Virus World

Immunocompromised people get a new drug to protect against Covid-19 for the first time since the Omicron variants forced another drug off the market. The Food and Drug Administration on Friday authorized a new antibody to protect immunocompromised individuals against Covid-19. The drug, known as Pemgarda and marketed by the biotech Invivyd, is the first such drug to become available since the agency pulled AstraZeneca’s Evusheld off the market in January 2023. New Omicron variants had rendered Evusheld ineffective. Some immunocompromised patients — a group that includes certain cancer patients, patients with some autoimmune or genetic disorders, and organ transplant recipients — have been eagerly awaiting the new prophylactic. Because their condition or drugs they take for it weaken their immune systems, they don’t always get adequate protection from vaccination. Antibody treatments can add additional protection.  There remains a need for additional Covid protections. Last week, over 10,000 patients with Covid-19 were admitted to U.S. hospitals. 

Still, it’s not clear how many patients will avail themselves of the new treatment. Invivyd, the drug’s developer, estimated there are 9 million immunocompromised people in the U.S., but its initial focus will be on the 485,000 with the most acute need: Stem cell transplant recipients, organ transplant recipients, and blood cancer patients. Evusheld itself had gone vastly underused when it was available, prompting the federal government to launch efforts to educate the public about its existence. And the need is probably less acute now for some: Although immunocompromised patients have a reduced response to vaccination, many may still gain some protection from multiple rounds of vaccination and exposure to the virus. Uptake for other measures to mitigate Covid risk, such as boosters and Paxlovid upon infection, has also declined precipitously, despite public health efforts. 

“We will explore having it available at our institution, so that our very compromised patients and the services and specialities that take care of those patients know that it’s an option,” said Priya Nori, an infectious disease specialist at Albert Einstein College of Medicine. “But we’re not expecting gangbusters in terms of interest.” Invivyd has not yet disclosed a price.  The company was originally founded in 2020 by antibody expert Tillman Gerngross, under the name Adagio, and raised $309 million in an IPO a year later. But the company’s original antibody — which had been designed to be all but variant-proof — was soon rendered ineffective by the advent of Omicron, eventually leading to Gerngross’s resignation and a series of high-level changes at the company. Pemgarda is a re-engineered version of the original antibody, designed to cover Omicron variants. That gave Invivyd a faster path to getting a new preventative on the market than competitors who started from scratch.

FDA EUA letter (March 22, 2024):

https://www.fda.gov/media/177068/download 

Invivyd Press release: 

https://investors.invivyd.com/news-releases/news-release-details/invivyd-announces-fda-authorization-emergency-use-pemgardatm 

Highlights

Summary

Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection. However, therapeutic mAbs for SARS-CoV-2 have been rendered obsolete by the emergence of mAb-resistant virus variants. Here we report the generation of a set of six human mAbs that bind the human angiotensin-converting enzyme-2 (hACE2) receptor, rather than the SARS-CoV-2 spike protein. We show that these antibodies block infection by all hACE2 binding sarbecoviruses tested, including SARS-CoV-2 ancestral, Delta and Omicron variants at concentrations of ~7–100 ng ml−1. These antibodies target an hACE2 epitope that binds to the SARS-CoV-2 spike, but they do not inhibit hACE2 enzymatic activity nor do they induce cell-surface depletion of hACE2. They have favourable pharmacology, protect hACE2 knock-in mice against SARS-CoV-2 infection and should present a high genetic barrier to the acquisition of resistance. These antibodies should be useful prophylactic and treatment agents against any current or future SARS-CoV-2 variants and might be useful to treat infection with any hACE2-binding sarbecoviruses that emerge in the future. A suite of human monoclonal antibodies block infection by all human ACE2 binding sarbecoviruses, including severe acute respiratory syndrome coronavirus 2 variants, at subnanomolar concentrations in cell culture and protect mice against severe acute respiratory syndrome coronavirus 2 infection.

Published in Nature Microbiology (May 15, 2023):

https://doi.org/10.1038/s41564-023-01389-9 

Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and to more effectively respond to SARS-CoV-2 variants. The emergence of Omicron and subvariants of SARS-CoV-2 illustrates the limitations of solely targeting the receptor binding domain (RBD) of the Spike (S)-protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors that target a conserved S2-region in the betacoronavirus spike fusion machinery. Select bnAbs showed broad in vivo protection against all three deadly betacoronaviruses, SARS-CoV-1, SARS-CoV-2 and MERS-CoV, that have spilled over into humans in past two decades. Structural studies of these bnAbs delineated the molecular basis for their broad reactivity and revealed common antibody features targetable by broad vaccination strategies. These bnAbs provide new insights and opportunities for antibody-based interventions and for developing pan-betacoronavirus vaccines.

Published in Immunity (Feb. 15, 2023):

https://doi.org/10.1016/j.immuni.2023.02.005 

[11/30/2022] The U.S. Food and Drug Administration today announced bebtelovimab is not currently authorized for emergency use in the U.S. because it is not expected to neutralize Omicron subvariants BQ.1 and BQ.1.1., according to data included in the Health Care Provider Fact Sheet.  

Nowcast data from the Centers for Disease Control and Prevention published last week estimates that the combined proportion of COVID-19 cases caused by the Omicron BQ.1 and BQ.1.1 subvariants to be above 57% nationally, and already above 50% in all individual regions but one, and data shows a sustained trend of increasing prevalence across all regions. Given that a COVID-19 infection is likely to be caused by a non-susceptible SARS-CoV-2 variant, and consistent with the terms and conditions of the Letter of Authorization, bebtelovimab is not currently authorized for emergency use in any U.S. region at this time.   Eli Lilly and its authorized distributors have paused commercial distribution of bebtelovimab until further notice by the Agency. Additionally, the Administration for Strategic Preparedness and Response (ASPR) has paused the fulfillment of any pending requests under its Bebtelovimab Product Replacement Initiative.  The U.S. Government recommends all product be retained in the event that SARS-CoV-2 variants susceptible to bebtelovimab, which are currently circulating at lower prevalence, become more prevalent in the future in the United States. Retained product must be appropriately held in accordance with storage conditions detailed in the authorized Fact Sheet for Health Care Providers and the Letter of Authorization for bebtelovimab.  Health care providers should use other approved or authorized products that are expected to retain activity against BQ.1 and BQ.1.1 as they choose appropriate treatment options for patients, which include the following: 

• Paxlovid is authorized for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. 
• Veklury is approved for the treatment of adults and pediatric patients (28 days of age and older and weighing at least 3 kg) with positive results of direct SARS-CoV-2 viral testing, who are not hospitalized and have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death. 
• Lagevrio is authorized for the treatment of mild-to-moderate COVID-19 in adults with positive results of direct SARS-CoV-2 viral testing who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate. 

In addition, COVID-19 convalescent plasma with high titers of anti-SARS-CoV-2 antibodies is authorized for the treatment of COVID-19 in patients with immunosuppressive disease or receiving immunosuppressive treatment, in inpatient or outpatient settings. Individuals for whom COVID-19 vaccination is recommended should consider getting vaccinated with the primary series or, if vaccinated with the primary series, boosted with an updated bivalent vaccine when eligible to increase protection against the most serious consequences of COVID-19, including hospitalization and death. For more information related to the therapeutic management of non-hospitalized patients with mild-to-moderate COVID-19, refer to the NIH COVID-19 Treatment Guidelines.  

All treatment sites can continue ordering Paxlovid, Veklury, and Lagevrio by following the existing ordering processes and reporting procedures, as applicable.  FDA will continue to work with ASPR, the CDC, and the National Institutes of Health on surveillance of variants that may impact the use of the therapies authorized for emergency use. We will provide further updates and consider additional action as new information becomes available.

Since the end of 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant outcompeted other variants and took over the world. After the emergence of original Omicron BA.1, Omicron BA.2 subvariant emerged and outcompeted BA.1. As of July 2022, some BA.2 subvariants, including BA.2.12.1, BA.4 and BA.5, emerged in multiple countries and begun outcompeting original BA.2. Moreover, a novel BA.2 subvariant, BA.2.75, was detected in eight countries including India at the end of June 2022, and preliminary investigations suggest that BA.2.75 is more transmissible over the other BA.2 subvariants. On July 7, 2022, the WHO classified BA.2.75 as a variant-of-concern lineage under monitoring. We have recently demonstrated that BA.4/5 is highly resistant to a therapeutic monoclonal antibody, cilgavimab, than BA.2. The resistance of SARS-CoV-2 variants to therapeutic antibodies can be attributed to the mutations in the viral spike protein. Compared to the BA.2 spike, BA.2.12.1 and BA.4/5 respectively bear two and four mutations in their spike proteins. On the other hand, the majority of BA.2.75 spike bears nine substitutions. The fact that the mutation number in the BA.2.75 spike is larger than those in the BA.4/5 spike raises the possibility that the BA.2.75 spike significantly reduces sensitivity towards therapeutic monoclonal antibodies than BA.2 and BA.4/5. In this study, we generated pseudoviruses harboring the spike proteins of BA.2.75, BA.4/5 and BA.2 and evaluated the efficacy of ten therapeutic monoclonal antibodies and three antibody cocktails against BA.2.75.

Preprint available in medRxiv (July 15, 2022):

 https://doi.org/10.1101/2022.07.14.500041 

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 omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for coronavirus disease 2019 (Covid-19), has spread rapidly around the world and has already become the predominant variant circulating in many countries. As of February 2022, omicron variants have been divided into four distinct sublineages: BA.1, BA.1.1, BA.2, and BA.3.1 Most circulating omicron variants belong to sublineage BA.1; however, in Denmark, India, and the Philippines, the sublineage BA.2 is now becoming dominant.

As compared with the Wuhan/Hu-1/2019 reference strain, the sublineage BA.2 of the omicron variant has 16 amino acid substitutions in the receptor-binding domain of the spike (S) protein of SARS-CoV-2,2 which is the primary target for monoclonal antibody–based therapy. The BA.2 and BA.1 variants share 12 of these 16 substitutions; however, BA.2 has four substitutions in the receptor-binding domain (i.e., S371F, T376A, D405N, and R408S) that differ from those in BA.1. These findings suggest that there may be differences in the effectiveness of monoclonal antibodies against these different omicron sublineages. Accordingly, we examined the neutralizing ability of therapeutic monoclonal antibodies that have been approved by the Food and Drug Administration, individually and in combination, against the omicron BA.2 subvariant hCoV-19/Japan/UT-NCD1288-2N/2022 (omicron/BA.2; NCD1288), which was isolated from a traveler who arrived in Japan from India. Whole-genome sequencing analysis of the NCD1288 virus stock confirmed that it had the 16 substitutions that are characteristic of the omicron variant in the receptor-binding domain of the S protein, as compared with the Wuhan/Hu-1/2019 reference strain...

The susceptibilities of omicron/BA.2 (NCD1288) to remdesivir, molnupiravir, and nirmatrelvir were similar to those of the ancestral strain and other variants of concern (i.e., 50% inhibitory concentration values for these three agents that differed by factors of 2.5 to 4.5, 0.7 to 1.6, and 1.5 to 3.3, respectively) (Table 1).3 Clinical studies are warranted to determine whether these antiviral therapies are indeed effective against omicron/BA.2 infections. Our data indicate that some therapeutic monoclonal antibodies (REGN10987–REGN10933, COV2-2196–COV2-2130, and S309) have lower neutralizing activity against omicron/BA.2 than against earlier variant strains.

Published in NEJM (March 9, 2022):

https://doi.org/10.1056/NEJMc2201933 

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 

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 

Doctors have a new option for the youngest patients who are vulnerable to the worst outcomes from Covid.  The Food and Drug Administration on Friday authorized Eli Lilly’s monoclonal antibody treatment for infants and children under age 12 with Covid-19 who are at high risk of becoming severely ill from the virus because they have a condition such as obesity or diabetes. Previously, high-risk Covid patients 12 or older had been eligible to get the drugs, which are typically administered intravenously at a clinic or hospital and have been shown to lower the risk of hospitalization and death. Until now, “we haven’t had something for young kids” with Covid that could keep them out of the hospital, said Dr. Walid F. Gellad, who is the director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh’s School of Medicine. The authorization comes as fears are rising about a winter surge fueled by the new Omicron coronavirus variant, which appears to be spreading because of a mix of its contagiousness and its ability to dodge the body’s immune defenses. It is not yet known how Omicron may affect young children compared to other versions of the virus or whether Lilly’s antibody treatment may be less effective against it.

Hospitalizations of children with Covid soared over the summer during a surge in Delta cases. Among the states that report the data, between 0.1 percent and 1.9 percent of all confirmed cases of Covid in children have resulted in hospitalization, according to the American Academy of Pediatrics. The F.D.A. said that body-weight-adjusted doses of Lilly’s treatment, a cocktail of two antibody drugs, were studied in a safety trial that enrolled 125 pediatric patients. “Parents of young kids, especially high-risk young kids, have had a difficult time because even though their kids are at lower risk, the focus has not been on that age, until recently with the vaccinations,” Dr. Gellad said. “It’s always good to have another option, but it’s always worth reiterating it doesn’t take the place of vaccination.”

FDA Press Release (DEc. 3, 2021): https://www.fda.gov/news-events/press-announcements/fda-expands-authorization-two-monoclonal-antibodies-treatment-and-post-exposure-prevention-covid-19 

Regeneron said that a single dose of its antibody cocktail REGEN-COV reduced the risk for COVID-19 by nearly 82% up to 8 months after administration in a phase 3 trial. REGEN-COV, which contains 600 mg each of the monoclonal antibodies casirivimab and imdevimab, was authorized for emergency use by the FDA in November 2020 for the treatment of mild to moderate COVID-19 in high-risk patients. The FDA expanded the emergency use authorization in July to include post-exposure prophylaxis.  Trial results announced Monday by Regeneron showed that, compared with placebo, people who received a single dose of REGEN-COV had an 81.6% reduced risk for developing COVID-19 during a 2-to-8-month follow-up period (95% CI, 59.8%-91.6%) and an 81.5% reduced risk for developing COVID-19 at any time during the 8 months after receiving REGEN-COV (95% CI, 70.6%-88.4%). Myron S. Cohen, MD, who leads the monoclonal antibody efforts for the NIH-sponsored COVID Prevention Network and is director of the Institute for Global Health & Infectious Diseases at the University of North Carolina at Chapel Hill, said the findings “demonstrate how a single dose of REGEN-COV can help protect people from COVID-19 for many months after administration.” "These results demonstrate that REGEN-COV has the potential to provide long-lasting immunity from SARS-CoV-2 infection, a result particularly important to those who do not respond to COVID-19 vaccines, including people who are immunocompromised,” Cohen said.

Regeneron said the data build on previously published findings in The New England Journal of Medicine, which reported a risk reduction of 81.4% in the first month. The newly announced findings were from an 8-month follow-up that continued to compare outcomes from more than 1,600 people assigned to receive a single dose of the cocktail or placebo. In all, seven people in the treatment arm and 38 in the placebo arm developed COVID-19 within 2 to 8 months. George D. Yancopoulos, MD, PhD, president and chief scientific officer at Regeneron, said the data “add to the increasing body of evidence supporting the use of REGEN-COV to prevent COVID-19 in uninfected individuals.” “With infections still occurring despite widespread vaccination, the immunocompromised face an ongoing risk of encountering the virus during their daily lives,” Yancopoulos said in a statement. “We intend to rapidly share these additional data with regulatory authorities to help those in most need of protection from COVID-19.”

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of existing vaccines and therapeutic antibodies and underscores the need for additional antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells collected from patients with coronavirus disease 2019. The three most potent antibodies targeted distinct regions of the receptor binding domain (RBD), and all three neutralized the SARS-CoV-2 Alpha and Beta variants. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the angiotensin-converting enzyme 2 receptor, and has limited contact with key variant residues K417, E484, and N501.

We designed bispecific antibodies by combining nonoverlapping specificities and identified five bispecific antibodies that inhibit SARS-CoV-2 infection at concentrations of less than 1 ng/ml. Through a distinct mode of action, three bispecific antibodies cross-linked adjacent spike proteins using dual N-terminal domain–RBD specificities. One bispecific antibody was greater than 100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a dose of 2.5 mg/kg. Two bispecific antibodies in our panel comparably neutralized the Alpha, Beta, Gamma, and Delta variants and wild-type virus. Furthermore, a bispecific antibody that neutralized the Beta variant protected hamsters against SARS-CoV-2 expressing the E484K mutation. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.

Published in Science Translational Medicine (Sept. 2021):

https://doi.org/10.1126/scitranslmed.abj5413 

Three coronaviruses have spilled over from animal reservoirs into the human population and caused deadly epidemics or pandemics. The continued emergence of coronaviruses highlights the need for pan-coronavirus interventions for effective pandemic preparedness. Here, using LIBRA-seq, we report a panel of 50 coronavirus antibodies isolated from human B cells. Of these antibodies, 54043-5 was shown to bind the S2 subunit of spike proteins from alpha-, beta-, and deltacoronaviruses. A cryo-EM structure of 54043-5 bound to the pre-fusion S2 subunit of the SARS-CoV-2 spike defined an epitope at the apex of S2 that is highly conserved among betacoronaviruses.

Although non-neutralizing, 54043-5 induced Fc-dependent antiviral responses, including ADCC and ADCP. In murine SARS-CoV-2 challenge studies, protection against disease was observed after introduction of Leu234Ala, Leu235Ala, and Pro329Gly (LALA-PG) substitutions in the Fc region of 54043-5. Together, these data provide new insights into the protective mechanisms of non-neutralizing antibodies and define a broadly conserved epitope within the S2 subunit.

Pre-print in bioRxiv (Jan. 16, 2024): 

https://doi.org/10.1101/2024.01.15.575741 

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been responsible for a global pandemic. Monoclonal antibodies (mAbs) have been used as antiviral therapeutics; however, these therapeutics have been limited in efficacy by viral sequence variability in emerging variants of concern (VOCs) and in deployment by the need for high doses. In this study, we leveraged the multi-specific, multi-affinity antibody (Multabody, MB) platform, derived from the human apoferritin protomer, to enable the multimerization of antibody fragments. MBs were shown to be highly potent, neutralizing SARS-CoV-2 at lower concentrations than their corresponding mAb counterparts.

In mice infected with SARS-CoV-2, a tri-specific MB targeting three regions within the SARS-CoV-2 receptor binding domain was protective at a 30-fold lower dose than a cocktail of the corresponding mAbs. Furthermore, we showed in vitro that mono-specific MBs potently neutralize SARS-CoV-2 VOCs by leveraging augmented avidity, even when corresponding mAbs lose their ability to neutralize potently, and that tri-specific MBs expanded the neutralization breadth beyond SARS-CoV-2 to other sarbecoviruses. Our work demonstrates how avidity and multi-specificity combined can be leveraged to confer protection and resilience against viral diversity that exceeds that of traditional monoclonal antibody therapies.

Published in ScienceTranslational Medicine (May 24, 2023):

https://doi.org/10.1126/scitranslmed.adf4549 

A study by UPMC and the University of Pittsburgh School of Medicine found that monoclonal antibody treatments significantly reduced the risk of hospitalization or death from COVID-19. The research underscores the importance of investing in infrastructure and healthcare professional skills to efficiently deliver these treatments, particularly in case of more lethal virus variants emerging in the future. The COVID-19 pandemic created a real-life experiment that demanded health care providers nationwide rapidly stand up clinics to administer an evolving offering of monoclonal antibody treatments that — while initially proven safe and effective in clinical trials and approved under federal emergency use authorization — had never been tested at such a scale. The task was massive and the real-world benefit was uncertain, particularly for monoclonals approved later in the pandemic based only on laboratory data. An analysis published today (April 3, 2023) in the Annals of Internal Medicine by UPMC and University of Pittsburgh School of Medicine clinicians and scientists shows that it was worth it. “The virus was a moving target, and, for two years, monoclonal antibodies were approved, revoked, sometimes reauthorized, and sometimes scarce,” said lead author Kevin Kip, Ph.D., vice president of clinical analytics at UPMC. “Using UPMC’s database of patients treated with monoclonal antibodies —one of the largest in the U.S. — we are finally able to conclude that pushing through all these challenges unequivocally saved lives and prevented hospitalizations.” Monoclonal antibodies are human-made antibodies specifically designed to prevent a pathogen — in this case, the virus that causes COVID-19 — from entering human cells, replicating, and causing serious illness. The U.S. Food and Drug Administration granted emergency use authorization to five different COVID-19 monoclonal antibody treatments at various times between 2020 and 2022. All were restricted to people aged 12 and older with risk factors that made them more susceptible to bad outcomes from COVID-19. The treatments had to be administered intravenously or through injection by a healthcare professional. As the virus evolved, new monoclonal antibodies were introduced and older ones, which were no longer effective, were removed.

Starting with the first authorization at the end of 2020, UPMC opened dozens of clinics, set up emergency department infrastructure, and arranged home visits to maximize its ability to provide monoclonal antibodies to patients in Pennsylvania, New York, and Maryland. After the emergency use authorization was revoked for the last monoclonal antibody on November 30, 2022, and no new monoclonal antibodies were introduced, UPMC pulled anonymous clinical data on 2,571 patients treated with monoclonal antibodies and matched them with data from 5,135 patients with COVID-19 who were eligible for monoclonal antibodies but did not receive them. On average, people who received monoclonal antibodies within two days of a positive COVID-19 test reduced their risk of hospitalization or death by 39% compared to their peers who did not receive the treatment. Patients with immunocompromising conditions, regardless of their age, had an even greater reduced risk. Patients treated when the alpha and delta variants of the virus were circulating experienced greater benefit than their untreated peers compared to those treated when the omicron variant was circulating, likely because earlier variants were more deadly and people had less prior immunity from previous infection or vaccination. By the time omicron was circulating, risk of death and hospitalization had fallen in general, so monoclonal antibody treatment had less overall benefit, but still clinically meaningful benefit, particularly in vulnerable patients, explained co-author Erin McCreary, Pharm.D., director of infectious diseases improvement and clinical research innovation at UPMC. “Right now, COVID-19 has a relatively low risk of death for the general population, but we have seen how quickly this virus can mutate and spread. Nobody can say with certainty that a future variant won’t be more deadly,” McCreary said. “Should that happen, our real-world data give reassurance that investing in the infrastructure and healthcare worker knowledge to quickly give antibody treatments keeps people in the communities we serve alive and out of the hospital.”

Study published April 4, 2023 (Annals of Int. Medicine):

https://doi.org/10.7326/M22-1286

The Food and Drug Administration has approved Tocilizumab for use against moderate to severe Covid-19 symptoms. The FDA has approved an early gift for those suffering from Covid-19 this holiday season. Tocilizumab, branded Actemra by pharmaceutical company Genentech, is a monoclonal antibody now approved for treating Covid-19 in hospitalized adult patients in moderate to severe conditions. All treatments to this point of the pandemic were only temporarily approved via emergency use authorization, speaking to the value of Tocilizumab. Here we discuss how the antibody was discovered and how it works. Unlike many monoclonal antibody treatments we discuss, Tocilizumab has a long history dating back 25 years. Clinical development of the antibody began in 1997 by Chugai Pharmaceuticals in Japan to treat rheumatoid arthritis. Chugai Pharmaceuticals and Genentech are now under the Roche Group umbrella, a Swiss multinational healthcare company. The researchers at Chugai Pharmaceuticals found that specific mouse antibodies contained anti-human IL-6 receptors. Interleukin-6, or IL-6, is a secreted cytokine protein expressed by white blood cells. In terms of disease, IL-6 stimulates inflammatory processes when the body is exposed to various pathogens and clinical conditions such as diabetes, multiple sclerosis, and rheumatoid arthritis.

Upon identifying the anti-human IL-6 receptors in mice, the researchers grafted the receptor onto a human IgG constant Fc region using recombinant DNA technology, effectively humanizing the receptor. Later research by Kishimoto et al. confirmed that the engineered mouse antibody receptor grafted to the human IgG constant Fc exclusively blocked IL-6 trans-signaling without affecting other significant pathways. IL-6 inhibition sufficiently blocks inflammation without inhibiting other immune defenses against infection. Contrary to popular belief, many of the classic symptoms we experience when we are sick are not directly caused by an invading pathogen but rather consequences of our immune system fighting off the pathogen. Inflammation is one of the most prominent causes of body pain, fatigue, fever, rash, and other significant symptoms most endure during sickness. In severe cases, inflammation may cause severe pain, lack of appetite, and severe headaches and chills. To produce the drug en masse, Chugai Pharmaceutical used genetic manipulation of host cells. They encoded the genes that code for tocilizumab production onto a human host T-cell. The encoded T-cell is then transfected into Chinese hamster ovary cells. These cells are then manipulated to express countless tocilizumab genes, creating a master that can be copied several times.

Vaccination represents the key strategy to control the COVID-19 pandemic through induction of neutralising antibody responses and T cell-associated immunity that substantially decrease the risk of developing severe disease.  However, individuals who are immunocompromised (eg, because of comorbidities, high age, or immunosuppressive treatment) might not mount a full adaptive immune response and thus remain susceptible. For individuals at high risk, individual monoclonal antibodies (mAbs) or cocktails of mAbs are administered as prophylaxis or therapy.  All mAbs currently approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) target the spike (S) protein.  During the course of the COVID-19 pandemic, several SARS-CoV-2 lineages evolved mutations that confer partial or full resistance against some mAbs. Consequently, only few mAbs remain suitable for treatment of individuals at high risk, and only bebtelovimab shows high efficacy against multiple omicron sublineages. However, novel omicron sublineages have been detected, harbouring additional S protein mutations within the epitopes of bebtelovimab and other mAbs. Novel sublineages include BA.4.6 (with increasing incidence in several countries worldwide), BA.2.75.2 (with increasing incidence in India), BJ.1 (mainly observed in India and Bangladesh; notably BJ.1 is one parental lineage of the currently increasing XBB recombinant), and BQ.1.1 (with increasing incidence in the USA and Europe).

Strategy may offer alternative to daily antiretrovirals.  Individuals with HIV who began taking antiretroviral therapy (ART) in the early stages of infection achieved a lengthy period of HIV suppression without ART after receiving two broadly neutralizing anti-HIV antibodies (bNAbs), according to a small study published today in the journal Nature. The findings suggest that combination bNAb therapy might offer a future alternative to daily ART for people living with HIV. The research was conducted by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, in collaboration with researchers at the NIH Clinical Center; the Maple Leaf Medical Clinic in Toronto; the Frederick National Laboratory for Cancer Research; Harvard Medical School, Boston; and The Rockefeller University, New York City. Although oral antiretrovirals are highly effective at keeping HIV levels under control, it can be difficult for some people with HIV to adhere to a daily medication regimen. Additionally, the medicines can present long-term side effects from lifetime usage and create the possibility for the development of drug-resistant virus. In previous research, single bNAbs showed only limited success in keeping virus levels low partly because bNAb-resistant HIV either already existed or emerged in the individual. To address this problem, researchers in the NIAID Laboratory of Immunoregulation tested a dual combination of bNAbs—called 3BNC117 and 10-1074—targeting different parts of the surface of HIV.

The researchers conducted a two-component clinical trial between September 2018 and January 2021. The first component was a Phase 1 randomized, placebo-controlled trial involving 14 participants with HIV. These individuals had started ART during the early phase of their infection. They were taken off antiretrovirals shortly after receiving their first infusion of the combination bNAbs or placebo. Participants received up to eight bNAb or placebo infusions—two in the first month and once monthly thereafter—for 24 weeks. HIV levels and CD4 T-cell counts were measured every two weeks.  The purpose of the study was to see if treatment with the bNAbs could suppress HIV in the absence of ART. None of the seven participants who received the bNAb treatment had to restart ART before 28 weeks post-infusion compared to six of the seven participants who received placebo. The median duration of time off antiretrovirals was 39.6 weeks (bNAb group) and 9.4 weeks (placebo), respectively. The second component of the study involved bNAb infusions in a group of 5 study participants who were not taking ART but still maintained low levels of HIV. In this smaller group, only two of the five study participants maintained complete suppression of the virus for an average of 41.7 weeks following the bNAb transfusions.

The authors note that the bNAb combination was ineffective in suppressing HIV if participants harbored virus resistant to either or both experimental antibodies before receiving the infusions. The presence of pre-existing antibody-resistant HIV poses a major challenge going forward, according to the authors. No safety issues occurred in the study, and the infusions were well-tolerated. The study authors conclude that the combination bNAb therapy can be highly effective in suppressing HIV in the absence of ART for extended periods, provided that antibody-resistant virus is not present at the time individuals begin antibody treatment. Larger studies are needed to confirm the findings, but as next-generation bNAbs with increased potency and durability become available, “there is reason to believe that infrequent administration (i.e., twice a year) of such antibodies, possibly along with a long-acting injectable antiretroviral drug, could lead to ART-free HIV suppression for extended periods (years) in infected individuals,” the authors wrote.

Research Cited Published in Nature (June 1, 2022):

https://doi.org/10.1038/s41586-022-04797-9 

Despite the success of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, there remains a need for more prevention and treatment options for individuals remaining at risk of coronavirus disease 2019 (COVID-19). Monoclonal antibodies (mAbs) against the viral spike protein have potential to both prevent and treat COVID-19 and reduce the risk of severe disease and death. Here, we describe AZD7442, a combination of two mAbs, AZD8895 (tixagevimab) and AZD1061 (cilgavimab), that simultaneously bind to distinct, nonoverlapping epitopes on the spike protein receptor binding domain to neutralize SARS-CoV-2. Initially isolated from individuals with prior SARS-CoV-2 infection, the two mAbs were designed to extend their half-lives and reduce effector functions. The AZD7442 mAbs individually prevent the spike protein from binding to angiotensin-converting enzyme 2 receptor, blocking virus cell entry, and neutralize all tested SARS-CoV-2 variants of concern. In a nonhuman primate model of SARS-CoV-2 infection, prophylactic AZD7442 administration prevented infection, whereas therapeutic administration accelerated virus clearance from the lung. In an ongoing phase 1 study in healthy participants (NCT04507256), a 300-mg intramuscular injection of AZD7442 provided SARS-CoV-2 serum geometric mean neutralizing titers greater than 10-fold above those of convalescent serum for at least 3 months, which remained threefold above those of convalescent serum at 9 months after AZD7442 administration. About 1 to 2% of serum AZD7442 was detected in nasal mucosa, a site of SARS-CoV-2 infection. Extrapolation of the time course of serum AZD7442 concentration suggests AZD7442 may provide up to 12 months of protection and benefit individuals at high-risk of COVID-19.

Published in Science Translational Medicine (March 2022):

https://doi.org/10.1126/scitranslmed.abl8124 

An injection of monoclonal antibodies was nearly 75 percent effective at preventing RSV-related lower respiratory tract infection in infants, study finds.  Dorina Bryant’s baby, Jaxtyn, was almost 2 weeks old when he caught a virus that left him hospitalized last summer.  His blood oxygen levels were dangerously low and his tiny chest heaved as he breathed. He tested positive for respiratory syncytial virus, or RSV. Despite his oxygen levels falling to 84 percent — 95 percent or higher is considered normal — he was sent home.  Bryant, who lives in Broken Bow, Oklahoma, drove him more than two hours to another hospital. The baby was put on high flow oxygen while his family waited two days for him to be airlifted to a pediatric intensive care unit in a children's hospital.  It took Jaxtyn’s lungs two months to recover. “Every time he coughed, you could tell he needed more time to heal,” Bryant said.  A few months later, in November 2021, Hollie Poore found herself in a similar situation. Across the country in South Jordan, Utah, a cold had run through her family of six. The symptoms lingered in her 3-month-old daughter, Susie. The infant tested positive for RSV and, like Jaxtyn, was sent home. Poore took her to the emergency room hours after she was sent home and noticed her daughter’s lips turning blue in the waiting room. “Immediately, there were tons of doctors in the room putting an oxygen mask on her and admitting her to the ICU,” said Poore. 

Almost all children are infected with RSV by the time they turn 2. For most babies, symptoms resemble a bad cold, but the respiratory virus can be dangerous for very young infants who may be vulnerable to complications such as pneumonia.  Jaxtyn and Susie are among the nearly 60,000 children hospitalized with RSV every year, according to Centers for Disease Control and Prevention data. They both survived, but the virus kills as many as 200 children under age 5 each year. In comparison, just over 300 children age 4 and under have died from Covid-19. “Lower respiratory tract infections kill more children under 5 than anything else and RSV is the No. 1 cause of those infections,” said Dr. Anne Moscona, a virologist and infectious disease physician at Columbia University.  Researchers have tried to discover a safe and effective RSV immunization for decades. New research published Wednesday in the New England Journal of Medicine shows that a one-time injection can protect against RSV complications. The drug, called nirsevimab, was nearly 75 percent effective at preventing RSV-related lower respiratory tract infection, the most common reason for RSV hospitalization in infants, AstraZeneca researchers found. After earlier trials demonstrated the drug's safety, the late-stage trial tested how well the drug works. The study included almost 1,500 infants from around the world who were randomly assigned to a placebo or nirsevimab — 994 received the novel drug and 496 received a placebo. All babies were either full-term or late-preterm infants who were at least 35 weeks. Fewer adverse events were reported in the nirsevimab group than the placebo group. The drug, developed by AstraZeneca, is not a vaccine since it does not require the host to make antibodies against a virus, a process called active immunization. Instead, nirsevimab inoculates babies with antibodies, a process called passive immunization. With nirsevimab, the antibodies stay in the bloodstream and provide protection against severe infection and complications for months, instead of waning quickly.  For infants not considered high risk, the immunization would be given just once, at the beginning of their first RSV season. High-risk babies could get another dose before their second RSV season. 

“This protects young infants in that most vulnerable period before their immune system has matured,” said Tonya Villafana, AstraZeneca's global franchise head, infection and a senior author on the research. "When they get exposed later in life, they can cope with the disease much better." The company expects to submit the trial data to the Food and Drug Administration within a few months.  There is a monoclonal antibody that can prevent RSV called palivizumab, but it requires a series of five monthly shots and is only approved for use in high-risk infants and toddlers. An inoculation like nirsevimab, which would be available to all infants, is badly needed, said Moscona, who was not involved in the research. She called the safety and efficacy studies "rigorous." Because the antibodies in nirsevimab have been altered to stay in the body longer — and provide longer-lasting protection — the inoculation is a a “significant improvement” over other antibody therapies, she said. “We tend to think about these respiratory viruses in kids as only affecting those with underlying illnesses, but globally that’s not the case," Moscona said. "If we look at the global numbers, most kids who get sick and die with RSV have absolutely no underlying issues."

How Covid's spread may have changed RSV

RSV typically circulates with other viruses during the fall through winter. That changed with the delta surge of the pandemic when RSV began spreading last summer, prompting the CDC to issue a warning to parents and doctors. Some experts believe RSV cases could spike again as Covid restrictions are lifted.  “The challenge is that we really don’t know what an RSV season is right now,” said Dr. Michele Kong, a professor at the University of Alabama at Birmingham School of Medicine. RSV may also impact children born during the pandemic differently than pre-pandemic babies, meaning the need for prevention may be even higher.  “Infants today are largely not exposed to RSV in the way their older siblings were a few years ago,” Kong said. “It’s unknown if they may get sicker because they haven’t had this exposure that builds an immune response.”  

The FDA has approved Eli Lilly’s new COVID-19 monoclonal antibody treatment bebtelovimab, granting it emergency authorization. Bebtelovimab can be used for the treatment of mild-to-moderate COVID-19 and has been shown to be effective against the omicron variant.  One day after the United States announced a supply deal for Eli Lilly’s new COVID-19 monoclonal antibody treatment, bebtelovimab, the FDA granted it emergency use authorization. Bebtelovimab can be used for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients, age 12 and older, who are at high risk for progression to severe COVID-19. The treatment has been shown to be active against the omicron variant. Three weeks ago, Lilly’s antibody cocktail of bamlanivimab and etesevimab was banned by the FDA because it was shown to be ineffective against omicron. Regeneron’s antibody, REGEN-COV, also was grounded that day for the same reason. The authorized dose of bebtelovimab is 175 mg given as an intravenous injection over at least 30 seconds. The dosage is considerably smaller and quicker to administer than previous antibody treatments approved for COVID-19. “With the emergence of variants such as omicron, treatment options remain limited,” Daniel Skovronsky, M.D., Ph.D., Lilly's chief scientific and medical officer, said in an announcement of the approval. “Lilly is pleased to provide another treatment option to help address the ongoing needs of patients and healthcare providers, who continue to battle this pandemic.”  The endorsement is based on the analyses of the phase 2 BLAZE-4 trial of nonhospitalized patients who were treated with bebtelovimab alone or together with bamlanivimab and etesevimab. Pseudovirus and authentic virus testing showed that bebtelovimab retained full neutralizing activity against omicron. In addition, the drug demonstrated neutralization against all other known variants of interest including omicron’s emerging subvariant BA.2.

The U.S. has agreed to a $720 million deal for bebtelovimab. Lilly will supply 600,000 courses of the treatment—300, 000 this month and 300,000 by the end of next month. The U.S. will have the option to buy 500,000 more antibody courses to be delivered by July 31. “Should the BA.2 subvariant grow in proportion in the U.S., this potential treatment will help ensure that we can continue to offer a monoclonal antibody treatment that works against that strain of the virus,” the Department of Health & Human Services said in a statement announcing the deal. The HHS will provide the treatment for free, it said. Lilly has been stockpiling the treatment, CEO David Ricks said last month in an interview for Fierce JPM Week. Meanwhile, Lilly also is hoping for a full approval for baricitinib, also known as Olumiant, the company’s Incyte-partnered rheumatoid arthritis drug, which according to Ricks, has become the standard-of-care for late-stage patients on ventilators, as it reduces the risk of death by 46%. Earlier this month, Lilly announced COVID-19 antibody sales of $2.24 billion for 2021, with $1.06 billion coming in the fourth quarter.

Eli Lilly's Press Release (Feb. 11, 2022):

https://investor.lilly.com/news-releases/news-release-details/lillys-bebtelovimab-receives-emergency-use-authorization 

FDA Letter of EUA  (Feb. 11, 2022):

https://www.fda.gov/media/156151/download 

The recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals.

Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb, retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab, S2X259 and S2H97, neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

Preprint Available at bioRxiV (Dec. 14, 2021):

https://doi.org/10.1101/2021.12.12.472269

Vir Biotechnology Press Release (Dec. 14, 2021):

https://investors.vir.bio/news-releases/news-release-details/preclinical-data-highlight-significant-antigenic-shift-omicron 

Glaxo (GSK) and Vir Biotechnology announce promising pre-clinical data from the study of their antibody candidate, sotrovimab, against mutations found in the Omicron variant. The antibody candidate has shown activity against several deadly mutants of coronavirus including Delta, Delta plus and Mu in clinical studies. Amid rising concerns of an Omicron outbreak, the encouraging pre-clinical data against the variant supports its strong potential as an enduring COVID-19 treatment option going forward.  Pre-clinical data included results of testing of sotrovimab against pseudo-viruses with each containing a specific individual mutation found in the Omicron variant. Glaxo and Vir Biotechnology are currently conducting an in-vitro test of their antibody drug against all mutations found in the Omicron variant in a single pseudo-virus. Data from this test will demonstrate the neutralizing ability of sotrovimab against a combination of the Omicron mutations. An update on the data from this in-vitro study is expected by the end of 2021. The companies stated that sotrovimab targets a specific portion of the coronavirus, which makes it more difficult for the variants to develop resistance against the candidate. We note that Glaxo and Vir Biotechnology’s sotrovimab, as an intravenous administration, was granted emergency use authorization (“EUA”) for treating mild-to-moderate COVID-19 in adult and pediatric patients in May. The intravenous drug is available under the tradename of Xevudy.

The approval was based on data from a late-stage study that demonstrated that treatment with sotrovimab achieved 79% reduction in risk of hospitalization or death. Glaxo’s shares have gained 12.7% so far this year compared with the industry’s 12.6% increase. In a separate press release, the companies announced that sotrovimab was granted conditional marketing authorization in the United Kingdom for the treatment of symptomatic adults and adolescents. The drug is authorized for use in patients with acute COVID-19 infection without any requirement of oxygen supplementation with increased risk of progressing to severe infection. The drug needs to be administered within five days of the onset of COVID-19 infection symptoms.  Glaxo and Vir Biotechnology already have a supply agreement in place with the government of the United Kingdom for the supply of sotrovimab. The investigational therapy is also authorized for temporary/conditional use in several other countries including Japan and Canada. It is also under review in Europe. Glaxo and Vir Biotechnology have agreements with several entities across the globe in place for supply of more than 750,000 doses of sotrovimab. The companies also have an agreement with the European Commission for additional doses.

A report released by another COVID-19 drugmaker, Regeneron REGN earlier this week stated that vaccine-induced and monoclonal antibody-conveyed neutralization activity will reduce against the Omicron variant, implying lower effectiveness of available COVID-19 solutions against the new variant of concern, including Regeneron’s antibody cocktail, REGEN-COV. Further tests are being conducted to understand the impact using the actual Omicron variant sequence.  Regeneron’s REGEN-COV comprises two monoclonal antibodies, casirivimab and imdevimab., which have demonstrated strong effectiveness against previous coronavirus strains. Regeneron added $3.5 billion to its top line from sales of REGEN-COV, leading to more than 100% increase in total revenues in the first nine months of 2021...

Vir Biotechnology press release (December 2, 2021):

https://investors.vir.bio/news-releases/news-release-details/preclinical-data-demonstrate-sotrovimab-retains-activity-against 

See also preprint here (Dec. 1, 2021):

https://doi.org/10.1101/2021.03.09.434607

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