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The evolution of ‘escape’ mutations in patients with prolonged SARS-CoV-2 infection
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Nikki Troxclair
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A new study led by Emory University researchers reveals the need to better understand the ramifications of different therapies for the treatment of COVID-19 in immunocompromised patients with prolonged infection.

A key question in the study of SARS-CoV-2 and COVID-19 disease is how the virus develops mutations that evade the body’s immune response and treatments. Emory researchers posed this question in a study of five immunocompromised patients with prolonged SARS-CoV-2 infection.

The results of that research are now online in the New England Journal of Medicine and in the June 23 print edition of the journal. Co-study leads Erin Scherer, PhD, DPhil, assistant professor of medicine in Emory’s division of infectious diseases, and Anne Piantadosi, MD, PhD, assistant professor of pathology and laboratory medicine and physician in the Emory division of infectious diseases, chose to study patients with prolonged infections because the longer infection period provides an opportunity to examine how the virus mutates over time.   

“There have been other research studies of this same patient population,” says Scherer, “but at the time, we had the largest cohort of patients in a study looking at viral evolution in combination with antibody and cellular immune responses.” 

The study focused on five immunocompromised patients with SARS-CoV-2 infection lasting 42 to 302 days after a first positive test. The study was approved by the institutional review board at Emory University. Informed consent was obtained from patients who donated whole blood samples for research. The five patients in the study all had B cell deficiencies, from cancers and other conditions that limit the body’s ability to generate its own antibody response to the virus. Researchers identified SARS-CoV-2 mutations from nasal swab samples from these patients and created variant pseudoviruses that could be used for testing.

(The pseudoviruses in this study were made with another virus’ core but with SARS-CoV-2 spike proteins on their surface. Since a pseudovirus cannot replicate, it can be studied in a lab with lower biosafety clearance.)

One patient did not receive any antibody treatments; two patients received bamlanivimab, a single monoclonal antibody drug, and two received convalescent plasma. The blood serum of the patients who received the monoclonal antibody treatment neutralized the original SARS-CoV-2 pseudovirus. However, testing revealed that the viruses from those two patients separately developed spike protein mutations that could not be neutralized with the antibody-rich serum. The study concluded that the spike mutations conferred “neutralization resistance to bamlanivimab.”

“The fact that their serum could no longer neutralize their virus means it had developed escape mutations under selective pressure from the monoclonal antibody,” says Piantadosi.  “When you use just one antibody treatment on SARS-CoV-2, the virus evolves to escape it. Our study corroborated this.”

“We’ve seen this in the lab, but it was striking to see it in real time in humans,” says Scherer. “It really hammers home the consequences of what happens in viral evolution when you apply a singular immune pressure in the absence of a broader immune response.”

The Emory study provides supplemental data on the five immunocompromised patients, including details of their B cell deficiencies, treatments, level of COVID-19 disease and viral mutations. The details illustrate how selective pressures, such as those from single monoclonal antibody treatment, may promote the emergence of SARS-CoV-2 escape mutations. Scherer and Piantadosi hope that studying SARS-CoV-2 mutations in immunocompromised patients will lead to improved treatments for these patients and potentially prevent the emergence of new SARS-CoV-2 variants of concern.

Piantadosi calls this process “an arms race to understand how this virus mutates to evade antibodies.”

“It gives us information on which mutations are significant and should be further studied,” she says.

The study involved a collaboration of many researchers, physicians, clinicians and infectious disease experts throughout Emory University and Emory Healthcare, as well as a researcher at La Jolla Institute of Immunology in California. The next step in this research, according to the study leaders, is to continue this work with a larger prospective study.

“In immunocompromised patients, mutations can emerge at an unusually high rate,” says Piantadosi. “That raises the question of whether new variants might arise from long-term human infection; another interesting possibility is that they could be transmitted from other species.”

This research was supported by grants from the Centers for Disease Control and Prevention, the National Institutes of Health, a Simons Foundation Award, the Pediatric Research Alliance and an Emory Woodruff Health Sciences Center CURE Award.

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