By Stevie Kiesel, Biodefense PhD Student
The constant flood of headlines decrying the US response to COVID-19 paints a bleak picture. From muddled messages at many levels of government to failures at ramping up contact tracing, from the breakdown in procuring enough personal protective equipment to a cultural resistance to wearing face masks, the US is rightly coming under scrutiny for its efforts to recover from the human and economic toll of this pandemic. But among the barrage of bad news are promising stories that are often overlooked. To draw attention to two potential safe and effective therapies for COVID-19, the American Society for Microbiology held a virtual briefing titled “From Remdesivir to Human Convalescent Plasma: Understanding COVID-19 Therapeutic Development.” Dr. Mark Denison from Vanderbilt University Medical Center discussed his work on two antiviral therapeutics, while Dr. Arturo Casadevall of the Johns Hopkins School of Public Health reviewed his work on convalescent plasma therapies.
Dr. Denison covered two antivirals that have so far shown promising results against COVID-19: remdesivir and EIDD-2801. Remdesivir was originally developed to treat Ebola Virus Disease (EVD), and while its effectiveness against EVD was limited, it did appear promising against coronavirus diseases such as SARS and MERS in animal studies. Both remdesivir and EIDD-2801 are nucleoside analogs that interfere with viral RNA synthesis. Viruses must enter a cell and replicate in order to survive. Once inside a cell, the virus will undergo translation and process proteins, replicate itself within the cell (what Dr. Denison calls “making virus factories”), copy the virus RNA genome, and then assemble and release the new virus to continue spreading throughout the host. These nucleoside analogs interrupt the process of copying the virus’ RNA genome.
In addition to their mechanism of action, these antivirals have other important similarities. Both potentially inhibit multiple coronaviruses (more study is needed to confirm); both have been proven to prevent disease and lessen disease severity when used early (in animal models); and both have been declared safe for human use. However, remdesivir is given intravenously, while EIDD-2801 is an oral drug. Options for antivirals given in multiple administration routes is important because while remdesivir may be given intravenously to patients in more critical condition in the hospital, EIDD-2801 can be prescribed for treatment at home. Both antivirals are available for human trials; EIDD-2801 is currently undergoing clinical testing, while remdesivir has been approved and provided for use in certain areas. Obviously, supply will outpace demand for these types of treatments for some time.
Dr. Casadevall then reviewed his work on the National COVID-19 Convalescent Plasma Project. Convalescent plasma is the liquid in the blood that holds blood cells; it can be obtained from donors through standard blood transfusion practices. Plasma from recovered patients contains antibodies that can neutralize a virus. For example, a recovered COVID-19 patient would donate their blood, and the virus-neutralizing antibodies found in their plasma would be extracted to make a therapy that can be used for prophylaxis (shortly after exposure to the coronavirus to prevent the virus taking hold) or therapeutically (to lessen the symptoms and/or duration of illness in a COVID-19 patient).
Convalescent plasma treatment has a long history of treating various diseases, such as the 1918 influenza epidemic, polio, mumps, measles, Argentine hemorrhagic fever, SARS, and MERS. We have learned that plasma can be an effective therapy for infectious diseases, particularly when administered early and in sufficient quantities for the particular agent being targeted. Dr. Casadevall believed early in the outbreak that convalescent plasma therapies had promise, and on March 1 he published an op-ed to bring attention to this possibility. Research into convalescent plasma therapies for COVID-19 soon picked up, and by March 27 the first US patients were treated with this therapy in Houston, Texas. Shortly after, the FDA expanded access to convalescent plasma treatment for COVID-19 patients, and by mid-April more than 1,000 medical centers offered this treatment option. Today, over 2,500 centers do so. China, Italy, Spain, and the United Kingdom have also seen success with convalescent plasma treatments. Italy, for example, has reported a 50% reduction in mortality in COVID-19 patients treated with convalescent plasma therapy when administered before admittance to an intensive care unit. Additional data from other countries will be made available in the coming weeks. Although the safety and efficacy of this treatment is not yet proven, Dr. Casadevall argues that there are positive signs: historical data, theoretical support based on antibody action, and early data during the pandemic.
Both Dr. Denison and Dr. Casadevall highlighted the likelihood that COVID-19 represents the new normal in emerging infectious diseases. Scientists have discovered a great number of coronaviruses in bats that could make the jump from bats to humans just as COVID-19 did. To combat this threat, research should be undertaken now to better understand zoonotic viruses and to develop antivirals that are broadly effective against coronaviruses. According to Dr. Denison, antiviral development should have several goals: a variety of routes of administration (oral, inhalation, and intravenous); a high barrier to resistance; safety; stability; scalability; and affordability. While COVID-19 has taught a great many lessons on how the US and countries around the world can improve their pandemic preparedness, this webinar highlighted the important research that must remain a priority not just at the height of the pandemic but as the world moves forward.