COVID-19 Vaccines Will Not Be Enough. We Also Need Effective Treatments

COVID-19 vaccines are the miracle that has significantly suppressed the pandemic in a number of countries, including the United States, where the current seven-day moving averages of cases and deaths are at levels not seen since March of 2020.  With continued aggressive vaccination, we can further suppress the numbers – getting us closer to pre-pandemic “normality.”

However, for several reasons, vaccines alone won’t be the whole solution.

First, in spite of the overwhelming and growing evidence of the importance, safety, and efficacy of the vaccines, there remains a core of the population who will refuse them.

Second, millions of Americans are taking immunosuppressive drugs — for cancer or autoimmune diseases, for example — that may attenuate the effect of the COVID-19 vaccines.  A study by researchers at the Johns Hopkins University School of Medicine of more than 650 organ recipients — who take drugs to suppress their immune system to prevent rejection of their transplanted organs – found that 46 percent had no antibody response after two doses of the Pfizer-BioNTech or Moderna vaccines.  In another study, a large group of academic researchers found that patients with conditions such as lupus, psoriasis and inflammatory bowel disease who were taking two types of drugs — glucocorticoids and B cell depleting agents — had a substantially impaired immune response to the Pfizer-BioNTech and Moderna vaccines.

Third, the proliferation of “variants of concern” – mutants of the original Wuhan strain of SARS-CoV-2 that are highly transmissible and may exhibit immune evasiveness in vaccinated subjects — in the future will likely compromise to some degree the efficacy of the currently available vaccines.  Increasing the likelihood of this outcome are the continuing significant outbreaks of COVID-19 in many of the world’s low- and middle-income countries, which provide opportunities for new, opportunistic mutants to emerge.

Fourth, in view of the above, the best-case scenario is probably that COVID-19 will not in the foreseeable future completely disappear but will become endemic like influenza virus and the coronaviruses that can cause the common cold. In order to save lives and modulate the severity of future COVID-19 infections, it will be critical to develop safe and effective treatments in addition to vaccines.

A few drugs are already being used to help COVID-19 patients recover. Remdesivir, a novel treatment that prevents SARS-CoV-2 from replicating, is the only drug that has been approved by the FDA for the treatment of COVID-19 to date.  After reviewing the data from several clinical trials, the FDA found it to be safe and effective for treating adolescents and adults hospitalized with COVID-19. While not yet fully approved by the FDA, the corticosteroid dexamethasone and monoclonal antibody tocilizumab have been found to improve the survival of critically ill patients, including those who require mechanical ventilation to help them breathe.  For outpatients with mild to moderate COVID-19 – but who are at high risk for disease progression – a panel of NIH experts recommends several antibody-based therapies, including bamlanivimab plus etesevimab or casirivimab plus imdevimab, during the earliest stages of infection.

Severely ill patients who have been hospitalized with COVID-19 may benefit from new drugs that directly address the cause of endothelial injury, one of the primary pathologies of the disease, no matter which variant causes the infection.  Research suggests that when the SARS-CoV-2 virus reaches the lungs, it can damage the nearby blood vessels, which in turn, causes excessive clotting, hyperinflammation, and complement activation/deposition.  As a very early event in COVID-19 infection, the first damage to endothelial cells activates an enzyme called MASP-2 and the body’s lectin pathway – a part of the complement system that helps the immune system respond to infection.  If the lectin pathway is hyper-activated, it can lead to a dangerous cycle of damage to blood vessels, and to blood clots and inflammation. In turn, activation of the lectin pathway causes more damage to endothelial cells, fueling a dangerous positive feedback loop.  The result is a high risk of severe respiratory distress, organ failure, and death.

A monoclonal antibody called narsoplimab inhibits the lectin pathway by blocking the MASP-2 enzyme, offering a way to interrupt the injurious process described above, in critically ill COVID-19 patients.  In advanced clinical trials for several illnesses marked by endothelial cell injury, narsoplimab has shown excellent responses.  Because the pathophysiology in these conditions is very similar to COVID-19, researchers have administered narsoplimab to a small number of infected patients, with encouraging results.

An initial study, conducted in Bergamo, Italy – an early COVID-19 hot spot—found that

(1) “[n]arsoplimab down-modulates SARS-CoV-2-induced activation of the lectin pathway and endothelial cell damage”; (2) “[n]arsoplimab can reduce the thrombotic risk of COVID-19 patients”; and (3) [a]ll patients treated with narsoplimab improved and survived without any drug-related adverse events.”  Compared to retrospective control groups, narsoplimab led to much better outcomes than would have been expected.  The monoclonal antibody has been used to treat critically ill COVID-19 patients in both Italy and the United States with similarly promising results, and is being further tested in the I-SPY COVID-19 trial.

In spite of the noteworthy success of COVID-19 vaccines, it is clear that they will not be enough to quell the pandemic entirely, and because people will continue to fall ill, there will be an ongoing need for effective treatments, which are currently in short supply.  Although some moderately effective drugs are already being used, new treatments are needed to treat severe COVID-19 infections.