Prevent COVID-19 Severity by Repurposing mTOR Inhibitors

COVID-19 has become a severe global public health concern. The critical illness has a mortality rate of 61.5%, and thus, reducing the severity and mortality is top priority. Currently, inflammatory storms are considered as the cause of critical illness and death due to COVID-19. However, After systematical review of the literature, we proposed that cross-reactive antibodies-associated antibody-dependent enhancement (ADE) may actually be the cause of cytokine storms. If the activation of memory B cells can be selectively inhibited in high-risk patients at an early stage of COVID-19 to reduce the production of cross-reactive antibodies of the virus, we speculate that the ADE can be avoided and severe symptoms can be prevented. The mammalian target of rapamycin (mTOR) inhibitors satisfy such conditions. We recommend that pharmaceutical companies conduct clinical trials urgently.


Introduction
COVID-19 has become a severe global public health concern. It has infected more than one million individuals as of April 3, 2020. About 20% of the patients with COVID-19 have developed severe illness, and 5% have further developed critical illness. The mortality rate of critical case illness is 61.5% 1 . Thus, reducing the severity and mortality of the disease is a top priority.
According to the general understanding of diseases, high antibody levels indicate that pathogens are easily controlled and infections can be alleviated. Conversely, Zhang and colleagues found that COVID-19 severity is associated with increased IgG response 2 .
What does this phenomenon suggest?
COVID-19 has many striking similarities to severe acute respiratory ryndrome (SARS) which outbroke 17 years ago. A previous study demonstrated that the peripheral blood CD4+ and CD8+ T cells in SARS-infected survivors showed a reversible decline. The decline and duration of T-cells and the severity of the disease are closely related, while the irreversible decline leads to mortality. T cell decline coexists with the increase in IL-6, TNFα, and other proinflammatory cytokines 3 . The recent data collected from COVID-19 patients also confirmed that T cell counts were negatively correlated with the changes in IL-6, TNFα, and other proinflammatory cytokines 4 .
Currently, the inflammatory storms are considered as the cause of critical illness and death. After systematical review of the literature, we proposed that cross-reactive antibodies-associated antibody-dependent enhancement (ADE) may actually be the cause of cytokine storms in highly pathogenic human coronavirus infection, including SARS and COVID-19. ADE is also the underlying pathology in elderly people, and those with comorbidity would be into a more severe situation.

Antibody-dependent enhancement characteristics of SARS and COVID-19
Patients with SARS who have developed antibodies earlier in the serum and have high antibody levels experienced severe infection 5 . The median time that SARS-CoV antibodies were detected in the serum was 16 days. It is remarkable that IgG antibodies were first detected in some patients as early as day 4 of the disease. The early occurrence of serum IgG antibodies is associated with a high incidence of entering the intensive care unit (ICU) 6 . This phenomenon has also been reported in patients with COVID-19 2 . Among the 80 patients who received convalescent plasma therapy, 33 showed good and 47 showed poor results. Among the 33 patients with good results, the majority (n=28, 58.3% of 48) received plasma therapy within 14 days of disease onset 7 . We speculate in here that patient's early high-level antibodies are not the same as those in the convalescent plasma. These premature antibodies may be cross-reactive antibodies related to memory immunity.
Therefore, we hypothesize that SARS and COVID-19 have the characteristic of

ADE. Briefly, when virus A enters the body, it activates memory B cells and inhibits
the activation of naive B cells. The memory B cells produce antibodies capable of binding to virus A. However, these are cross-reactive antibodies, based on the immune memory of the previous infection by virus A1 which has one or more similar epitopes to that virus A. These cross-reactive antibodies are capable of delivering the virus to monocytes-macrophages via the Fc receptor, following which, a large number of viruses are replicated and released outside the cells after the immune escape. This is the process of ADE.

ADE can explain numerous laboratory and clinical characteristics of COVID-19
Pathological observations revealed that the exuding cells in the alveolar cavity of the patients died due to COVID-19 were mainly monocytes-macrophages. Virus

mTOR inhibitor would be the solution for ADE
If the activation of memory B cells can be selectively inhibited in these high-risk patients at an early stage to reduce the production of cross-reactive antibodies of the virus, we speculate that the ADE process can be avoided and severe symptoms can be prevented. mTOR inhibitors can suppress early B-cell production in germinal centers 17 . Therefore, we are expected to reduce early cross-reactive antibody production and further prevent ADE. There is a variety of mTOR inhibitor on the market used for immunosuppressants during organ transplantation, which is clinically safe. Therefore, The primary endpoint should be the incidence of severe and critical symptoms.
The secondary endpoints should include 28-day recovery and mortality, changes in lymphocyte subpopulation count, viral load, cytokine levels, and incidence of lung injury and respiratory distress.

Significance
It would be more difficult to develop vaccines for highly pathogenic human coronavirus if we consider their ADE characteristics. Therefore, it is emergency to find an effective way to prevent the occurrence of severe illness before the development of SARS-CoV-2 specific drugs or vaccines is completed. It will greatly ease the tension of medical resources and save countless lives worldwide.

Contribution
YZ proposed the concept, searched the literature, and wrote the first draft.