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Clinical Trials

1 Combination With Inhibitor of Neutrophil Elastase (All-trans Retinoic Acid ) and Isotretinoin May Enhances Neutralizing Antibodies in COVID -19 Infected Patients Better Than COVID-19 Inactivated Vaccines

Unfortunately, All of the vaccinated monkeys treated with the Oxford vaccine known as ChAdOx1 nCoV-19, is undergoing trials in Britain.became infected when challenged as judged by recovery of virus RNA from nasal secretions," said Dr William Haseltine, a former Harvard Medical School professor who had a role in the development of early Aids treatments. and in general future COVID-19 vaccination which depends on inactivated viral vaccine will be restricted to healthy people with strong immunity and It will not be given to patients with History of contact with COVID-19 infection. In addition to the COVID-19 antigens with hyper mutation lead to (ADE) phenomenon in which IgG antibodies facilitate viral entry and fusion with infected cell through uptake of the virus-IgG complex via the Fc receptors and later viral fusion with antigen presenting cells like macrophages and B cells via FcR , through the neonatal FcR instead of antibodies induced viral agglutination and this is known as antibody dependent enhancement (ADE)(2) There are various hypotheses on how ADE happens and there is a likelihood that more than one mechanism exists. In one such pathway, some cells of the immune system lack the usual receptors on their surfaces that the virus uses to gain entry, but they have Fc R that bind to one end of antibodies. The virus binds to the antigen-binding site at the other end, and in this way gains entry to and infects the immune cell. Dengue virus can use this mechanism to infect human macrophages.(3) An ongoing question in the COVID-19 pandemic is whether—and if so, to what extent—COVID-19 receives ADE from prior infection with other COVID-19. ADE can hamper vaccine development, as a vaccine may cause the production of antibodies which, via ADE, worsen the disease the vaccine is designed to protect against. Vaccine candidates for Dengue virus and feline infectious peritonitis virus had to be stopped because they elicited ADE.(4) ADE in COVID-19 infection can be caused by high mutation rate of the gene that encodes spike (S) protein. A thorough analysis of amino acid variability in COVID-19 virus proteins, that included the S-protein, revealed that least conservative amino acids are in most exposed fragments of S-protein including receptor binding domain (RBD).(5) A study reported that Inhibitors of NET stimulate murine B lymphocyte differentiation into IgG- and IgA-producing cells via immunoglobulin class switching . A study demonstrated that depletion of NET improves the production of mucosal IgA and IgG after sublingual immunization with Bacillus anthracis edema toxin as adjuvant and also, another study demonstrated that extracellular traps (NETs)—may contribute to organ damage and mortality in COVID-19 and also reported that there is aberrant linking between NET formation and pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19. So,the principal investigator expects that High NETs in covid-19 infection may be the reason of delayed antibody response and severe complications.Currently, only limited information is available on the host innate immune status of COVID-19 infected patients. In one report where 99 cases in Wuhan were investigated, increased total NETs (38%), reduced total lymphocytes (35%) and increased serum IL-6 (52%) .25 In a separate report also from Wuhan, it revealed that in 41 patients, increased total NETs, decreased total lymphocytes in patients of ICU vs. non-ICU care were found to be statistically different. Increased NETs and decreased lymphocytes also correlate with disease severity .(10) B cells/plasma cells produce COVID-19 specific Abs that may help neutralize viruses.(11) Humoral immune response, especially production of neutralizing antibody, plays a protective role by limiting infection at later phase and prevents reinfection in the future. In Covid-19, both T and B cell epitopes were extensively mapped for the structural proteins, S, N, M and E protein.(12) ,(14) Delayed antibodies response and secretion after covid -19 symptoms onset may be responsible for antibody dependent enhancement (ADE) Because this immune response takes a while to show up, antibody tests will be negative for those newly infected with COVID-19, which is why they're not used for diagnosis. "If it's the beginning of the infection, you don't pick it up, it's something that only develops later," Dr. Melanie Ott, a virologist at the Gladstone Institutes Finally, according to this protocol the investigator will treat with potent inhibitor of NET elastase plus Isotretinoin and the mechanism of action will be discussed in Detailed Description

NCT04396067 COVID -19 Drug: Aerosolized 13 cis retinoic acid Drug: Aerosolized All trans retinoic acid Other: Placebo

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