Virus World

BACKGROUND

Respiratory syncytial virus (RSV) is an important cause of acute respiratory infection, lower respiratory tract disease, clinical complications, and death in older adults. There is currently no licensed vaccine against RSV infection.

METHODS

In an ongoing, international, placebo-controlled, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive a single dose of an AS01E-adjuvanted RSV prefusion F protein–based candidate vaccine (RSVPreF3 OA) or placebo before the RSV season. The primary objective was to show vaccine efficacy of one dose of the RSVPreF3 OA vaccine against RSV-related lower respiratory tract disease, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), during one RSV season. The criterion for meeting the primary objective was a lower limit of the confidence interval around the efficacy estimate of more than 20%. Efficacy against severe RSV-related lower respiratory tract disease and RSV-related acute respiratory infection was assessed, and analyses according to RSV subtype (A and B) were performed. Safety was evaluated.

RESULTS

A total of 24,966 participants received one dose of the RSVPreF3 OA vaccine (12,467 participants) or placebo (12,499). Over a median follow-up of 6.7 months, vaccine efficacy against RT-PCR–confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% confidence interval [CI], 57.9 to 94.1), with 7 cases (1.0 per 1000 participant-years) in the vaccine group and 40 cases (5.8 per 1000 participant-years) in the placebo group. Vaccine efficacy was 94.1% (95% CI, 62.4 to 99.9) against severe RSV-related lower respiratory tract disease (assessed on the basis of clinical signs or by the investigator) and 71.7% (95% CI, 56.2 to 82.3) against RSV-related acute respiratory infection. Vaccine efficacy was similar against the RSV A and B subtypes (for RSV-related lower respiratory tract disease: 84.6% and 80.9%, respectively; for RSV-related acute respiratory infection: 71.9% and 70.6%, respectively). High vaccine efficacy was observed in various age groups and in participants with coexisting conditions. The RSVPreF3 OA vaccine was more reactogenic than placebo, but most adverse events for which reports were solicited were transient, with mild-to-moderate severity. The incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups.

CONCLUSIONS

A single dose of the RSVPreF3 OA vaccine had an acceptable safety profile and prevented RSV-related acute respiratory infection and lower respiratory tract disease and severe RSV-related lower respiratory tract disease in adults 60 years of age or older, regardless of RSV subtype and the presence of underlying coexisting conditions. (Funded by GlaxoSmithKline Biologicals; AReSVi-006 ClinicalTrials.gov number, NCT04886596. opens in new tab.)

Published in NEJM (Feb. 16, 2023):

https://doi.org/10.1056/NEJMoa2209604 

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/ 

(Reuters) - GlaxoSmithKline Plc said an injection of its cabotegravir drug given every two months, in combination with Johnson & Johnson’s rilpivirine, was recommended for approval to treat HIV infections by a panel of the European health regulator. The treatment is a long-acting regimen, which can reduce the number of doses required to 12 or six per year instead of a daily intake of pills. If approved, it would be the first complete long-acting HIV regimen requiring dosing just once in two months (in the EU region), GSK said. The combination as an injection is already approved in Canada and is currently under review in the United States. Shares of GSK were trading up 2.5% at 1410.4p, while J&J shares were marginally up during premarket trading. Gilead’s Truvada daily oral pill is currently the standard of care for preventing HIV, but GSK hopes to challenge its dominance by making shorter, long-lasting regimens and less toxic alternatives through its ViiV Healthcare unit.

The positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency comes months after GSK said cabotegravir was found to be 66% more effective in preventing HIV infections than Truvada. Some 75 million people worldwide have been infected with HIV and about 32 million people have died since it began in the 1980s. While final approvals are up to the European Commission, it generally follows the CHMP’s recommendation and endorses them within a couple of months.

GSK public announcement (Oct. 16, 2020):

https://www.gsk.com/en-gb/media/press-releases/viiv-healthcare-receives-positive-chmp-opinion-for-long-acting-regimen-for-the-treatment-of-hiv/

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.

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 

Vir Biotechnology and GlaxoSmithKline are stopping a phase 3 clinical trial of their COVID-19 antibody early for efficacy after seeing an 85% reduction in hospitalization or death at an interim review. The trial provided further evidence of the efficacy of anti-SARS-CoV-2 antibodies in ambulatory patients.  As of the interim review, 583 people recently infected with COVID-19 had received VIR-7831, also known as GSK4182136, or placebo. The participants were all at high risk of progression, based on their age or other factors, but were unlikely to require hospitalization in the next 24 hours and had oxygen saturation of 94% or greater at the time of enrollment. In those patients, the anti-SARS-CoV-2 antibody reduced the number of patients who died or needed hospitalizing for more than 24 hours in the 29 days after randomization by 85%. The effect was large enough to prompt the independent data monitoring committee to recommend stopping enrollment.     The study remains blinded while Vir and GSK complete the 24 weeks of follow-up on patients already in the study. Vir and GSK plan to share additional data once the clinical trial is complete but already see enough promise to outline plans to seek emergency use authorization in the U.S. and equivalent approvals in other markets.

One ingredient used in some COVID-19 vaccine candidates is squalene, a natural oil made in the liver of sharks. Squalene is currently used as an adjuvant in medicine - an ingredient that increases the effectiveness of a vaccine by creating a stronger immune response. British pharmaceutical company GlaxoSmithKline currently uses shark squalene in flu vaccines. The company said it would manufacture a billion doses of this adjuvant for potential use in coronavirus vaccines in May. Around 3,000 sharks are needed to extract one tonne of squalene.

Shark Allies, a California-based group, suggests that if the world's population received one dose of a COVID-19 vaccine containing the liver oil, around 250,000 sharks would need to be slaughtered, depending on the amount of squalene used. If two doses are needed to immunise the global population, which is likely according to researchers, this would increase to half a million. To avoid threatening shark populations, scientists are testing an alternative to squalene - a synthetic version made from fermented sugar cane. Stefanie Brendl, founder and executive director of Shark Allies, said: "Harvesting something from a wild animal is never going to be sustainable, especially if it's a top predator that doesn't reproduce in huge numbers. "There's so many unknowns of how big and how long this pandemic might go on, and then how many versions of it we have to go through, that if we continue using sharks, the numbers of sharks taken for this product could be really high, year after year after year."

According to estimates made by conservationists, around three million sharks are killed every year for squalene, which is also used in cosmetics and machine oil. There are fears that a sudden rise in demand for the liver oil could threaten populations and see more species become endangered as many species rich in squalene, such as the gulper shark, are already vulnerable.