Insights into standards of care: dexamethasone and antibodies against COVID-19 in hamster models

Wyler, E.; Adler, J. M.; Eschke, K.; Teixeira Alves, G.; Peidli, S.; Pott, F.; Kazmierski, J.; Michalik, L.; Kershaw, O.; Bushe, J.; Andreotti, S.; Pennitz, P.; Abdelgawad, A.; Postmus, D.; Goffinet, C.; Kreye, J.; Reincke, S. M.; Prüss, H.; Blüthgen, N.; Gruber, A. D.; Kuebler, W. M.; Witzenrath, M.; Landthaler, M.; Nouailles, G.; Trimpert, J.

doi:10.1101/2021.12.17.473180

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bioRxiv · 10.1101/2021.12.17.473180

Insights into standards of care: dexamethasone and antibodies against COVID-19 in hamster models

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Abstract

RationaleIn face of the ongoing SARS-CoV-2 pandemic, effective and well-understood treatment options are still scarce. While vaccines have proven instrumental in fighting SARS-CoV-2, their efficacy is challenged by vaccine hesitancy, novel variants and short-lasting immunity. Therefore, understanding and optimization of therapeutic options remains essential. ObjectivesWe aimed at generating a deeper understanding on how currently used drugs, specifically dexamethasone and anti-SARS-CoV-2 antibodies, affect SARS-CoV-2 infection and host responses. Possible synergistic effects of both substances are investigated to evaluate combinatorial treatments. MethodsBy using two COVID-19 hamster models, pulmonary immune responses were analyzed to characterize effects of treatment with either dexamethasone, anti-SARS-CoV-2 spike monoclonal antibody or a combination of both. scRNA sequencing was employed to reveal transcriptional response to treatment on a single cell level. Measurements and main resultsDexamethasone treatment resulted in similar or increased viral loads compared to controls. Anti-SARS-CoV-2 antibody treatment alone or combined with dexamethasone successfully reduced pulmonary viral burden. Dexamethasone exhibited strong anti-inflammatory effects and prevented fulminant disease in a severe COVID-19-like disease model. Combination therapy showed additive benefits with both anti-viral and anti-inflammatory potency. Bulk and single-cell transcriptomic analyses confirmed dampened inflammatory cell recruitment into lungs upon dexamethasone treatment and identified a candidate subpopulation of neutrophils specifically responsive to dexamethasone. ConclusionsOur analyses i) confirm the anti-inflammatory properties and indicate possible modes of action for dexamethasone, ii) validate anti-viral effects of anti-SARS-CoV-2 antibody treatment, and iii) reveal synergistic effects of a combination therapy and can thus inform more effective COVID-19 therapies.

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Wyler, E., Adler, J. M., Eschke, K., Teixeira Alves, G., Peidli, S., Pott, F., Kazmierski, J., Michalik, L., Kershaw, O., Bushe, J., Andreotti, S., Pennitz, P., Abdelgawad, A., Postmus, D., Goffinet, C., Kreye, J., Reincke, S. M., Prüss, H., Blüthgen, N., Gruber, A. D., Kuebler, W. M., Witzenrath, M., Landthaler, M., Nouailles, G., Trimpert, J.. 2021-12-20. Insights into standards of care: dexamethasone and antibodies against COVID-19 in hamster models. https://doi.org/10.1101/2021.12.17.473180

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