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

26 Pages Posted: 3 Mar 2020

See all articles by Darrell Ricke

Darrell Ricke

Massachusetts Institute of Technology (MIT) - Lincoln Laboratory

Robert W. Malone

Alchem Laboratories



Background: In 80% of patients, COVID-19 presents as mild disease. 20% of cases develop severe (13%) or critical (6%) illness. More severe forms of COVID-19 present as clinical severe acute respiratory syndrome, T-predominant lymphopenia, high circulating levels of proinflammatory cytokines and chemokines, accumulation of macrophages and neutrophils in lungs, and immune dysregulation including immunosuppression.

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: 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 FCoV SARS-CoV-1 and Middle East Respiratory Syndrome coronavirus (MERS-CoV) 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 disease and may be accelerated by APC infection. Sequence and structural conservation of S suggests that SARS and MERS vaccine ADE risks may foreshadow SARS-CoV-2 vaccine risks. Autophagy inhibitors may reduce APC infection and T-cell depletion. Amino acid residue variation analysis identifies multiple constrained domains suitable as T cell vaccine targets. Evolutionary constraints on 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.

Funding Statement: U.S. Air Force Contract No. FA8702-15-D-0001.

Declaration of Interests: Dr. Ricke and Dr. Malone have nothing to disclose.

Ethics Approval Statement: Missing.

Keywords: COVID-19, 2019-nCoV, SARS, SARS-CoV, ADE, antibody-dependent enhancement

Suggested Citation

Ricke, Darrell and Malone, Robert W., Medical Countermeasures Analysis of 2019-nCoV and Vaccine Risks for Antibody-Dependent Enhancement (ADE) (2/27/2020). Available at SSRN: or

Darrell Ricke (Contact Author)

Massachusetts Institute of Technology (MIT) - Lincoln Laboratory ( email )

244 Wood Street
Lexington, MA 02420-9108
United States

Robert W. Malone

Alchem Laboratories ( email )

13305 Rachel Blvd
Alachua, FL 32615
United States