Early post-infection treatment of SARS-CoV-2 infected macaques with human convalescent plasma with high neutralizing activity reduces lung inflammation (preprint)

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 levels of antiviral antibodies after infusion. In comparison to the control animals, they had similar levels of virus replication in the upper and lower respiratory tract, but had significantly reduced interstitial pneumonia, as measured by comprehensive lung histology. 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. Author summaryThe results of treating SARS-CoV-2 infected hospitalized patients with COVID-19 convalescent plasma (CCP), collected from survivors of natural infection, have been disappointing. The available data from various studies indicate at best moderate clinical benefits only when CCP with high titer of neutralizing antibodies was infused early in infection. The macaque model of SARS-CoV-2 infection can be useful to gain further insights in the value of CCP therapy. In this study, animals were infected with SARS-CoV-2 and the next day, were infused with pooled human convalescent plasma, selected to have a very high titer of neutralizing antibodies. While administration of CCP did not result in a detectable reduction in virus replication in the respiratory tract, it significantly reduced lung inflammation. These data, combined with the results of monoclonal antibody studies, emphasize the need to use products with high titers of neutralizing antibodies, and guide the future development of CCP-based therapies.

Monoclonal Antibodies Protect Aged Rhesus Macaques From SARS-CoV2 Induced Immune Activation (preprint)

Anti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from COVID-19 in high-risk populations such as aged and diabetic individuals, however, data on their efficacy in these populations is limited. We demonstrate that prophylactic mAb treatment prevented viral replication specifically in the upper respiratory tract in aged, type-2-diabetic rhesus macaques. While activation of innate inflammatory pathways was observed, mAb infusion dramatically curtailed SARS-CoV-2-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing the development of interstitial pneumonia. Effector T cell differentiation was reduced in the draining mediastinal lymph nodes, resulting in significantly lower representation of activated cells in the spleen and blood. Consequently, mAb infusion significantly dampened the greater than three-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data indicate that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.Funding Information: This study was supported by grants R21 AI143454-02S1 (SSI), FAST GRANT- George Mason 358 University (SSI), 3RF1AG061001-01S1 (SSI/JHM) and the CNPRC base grant P51OD011107Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All study procedures were approved by the Institutional Animal Care and Use Committee at UC Davis.