Investigating the Role of 13cis Retinoic Acid in the Treatment of COVID-19 and Enhancement of Its Spike Protein Based Vaccine Efficacy and Safety.

The study is an urgent randomized interventional comparative Phase II trial for investigating the expected long term side effects of spike protein based vaccine which may vary from thrombosis, platelet aggregation, autoantibodies against ACE2, to lung damage and other ACE2 expressing cell damage. This clinical study is conducted on 360 adult male and female participants, Here, we submitted this clinical trial depending on studies with up to date literature guidance to indicate that 13 cis Retinoic Acid will provide complete protection against COVID-19 and will be better option for effective and safe COVID-19 vaccine owing to its ability to induce mucosal IgA antibodies that are less prone to ADE phenomenon and responsible for passive mucosal immunity in the respiratory tract. Retinoic acid strengthens mucosal immunity via inducing IgA antibodies and considered potent IgA isotype Furthermore, its impact on ACE2 receptors, Memory T cells, CD4+/CD8+ ratio, Neutrophil Chetnotaxis, Interferon Type1, Thrombin, Transmembrane serine protease 2 (TMPRSS2), toll-like receptor 3 (TLR3), mitochondrial antiviral-signaling protein (MAVS), papain-like protease (PLpro), and Interleukin 6 ( Il-6).

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The SARS-CoV-2 spike protein directly binds with the host cell surface Angiotensin-converting enzyme 2 (ACE2) facilitating virus entry, invading and replication.[1][5][6][7][8][9][10].Further analysis even suggested that COVID-19 recognizes human ACE2 more efficiently than SARS-CoV increasing the ability of COVID-19 to transmit from human to human [11][12] Upregulation of human ACE2 enhanced and induced disease severity in a mouse model of SARS-CoV infection, demonstrating that viral entry into cells is a critical step[13][14] Receiving Vaccine based on COVID-19 spike protein may increase the risk of Cellular ACE2 autoimmunity via production of autoantibodies . Many studies demonstrated that autoimmune response to Angiotensin-converting enzyme 2 ( ACE2) induced by forced presentation of the ACE2 protein in a complex with CoV Spike protein in Fc Receptor positive Antigen Presenting Cells in the lung [3][4] According to this we hypothesis that spike proteins produced by Vaccine based on the spike protein which would potentially bind to the elevated levels of soluble ACE2 enzyme. This complex of spike protein with multiple soluble ACE2 enzymes which is similar to COVID-19 binding with cellular and soluble ACE2 will be presented to macrophages to highlight antigens for antibody production. It is very possible that Abs will be produced that target the Angiotensin Converting Enzyme 2 of host cells enzyme. The combination of the virus spike protein or vaccine spike protein with the soluble ACE2 receptor becomes antigenic, which may cause the formation of antibodies against not only the virus spike protein or vaccine spike protein , but also parts of the ACE and ACE2 receptor. Therefore we hypothesize that Vaccines based on the spike protein might initiate Autoantibodies and T cells to ACE2 via binding of spike protein particles produced by vaccine with its receptors ACE2 and The development of autoantibodies to ACE2 might make damage to the host epithelial cell in lungs and the other different organs which express ACE2 in lung, heart and kidney would lead to inflammation at those sites. This pattern of lung injury also occurs in Pulmonary Hypertension secondary to Scleroderma with elevated levels of anti ACE2 antibodies.[73][78].In addition, we expect that any drug upregulation of ACE2 as in diabetic and hypertensive patients will increase the risk of autoantibodies in case of immunization by Vaccine based on the COVID-19 spike protein. As a result we think that covid-19 vaccine developer should use a suitable ACE2 modulator to decrease this possible risk via helping in formation of antibodies targeting spike protein not antibodies targeting ACE2 and spike protein complex which may increase the risk of cellular ACE2 auto antibodies , The COVID-19 vaccine may be altered each year to counter changes to circulating strains therefore, the possible risk of cellular ACE2 damage by autoantibodies produced by vaccine based on COVID-19 vaccine may increase with vaccination .After searching, we found a study analyzed a broad set of 672 clinically approved drugs for treatment in cell lines demonstrated that isotretinoin was the potent and strongest downregulator of Angiotensin-converting enzyme 2 (ACE2) receptors [15] and further, studies reported that it may prevent the cellular entry of SARS-CoV-2 and can be a taken as a targeted therapy in COVID-19 [16][17][18]. The primary isomers of RA formed in vivo are 9-cis-retinoic acid (9cRA) and All-trans-Retinoic Acid (atRA) and; each binds separate RA receptor types, thus acting upon a select subset of genes [76]. 13cRA is a synthetic form that may function similar to the other produced isoforms, or by isomerization to atRA and 9c RA. Although the exact mechanism of action is unclear; in other words, therefore we hypothesis that isotretinoin binds directly to ACE2 receptors and leads to its downregulation via blocking ACE2 binding capacity and this mechanism may lead to block of COVID-19 binding to cellular and soluble ace2 receptors