Genetic Deletions Drive SARS-CoV-2 Antibody 'Escape'

Damian McNamara

February 10, 2021

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Recurrent genetic deletions in the SARS-CoV-2 spike protein can change the shape of the virus and allow it to elude the antibody lock-and-key fit, new research reveals.

Viral mutations leading to numerous variants are nothing new, but the SARS-CoV-2 virus comes with a self-correcting feature, a polymerase that "fixes" many mutations. However, deletions are another story, and the virus cannot correct them.

Dr W. Paul Duprex

"The take-home message is the virus is doing what viruses do. They morph," senior study author W. Paul Duprex, PhD, told Medscape Medical News.

"It's about the shape and how the immune system sees the virus," said Duprex, director of the Center for Vaccine Research at the University of Pittsburgh, Pittsburgh, Pennsylvania.

The study was published online February 3 in Science.

Changing the Transmission?

The shifting epidemiology of SARS-CoV-2 poses "an interesting question for virologists," said Duprex, who is also a professor of microbiology and molecular genetics at the University of Pittsburgh. "That's work in progress."

Virologists generally reserve their opinions on whether the deletion-driving variants ultimately increase or decrease transmission until animal experiments are complete, he said.

"But what virologists ― that is my discipline ― have to remember is that there are these big, big events happening globally," Duprex added. In other words, although preclinical lab work and genetic sequencing are underway, experts can act as sleuths and evaluate the shifting patterns of emerging variant outbreaks on a global scale.

When asked to speculate on the changes to transmissibility, Duprex said, "The virology answer to the question is, 'I don't know.' "

Many mutations in SARS-CoV-2 don't significantly alter the shape or behavior of the virus. These go into the "chasm of nontransmissibility," he said. The ultimate goal, he added, would be to identify in advance which variants are on the cusp of a "take-off event."

Starting With One Patient

Duprex and other researchers demonstrated that deletions occur over time in the amino (N)-terminal domain (NTD) of the virus' S glycoprotein. These alterations can occur during long-term infections of immunocompromised people.

Their line of study started with an immunocompromised patient with cancer who was infected with SARS-CoV-2 and was admitted to the University of Pittsburgh Medical Center. The man, who was in his 70s, was treated with remdesivir, dexamethasone, and convalescent plasma, to no avail. The patient died 74 days after diagnosis of COVID-19. The case report was outlined in a preprint article. Duprex and colleagues sequenced a sample of the virus from the patient and identified two variants with deletions in the NTD.

The research team then analyzed a large genetic database for other S glycoprotein deletions. They found that 90% of 1108 such viruses mapped to four discrete sites within the NTD.

"We find that adaptive evolution of S glycoprotein is augmented by a tolerance for deletions, particularly within RDRs [recurrent deletion regions]. The RDRs occupy defined antibody epitopes within the NTD, and deletions at multiple sites confer resistance to a neutralizing antibody," the researchers note.

"Deletions represent a generalizable mechanism through which S glycoprotein rapidly acquires genetic and antigenic novelty of SARS-CoV-2," they add.

Dr Jonathan Li

Jonathan Li, MD, and colleagues reported a similar case of long-term COVID-19 in December 2020 in The New England Journal of Medicine.

"Over the course of our patient's illness, we detected the emergence of several deletions in the NTD region of the SARS-CoV-2 genome," Li told Medscape Medical News. "This report in Science provides additional data to confirm our suspicion that these deletions may play an important role in how the virus is escaping from immune pressures."

NTD deletions in these new variants "highlight the role that escape from these NTD antibodies are also part of the selective pressure that brought about these new variants," said Li, an associate professor of medicine at Harvard Medical School and a faculty member in the Division of Infectious Diseases at Brigham and Women's Hospital in Boston.

A Complex Picture

"During evaluation of this manuscript, multiple lineages with altered antigenicity and perhaps increased transmissibility have emerged and spread," the researchers note in their Science article. "These variants of global concern are RDR variants and include Mink Cluster 5 Δ69-70, B.1.1.7 Δ69-70 and Δ144/145, and B.1.351 Δ69242-244." Duprex and colleagues add, "our analysis preceded the description of these lineages."

"Regarding D69-70 and B.1.1.7, I would caution against the interpretation that immune evasion is a driver of the recent rapid growth of B.1.1.7," Erik M. Volz, PhD, senior lecturer in the Department of Infectious Disease Epidemiology at Imperial College London, London, United Kingdom, wrote in an email to Medscape Medical News when asked to comment on the research. "That is not the case.

"These deletions on their own have low predictive power for which lineages will expand. Other lineages have these deletions but have not experienced rapid growth," he said.

Research Will Evolve, Too

The next step in his research is to "start picking apart the whole process. You begin to determine whether or not you can go from pattern recognition to predictive virology," Duprex said.

Discerning among different routes of transmission will likewise be essential, he said. "Every transmission event is not the same," he said. Asymptomatic transmission, symptomatic transmission, familial transmission, and transmission at sporting events and other mass gatherings could differ.

"This is where we need to be humble and say this is complex science," he said. "This isn't just about the coronavirus, it's about viruses in general."

The complexity "gives you a lot more noise, and that is where prediction gets very, very hard," Duprex said. "But we're never going to understand anything if we cannot understand patterns."

Duprex, Li, and Volz have disclosed no relevant financial relationships.

Science. Published online February 3, 2021. Full text

Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology and neurology. Follow Damian on Twitter: @MedReporter.

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