Rapid improvements in prevention and treatment could end the pandemic sooner than people think.
Rapid improvements in prevention and treatment could end the pandemic sooner than people think.
W hen the announcement came on October 2 that President Trump had tested positive for COVID-19, his supporters — and more than a few critics — prayed for his speedy recovery. At the age of 74 and with at least one significant comorbidity, Trump was at high risk of a severe and potentially fatal bout of COVID-19.
Little did he or anyone else know, his timing could not have been better. Just three days earlier, a company called Regeneron Pharmaceuticals announced that clinical trials of its futuristic new treatment had succeeded in reducing both infection and the time it takes for alleviation of symptoms. The results did not come as a complete surprise: Regeneron’s treatment is among the few entirely new medicines to meet the stringent requirements of Operation Warp Speed, the administration’s “Manhattan project” for COVID-19, and had already received major federal funding.
At Walter Reed hospital, doctors moved fast to get “compassionate care” approval to administer the medicine to the president. (Such case-by-case authorizations are made for treatments that have not yet been proven safe, if there is even a small chance of saving a patient’s life). He may go down in history as one of the first of millions of patients saved from severe COVID-19 disease by a medicine invented during the pandemic.
Operation Warp Speed and Regeneron
In May 2020, the Trump administration launched “Operation Warp Speed,” a crash program to develop a cure for COVID-19. The program combines the staff resources of multiple federal agencies with a substantial budget to absorb the financial risk of developing, testing, and mass-producing potential cures. Some promising treatments are already being mass-produced so that they will be available in large quantities as soon as the Food and Drug Administration (FDA) grants preliminary approval under an Emergency Use Authorization.
Operation Warp Speed has been billed as the government’s “Manhattan project” for developing a vaccine, but that is not its only focus. It is also, crucially, focused on the development of prevention and therapeutics. On September 15, several of the program’s leading scientists published a short but important update in the New England Journal of Medicine. “We have used three criteria to select candidate therapeutics to support,” the authors explain: “timeliness, robust science, and ability to manufacture quickly at scale.” First, the timeline set in May required that the therapeutic be in clinical studies by early fall (i.e., now) with the potential for FDA’s Emergency Use Authorization by the end of 2020. Second, the therapeutic strategy must be based on sound pre-clinical scientific data. Third, the therapeutic must be deliverable on a large scale by the end of 2020.
The authors go on:
Although challenging, this time frame permits repurposed drugs — those already approved by the Food and Drug Administration (FDA) or in human trials for other indications — to be rapidly evaluated for COVID-19 and further developed if clinical activity is detected. In addition, new antibody therapies for SARS-CoV-2 have been discovered and developed very quickly, thanks to advances in technology and extensive clinical experience with this drug class.
The latter is a clear reference to Regeneron, among others. Unlike Remdesivir and Dexamethasone, which have been repurposed from other illnesses and have both been around for a while, the Regeneron treatment is entirely new. It was developed earlier this year by testing hundreds of different candidate antibodies produced by infected mice that had been genetically engineered to have human immune systems (!). Scientific studies announced in early June established the treatment’s potential effectiveness, and the company proceeded immediately to clinical trials. It has already arranged for mass-production of the treatment for use both inside and outside the United States.
The Regeneron treatment — and a similar one developed by Ely Lilly — are “cocktails” of two monoclonal antibodies that work by binding to the virus’s “spike” protein, the protein that opens a channel through the cell membrane and allows the virus to invade the cell, for example a respiratory cell. That binding action snarls the spike protein and prevents the virus from invading new cells and taking over their genetic machinery to make many new copies of itself, which is how viruses propagate, destroying host cells along the way.
Viruses are prone to mutate at the molecular level, which can fool antibodies. Our immune systems overcome that challenge through “somatic hyper-mutation.” We are nowhere near replicating that awe-inspiring feat of evolutionary biology. But using a pair of pharmaceutical antibodies that bind to different parts of the spike protein substantially reduces the statistical probability that a mutation in some part of the protein will cause the treatment to fail, a strategy similar to that of “two-factor authentication” in cybersecurity.
Much remains unknown about the course of COVID-19 infection, but it appears to be the case that nearly half of infected persons develop a rapid immune response on their own, and suffer mild or no symptoms. Severe symptoms happen when the body takes longer to develop an effective immune response and the virus runs rampant throughout the body. In the Regeneron clinical trials, those patients with the highest viral loads at the start of treatment had their viral loads reduced by 95 percent or more, with substantial alleviation of symptoms within seven days of starting treatment.
The Regeneron trial just announced focused on non-hospitalized patients, but even with that caveat, the other major treatments we have for COVID-19 are nowhere near that level of effectiveness. For example, the most common treatment for hospitalized patients on supplemental oxygen has been Remdesivir, one of the other two therapeutics given to President Trump. Whereas Regeneron’s treatment prevents the virus from invading cells in the human body, Remdesivir interferes with the process (RNA polymerase) by which a virus already inside the cell takes over the cell’s genetic machinery to make copies of itself. It was originally developed as an antiviral for hepatitis, but was not successful against it or several other viruses. It has had more luck against COVID-19. The New England Journal of Medicine reports on a clinical trial completed just days ago: Among the 1,062 hospitalized patients in the study, the mortality rate was reduced from 15.2 percent to 11.4 percent with Remdesivir, a reduction of 25 percent. That’s not nothing, but it still leaves us with a pandemic many times more deadly than the flu.
The third therapeutic given to President Trump, dexamethasone, targets the disease rather than the infection, in particular the inflammatory immune response that makes COVID-19 so deadly. Dexamethasone is a corticosteroid designed to reduce inflammation by suppressing several aspects of the body’s immune response. Suppressing the immune system precisely when you need it most is a desperate gambit, so dexamethasone is normally reserved for the most severely ill patients; namely, those on mechanical ventilation. In that group, according to a clinical study completed in June, the treatment lowered the death rate from 41.4 percent to a still-staggering 29.3 percent. Among those receiving low-dose supplemental oxygen the effect was far less noticeable, lowering the fatality rate from 26.2 percent to just 23.3 percent. And among those hospitalized but not on supplemental oxygen of any kind, the death rate in the dexamethasone group was actually significantly higher, 17.8 percent as opposed to 14.0 percent.
It remains unclear whether President Trump simply developed a rapid immune response on his own, or was helped by Regeneron. What is clear is that a single highly effective therapy for severe disease would instantly turn COVID-19 into little more than a common cold with special remedies.
Multiple trials for Regeneron in hospitalized patients are now underway. Results are expected soon. If the treatment is as successful in lowering the viral dose in hospitalized patients as it is in non-hospitalized patients, the worst of the pandemic could be over just like that. As Scott Gottlieb and Mark McClellan caution in the Wall Street Journal, monoclonal antibodies don’t confer immunity or prevent spread like a vaccine does, and the treatments may not be deliverable soon enough in the quantities we need them. But in the meantime, reserving these treatments — and the eventual vaccine — for those most at risk of severe disease could save countless lives.
Focused Protection and the Role of Therapeutics
Work on a vaccine proceeds apace, and at least two different vaccines could be ready to start mass-production this month or next, according to the Center for Disease Control and Prevention (CDC). But as my colleague Dr. Joel Zinberg shows in a new report for the Competitive Enterprise Institute, a vaccine cannot be relied upon to the end the pandemic for a variety of reasons, including uncertain compliance (a large number of people don’t get the flu vaccine despite the tens of thousands dead every year).
It has been clear for some time that overcoming the COVID-19 pandemic will require a broader strategy of prevention and therapeutics focused on those populations that are at greatest risk of severe disease: the elderly and infirm. COVID-19 is at least six times deadlier than the flu, but its deadliness is extremely concentrated among the elderly and people with certain comorbidities such as hypertension and pulmonary disease. In Indiana, for example, nursing-home residents accounted for 54.9 percent of all COVID-19 deaths. But in other groups, particularly children and young adults, COVID-19 is actually less dangerous than the flu.
Under auspices of the American Institute for Economic Research in Great Barrington, Massachusetts, thousands of medical-health experts have signed a declaration that embraces “Focused Protection.” The “Great Barrington Declaration” has unfortunately proved greatly controversial, and has even been banned by outlets such as Reddit.
The trouble is the Declaration’s reliance on herd immunity — the idea that if enough people get sick and recover, their aggregate immunity will protect those who may not be immune:
The most compassionate approach that balances the risks and benefits of reaching herd immunity, is to allow those who are at minimal risk of death to live their lives normally to build up immunity to the virus through natural infection, while better protecting those who are at highest risk. We call this Focused Protection.
The authors’ confidence in herd immunity is arguably misplaced, for several reasons: First, COVID-19 could be as much as ten times as deadly as the flu, and even for those in the prime of life, can be a grave and sometimes fatal illness. Second, herd immunity may take a long time to achieve, even with a vaccine. And finally, herd immunity simply is not necessary for a proper strategy of “Focused Prevention.” Prevention and therapeutics are much more valuable than herd immunity, yet the Barrington Declaration mentions neither.
Still, the Declaration’s most basic point, that we should focus our efforts on protecting those who are most at risk, while minimizing the impact for others, is indisputably correct. Any other position violates a basic principle of sound public policy: to maximize social benefits while reducing unjustifiable social costs.
As Michael Barone powerfully argues in the Washington Examiner, “one-dimensional risk-aversion has produced extended lockdowns with significant public health costs: reduced cancer and cardiac screening, fewer childhood vaccinations, undue skepticism toward any COVID vaccine,” and, one might add, the terrible impact on children’s education and their parents’ livelihoods. Yet, Barone writes, “extreme risk aversion imposes few costs for affluent liberals who can work comfortably and at full pay on home computers.”
Steadily Declining Mortality Rate
Data on recent trends in the overall infection-mortality rate (the mortality among all infected people) are hard to find because confirmed cases are only a subset of the overall population of infected. A recent study that randomly tested a large number of people in Indiana found that nearly 40 percent of those who tested positive had no symptoms at all.
Here is the overall trend in new cases reported daily since the start of the year, according to the CDC.
Here is the trend in new deaths reportedly daily since the start of the year, in the same data set:
Here is another CDC visualization. This gives the percentage of daily deaths in the United States due to pneumonia, influenza, and COVID-19 over the last several years. The tallest peak corresponds to the first wave, the second spike corresponds to the (much larger) second wave, and since July, the percentage of deaths due to all three categories of infectious pulmonary disease has dropped dramatically (though there is reporting lag at the tail end).
Studies from England and Germany also indicate declining mortality even while the number of new infections is remaining steady or rising.
This strongly suggests that we are succeeding both in protecting the most at-risk people, and in effective therapeutics. For example, new data suggest that the median age of infected persons has dropped by nearly a decade (from 46 to 38), a dramatic decrease in the proportion of old people getting COVID-19 relative to young people. Clearly part of that is due to many young people “getting back to normal” and socializing again, but part of it is almost certainly due to greater success in isolating and protecting the elderly. Meanwhile, increasing success with therapeutics will not take long to start appearing in the overall data.
Prevention remains a key: wearing masks, washing hands frequently, observing social distancing. But effective therapeutics are starting to appear on the scene, with effective vaccines close behind. We won’t have enough of either for everyone in the population until well into 2021. But if we can focus limited therapeutics and vaccines on the most at-risk population, we could see dramatically declining mortality in coming months. We can finally see light at the end of the pandemic.