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

Abstract

Early in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable but low levels of antiviral antibodies after infusion. In comparison to the control animals, CCP-treated animals had similar levels of viral RNA in upper and lower respiratory tract secretions, similar detection of viral RNA in lung tissues by in situ hybridization, but lower amounts of infectious virus in the lungs. CCP-treated animals had a moderate, but statistically significant reduction in interstitial pneumonia, as measured by comprehensive lung histology. Thus overall, therapeutic benefits of CCP were marginal and inferior to results obtained earlier with monoclonal antibodies in this animal model. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses.

Infant rhesus macaques immunized against SARS-CoV-2 are protected against heterologous virus challenge 1 year later

“…We therefore used data from all eight control RMs in further analyses. In a prior study, the comprehensive pathology evaluation proved to be more sensitive in detecting lung pathology than radiographs ( 41 ), and therefore we selected the average combined lung pathology score, referred to as lung pathology score, in subsequent analyses of challenge outcome and in the identification of immune correlates of protection.…”

Administration of vaccine-boosted COVID-19 convalescent plasma to SARS-CoV-2 infected hamsters decreases virus replication in lungs and hastens resolution of the infection despite transiently enhancing disease and lung pathology

“…Plasma pools (Table 2) made from aliquots of frozen plasma collected from human donors were used. Details of the control pool of normal plasma containing no anti-SARS-CoV-2 antibodies and CCP pool have been provided in previously published studies [27,28]. The CCP pool had a 50% neutralization titer (NT50) of 1,149 in a reporter virus assay (23).…”

Aerosol delivery of SARS-CoV-2 human monoclonal antibodies in macaques limits viral replication and lung pathology

“…Several animal models of SARS-CoV-2 infection have been developed that have provided critical data on pathogenesis, correlates of protection, and efficacy of prophylactic and therapeutic interventions 8 , 9 . Experimental infection of nonhuman primates (NHPs), including rhesus macaques ( Macaca mulatta ), cynomolgus macaques ( Macaca fascicularis ), and pigtail macaques ( Macaca nemestrina ) with an initially described strain of SARS-CoV-2 (WA-1) did not result in severe disease but was characterized by rapidly peaking, high levels of viral replication for several days, viral shedding for ~2 weeks, and mild to moderate pulmonary disease with signs of interstitial pneumonia and accumulation of inflammatory monocytes, macrophages and neutrophils in the lungs 10 , similar to that seen in humans 11 . In addition, NHPs develop immune responses to the virus comparable to those responses observed in infected humans.…”