COVID-19: Updates on Treatment and Prevention

“A COVID-19 vaccination strategy demands a whole-of-society response—incorporating business, trade unions, faith communities, charities, media, entertainment, and sports. A vaccine to protect the public against SARS-CoV-2 is the most important and immediate technical challenge humanity has ever faced—at a moment when public trust in science and government is alarmingly brittle.”

- Richard Horton, Editor, The Lancet

“The COVID-19 pandemic has shown that with the right impetus, change can happen. . . we could use the momentum of COVID-19 to firmly embed kindness into research practice, extending greater goodwill beyond this, temporary, situation.”

- Gemma Derrick, Senior Lecturer in Higher Education, Lancaster University

Less than one year ago SARS-CoV-2, the coronavirus that causes COVID-19, wasn’t even known to exist. Since it emerged as a cause of pneumonia in Wuhan, China in December 2019, it has essentially been waging a war on the human race. This past week was brutal. Throughout the world, the number of new COVID-19 cases, hospitalizations and deaths surged. Fortunately, many of the world’s brightest scientists, clinical researchers, and public health investigators are working collaboratively in academic centers, non-profit organizations and in the pharmaceutical industry to combat this fiendish enemy. The purpose of this Germ Gem post is to provide an update on what’s in our armamentarium to treat and prevent this viral infection at this critical junction in the battle.

Treatments of COVID-19. Globally, the Infection Mortality Rate (IMR) of COVID-19 is about 1.15%, a figure that varies considerably according to patient age, underlying comorbid conditions, access to medical care, etc. For patients requiring hospitalization, the IMR is, of course, much higher, especially for those needing treatment in an intensive care unit. The good news, however, is that the death rate of hospitalized patients with COVID-19 has been declining worldwide. No one is sure whether this is a trend or just a blip. Scientists therefore warn against complacency in this ‘cliffhanger moment,’ saying even with reduced lethality millions more lives will be lost.

One factor that appears to explain, at least in part, the reduced death rate of hospitalized patients is improved knowledge of best practices for oxygenation, including use of ventilators and extracorporeal membrane oxygenation. In addition to this improved supportive care, a growing number of medications have been evaluated in randomized clinical trials (RCTs) that have mainly targeted hospitalized patients. The drugs studied are usually selected based on what is thought to be the pathogenic mechanisms of SARS-CoV-2, that is, the way the virus enters cells, damages tissues, and evades our immune defenses.

Dexamethasone, a corticosteroid that has been used for decades as a potent anti-inflammatory agent, leads the list of successful drug therapies. In a large RCT coordinated by Oxford University this spring, treatment of patients with dexamethasone who had severe COVID-19 and were receiving supplemental oxygen or on mechanical ventilation resulted in a significantly reduced mortality. Other researchers corroborated these findings and dexamethasone is now the standard treatment for patients with severe COVID-19.

Based upon thinking about the broad beneficial immunomodulatory effects of dexamethasone, a number of clinical trials recently were carried out with agents that more selectively inhibit an overly exuberant immune response (the so called “cytokine storm”). But as reported on November 1 in an article in NEJM Journal Watch (“A Series of Disappointing Results of Immune-Based Therapies for COVID-19”), the more selective inhibition of the immune response with the drug tocilizumab, an inhibitor of the cytokine interleukin 6 (IL-6), was found in several studies neither to decrease mortality nor to reduce the need for intubation of patients with severe COVID-19. Similarly, an open-label trial of anakinra, an IL-1 inhibitor, in hospitalized COVID-19 patients recently was halted because of an increased mortality in those treated with anakinra. (To me, the results of these studies suggest that we go “back to the drawing board” regarding our understanding of the pathogenesis of SARS-CoV-2, especially as evidence is emerging that a “cytokine storm” isn’t such a key factor in the pathogenesis.)

Results of trials aimed at “boosting” the immune response to SARS-CoV-2 through the use of monoclonal antibodies also disappointed many researchers. These negative studies included RCTs of monoclonal antibodies (mAb) developed by Lilly ( LY-CoV555, a potent, neutralizing IgG1 mAb directed against the spike protein of SARS-CoV-2 designed to block viral attachment and entry into human cells) and Regeneron (REGN-COV2, a combination of two mAbs that block infectivity of SARS-CoV-2). Both trials were halted due to low likelihood of clinical benefit in hospitalized COVID-19 patients. (REGN-COV2 may ring a bell with some readers as it was one of several therapies given to President Trump during his recent stay at Walter Reed Medical Center.)

Although treatment with Lilly’s LY-CoV55 mAb (bamlanivimab) was found not to be beneficial in hospitalized patients with severe COVID-19, on November 9 it became the first mAb drug to treat COVID-19 patients to receive an emergency use authorization (EUA) by the Food and Drug Administration. The EUA was based on its potential benefit in both adults and children weighing at least 88 pounds with mild to moderate COVID-19 in preventing progression to severe disease. It is administered as a single dose intravenously.

In May, the FDA gave EUA approval to the antiviral drug remdesivir. Like bamlanivimab, remdesivir doesn’t reduce mortality in those with severe COVID-19. And, although it may shorten recovery time, remdesivir recently has been linked to liver damage. Its use may now be more limited due to this toxicity.

On November 12, the Journal of the American Medical Association published the results of a trial of the over-the-counter antidepressant, fluvoxamine. The researchers found that this drug decreased clinical deterioration in outpatients with COVID-19. A JAMA editor of the paper commented that although this was a small study, it was RCT, double-blind, and placebo-controlled. He stated that these criteria were not met by most of the more than 10,000 COVID-19 papers submitted to JAMA since February. On an optimistic note, this more than 10,000 figure underscores the size of the pipeline of drugs that may ultimately be of benefit in the treatment of COVID-19. As with so many things in this pandemic, however, we will just have to wait to see what works.

Measures that prevent COVID-19. Most of the world’s public health experts agree that a lynchpin to getting on top of this pandemic is the development and global distribution of an effective vaccine. This is the primary goal of the $9 billion joint U.S. government and private sector’s Operation Warp Speed program that has been highlighted in several Germ Gem posts since April 2. Thus the whole world cheered on November 9 when the pharmaceutical companies Pfizer and BioNTech announced that early findings from their phase three trial of a frontrunner mRNA COVID-19 vaccine showed that it prevented infection by SARS-CoV-2 with an efficacy of up to 90%. This announcement prompted Dr. Tony Fauci, director of the U.S. National Institute on Allergy and Infectious Diseases, to comment that this is “a big deal” and to suggest the U.S. could begin distributing a COVID-19 vaccine by year’s end.

To top off the Pfizer/BioNTech announcement, on November 16, the Massachusetts-based biotechnology firm Moderna announced that a preliminary analysis of the results of the trial with their mRNA vaccine showed nearly 95% effectiveness at preventing illness. Dr. Fauci, who is one of three people briefed on the findings of the study, suggested this is “extremely good news,” and the data on severe cases was “quite impressive.” To add to the excitement, we can anticipate learning soon of the results of other companies regarding their phase 3 trials of adenovirus-vectored vaccines. At this same time, dozens of other COVID-19 vaccines are in development in the U.S. and elsewhere. And intriguingly, on November 11 Russia announced that its Sputnik V COVID-19 vaccine is 92% effective.

All COVID-19 vaccine candidates work in different ways, and none will be perfect for all. Thus, we’ll need more than one vaccine to beat the pandemic. While the details of these trials are yet to be published, and many huge challenges loom related to vaccine storage and equitable distribution, this appears to be a watershed moment in the battle against SARS-CoV-2; we may finally be on the road to winning this war.

But even if we have one or more effective SARS-Cov-2 vaccines available by early 2021, we need to do something NOW to stem the COVID-19 tsunami. And we have it in our power to do so. It has become increasingly clear that low-tech maneuvers like wearing masks and social distancing are amazingly effective. In his November 3 weekly newsletter, Dr. Francis Collins, Chief of the National Institutes of Health, stated: “[I]f most Americans pulled together to do the right thing and wore a mask in public, this simple, selfless act would save more than 130,000 lives in the next few months alone. If mask-wearers increased to just 85 percent, the model predicts it would save about 96,000 lives across the country. What’s important here aren’t the precise numbers. It’s the realization that, under any scenario, this pandemic is far from over, and, together, we have it within our power to shape what happens next. If more people make the decision to wear masks in public today, it could help to delay—or possibly even prevent—the need for future shutdowns. As such, the widespread use of face coverings has the potential to protect lives while also minimizing further damage to the economy and American livelihoods.”

What’s next. We have another reason to be optimistic about our chances of victory over SARS-CoV-2 in 2021: the change in the COVID-19 Task force, America’s COVID army, now led by and composed of highly regarded scientists and health care professionals. The three co-chairs of president-elect Joe Biden’s recently assembled COVID-19 Task Force are:

- David Kessler, who served as FDA commissioner under the administrations of former Presidents George H.W. Bush and Bill Clinton;

- Vivek Murthy, who served as surgeon general under former President Barack Obama’s administration; and

- Marcella Nunez-Smith, a physician, researcher, and professor at Yale University.

The ten remaining members of this interdisciplinary team are also outstanding and experts in their respective fields. One whom I’ve known and worked with on many occasions over the past four decades is Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota. In my estimation, he is the top infectious diseases epidemiologist in our country and can be trusted to work collaboratively on our behalf.

With this extraordinary team in place, there is no question in my mind that the battle plan to defeat SARS-CoV-2 will be based on Science. And Science is our biggest hope in defeating this deadly enemy.