Virus World

The 20-month-long infection is the longest known and highlights how prolonged infections enable the pandemic virus to accumulate genetic changes—potentially spawning new variants of concern. A Covid-19 patient with a weakened immune system incubated a highly mutated novel strain over 613 days before succumbing to an underlying illness, researchers in the Netherlands found. The patient, a 72-year-old man with a blood disorder, failed to mount a strong immune response to multiple Covid shots before catching the omicron variant in February 2022. Detailed analysis of specimens collected from more than two dozen nose and throat swabs found the coronavirus developed resistance to sotrovimab, a Covid antibody treatment, within a few weeks, scientists at the University of Amsterdam’s Centre for Experimental and Molecular Medicine said. It later acquired over 50 mutations, including some that suggested an enhanced ability to evade immune defenses, they said.

The 20-month-long SARS-CoV-2 infection is the longest known, according to the researchers, who are presenting the case at a medical meeting in Barcelona next week. While his mutant virus wasn’t known to have infected other people, it highlights how prolonged infections enable the pandemic virus to accumulate genetic changes, potentially spawning new variants of concern. “This case underscores the risk of persistent SARS-CoV-2 infections in immunocompromised individuals,” the authors said. “We emphasize the importance of continuing genomic surveillance of SARS-CoV-2 evolution in immunocompromised individuals with persistent infections.” Scientists studying genomic data collected from wastewater samples have reported evidence of individuals in the community shedding heavily mutated coronaviruses for more than four years. Such persistent infections may also be causing patients to experience long Covid symptoms, research suggests.

Federal health officials on Friday restricted use of a Covid monoclonal antibody drug in eight states in the Northeast and two territories, citing evidence that it is unlikely to be effective against the highly transmissible Omicron subvariant known as BA.2 that is now dominant in those regions and quickly gaining ground across the country. The federal government said it would immediately pause shipments of the infused treatment, known as sotrovimab, to the 8 affected states, and Puerto Rico and the U.S. Virgin Islands. The Food and Drug Administration said the drug is no longer authorized for use in those places. The move, likely to soon extend to other parts of the country as BA.2 continues to spread, leaves doctors in the Northeast with one fewer option to treat high-risk Covid patients at the same time that a funding crunch is narrowing the menu of treatments. With an aid package in Congress stalled, the Biden administration is out of money for more antibody treatments and was forced to reduce shipments this week. For now, physicians treating high-risk patients still have access to one monoclonal antibody drug, known as bebtelovimab and made by Eli Lilly, as well as three antiviral treatments, though the funding shortfall threatens future shipments and orders of some of the drugs. Those remaining therapies have been found in laboratory tests to retain potency against BA.2.

Sotrovimab had been widely used in recent months because it was the only authorized antibody treatment that worked against BA.1, the Omicron subvariant that was responsible for the massive surge in cases. This past winter, federal officials restricted use of two other antibody treatments, from Eli Lilly and Regeneron, that had been widely used during the Delta surge because they were not potent against BA.1. Those drugs are not expected to work against BA.2, either. Sotrovimab’s manufacturers, GlaxoSmithKline and Vir Biotechnology, said on Friday that their laboratory testing had found that the authorized dosage of the drug was not sufficiently potent against BA.2, matching earlier findings from independent researchers. The drug makers said they were preparing to submit data to regulators for a higher dose of the drug, which is currently given as an intravenous infusion at 500 milligrams, that they hope will work against BA.2.

Several Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) neutralising monoclonal antibodies (mAbs) have received emergency use authorisation by regulatory agencies for treatment and prevention of Coronavirus Disease 2019 (COVID-19), including in patients at risk for progression to severe disease. Here we report the persistence of viable SARS-CoV-2 in patients treated with sotrovimab and the rapid development of spike gene mutations that have been shown to confer high level resistance to sotrovimab in vitro. We highlight the need for SARS-CoV-2 genomic surveillance in at risk individuals to inform stewardship of mAbs use and prevent potential treatment failures.

Preprint available in medRxiv (Dec. 21, 2021):

https://doi.org/10.1101/2021.12.18.21267628 

The U.S. Food and Drug Administration gave an emergency use authorization to the antibody treatment developed by Vir Biotechnology (VIR.O) and GlaxoSmithKline (GSK.L) for treating mild-to-moderate COVID-19 in people aged 12 years and older.  The antibody drug, Sotrovimab, is not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy, the health regulator said on Wednesday. (https://bit.ly/3uorQZ8) Sotrovimab belongs to a class of drugs called monoclonal antibodies, which mimic natural antibodies that the body generates to fight off infection. The antibody treatment will be available for COVID-19 patients in the coming weeks, GSK and Vir said, adding that they plan to submit a marketing application to the FDA in the second half of 2021.  Similar COVID-19 therapies by Regeneron Pharmaceuticals (REGN.O) and Eli Lilly (LLY.N) have been authorized for emergency use in the United States. The European Union's drug regulator last week backed the use of Sotrovimab for COVID-19 patients who were at risk of severe disease and do not need supplemental oxygen.

FDA Emergency Use Authorization Letter (May 26, 2021):

https://www.fda.gov/media/149532/download 

Glaxo Press Release (May 26, 2021):

https://www.gsk.com/en-gb/media/press-releases/vir-biotechnology-and-gsk-announce-vir-7831-reduces-hospitalisation-and-risk-of-death-in-early-treatment-of-adults-with-covid-19/ 

The Omicron variant of SARS-CoV-2 evades antibody-mediated neutralization with unprecedented efficiency. At least three Omicron sublineages have been identified, BA.1, BA.2 and BA.3, with BA.2 exhibiting increased transmissibility. However, it is currently unknown whether BA.2 differs from the other sublineages regarding cell entry and antibody-mediated inhibition. Here, we show that BA.1, BA.2 and BA.3 enter and fuse target cells with similar efficiency and in an ACE2-dependent manner. However, BA.2 was not efficiently neutralized by seven of eight antibodies used for COVID-19 therapy, including Sotrovimab, which robustly neutralized BA.1. In contrast, BA.2 and BA.3 but not BA.1 were appreciably neutralized by Cilgavimab, which may constitute a treatment option. Finally, all sublineages were comparably and efficiently neutralized by antibodies induced by BNT162b2 booster vaccination after previous two-dose homologous or heterologous vaccination. Collectively, the Omicron sublineages show comparable cell entry and neutralization by vaccine-induced antibodies but differ in susceptibility to therapeutic antibodies.

Published in Cell Host  Microbe (May 5, 2022):

https://doi.org/10.1016/j.chom.2022.04.017 

The BA.2 COVID variant now spreading worldwide disarms a crucial monoclonal-antibody therapy in laboratory tests.  The rapidly spreading BA.2 variant of SARS-CoV-2 could once again make doctors rethink antibody treatments for COVID-19. Manufactured immune molecules called monoclonal antibodies are essential for keeping people with COVID-19 out of hospital. Now, early laboratory data1,2 hint that the key antibody sotrovimab could lose effectiveness against the rapidly spreading BA.2 variant. Sotrovimab is one of the few therapies for COVID-19 caused by the Omicron variant, which overpowers several antibody treatments that were effective against previous strains. Just in time, US regulators have given emergency approval to another monoclonal antibody, bebtelovimab, that inhibits both the original Omicron strain3 and BA.21 in laboratory assays.  But for many researchers, the sotrovimab findings are a testament to the uphill battle of keeping up with SARS-CoV-2 as it evolves to evade immune systems, antibody treatments and vaccines. “With monoclonal antibodies, we’re trying to hit a moving target,” says David Ho, a virologist at Columbia University in New York City and a co-author of one of the studies. “It’s a really difficult endeavour to chase after a virus.” Most antibody treatments target and attach to SARS-CoV-2’s spike protein, which the virus uses to enter cells. But the protein is also a hotbed for mutations as the coronavirus evolves to evade the immune system. Omicron, for example, has dozens of new mutations in its spike protein. These might explain why two monoclonal-antibody cocktails used to treat the highly virulent Delta variant proved powerless against Omicron4. That left sotrovimab as the only FDA-approved monoclonal-antibody treatment option for infected people at high risk of developing severe COVID-19. The first known variant of Omicron, named BA.1, remains the most prevalent variety of the virus in many countries, including the United States and the United Kingdom. But cases of BA.2, which is related to BA.15, are rising in countries including Denmark, India and China.

Antibody escape

To see how common antibody treatments stood up to the newer varieties of SARS-CoV-2, Ho and his colleagues tested the treatments against a purpose-built virus that included the BA.2 spike. The results1, which have not been peer reviewed, revealed a steep drop in sotrovimab’s ability to neutralize BA.2. Those findings were reinforced by another preprint2, in which a team at the New York University Grossman School of Medicine reported a similar reduction in sotrovimab’s neutralization strength against BA.2. But researchers caution that it is too early to say what these numbers mean for the front-line treatment of COVID-19. “We cannot extrapolate laboratory findings to human treatment outcomes,” says Ho. “We’re just drawing attention to the fact that BA.2 is quite resistant to sotrovimab in the lab, and that raises questions about whether you can adequately cover BA.2 in patients.” Ho notes that sotrovimab also showed reduced efficacy against BA.2 in a preprint6 posted 18 February by scientists at Vir Biotechnology, the company based in San Francisco, California, that produces the antibody. The study has not yet been peer reviewed. In a statement, Vir says the research suggests that sotrovimab “retains neutralizing activity” against BA.2.

A new antibody to the rescue?

Regardless of sotrovimab’s abilities, bebtelovimab could become a go-to antibody to prescribe for people infected with BA.2. Ho and his colleagues found that it is active against both BA.1 and BA.2. The possibility of sotrovimab losing its edge against a new variant isn’t unexpected, says Miles Davenport, an immunologist at the University of New South Wales in Sydney, Australia. Like vaccines, he says, antibody treatments can become less effective when the virus evolves. But he adds that even if sotrovimab doesn’t provide the same level of protection that it did against previous variants, it could still give some relief to people infected with BA.2. “Just because monoclonal antibodies bind less well to the variants, does not mean they will be useless,” he says.

Keeping ahead of the virus

Rajesh Gandhi, an infectious-disease physician at Massachusetts General Hospital in Boston, says that sotrovimab will probably continue to be used while BA.1 remains prevalent. In the meantime, he and other experts say that the questions about sotrovimab underline the need to develop and deploy treatments for COVID-19 that remain effective even when the virus mutates. “If COVID has taught us anything, it’s that we need to prepare,” says Gandhi. “If BA.2 doesn’t become the most dominant variant, good. But if it does, it’s good to have some thoughts around it, so we can optimize treatments for our patients.”

Published in Nature (Feb. 23, 2022): 

https://doi.org/10.1038/d41586-022-00419-6 

BACKGROUND

Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization or death in older patients and those with underlying conditions. Sotrovimab is a pan-sarbecovirus monoclonal antibody that was designed to prevent progression of Covid-19 in high-risk patients early in the course of disease.

METHODS

In this ongoing, multicenter, double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, nonhospitalized patients with symptomatic Covid-19 (≤5 days after the onset of symptoms) and at least one risk factor for disease progression to receive a single infusion of sotrovimab at a dose of 500 mg or placebo. The primary efficacy outcome was hospitalization (for >24 hours) for any cause or death within 29 days after randomization.

RESULTS

In this prespecified interim analysis, which included an intention-to-treat population of 583 patients (291 in the sotrovimab group and 292 in the placebo group), 3 patients (1%) in the sotrovimab group, as compared with 21 patients (7%) in the placebo group, had disease progression leading to hospitalization or death (relative risk reduction, 85%; 97.24% confidence interval, 44 to 96; P=0.002). In the placebo group, 5 patients were admitted to the intensive care unit, including 1 who died by day 29. Safety was assessed in 868 patients (430 in the sotrovimab group and 438 in the placebo group). Adverse events were reported by 17% of the patients in the sotrovimab group and 19% of those in the placebo group; serious adverse events were less common with sotrovimab than with placebo (in 2% and 6% of the patients, respectively).

CONCLUSIONS

Among high-risk patients with mild-to-moderate Covid-19, sotrovimab reduced the risk of disease progression. No safety signals were identified. (Funded by Vir Biotechnology and GlaxoSmithKline; COMET-ICE ClinicalTrials.gov number, NCT04545060. opens in new tab.)

Published in New England Journal of Medicine (Oct. 27, 2021):

https://doi.org/10.1056/NEJMoa2107934