Fine-Tuning Treatments for COVID-19Fri Nov 20 2020. 2 min read
Vaccines won't be enough; the research community needs to push hard on new therapies, too
by Henry I. Miller
President Trump's COVID-19 recovery has thrust into the spotlight the possibilities of novel, experimental therapies for this potentially deadly disease. During his stay at Walter Reed National Military Medical Center, he was treated with at least three drugs that have since received substantial attention in the media: the anti-viral remdesivir, the glucocorticoid steroid dexamethasone, and the monoclonal antibody cocktail REGN-COV2.
While evidence suggests these drugs may be effective (and remdesivir just received full marketing approval from the FDA), there are other potential game-changers that have not yet attracted much attention; in fact, almost 2,000 clinical trials of drugs and vaccines (mostly the former) have been registered on the federal government's database. Many of these focus on individuals' immune system, either by eliciting an immune response (vaccines) or modulating it, in order that a response is not deleterious.
We Need Vaccines and Therapeutics
While much attention has been paid to the roughly five dozen potential vaccine candidates for COVID-19 currently in development, even the approval of one or more will not be the end of the COVID-19 pandemic saga. First of all, no vaccine is 100% effective, able to prevent infection, or even symptoms, in all recipients. (The overall average for flu vaccines is 40-60%, while for the first shingles vaccine, it was about 70%).
But as I discussed in a recent article, even an excellent vaccine is no good if no one takes it, and surveys have found significant resistance. A Kaiser Family Foundation poll published last month found that only about 42% of Americans would opt for a free COVID-19 vaccination before the presidential election. A similar result emerged from a more recent survey by Morning Consult, which found that only 38% would get a coronavirus vaccine if one became available. Those data are in line with the poor uptake of other vaccines intended for adults.
If the poll numbers hold up, even after vaccines are available, we could see continuing high levels of COVID-19 infections, with sporadic surges above baseline. It has been estimated that we will need immunity in roughly 70% of the population, through either natural infection or vaccine administration, in order to achieve "herd immunity," or "community immunity," which occurs when a sufficiently large portion of a community (the herd) becomes immune to a disease that the spread of disease from person to person becomes unlikely. That protects the whole community — not just those who are immune. Clearly, we will never even approach that, if a significant fraction of the population rejects the vaccine. Thus, there will be an ongoing need to wear masks, for social distancing, avoidance of crowds indoors, and also for better drug treatments for people who do become infected.
The Immune Response: Too Little or Too Much?
The immune system wanes as people age, resulting in a diminished ability to fight off infections or to mount a vigorous immune response to vaccines – hence, the high mortality rate in patients with COVID-19 and the special, higher-dose versions of flu vaccine for seniors. However, in many patients with severe COVID-19, the body's own exaggerated immune response can be just as damaging — if not more so — than the virus itself. It can take several forms, including injury to the endothelium (i.e., the cells lining the inside of blood vessels), "cytokine storm" (the uncontrolled release of proinflammatory proteins, as part of the immune response), or excessive coagulation. These can lead to life-threatening acute respiratory distress syndrome (ARDS) and multi-organ damage. Studies conducted earlier this year showed that the nucleocapsid, or N-protein, of SARS-CoV-2 is involved in activating the lectin pathway, an essential part of the complement system, which provides an organism's effective defense against invading pathogens. The lectin pathway itself is also a proteolytic cascade of molecular events that gives rise to, among other things, the adaptive immune response.
More specifically, a group of Chinese researchers found in studies in mice that the N-proteins of SARS-CoV-2 and other highly pathogenic coronaviruses bind to MASP-2, the key serine protease in the lectin pathway of complement activation, which results in aberrant complement activation and severe inflammatory lung injury. This N-protein-induced complement hyper-activation was also observed in COVID-19 human patients, and "a promising suppressive effect was observed when the deteriorating patients were treated with anti-C5a monoclonal antibody." Therefore, they concluded that, "Complement suppression may represent a common therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses."
A promising drug candidate that targets this pathway is a monoclonal antibody called narsoplimab that blocks the MASP-2 enzyme and inhibits activation of the lectin pathway. By blocking the activation of this part of the body's immune system, narsoplimab should dampen the impact of the overactive immune response and prevent a dangerous cascade of complications including coagulation and blood clots, while leaving the anti-infection activity of the adaptive immune response intact.
Narsoplimab is currently being evaluated by the FDA to treat hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) and is in Phase 3 clinical trials in IgA nephropathy and atypical hemolytic uremic syndrome. FDA has granted the drug breakthrough therapy designation for both HSCT-TMA and IgA nephropathy. Since injury to endothelial cells (the cells that line blood vessels) is central to the pathophysiology of both COVID-19 infection and HSCT-TMA, the drug's potential to help treat COVID-19 patients is promising. A peer-reviewed study conducted by Italian and American doctors in Bergamo, Italy — an early COVID-19 hotspot — suggests that narsoplimab could be an effective treatment for critically ill COVID-19 patients with ARDS and multi-organ disease in patients requiring mechanical ventilation. After two to four weeks of treatment, all six patients in the study recovered and were discharged from the hospital after showing a sustained reduction in all assessed markers of endothelial damage, inflammation, and coagulation. Further, researchers reported no drug-related adverse reactions from any patients in the study and also suggested that two of the patients who had massive bilateral pulmonary thromboses may have benefited from narsoplimab's anticoagulant effects.
Due to the emergent nature of narsoplimab's use in Bergamo, the administration of the drug was not performed as part of a formal, prospective, controlled clinical trial, and the physicians were only able to compare the patients to a control group retrospectively, with the controls showing mortality in excess of 50%. The growing body of literature on the need to stop the cascade of complement activation, coagulation, and inflammation suggests the need for further research on this promising approach to COVID-19, especially in sicker patients in jeopardy of, or experiencing, cytokine storm.
We might, indeed, have to "live with" COVID-19 infections at some level in the community for the foreseeable future, but it should be with as few hospitalizations and deaths as possible. Therefore, moving forward, the research community should pursue every promising drug and vaccine candidate.
Henry I. Miller, a physician and molecular biologist, is a Senior Fellow at the Pacific Research Institute. He was the founding director of the FDA's Office of Biotechnology.