Convalescent Plasma for Treating COVID-19

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On August 23, 2020, the US-FDA issued an Emergency Use Authorization (“EUA”) allowing the off-label use of convalescent plasma to treat COVID-19, having concluded that the totality of evidence supported this use. An EUA allows for use of an unapproved therapeutic product by clinicians when needed during public health emergencies. The FDA granted the EUA based on convalescent plasma safety and effectiveness data submitted by the Mayo Clinic under an Expanded Access Program (“EAP”). The EAP, also known as “compassionate use”, allows for treatment outside of clinical trials for patients with serious or life-threatening disease, when there is no comparable or satisfactory alternative treatment. Under an EAP, the Mayo Clinic enrolled about 90,000 COVID-19 patients (as of August 13) and provided safety data for 20,000 patients to the FDA. In deciding to grant the EUA, the FDA reviewed the following information about treating COVID-19 patients with convalescent plasma: (1) patient data supplied by the Mayo Clinic; (2) unpublished clinical trial data; and (3) reports of trials published in peer-reviewed clinical journals during the first 8 months of 2019.

 

The first published reports of use of convalescent plasma for treating COVID-19 describe many small clinical trials, both controlled and uncontrolled, and one randomized, placebo-controlled trial. Theoretically, convalescent plasma should be effective for treating COVID-19 because the plasma contains antibodies to the SARS-CoV-2 virus. As convalescent plasma transfusion was successfully used in China to treat SARS, clinicians began using this therapy for treating COVID-19 infections. Prior to the initiation of FDA’s EAP for convalescent plasma, most information available about its safety and effectiveness was from small case study trials and observational trials of COVID-19 patients, all of which are published in peer-reviewed clinical journals. Results from one large, randomized, placebo-controlled trial of convalescent plasma-treated patients in China are also published. Findings from all trials published to date suggest that convalescent plasma is effective for treating severe COVID-19 infections.

 

The small trials of convalescent plasma safety and effectiveness used a variety of study designs and conditions. Trials were conducted in China, Korea, and the US from Jan. – Apr. 2020 and used from 2 to 25 patients. Two matched control trials compared effects in convalescent plasma-treated patients with effects in control patients matched for demographics, co-morbidities, and disease severity. Patients were hospitalized males and females, ranging in age from 28 to 75 years. The most frequent co-morbidities were cardiovascular disease, high blood pressure, and diabetes. Patients were diagnosed with severe infections if they had pneumonia and signs of respiratory failure. Patients were diagnosed with critical infections if they required invasive mechanical ventilation, and experienced either shock or multiple organ failure requiring treatment in an ICU.  Convalescent plasma was obtained from recovered patients who had been infected with COVID-19 and were 7-21 days from recovery. The volumes of plasma transfused to the hospitalized patients ranged from 200 to 300 mL per treatment. Some transfused patients in these trials received several transfusions given at least 2 days apart. Viral loads before and after transfusions were tested in swabs from patients’ throats, nasopharyngeal areas, sputum, or serum. Patients were receiving many different therapies, including hydroxychloroquine; antiviral drugs; antibiotic drugs; steroids; gamma globulin, and/or the immunomodulator interferon α-2b. In several Chinese trials, patients also received Chinese traditional medicines. Most of the hospitalized patients received either supplemental oxygen or ventilator treatment, either non-invasive or invasive, depending on disease severity.

 

In small, observational trials, many of the COVID-19 patients who received convalescent plasma had dramatic reductions in SARS-CoV-2 viral loads. Rapid and dramatic reductions in SARS-CoV-2 viral loads occurred in the patients who received convalescent plasma. The SARS-CoV-2 viral loads were negative in 100% of the patients who received convalescent plasma by several days after transfusion. By comparison, only 30-40% of control patients in the matched control trials had negative SARS-CoV-2 test results, often not until the end of the study observation period.

 

In the observational trials, clinical improvement occurred in patients receiving convalescent plasma, with improvement more pronounced in severe disease than in critical disease. In severely-infected hospitalized patients, clinical improvement rates and study discharge rates were relatively high during the study observation periods, which ranged from 14 to 28 days. In patients with severe infections treated with convalescent plasma, 70% to 100% of patients showed clinical improvement and 30 to 100% were discharged from the hospital. Mortality was 0% in patients with severe COVID-19 in all trials, but 30% in controls in the matched control trial. Clinical improvement was generally not as pronounced in patients with critical COVID-19 infections who received convalescent plasma. Among convalescent plasma-treated critically ill patients, 75% to 100% showed clinical improvement and 60 to 75% were discharged from the hospital. In the one matched control trial of patients with critical infections, clinical improvement occurred in 16% of the patients who received convalescent plasma and in 7% of the matched controls. All other patients in both the convalescent plasma-treated and control groups died. This was despite the fact that 100% of patients who received convalescent plasma had negative viral loads within days after the transfusions. The investigators observed that all patients in the convalescent plasma-treated group who died did not receive their transfusions until more than 20 days after hospital admission; thus the late initiation of treatment may have contributed to the high mortality rate.

 

In a randomized placebo-controlled trial conducted in China, treatment with convalescent plasma produced clinical improvement in patients with severe COVID-19 disease but not with critical COVID-19 disease; however, the trial was halted early due to lack of availability of patients. This trial investigated 103 patients, of whom 43 were diagnosed with severe COVID-19 disease and 50 with critical COVID-19 disease. Patients were males and females, with an average age of 50 years. All patients were receiving supportive therapies in addition to convalescent plasma. Outcomes were good in the patients with severe disease who received convalescent plasma. Within the 28-day observation period, clinical improvement occurred in 91% of severely-infected patients who received convalescent plasma treatment, compared to 68% of severely-infected control patients. In addition, no convalescent plasma-treated patients with severe infections died, compared to 9% of control patients. Finally, severely-infected patients receiving convalescent plasma were discharged from the hospital sooner than severely-infected control patients – at a median of 13 days versus 19 days. By contrast, in the patients with critical disease, there was no difference between the convalescent plasma-treated group and the control group with respect to clinical improvement or mortality – 29% of the treated group patients died compared to 36% of the control group patients. Viral loads were negative in most trial patients, regardless of infection severity, by 72 hours after convalescent plasma transfusions. Two patients in this trial – one with severe infection and one with critical infection – suffered mild allergic-type reactions following convalescent plasma transfusions and these adverse reactions were quickly resolved following corticosteroid therapy.

 

Data supplied by the Mayo clinic to the FDA provided strong evidence of convalescent plasma effectiveness for treating patients with severe COVID-19 infections. In addition, the Mayo clinic studies compared effects of convalescent plasma with high antibody titers to effects of convalescent plasma with low antibody titers. Antibody titers were assayed in convalescent plasma by determining ability to neutralize native SARS-CoV-2 virus and ability to neutralize the SARS-CoV-2 virus spike protein. FDA scientists performed the data analyses. FDA scientists found that there was a 21% reduction in 7-day mortality (from 14% to 11%) in patients transfused with high versus low titer convalescent plasma. FDA concluded that the dose-response between antibody level and reduction of mortality provided evidence that anti-SARS-CoV-2 antibody is the active agent in convalescent plasma for treating COVID-19.

 

Convalescent plasma treatment showed a good safety profile in clinical trials and in the Mayo clinic data. In only one of the published trials, did two transfused patients show a possible allergic response, which resolved in a few days with corticosteroid treatment. No safety signals attributable to the transfusions were observed in any of the other published trials. In the Mayo clinic safety data from 20,000 patients, the incidence of allergic transfusion reactions was < 1%, the incidence of blood clotting reactions was < 1%, and the incidence of cardiac events was 3%. The FDA and Mayo clinic both concluded that the majority of blood clotting and cardiac adverse events seen in the 20,000 patients were not related to the convalescent plasma treatment.

 

The FDA concluded that the benefits of treating COVID-19 patients with convalescent plasma outweigh the risks. In addition, although most studies show greater effectiveness in patients with severe disease, the FDA concluded that convalescent plasma treatment can potentially provide benefit to COVID-19 patients with either severe or critical disease. On its website, the FDA asks recovered COVID-19 patients to consider donating plasma to help treat others with COVID-19 disease. The FDA also issued a Guidance for Industry on administration, study, and quality control of convalescent plasma for treating COVID-19.

 

In conclusion, results of the clinical trials published to date and FDA’s benefit-risk analysis suggest that convalescent plasma treatment is safe and effective for treating COVID-19. Convalescent plasma transfusion appears to be most effective for treating patients with severe COVID-19 infections. Notably, in most trials, 100% of the transfused patients had negative SARS-CoV-2 viral loads within days following the transfusions. Available evidence to date suggests that it is reasonable to consider including convalescent plasma as a component of COVID-19 treatment regimens. The FDA also came to this conclusion in granting an EUA for use of convalescent plasma in treating COVID-19. In its EUA documentation, the FDA recommends starting such convalescent plasma treatment as early as possible during the course of COVID-19 disease. Finally, the FDA stresses that randomized controlled clinical trials are needed to provide definitive safety/effectiveness evidence.

 

Tocilizumab And COVID-19

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Scientists began to investigate Tocilizumab in clinical trials as a possible therapy for COVID-19 because of the drug’s potent anti-inflammatory properties. Tocilizumab, a monoclonal antibody drug manufactured by Hoffman-La Roche, is marketed in the US as Actrema® and is approved for treating arthritis. Tocilizumab effectively treats arthritis by reducing the progression of inflammation in the body. Specifically, Tocilizumab reduces inflammation by blocking the effects of the cytokine interleukin-6 (“IL-6”). Cytokines such as IL-6 are substances produced by the body to regulate normal immune response. In COVID-19, levels of IL-6 and other cytokines increase to much higher than normal levels in attempting to rid the body of the SARS-CoV-2 virus. Clinicians and immunologists refer to this phenomenon as a “cytokine storm.” Exposure of the body’s tissues to sustained high cytokine levels produces sustained tissue inflammation, particularly in the lungs. Sustained inflammation is not a normal response and can severely damage the lungs. Damaged lungs of COVID-19 patients viewed by CT scan are often infiltrated by opaque areas that resemble ground glass, and thus are called “ground glass” opacities. The damaged lungs can no longer expand properly upon inhalation and exhalation. Patients can develop pneumonia, and; in severe cases, respiratory failure leading to death. As the progression of severe inflammation leading to COVID-19 pneumonia may be triggered by a cytokine storm, it seems reasonable to consider that a drug that selectively blocks cytokine activity could effectively treat the disease. Thus, it was hypothesized that Tocilizumab’s ability to block IL-6 activity could help alleviate the cytokine storm of COVID-19 infection and lead to clinical cure. Since Tocilizumab is available in worldwide markets, international investigators began actively investigating its role as a COVID-19 therapy in late winter of 2020.

 

Several clinical trial designs were used to investigate Tocilizumab safety and effectiveness for treating COVID-19 disease. Patients in these trials were hospitalized males and females, ranging in age from 22 to 99 years. Patient comorbidities included cancer; sickle-cell anemia; hypertension; diabetes; stroke; chronic obstructive pulmonary disease (“COPD”); chronic heart disease; chronic kidney disease; and obesity. Trials were conducted in China, France, Italy, and the U.S. Tocilizumab was given either intravenously at 4- or 8-mg/kg body weight or subcutaneously at 162- or 324-mg doses, as either single doses or 2-3 doses given 12-72 hours apart. Trial designs included observational (8 trials), observational with matched controls (5 trials), or randomized placebo-controlled (2 trials). Two trials were designed to evaluate Tocilizumab as part of a combination regimen, and 3 trials studied Tocilizumab safety.

In observational trials, COVID-19 patients improved when treated with Tocilizumab as adjunct therapy in standard drug treatment regimens, but trials had no control groups for comparison. Patients in these trials had either severe or critical COVID-19 infections. Severe COVID-19 infections are diagnosed by CT scans or X-rays showing infiltrates in more than 50% of the lung field and by lung function measurements – such as pulse oximetry values – below normal ranges. Critical infections are diagnosed in patients who progress to shock, multiple organ failure, or respiratory failure requiring invasive mechanical ventilation. In the observational trials, Tocilizumab was given to patients with severe or critical COVID-19 infections as adjunct therapy added to standard treatment protocols. Standard treatment consisted of regimens of lopinavir/ritonavir, hydroxychloroquine, azithromycin, ribavirin, interferon-α, or methylprednisolone. Clinical improvement occurred shortly after Tocilizumab treatment. Fevers generally resolved within 24-48 hours. Lung ground glass opacities and infiltrates disappeared, respiratory function improved, and many patients who had been ventilated no longer required mechanical ventilation. Patient mortality ranged from 0 to 20%. Many or all of the patients in each trial were discharged by 6 to 40 days after hospitalization. Blood levels of the “immune markers” C-reactive protein, D-dimer, and ferritin, which are high in a cytokine storm, were elevated in patients’ blood at the time of hospitalization and declined to nearly normal levels after Tocilizumab treatment. Although the improvement in Tocilizumab-treated patients in these early trials was rapid and remarkable, it is not known if patients would have recovered as quickly without Tocilizumab, because there were no controls for comparison. Also, it is not known to what extent the concomitant standard drug treatment regimens contributed to disease recovery.

In two small observational trials designed to evaluate Tocilizumab in combination with another drug, COVID-19 patients with severe or critical disease improved rapidly and dramatically. Both trials did not include controls. The first trial used Tocilizumab in combination with the steroid hormone drug Methylprednisolone. In this trial of 21 patients with critical infections who needed invasive mechanical ventilation, 20/21 were disconnected from ventilators within an average of 8 days after receiving Tocilizumab. No patients died. The second trial studied a single pregnant patient with severe disease treated with a combination of Tocilizumab and the antiviral drug Remdesivir. The patient had many co-morbidities and required supplemental oxygen. One day after receiving Tocilizumab, her attending physicians were able to reduce the level of oxygen that she needed. One day after her Remdesivir 5-day treatment ended, she was released from the hospital. At a 14-day follow-up, her blood IL-6, C-reactive protein, ferritin, and D-dimer levels had all returned to normal. Notably, both Methylprednisolone and Remdesivir are known to be effective in treating COVID-19 infections. Thus, the relative contribution of Tocilizumab as adjunct therapy in these trials is not known.

Effectiveness of Tocilizumab as adjunct therapy for COVID-19 disease treatment seemed to vary with disease severity in several trials that used matched control groups. These trials studied from 45 to 239 patients who received lopinavir/ritonavir, hydroxychloroquine, azithromycin, or corticosteroids throughout the trials. Tocilizumab did not reduce mortality in patients with moderate infections. In 3 trials of patients with severe infections, Tocilizumab either did not reduce mortality or slightly reduced mortality. In one trial, mortality was similar in Tocilizumab-treated patients and controls. In the second trial, mortality in Tocilizumab-treated patients was 16% versus 33% in controls; in the third trial, mortality in Tocilizumab-treated patients was 25% versus 48% in controls. These differences were not statistically significant due to the small numbers of patients. In a large trial that studied patients with critical infections on ventilators, Tocilizumab did significantly reduce mortality at 28 days compared to controls; values were 18% versus 36%. Regarding Tocilizumab effects on clinical outcome, results of these trials were mixed. In only 2 trials of patients with severe disease, time in hospital and time to clinical improvement were shorter in Tocilizumab-treated patients. In the other trials of patients with either severe or critical disease, clinical outcomes were similar in Tocilizumab-treated patients and controls. Interpretation of the results of these matched controlled trials is confounded because (1) there is the possibility of bias in selecting the “matched” control group; and (2) the relative contributions of the other therapies to patient outcome is not known.

In two large, randomized, placebo-controlled trials, Tocilizumab as monotherapy did not improve either survival or clinical status of COVID-19 patients. The first of these trials was a late stage trial in 450 patients with severe COVID-19 infections, sponsored by Hoffmann-La Roche, and intended to be submitted to the FDA to support Tocilizumab approval for treating COVID-19 infections. The trial was conducted at multiple centers in the US and patients were randomly assigned to receive either single doses of Tocilizumab as monotherapy or placebo. After 4 weeks of observation, mortality was similar in the Tocilizumab-treated patients and controls. In addition, Tocilizumab did not improve clinical status compared to controls, although it did reduce time to hospital discharge. Limited information is available about the second trial, which was conducted in Italy. The second trial was stopped early with the support of the Italian Medicines Agency, after treating 126 patients, because Tocilizumab did not reduce severe respiratory symptoms, intensive care visits, or mortality, compared to standard treatments.

Three recent trials identified safety issues with Tocilizumab treatment of COVID-19 patients. As Tocilizumab suppresses the immune system, a concern is that its use can induce severe infections that follow the original COVID-19 infection. In one trial, about 50% of patients developed bacterial pneumonia after Tocilizumab treatment. In another trial, about 7% of Tocilizumab-treated patients developed candidaemia, which is the presence of a Candida ablicans – yeast – infection in the bloodstream. Extremely concerning are the results of an observational trial in which blood levels of cytokines and immune markers in two COVID-19 patients increased by 10-40 fold rather than decreasing after Tocilizumab treatment. The two patients died. The authors of this last trial speculated that if Tocilizumab is given at the wrong time during COVID-19 disease progression, this could lead to aggravation rather than alleviation of the cytokine storm. The authors of all three of these safety trial reports cautioned that, since Tocilizumab is not yet approved for treating COVID-19, it should not be used outside of a clinical trial. Notably, the FDA has not issued an Emergency Use Authorization promoting the off-label use of Tocilizumab for treating COVID-19.

Large placebo-controlled trials are needed to determine whether Tocilizumab has a role in treatment of COVID-19 infections and to further characterize its safety. Results of small uncontrolled clinical trials conducted to date suggest that Tocilizumab may be effective as adjunct therapy if given in combination with drugs known to be effective in treating COVID-19 infections, in particular Remdesivir or Methylprednisolone. In controlled trials, Tocilizumab effectiveness varied with disease severity; having no effect in moderate disease, modest effects in severe disease, and the most pronounced effects in critical disease. Tocilizumab as monotherapy was not effective in treating COVID-19 patients in two large, randomized, placebo-controlled clinical trials. Several recent trials identified safety concerns with Tocilizumab treatment, notably onset of new infections and the possibility of aggravating rather than reducing COVID-19-associated cytokine levels. Additional randomized, placebo-controlled trials can be designed to determine how to optimize the role of Tocilizumab in COVID-19 disease management by identifying the appropriate (1) patient population; (2) timing for treatment initiation; (3) drugs for co-administration; and (4) strategies to minimize adverse events.

Developing a Vaccine to Prevent Covid-19 Disease

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Vaccination against COVID-19 aims to produce an initial immune response to enable the body to quickly respond to attack and destroy SARS-CoV-2 whenever the vaccinated individual is later infected with the virus. All vaccines aim to expose the body to an agent, called an antigen, to provoke an initial immune response. In the initial immune response, the vaccinated individual produces antibodies and effector lymphocyte cells. Both the antibodies and the effector lymphocyte cells attack and destroy the antigen – in this case, the SARS-CoV-2 virus. Two major types of lymphocytes involved in vaccination response are the B cells, which produce antibodies, and the T cells, which directly attack the antigen. After the initial immune response following vaccination, the effector lymphocytes become memory cells, which remain in the body and retain the ability to attack the antigen upon a subsequent infection.

Vaccines against COVID-19 are designed based on an understanding of the SARS-CoV-2 viral structure. Like all viruses, the SARS-CoV-2 virus is a simple structure. It consists a core encased by a protein envelope. The core consists of the genetic code material ribonucleic acid (“RNA”) combined with nucleocapsid protein. The envelope is comprised of membrane protein, envelope protein, and spike (“S”) protein. The S proteins indeed resemble spikes and stud the virus envelope, giving the virus its crown- or corona-like appearance. The spikes are essential to the process whereby the coronavirus invades its host. Once the virus enters the human body, the spikes attach to cellular receptors, allowing the virus to enter the cell, begin to replicate, and cause the symptoms of COVID-19 disease in the human host.

Vaccines against SARS-CoV-2 infection use several platforms. The SARS-CoV-2 vaccine platforms under development include the following: inactivated virus; protein-based; viral vector; and nucleic acid-based. An inactivated virus is treated with chemical compounds that render it inactive but still able to stimulate the body’s immune system to respond. Protein-based vaccines involve injecting fragments of the SARS-CoV-2 protein envelope into the body. Viral vector and nucleic acid-based viruses are developed by genetic engineering.

Genetic engineering techniques facilitated rapid development of SARS-CoV-2 vaccines. Genetically-engineered viruses are based on either viral RNA or deoxyribonucleic acid (DNA). Molecular biologists use the viral RNA code as a template to create the DNA for DNA-based vaccines. In designing genetically-engineered vaccines against COVID-19, scientists create DNA or RNA polymers that code for the SARS-CoV-1 S protein. RNA vaccines are encased in a lipid capsule. DNA vaccines can be given as part of an adenovirus “vector.” An adenovirus is a type of virus that causes mild respiratory infections. Using genetic engineering techniques, DNA is incorporated into the adenovirus. Both encapsulated RNA vaccines and adenovirus vector vaccine particles are given by IM injection. The DNA or RNA from these genetically engineered vaccines is able to enter the subject’s cells. Within the subject’s cells, the DNA or RNA codes for the viral S protein, which is released into the systemic circulation. The body then initiates an immune response to the viral protein which it synthesized internally.

Clinical trials of vaccines against COVID-19 are designed to establish vaccine safety and effectiveness. In the US, drug development proceeds through a preclinical and clinical phase. Preclinical studies are conducted (1) with laboratory reagents or tissue cell cultures (“in vitro” or “test tube”); and (2) in experimental animals, usually mice, rats, and nonhuman primates. Clinical trials are designated as “early” or “late” stage. Early stage Phase I trials use single-doses in healthy normal subjects; involve single doses of the vaccine; and focus on safety. Early stage Phase II trials establish effectiveness in addition to safety and can use single or multiple doses. The late stage Phase III trials are large adequate and well-controlled trials required by law to establish safety and effectiveness for vaccine licensing. Current thinking is that it is not ethical to challenge subjects with exposure to COVID-19 after vaccination. Finally, for vaccine development, both Phase II and Phase III trials include placebo controls. Informed consent is crucial to these trials. Subjects should be fully informed of the benefits and risks of the trial and should be able to decide not to participate in the trial or withdraw at any time.

Several published reports of completed Phase II clinical trials of COVID-19 vaccines showed good safety and effectiveness. ModernaTX (“Moderna”), CanSino, and Oxford University (“Oxford”) published in peer-reviewed clinical journals results of Phase II trials of COVID-19 vaccines. All three vaccines were genetically engineered and coded for the SARS-CoV-2 S protein. Moderna used an RNA vaccine. CanSino used a nonreplicating Ad5 adenovirus vector DNA vaccine. A5 is a type of adenovirus that causes mild respiratory infections in humans. Oxford’s vaccine is a nonreplicating adenovirus vector, consisting of DNA delivered by the ChAdOx1 adenovirus, which infects chimpanzees. The trials enrolled from 45 to over 1000 healthy male and female subjects from 18 to 60 years of age and included both treatment groups and placebo groups. Moderna and Oxford gave two doses; an initial dose and a booster 28 days later. CanSino gave single doses. Follow-up was to 56 days. The most common local adverse events were pain and tenderness at the injection site. The most common systemic adverse events were headache, muscle ache, chills, fatigue, joint pain, and fever. The majority of adverse events were mild-to-moderate and resolved within several days.  Oxford found that giving acetaminophen for the first 24 hours after dosing reduced many of the adverse events. All three vaccines produced strong T cell responses and high antibody titers against the S protein and against live SARS-CoV-2 virus. Vaccines produced higher antibody responses than convalescent plasma samples from recovered COVID-19 patients. However, antibody titers against SARS-CoV-2 virus in senior subjects were about half those observed in younger subjects.

The World Health Organization (“WHO”) maintains a website that tracks worldwide trials of vaccine candidates against COVID-19 and lists 6 Phase III trials in progress. The vaccine candidates in Phase III are from Moderna, AstraZeneca/Oxford, Pfizer/BioNTech (“Pfizer”), Sinovac, and Sinopharm. The Pfizer vaccine is an RNA-based vaccine. The Sinovac and Sinopharm vaccines are chemically-inactivated viruses. Many scientists believe that inactivated virus vaccines induce a stronger immune response than genetically engineered vaccines. The Moderna and Pfizer Phase III trials are taking place in US. AstraZeneca/Oxford will conduct one Phase III trial in the UK and one in Brazil. The Sinovac trial will also take place in Brazil. The Sinopharm trial will take place in the United Arab Emirates. The Phase III trials will be run at multiple clinical sites and will enroll from 2,000 to 30,000 healthy male and female subjects, of ages ranging from 18 years to “over 70.” Subjects will receive initial and booster vaccinations. The Moderna trial will enroll health care workers at high risk of contracting COVID-19. All other trials will use subjects in the community. All trials will investigate safety, anti-SARS-CoV-2 antibody titers in serum, and T-cell responses in blood. Subjects will be monitored for 1-2 years after immunization. A primary endpoint in the trials will be the percentage of subjects who contract COVID-19 in the community.

As per the WHO website, 10 different Phase II trials and 10 different Phase I trials of COVID-19 vaccine candidates are in progress. Companies running Phase II trials are Anhui of China; the Institute of Medical Biology of China; Inovio of South Korea; Takara Bio of Japan; Cadila of India; Genexine of South Korea; Novavax of Australia; Kentucky Bioprocessing of the US; Arcturas of Singapore; and Janssen/Johnson & Johnson of the US. Platforms include protein subunit, inactivated virus, DNA-based, RNA-based, and adenovirus vector. Primary endpoints are safety; secondary endpoints are antibody titers and T-cell responses. Companies running Phase I trials are based in Russia, Australia, the UK, Belgium, China, Canada, and Taiwan. Platforms include adenovirus vector, protein subunit, and RNA. A novel platform being tested in Phase I by Medicago of Canada is plant-derived virus-like particles, which are thought to produce a strong immune response despite being plant-derived. The WHO website also states that, as of July 31, 2020, 139 vaccine candidates are in in preclinical development worldwide.

The FDA is facilitating rapid availability of COVID-19 vaccines for the US. The Agency posted a Guidance for Industry on how to develop vaccines for licensing. The FDA has stated that it may consider granting an Emergency Use Authorization (“EUA”) for vaccines. Under an EUA, a vaccine would be made available to the public even though it has not yet undergone all the clinical testing normally required for licensing. The FDA has also stated that it will consider granting licenses for COVID-19 under the Accelerated Approval program before all the Phase III testing is complete. For both an EUA and Accelerated Approval, the vaccine must show preliminary evidence of safety and effectiveness in humans and strict criteria must be met.

Ethical issues arise once a vaccine is available. For example, if initial quantities are limited, this raises questions of prioritization for distribution. Priority might be granted to health care workers and other essential workers. Priority also might be granted to the more vulnerable populations, such as the elderly and those with pre-existing conditions. An additional question is how low-cost vaccines can be made available to all.

In summary, a tremendous worldwide effort is underway to rapidly develop a safe and effective vaccine against COVID-19 disease. Vaccines are based on a variety of different platforms. The most rapid progress has been made with genetically engineered vaccines. Several developers showed good vaccine safety and effectiveness in early-stage clinical trials and are now conducting late-stage clinical trials. Many other vaccine candidates are being actively studied in early-stage clinical trials. In vitro and animal studies are underway for even more vaccine candidates. Government and industry are collaborating to expedite vaccine availability, and it is conceivable that a vaccine against COVID-19 could be available by late 2020-early 2021. It is hoped that government and industry will also collaborate effectively to make affordable vaccines available to as many individuals as possible.

Corticosteroid Hormones and COVID-19

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CORTICOSTEROID HORMONES AND COVID-19

Introduction. The corticosteroid hormone drugs Dexamethasone and Methylprednisolone have both been successfully used to treat COVID-19 patients. Dexamethasone, approved by the FDA in 1958, is marketed for treating severe or incapacitating allergic conditions. Methylprednisolone, approved by the FDA in 1959, is marketed for treating severe allergic conditions and some types of autoimmune diseases. Corticosteroid drugs are thought to effectively treat these diseases because of their ability to modify the body’s immune response.  Since a strong sustained immune response causes many of the life-threatening symptoms of COVID-19, clinicians began to add low-dose corticosteroids to treatment regimens. Thus, the objective of low-dose corticosteroid treatment in COVID-19 patients to control disease progression by modifying the immune response. A strong sustained immune response can occur in COVID-19 disease as the body’s immune system attempts to destroy the SARS-CoV-2 virus infection. Unfortunately, a sustained immune response can begin to damage body tissues, in particular the lungs. As lungs become more severely damaged, this leads to pneumonia, which can become life-threatening. Adding immune response modulators such as corticosteroids to a COVID-19 treatment regimen should improve clinical condition and survival by reducing the immune response that is responsible for the damaging symptoms of the disease.

Only low doses of corticosteroids are recommended for treating COVID-19 disease because the drugs can cause serious toxicities. Dexamethasone and Methylprednisolone are synthetic versions of corticosteroid hormones that the body produces naturally. Among other effects, corticosteroids regulate glucose metabolism in the body as well as the immune response. Thus, the toxic effects of corticosteroid drugs are extensions of their beneficial properties – notably, hyperglycemia and immune response suppression. Both of these responses are harmful. Sustained hyperglycemia, which means that too much glucose is circulating in the blood, can damage the heart, eyes, nerves, and kidneys and even lead to diabetic coma. Suppression of the immune response can lead to severe infections, as the body’s infection-fighting ability is impaired. Thus, it is crucial in corticosteroid therapy of COVID-19 disease to use only low doses of the drugs.

Effects of Methylprednisolone on COVID-19 disease progression were studied in a small trial conducted in China. This was a retrospective observational trial in COVID-19 patients with pneumonia and severe disease, of whom 26 received Methylprednisolone and 20 did not. The doses of Methylprednisolone were low, ranging from 1-2 mg/kg given intravenously over 5-7 days. Although mortality was low and similar in the two groups (about 6%), clinical improvement was more rapid in the Methylprednisolone-treated patients. CT scans of lungs showed that the ground-glass opacities that occur in COVID-19 patients disappeared more rapidly in the Methylprednisolone-treated patients. A lower percentage of Methylprednisolone-treated patients needed mechanical ventilation than control patients (12% versus 35%). In addition, Methylprednisolone-treated patients spent less time on the ventilators, less time in the ICU, and were discharged more rapidly from the hospital than the control patients (median stay of 14 days versus median stay of 22 days). Finally, levels of chemical substances that circulate in the blood in high amounts during a sustained immune response, notably interleukin-6, C-reactive protein, and ferritin, dropped twice as rapidly in Methylprednisolone-treated patients as in control. The investigators added immunoglobulin and thymosin (only approved in China) to the Methylprednisolone regimens to prevent suppression of the immune response. Both immunoglobulin and thymosin are used in clinical practice in China to increase the immune response. No Methylprednisolone-related adverse events occurred in this trial.

Effects of Dexamethasone on mortality in COVID-19 were studied in a large clinical trial in the United Kingdom. Dexamethasone reduced mortality in severely-infected COVID-19 patients who were treated in the United Kingdom (“UK”) Randomised Evaluation of COVID-19 Therapy (“RECOVERY”) trial. The RECOVERY trial is investigating possible treatments for COVID-19 in patients hospitalized in at least 175 clinical centers throughout the UK. Up to 12,000 patients will be enrolled in the trial, which is open to adult, elderly, and pediatric patients (older than one year of age). Recruitment for the study began on March 19, 2020. The treatments being studied are Lopinavir/Ritonavir, Hydroxychloroquine, Azithromycin, Tocilizumab, Convalescent Plasma, and Dexamethasone. The trial includes a control group of 4321 COVID-19 patients who are receiving only standard hospital care for their symptoms. In the Dexamethasone group, 2140 patients received oral Dexamethasone at 6 mg/day for 10 days.

Dexamethasone treatment in the RECOVERY trial was stopped early because Dexamethasone significantly improved survival in COVID-19 patients. The RECOVERY trial Steering Committee concluded that enough patients were enrolled to show that Dexamethasone improved patient survival, assessed at Day 28 of the study observation period. Thus, as of June 16, 2020, the investigators stopped recruiting patients for the Dexamethasone treatment group. The investigators found that Dexamethasone, compared to control, reduced mortality by 35% in patients on mechanical ventilators and by 20% in patients receiving oxygen only. This means that, for every 8 COVID-19 patients requiring treatment with ventilators, Dexamethasone treatment will prevent one death, and; for every 24 COVID-19 patients that need supplementation with oxygen only, Dexamethasone treatment will prevent one death. The UK Government’s Chief Scientific Advisor concluded that Dexamethasone is the first drug shown to reduce mortality from COVID-19. The RECOVERY trial principal investigators recommend that Dexamethasone should become the standard of care for COVID-19 patients who are sick enough to require oxygen treatment. In the interest of advancing the public health, the investigators plan to soon publish the full Dexamethasone treatment results from the RECOVERY trial.

Summary and Conclusion. Limited clinical trial results show that both Methylprednisolone and Dexamethasone are effective for treating severe COVID-19 disease. Methylprednisolone-treated patients recovered faster than controls. Dexamethasone improved patient survival compared to controls. Methylprednisolone treatment is given IV; Dexamethasone is easier to administer as it can be given orally. As both suppress the immune system, patients should be monitored for infections while undergoing treatment. Also, since both affect the immune response to COVID-19, it is important to administer either at an optimal time period during disease progression in order to achieve maximal benefit. Larger well-controlled trials are needed to further explore the role of corticosteroid hormones in COVID-19 disease treatment, either as monotherapy or as part of a combination regimen.