Preprint Hypothesis Version 1 Preserved in Portico This version is not peer-reviewed

Medical Countermeasures Analysis of 2019-nCoV and Vaccine Risks for Antibody-Dependent Enhancement (ADE)

Version 1 : Received: 6 March 2020 / Approved: 8 March 2020 / Online: 8 March 2020 (15:35:27 CET)

How to cite: Ricke, D.O.; Malone, R.W. Medical Countermeasures Analysis of 2019-nCoV and Vaccine Risks for Antibody-Dependent Enhancement (ADE). Preprints 2020, 2020030138 (doi: 10.20944/preprints202003.0138.v1). Ricke, D.O.; Malone, R.W. Medical Countermeasures Analysis of 2019-nCoV and Vaccine Risks for Antibody-Dependent Enhancement (ADE). Preprints 2020, 2020030138 (doi: 10.20944/preprints202003.0138.v1).

Abstract

Background: In 80% of patients, COVID-19 presents as mild disease1,2. 20% of cases develop severe (13%) or critical (6%) illness. More severe forms of COVID-19 present as clinical severe acute respiratory syndrome, but include a T-predominant lymphopenia3, high circulating levels of proinflammatory cytokines and chemokines, accumulation of neutrophils and macrophages in lungs, and immune dysregulation including immunosuppression4. Methods: All major SARS-CoV-2 proteins were characterized using an amino acid residue variation analysis method. Results predict that most SARS-CoV-2 proteins are evolutionary constrained, with the exception of the spike (S) protein extended outer surface. Results were interpreted based on known SARS-like coronavirus virology and pathophysiology, with a focus on medical countermeasure development implications. Findings: Non-neutralizing antibodies to variable S domains may enable an alternative infection pathway via Fc receptor-mediated uptake. This may be a gating event for the immune response dysregulation observed in more severe COVID-19 disease. Prior studies involving vaccine candidates for FCoV5,6 SARS-CoV-17-10 and Middle East Respiratory Syndrome coronavirus (MERS-CoV) 11 demonstrate vaccination-induced antibody-dependent enhancement of disease (ADE), including infection of phagocytic antigen presenting cells (APC). T effector cells are believed to play an important role in controlling coronavirus infection; pan-T depletion is present in severe COVID-19 disease3 and may be accelerated by APC infection. Sequence and structural conservation of S motifs suggests that SARS and MERS vaccine ADE risks may foreshadow SARS-CoV-2 S-based vaccine risks. Autophagy inhibitors may reduce APC infection and T-cell depletion12 13. Amino acid residue variation analysis identifies multiple constrained domains suitable as T cell vaccine targets. Evolutionary constraints on proven antiviral drug targets present in SARS-CoV-1 and SARS-CoV-2 may reduce risk of developing antiviral drug escape mutants. Interpretation: Safety testing of COVID-19 S protein-based B cell vaccines in animal models is strongly encouraged prior to clinical trials to reduce risk of ADE upon virus exposure.

Supplementary and Associated Material

https://doi.org/10.7910/DVN/XWVOA8: Medical Countermeasures Analysis of 2019-nCoV / SARS-CoV-2 for COVID-19 data files

Subject Areas

2019-nCoV; SARS-CoV-2; COVID-19; ADE; antibody depedendent enhancement

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