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

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.

(which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC The copyright holder for this preprint this version posted September 1, 2021. ; https://doi.org/10.1101/2021.09.01.458520 doi: bioRxiv preprint indicates 95% as the lower end cut-off of the normal range. Total clinical scores, including the markers not graphed above, are presented in Fig. 4. 105 and is also made available for use under a CC0 license.
(which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC

IP-10
105 and is also made available for use under a CC0 license.
(which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC   (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC

1.4
Lung score

A B
105 and is also made available for use under a CC0 license.
(which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC  In an earlier study that used the same experimental procedures, we demonstrated that a combination of 2 potent anti-SARS-CoV-2 monoclonal antibodies (mAb; C135-LS and C144-LS) administered one day after virus inoculation reduced lung interstitial cellularity scores in 8 treated animals comparison to 4 animals treated with a control mAb [27]. Comparison of the CCP-treated and SARS-CoV-2 mAb-treated groups demonstrated that mAbs are more effective than CCP in reducing interstitial cellularity scores (p=0.004, unpaired t test).
Because in the monoclonal antibody study, scores were based on 3 lung lobes, the data of the CCP study presented in this figure are tabulated based on those same 3 lung lobes; using the data of all 7 lung lobes on the current CCP study (presented in Fig. 5) resulted in the same conclusions. Monoclonal antibody study Convalescent plasma study p=0.01 105 and is also made available for use under a CC0 license.
(which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC   105 and is also made available for use under a CC0 license.
(which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC The copyright holder for this preprint this version posted September 1, 2021. ; https://doi.org/10.1101/2021.09.01.458520 doi: bioRxiv preprint Table S3. Summary of radiological scoring.
All thorax radiographs were scored blinded by a veterinary radiologist, with scores of 0 to 3 assigned to each of the 7 lung lobes. For each time point, the total score of all lung lobes was tabulated. Thus, the maximum score per time point is 21.

Control plasma Convalescent plasma
105 and is also made available for use under a CC0 license.
(which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC The copyright holder for this preprint this version posted September 1, 2021. ; https://doi.org/10.1101/2021.09.01.458520 doi: bioRxiv preprint