Variants of SARS-CoV-2 Variants Emerge in Brazil

Brenda Goodman and Roxana Tabakman

March 23, 2021

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

The unchecked spread of the more contagious SARS-CoV-2 variants in Brazil appears to have created even more dangerous versions of the virus that causes COVID-19.

The changes are documented by a team of researchers from FIOCRUZ, a large public health research lab run by Brazil's Ministry of Health. 

The findings were recently posted in a preprint on Virological.org, ahead of peer review.

The study describes 11 SARS-CoV-2 sequences from five different Brazilian states.  Each had telltale changes to the receptor binding domain, making it one of the known variants of concern or variants of interest. Each one also had additional changes to another important region on the virus: the N-terminal domain (NTD).

The NTD changes were deletions of important antibody-binding sites.  Many of these were key deletions around Y144, a mutation that has arisen independently in other circulating variants and has been documented in viral mutations in convalescent patients with cancer, suggesting that it conveys an important advantage to the virus.

Since the beginning of the pandemic, scientists expected the virus to mutate, or change. In addition to point mutations, which are exchanges of nucleotides in a specific place in a virus's genome, viruses can also lose or gain portions of their genetic code. Molecular biology has a term for it: indel, which means insertion or deletion.

These insertions or deletions of bases in an organism's genome constitute a more abrupt change than a point mutation. When they occur in the spike protein, they can modify the shape of SARS-CoV-2, allowing it to escape the grasp of "lock and key" antibodies that fit onto these binding sites.

"There are many antibodies that are generated for this NTD region. So these mutations are very likely to make the virus even more resistant to being neutralized," study author Felipe Naveca, MD, vice president of Research and Innovation at Fiocruz Amazonia, told Medscape Medical News.

Modeling by Naveca and his team suggests the deletions will further disrupt the ability of antibodies to grab these viruses and block them from infecting us.

He clarifies that these variants with indels are still uncommon. They were observed early, and scientists believe that they are not yet widespread.

"But the detection serves as a warning and we need to monitor their occurrence. That is why genomic surveillance is done," the researcher said.

Need to "Shut Down Replication"

Brazil is in the midst of another devastating wave of COVID-19 infections, fueled by variants and political inaction. Hospitals have run out of beds and other key supplies, like ventilators and oxygen, and Brazilian president Jair Bolsonaro has balked at the idea of asking citizens to wear masks and refuses to implement lockdowns, saying the price to the country's economy would be too high.

Researchers who were not involved in the study said the findings should put the rest of the world on alert.

John Mellors, MD, chief of infectious diseases at the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, said the finding was "not surprising, but concerning."

Mellors and his colleagues were part of a team of researchers who documented one of the same changes — a deletion at position 144 of the N-terminal domain — in a patient with cancer who fought the virus for more than 2 months. 

Over time, genome sequencing revealed that the patient, who was treated with convalescent plasma and the antiviral drug remdesivir to try to boost his immune response, was the host of at least six different SARS-CoV-2 variants. The variants had many of the mutations that are carried by the variants of concern that have arisen in the United Kingdom, South Africa, and Brazil.

The NTD deletions documented in the new preprint have been detected in other parts of the world as well.

"The fact that the same deletions are being selected for, independently of one another, it really suggests that these domains are really important for antibody neutralization," said Kevin McCormick, PhD, a postdoctoral researcher in infectious disease at the University of Pittsburgh School of Medicine.

A separate study, published earlier this month in the journal Science, found that deletions at position 144 disrupt the binding of antibody 48A.

In response to infection or a vaccine, our bodies make a whole orchestra of y-shaped antibodies that are each designed to grab onto a virus in slightly different places. So losing one of these antibody docking sites on the virus, by itself, isn't necessarily cause for alarm. But the more the SARS-CoV-2 shape shifts and changes, the more our immune defenses lose their collective punch, and eventually the changes allow the virus to cause a reinfection or to defeat the protection created by a vaccine.

Other researchers, who were not involved in the study, said that while the findings were interesting and worth watching, it was still too early to know for sure what this particular combination of mutations could mean.

"I'm sure there will be a follow-up paper that will profile these to death and explain what are the exact effects of each of these, and I'm sure that's probably just around the corner," said Pavitra Roychoudhury, PhD, an instructor in the department of laboratory medicine at the University of Washington in Seattle.

Right now, according to the Centers for Disease Control and Prevention, which is tracking the variants, there are no virus variants that cause tests, vaccines, or treatments to fail completely.

"The biggest move we all need to make is to vaccinate as far and wide as we possibly can to prevent the virus from replicating," said Mellors. "No replication, no evolution. So if we shut down replication and spread, we'll be OK, and that's a huge, enormous undertaking across the globe to shut it down."

Lockdown Now

The variables that most influence the evolution of the virus are the number of people who are infected and the length of time they spend infected. Scientists agree that, in order to slow down the evolution of the virus, it is essential to vaccinate quickly and keep people from circulating — something that's currently not happening in Brazil.

"This is very important in order to guarantee the effectiveness of the vaccines in the future. They were not designed to cope with this amount of mutations," stressed study author Tiago Gräf, who is also with Fiocruz.

"We defend the use of vaccines, and we believe that they will continue to protect against serious disease. But the virus is becoming so different from the original that new tests will be needed to understand how effective they will be," he told Medscape Medical News.

"We are showing that new variants have arisen, and their danger. But the public administration ignores our warnings. The situation that we see today is the result of this," Graf said.

Sources:

John Mellors, MD, chief of infectious diseases, at the University of Pittsburgh School of Medicine, Pittsburgh, PA

Pavitra Roychoudhury, PhD, Instructor, Department of Laboratory Medicine, University of Washington in Seattle

Virological.org. Published March 18, 2021. Preprint

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