Dornase alfa, the recombinant form of the human DNase I enzyme, breaks down neutrophil extracellular traps (NET) that include a vast amount of DNA fragments, histones, microbicidal proteins and oxidant enzymes released from necrotic neutrophils in the highly viscous mucus of cystic fibrosis patients. Dornase alfa has been used for decades in patients with cystic fibrosis to reduce the viscoelasticity of respiratory tract secretions, to decrease the severity of respiratory tract infections, and to improve lung function. Previous studies have linked abnormal NET formations to lung diseases, especially to acute respiratory distress syndrome (ARDS). It is well known that novel Coronavirus disease 2019 (COVID-19) pneumonia progresses to ARDS and even multiple organ failure. High blood neutrophil levels are an early indicator of COVID-19 and predict severe respiratory diseases. Also it is reported that mucus structure of COVID-19 is very similar to cystic fibrosis due to the accumulation of excessive NET in the lungs. In this study, we showed the recovery of three COVID-19 patients after including Dornase alfa in their treatment. We followed clinical improvement in the radiological analysis (2-of-3 cases), oxygen saturation (SpO 2 ), respiratory rate, disappearing of dyspnea, coughing and a decrease in NET formation and SARS-CoV-2 viral load after the treatment. Also here, we share our preliminary results suggesting that Dornase alfa has an anti-viral effect against SARS-CoV-2 infection in a green monkey kidney cell line, Vero, and a bovine kidney cell line, MDBK without determined cytotoxicity on healthy peripheral blood mononuclear cells.
The novel coronavirus pneumonia, which was named later as coronavirus disease 2019 , is caused by the severe acute respiratory syndrome coronavirus 2, namely SARS-CoV-2. It is a positive-strand RNA virus that is the seventh coronavirus known to infect humans. The COVID-19 outbreak presents enormous challenges for global health behind the pandemic outbreak. The first diagnosed patient in Turkey has been reported by the Republic of Turkey Ministry of Health on March 11, 2020. In May, over 150,000 cases in Turkey, and 5.5 million cases around the world have been declared. Due to the urgent need for a vaccine and antiviral drug, isolation of the virus is crucial. Here, we report 1 of the first isolation and characterization studies of SARS-CoV-2 from nasopharyngeal and oropharyngeal specimens of diagnosed patients in Turkey. This study provides an isolation and replication methodology,and cell culture tropism of the virus that will be available to the research communities.
The SARS-CoV-2 virus caused one of the severest pandemic around the world. The vaccine development for urgent use became more of an issue during the pandemic. An inactivated virus formulated vaccines such as Hepatitis A, inactivated polio, and influenza has been proven to be a reliable approach for immunization for long years. In this pandemic, we produced an inactivated SARS-CoV-2 vaccine candidate by modification of the oldest but the most experienced method that can be produced quickly and tested easily rather than the recombinant vaccines. Here, we optimized an inactivated virus vaccine which includes the gamma irradiation process for the inactivation as an alternative to classical chemical inactivation methods so that there is no extra purification required. Also, we applied the vaccine candidate (OZG-38.61.3) using the intradermal route in mice which decreased the requirement of a higher concentration of inactivated virus for proper immunization unlike most of the classical inactivated vaccine treatments. Thus, the novelty of our vaccine candidate (OZG-38.61.3) is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. We first determined the efficiency and safety dose (either 1013 or 1014 viral copy per dose) of the OZG-38.61.3 in Balb/c mice. Next, to test the immunogenicity and protective efficacy of the OZG-38.61.3, we immunized human ACE2-encoding transgenic mice and infected them with a dose of infective SARS-CoV-2 virus for the challenge test. We showed that the vaccinated mice showed lowered SARS-CoV-2 viral copy number in oropharyngeal specimens along with humoral and cellular immune responses against the SARS-CoV-2, including the neutralizing antibodies similar to those shown in Balb/c mice without substantial toxicity. This study encouraged us towards a new promising strategy for inactivated vaccine development (OZG-38.61.3) and the Phase 1 clinical trial for the COVID-19 pandemic.
The COVID-19 outbreak caused by SARS-CoV-2 has created an unprecedented health crisis since there is no coronavirus vaccine in the market due to the novelty of this virus. Therefore, SARS-CoV-2 vaccines have become very important to reduce morbidity and mortality. At this point, inactivated vaccines are important because the straightforward process of existing infrastructure used for several licensed human vaccines can be used for SARS-CoV-2. Inactive vaccines provide an antigenic presentation similar to that when they encounter invasive virus particles of the immune system. In this study, in vitro and in vivo safety and efficacy analyzes of lyophilized vaccine candidates inactivated by gamma-irradiation were performed. Our candidate OZG-3861 version 1 (V1) is an inactivated SARS-CoV-2 virus vaccine, and SK-01 version 1 (V1) is the GM-CSF adjuvant added vaccine candidate. We applied the candidates intradermal to BALB/c mice to assess the toxicity and immunogenicity of the OZG-3861 V1 and SK-01 V1. Here, we report our preliminary results in vaccinated mice. When considered in terms of T and B cell responses, it was observed that especially the vaccine models containing GM-CSF as an adjuvant caused significant antibody production with neutralization capacity in absence of the antibody-dependent enhancement feature. Another finding showed that the presence of adjuvant is more important in T cell response rather than B cell. The vaccinated mice showed T cell response upon restimulation with whole inactivated SARS-CoV-2 or peptide pool. This study encouraged us to start the challenge test using infective SARS-CoV-2 viruses and our second version of gamma-irradiated inactivated vaccine candidates in humanized ACE2+ mice.
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