from occurring ( Fig. 3 ) [ 9 ]. Mitsuya and his group have started a randomized clinical trial to evaluate the effect of highly neutralizing COVID-19-convalescent plasma transfer to seniors and those at high risks of having severe COVID-19, which began in February 2021 in multiple medical centers in Tokyo and is ongoing.…”

“…While Syrian hamsters, which were SARS-CoV-2-inoculated and received control healthy plasma developed severe pneumonia by day 8 following viral inoculation (upper left), hamsters which were inoculated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but received COVID-19-convalescent human plasma (D43) were protected from infection by SARS-CoV-2 and developed no pneumonia (upper right). The two lower left insets show that many airway cells of the hamster had been infected with SARS-CoV-2 and stained in dark brown; however, the two lower right insets show no infection on the airway cells [ 9 ].…”