New data on neutralizing monoclonal antibodies (nMAbs) pose a challenge to COVID-19 researchers across the globe: The drugs were highly safe and effective at reducing the severity of COVID-19 infections—especially among unvaccinated people—but they are now not used due to in vitro drug resistance among currently circulating SARS-CoV-2 variants.
The study, published in JAMA Network Open yesterday, offers insight into how and why scientists should continue looking at nMAbs to treat current and future variants.
Use of 4 treatments analyzed
The study was based on results seen in 14 months' use of nMAbs among 167,183 nonhospitalized COVID-19 patients from a consortium of four healthcare systems based in California, Minnesota, Texas, and Utah. Patients had a confirmed COVID-19 test collected from November 9, 2020, to January 31, 2022.
During that time the US Food and Drug Administration authorized the emergency use of four monoclonal antibodies: bamlanivimab, bamlanivimab-etesevimab, casirivimab-imdevimab, and sotrovimab.
To be prescribed nMAbs, all patients had to meet at least one emergency use authorization criterion for risk of a poor outcome from COVID-19 infection, which included being 65 and older or pregnant, or having chronic lung disease, sickle cell disease, or diabetes, among other health conditions.
The average age of participants was 47 years, 57.2% were females, and 83.4% were white. A total of 25,241 patients (15.1%) were treated with nMAbs; of those, 16,640 (65.9%) received casirivimab-imdevimab, 4,735 (18.8%) received bamlanivimab, 1,948 (7.7%) received bamlanivimab-etesevimab, and 1,918 (7.6%) received sotrovimab.
During the study period, treatment with nMAbs was safe, with potential adverse drug events identified in 38 treated patients (0.2%).
Antibodies most effective during Delta period
Patients who received nMAbs were grouped into four different variant periods, including pre-Delta (November 9, 2020, to June 30, 2021), Delta (July 1 to November 30, 2021), Delta as well as Omicron BA.1 (December 1 to 31, 2021), and Omicron BA.1 (January 1 to 31, 2022), the authors said.
Outcomes measured by the study included emergency department (ED) visits, hospitalization, death, and a composite of hospitalization or death within 14 days and 30 days of the first positive COVID-19 test.
In general, treatment with nMAbs was associated with 24% lower odds of ED visits within 14 days (odds ratio [OR], 0.76), 48% less risk of hospitalization within 14 days (OR, 0.52), and an 86% lower death rate within 30 days (OR, 0.14).
Overall, some trends emerged as hallmarks of treatment with nMAbs: In each timeframe, unvaccinated and immunocompromised patients and those most at risk of serious complications from COVID-19 infections benefited the most.
As immunity grew, nMAb effect weakened
As time went on, however, the ability of nMAbs to prevent hospitalizations weakened. "The association of nMAb treatment with reduced risk of hospitalizations within 14 days was strongest during the Delta variant epoch (OR, 0.37; 95% [confidence interval] CI, 0.31-0.43) but not during the Omicron BA.1 epoch (OR, 1.29; 95% CI, 0.68-2.47)," the authors said.
"This may be related to the decoupling phenomenon observed during the Omicron epoch, in which the incidence of severe disease and death decreased substantially relative to the number of new cases partially due to increasing net population immunity from vaccination and natural infection," the authors said.
Effective treatments are only effective if they can be readily administered to patients
In a commentary on the study, Erin K. McCreary, PharmD, of the University of Pittsburgh, and colleagues noted that currently all emergency use authorizations for nMAbs have been revoked due to in-vitro drug resistance. They also point out that monoclonal antibodies were challenging to administer when needed during the pandemic because of shortages, cost, and intravenous infusion.
"Effective treatments are only effective if they can be readily administered to patients," the commentary authors write. "Acknowledging that mAb development and implementation seems like a constant race against the clock, scientists and manufacturers will need incentives to produce safe and effective therapies that are at risk of becoming obsolete."
