Clinical Trials and Expanded Access

This is a phase II, randomised, double-blinded and placebo-controlled clinical trial in healthy adults above 18 years of age. This clinical trial is designed to evaluate the immunogenicity and safety of Ad5-nCoV which encodes for a full-length spike (S) protein of SARS-CoV-2.

Passive immunization with immunoglobulins is occasionally used as therapy for the treatment of viral infectious diseases. Immunoglobulins are used for the treatment of CMV disease, and is effective as prophylaxis when given soon after exposure to varicella zoster virus, rabies, and hepatitis B virus. Neutralizing antibodies against MERS, SARS-CoV-1 and SARS-CoV-2 have been shown to be present in patients previously infected with MERS, SARS-CoV-1 and SARS-CoV-2 respectively. During the 2003 SARS outbreak in Hong-Kong,a non-randomized study in hospitalized SARS patients showed that treatment with convalescent plasma (convP) from SARS-recovered donors significantly increased the day 22 discharge rate and decreased mortality. A study in non-human primates showed that rhesus macaques could not be re-infected with SARS-CoV-2 after primary infection. With no proven effective therapy against COVID, this study will evaluate the safety and efficacy of convalescent plasma from COVID-recovered donors as a treatment for hospitalized patients with symptomatic COVID-19. The study will focus on patients who tested positive for SARS-CoV-2 in the last 96 hours before inclusion Primary objectives • Decrease overall mortality in patients within COVID disease Study design: This trial is a randomized comparative trial. Patients will be randomized between the infusion of 300mL of convP with standard of care. Patient population: Patients with PCR confirmed COVID disease, age >18 years Donors will be included with a known history of COVID who have been asymptomatic for at least 14 days. Intervention: 300mL of convP Duration of treatment: ConvP will be given as a one-time infusion Duration of follow up: For the primary endpoint: until discharge or death before day 60, whichever comes first. For the secondary endpoints (with separate consent) up to 1 year. Target number of patients: 426 Target number of donors: 100 Expected duration of accrural: 36 months

The purpose of this study is to assess the feasibility of delivering anti-SARS-CoV-2 convalescent plasma to hospitalized patients with severe or life-threatening COVID-19. Beyond supportive care, there are currently no proven treatment options for coronavirus disease (COVID-19), the infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Human convalescent plasma is an option for treatment of COVID-19 and could be rapidly available when there are sufficient numbers of people who have recovered and can donate high titer neutralizing immunoglobulin-containing plasma. Hypothesis: Collecting and administering convalescent plasma requires a level of logistical coordination that is not available in all centers. Objective: To establish feasibility for a hospital-based integrated system to collect and administer convalescent plasma to patients with severe or life-threatening COVID-19.

The purpose of this study is to collect blood from previously COVID-19 infected persons who have recovered and use it as a treatment for those who are currently sick with a severe or life-threatening COVID-19 infection.

The purpose of this study is to find out if transfusion of blood plasma containing antibodies against COVID-19 (anti-SARS-CoV-2), which were donated from a patient who recovered from COVID-19 infection, is safe and can treat COVID-19 in hospitalized patients. Antibodies are blood proteins produced by the body in response to a virus and can remain in the person's bloodstream (plasma) for a long time after they recover. Transferring plasma from a person who recovered from COVID-19 may help neutralize the virus in sick patients' blood, and/or reduce the chances of the infection getting worse.

Why is the research needed? The pandemic known as COVID-19 is now spreading across the world with currently (April 10, 2020) more than 1 115 530 active cases and 96 791 deaths. In most affected countries the current goal is to 'flatten the curve' of the epidemic since there is no health care system that is able to treat an extremely high volume of patients all at once. There is a need for immediately applicable treatments for the patients at highest risk, which gains time until targeted therapies become available. A key feature in the pathomechanism of the disease is that the virus elicits an immunological over-reaction in the human body termed 'cytokine storm'. In susceptible patients this hyper-inflammation itself is a significant burden and may even inhibit the body to generate antibodies against the virus in adequate quantities. Therefore, identifying the subset of patients with excess cytokine response and supplementing them with convalescent plasma from recovered donors may be a life-saving treatment option. What is our study about? In light of recent promising data on plasma therapy in the treatment of COVID-19 and other viral epidemics, there is a need for better understanding the cytokine response to the virus in order to better characterize the target population for convalescent plasma therapy. Our hypothesis is that convalescent plasma transfusion from healthy donors who recovered from SARS CoV-2 is able to reduce the cytokine storm in addition to replenish the patient's own antibodies in the acutely infected phase of the disease. A plasmapheresis donation of 400ml will be performed in subjects who recovered from COVID-19 and who are otherwise eligible for plasma donation. The sample will be tested for anti-SARS CoV-2 neutralizing antibody titers and those that reach the level of 1:320 will be processed for transfusion at the Hungarian National Transfusion Service. Recipients will be COVID-19 patients requiring hospitalization regardless of the severity of the disease or other co-morbidities. A blood-type matched transfusion of 200 ml convalescent plasma will be infused in a single sitting through an iv. infusion of 4 hours. Recipients will be followed up at days 1, 3,7,12, 17, 28 for clinical symptoms, antibody levels and cytokine response.

Immunotherapy based on Adoptive Cellular Transfer (ACT) uses several types of immune cells, including dendritic cells, cytotoxic T lymphocytes, lymphokine-activated killer cells, and NK cells. NK cell-based immunotherapies are an attractive approach for treating diseases because of their characteristic recognition and killing mechanisms; they are involved in the early defense against infectious pathogens and against MHC class-I-negative or -low-expressing targets without the requirement for prior immune sensitization of the host and are able to lyse target through the release of perforin and granzymes and using antibody-dependent cellular cytotoxicity pathways mediated by Fc receptor for IgG (CD16). The aim of this project is to evaluate the safety and immunogenicity of allogeneic NK cells from peripheral blood mononuclear cells (PBMCs) of healthy donors in patients infected with COVID-19 collected by apheresis. This allows us to collect cGMP PBMCs and immunomagnetic remove several types of undesirable cells including B, T and CD33+ cells with enrichment of NK cells that will be expanded in bioreactors with GMP culture media (AIM-V) supplemented with human AB serum and GMP grade IL-2, and IL-15. After quality control verification the final NK cell product will be resuspended in 300 mL saline solution for intravenous infusion. Initially, we will enroll in this study ten COVID-19 infected adult patients with moderate symptoms (NEWS 2 scale score>4). Consent forms will be signed by the patient before the therapy. Patients will be treated with three different infusions of NK cells 48 h apart with 1, 10, and 20 million cells/kg body weight. We will follow the patients for any adverse effect, clinical response and immune effects by flow cytometry including markers for NK cells expressing different markers (CD158b, NKG2A, and IFN-y). We anticipated that the release of IFN-y by exogenous NK cells could attract other immune cell populations to boost the immune response against COVID-19.

Coronavirus Disease 2019 (COVID-19) is spreading worldwide and has become a public health emergency of major international concern. Currently, no specific drugs or vaccines are available. For severe cases, it was found that aberrant pathogenic T cells and inflammatory monocytes are rapidly activated and then producing a large number of cytokines and inducing an inflammatory storm.Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate the safety and efficacy of intravenous infusion of mesenchymal stem cells in severe patients with COVID-19.

Phase III Placebo-controlled adaptive multi-centre randomized controlled trial Interventional (Clinical Trial). The study will include nine hundred healthcare workers in the isolation hospitals for COVID-19 cases; they will be randomly assigned to receive either BCG vaccine or normal saline.

This is a Phase II study. This research study is being conducted to use convalescent donor plasma in seriously ill patients who have COVID-19.