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Study identifies four new monoclonal antibodies with broad neutralizing potencies that target conserved SARS-CoV-2 epitopes

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In a recent study posted to the bioRxiv* preprint server, researchers described four novel monoclonal antibodies with potent and broad neutralization activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, including the current globally dominant Omicron BA.4/BA.5.

Study: Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection. Image Credit: Corona Borealis Studio/Shutterstock

Background

Although the early impetus to develop coronavirus disease 2019 (COVID-19) vaccines and the use of monoclonal antibody therapies successfully limited the severity of SARS-CoV-2 infections, the emergence of Omicron subvariants with mutations in the spike protein receptor binding domain (RBD) is challenging the vaccine-induced immunity.

Since early vaccines and monoclonal antibodies targeted the receptor binding motif that binds to the angiotensin-converting enzyme-2 (ACE-2) receptor, these novel mutations allow the emergent Omicron subvariants to escape the neutralizing antibodies generated against the RBD of earlier variants, reducing the efficacy of the therapeutic monoclonal antibodies in clinical use.

Combining monoclonal antibodies that target a wide variety of epitopes, including conserved regions inside and outside the RBD, might not only broaden the therapeutic antibodies’ neutralizing activity but also help reduce the selection pressure driving the development of new variants of concern.

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About the study

In the present study, the researchers isolated monoclonal antibodies specific for SARS-CoV-2 spike proteins from a patient who experienced a Delta variant breakthrough infection two months after completing the primary vaccination regimen with the Pfizer-BioNTech messenger ribonucleic acid (mRNA) vaccine. Peripheral blood mononuclear cells (PBMCs) were collected after 30 days of the onset of symptoms to isolate memory B cells using spike-subunit 2 or Delta spike protein peptide baits. Variable regions of the heavy and light chain immunoglobulin genes were recovered and cloned into immunoglobulin G (IgG) kappa, lambda, or gamma constructs to produce monoclonal antibodies.

Enzyme-linked immunosorbent assays (ELISA) were used to screen these monoclonal antibodies using a panel of SARS-CoV-2 spike glycoproteins from multiple variants. Biolayer interferometry (BLI) was performed to assess the binding affinity of the identified monoclonal antibodies to spike proteins from Omicron subvariants BA.1, BA.2, and BA.4/BA.5, as well as from the ancestral Wuhan-Hu-1 and SARS-CoV-1 spike glycoproteins.

Neutralization assays using spike-pseudotyped lentivirus and live SARS-CoV-2 were conducted to test the neutralizing potency of the monoclonal antibodies. The neutralizing activity of the selected monoclonal antibodies was also compared to that of monoclonal antibodies authorized for treating SARS-CoV-2 infections. The neutralization assay with pseudotyped lentivirus also assessed the neutralizing capacity of the plasma samples collected from the participant.

The live virus neutralization assay tested the efficacy of the monoclonal antibodies against a wide range of variants, including the ancestral Wuhan-Hu-1 strain and the Alpha and Delta variants. The Omicron subvariants BA.1, BA.2, and BA.2.12.1.

Additionally, various recombinant spike subdomain peptides were used to identify the spike glycoprotein regions to which the monoclonal antibodies were binding. Commercial monoclonal antibodies belonging to RBD classes based on the structural analysis of contact residues and epitope accessibility and deep mutational scanning were employed for competition ELISA to refine the epitopes of the selected monoclonal antibodies.

Fluorescence-activated cell sorting-based assay and yeast display libraries of mutated RBDs were used to determine the effect of a single amino acid substitution mutation on the binding of the monoclonal antibody to the epitope. Structural methods such as cryogenic electron microscopy (cryo-EM) structure determination and hydrogen-deuterium exchange mass spectrometry were also conducted to examine the epitopes targeted by selected monoclonal antibodies.

Results

The results described four monoclonal antibodies isolated from a patient with a heterologous antigen exposure to the spike proteins from the ancestral Wuhan-Hu-1 strain through vaccination and the Delta variant spike protein from breakthrough infections. In the neutralization assays using pseudotyped lentiviruses and live SARS-CoV-2 viruses, these four antibodies displayed neutralizing activity against the currently dominant Omicron subvariants BA.4/BA.5 while retaining potent neutralizing capacity against the Wuhan-Hu-1 strain and the Delta variant. One of the monoclonal antibodies was also able to neutralize SARS-CoV-1.

Compared to the monoclonal antibodies currently in clinical use, the potency of the newly isolated monoclonal antibodies against the Omicron subvariants was higher than all the currently approved therapeutic monoclonal antibodies except one. The epitopes targeted by these monoclonal antibodies included one in subdomain 1 in an invariant region outside the RBD and three in the RBD. The deep mutational scanning analysis to identify escape pathways from single amino acid substitutions showed that these monoclonal antibodies targeted conserved and constrained regions of the spike glycoprotein. These findings suggested that viruses could evolve to escape these monoclonal antibodies only at a fitness cost.

Conclusions

To summarize, the study identified four novel monoclonal antibodies that exhibited broad neutralization of a range of SARS-CoV-2 variants, including the Omicron subvariants BA.4/BA.5 and the ancestral Wuhan-Hu-1 strain and the Delta variant. These monoclonal antibodies target three epitopes in the RBD and one in subdomain 1 outside the RBD. Since these epitopes are highly conserved, the evolution of the virus to escape neutralization by these monoclonal antibodies could be detrimental to its fitness.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Jamie Guenthoer, Michelle Lilly, Tyler N Starr, Bernadeta Dadonaite, Klaus N Lovendahl, Jacob T Croft, Caitlin I Stoddard, Vrasha Chohan, Shilei Ding, Felicitas Ruiz, Mackenzie S Kopp, Andrés Finzi, Jesse D Bloom, Helen Y Chu, Kelly K Lee, and Julie Overbaugh. (2022). Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection. bioRxiv. doi: https://doi.org/10.1101/2022.12.15.520606 https://www.biorxiv.org/content/10.1101/2022.12.15.520606v1

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Governments seek buyer as Quebec COVID-19 vaccine manufacturer Medicago set to close

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MONTREAL — The Quebec government says it’s looking to find a buyer for Medicago Inc., the Quebec-based COVID-19 vaccine manufacturer that will be shut down by parent company Mitsubishi Chemical.

Quebec Economy Minister Pierre Fitzgibbon said Friday the province has had preliminary talks with potential buyers in the pharmaceutical sector to keep Medicago’s expertise and skilled workforce in Quebec. He said both the Quebec and federal governments would be willing to put in money to secure a deal.

“We can’t operate it ourselves; the government will not be the main shareholder,” Fitzgibbon said. “But if there is a pharmaceutical company that considers it’s worth continuing, we’re ready to help.”

Mitsubishi Chemical said Thursday it would stop marketing the Medicago-produced Covifenz vaccine, which is plant-based and was approved by Health Canada one year ago for adults aged 18 to 64.

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The Japanese chemical company said it had been preparing to commercially produce the Covifenz vaccine but decided against doing so because of the “significant changes” in the COVID-19 vaccine environment. The company said it would dissolve Medicago because it is no longer “viable” to continue marketing its products.

“In light of significant changes to the COVID-19 vaccine landscape since the approval of Covifenz, and after a comprehensive review of the current global demand and market environment for COVID-19 vaccines and Medicago’s challenges in transitioning to commercial-scale production, the (company) has determined that it will not pursue the commercialization of Covifenz,” Mitsubishi Chemical said in a statement.

Following the announcement, Medicago issued a statement thanking its employees. “The Medicago team has pushed scientific boundaries and we know that they will continue to make incredible contributions to innovation and biopharmaceutical’s sector.”

Canada invested $173 million in Medicago in 2020 to support development of the Covifenz vaccine and help Medicago expand its production facility in Quebec City.

On Thursday, Innovation, Science and Industry Minister François-Philippe Champagne told reporters the federal government is in “solution mode.”

“Our first order of business is really to try to find a partner who can help us preserve the jobs, preserve the technology and the intellectual property,” Champagne said.

The minister acknowledged that mRNA vaccine technology for COVID-19 became dominant as it “seemed to be most effective.”

But Medicago’s plant-based vaccine was still “promising,” Champagne said.

“Everyone agreed that the plant-based vaccine could very well help in a future pandemic,” Champagne said.

Speaking to reporters on Montreal’s South Shore Friday, Fitzgibbon said the company informed the province at the end of December it intended to pull the plug on Medicago.

In May 2015, Quebec and Ottawa announced loans of $60 million and $8 million, respectively, for the construction of a complex in the Quebec City region to house Medicago’s activities.

“The challenge is not (getting the loan repaid), it’s how we can save the jobs, save this company,” Fitzgibbon said.

While Canada authorized Medicago’s vaccine in February 2022, it was rejected for emergency use by the World Health Organization in March because tobacco company Philip Morris was a minority shareholder in the company, contravening a policy adopted in 2005 by the United Nations agency.

Quebec City Mayor Bruno Marchand said on Twitter he was saddened by the closure of the company.

“My thoughts are with the families who learned some very sad news,” Marchand said Thursday evening. “We have to roll up our sleeves to keep all this expertise in the field of health innovation in Quebec City.”

This report by The Canadian Press was first published Feb. 3, 2023.

 

Sidhartha Banerjee, The Canadian Press

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Bird flu keeps spreading beyond birds. Scientists worry it signals a growing threat to humans, too

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As a deadly form of avian influenza continues ravaging bird populations around much of the world, scientists are tracking infections among other animals — including various types of mammals more closely related to humans.

Throughout the last year, Canadian and U.S. officials detected highly pathogenic H5N1 avian flu in a range of species, from bears to foxes. In January, France’s national reference laboratory announced that a cat suffered severe neurological symptoms from an infection in late 2022, with the virus showing genetic characteristics of adaptation to mammals.

Most concerning, multiple researchers said, was a large, recent outbreak on a Spanish mink farm.

Last October, farm workers began noticing a spike in deaths among the animals, with sick minks experiencing an array of dire symptoms like loss of appetite, excessive saliva, bloody snouts, tremors, and a lack of muscle control.

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The culprit wound up being H5N1, marking the first known instance of this kind of avian influenza infection among farmed minks in Europe, notes a study published in Eurosurveillance this month.

“Our findings also indicate that an onward transmission of the virus to other minks may have taken place in the affected farm,” the researchers wrote.

Eventually, the entire population of minks was either killed or culled — more than 50,000 animals in total.

That’s a major shift, after only sporadic cases among humans and other mammals over the last decade, according to Michelle Wille, a researcher at the University of Sydney who focuses on the dynamics of wild bird viruses.

“This outbreak signals the very real potential for the emergence of mammal-to-mammal transmission,” she said in email correspondence with CBC News.

It’s only one farm, and notably, none of the workers — who all wore face shields, masks, and disposable overalls — got infected.

But the concern now, said Toronto-based infectious disease specialist Dr. Isaac Bogoch, is if this virus mutates in a way that allows it to become increasingly transmissible between mammals, including humans, “it could have deadly consequences.”

“This is an infection that has epidemic and pandemic potential,” he said. “I don’t know if people recognize how big a deal this is.”

 

‘Explosive’ avian flu surge hits global bird populations

Global bird populations are being ravaged by a deadly strain of avian flu, wiping out flocks of domestic poultry and killing wild birds. Some researchers warn the virus could eventually evolve to better infect humans and potentially start a future pandemic.

H5N1 has high mortality rate

Among birds, the mortality rate of this strain of highly pathogenic avian influenza can be close to 100 per cent, causing devastation to both wild bird populations and poultry farms.

It’s also often deadly for other mammals, humans included.

The World Health Organization (WHO) has documented 240 cases of H5N1 avian influenza within four Western Pacific countries — including China, Cambodia, Laos, and Vietnam — over the last two decades. More than half of the infected individuals died.

Global WHO figures show more than 870 human cases were reported from 2003 to 2022, along with at least 450 deaths — a fatality rate of more than 50 per cent.

Bogoch said the reported death toll may be an overestimate, since not all infections may be detected, though it’s clear people can “get very, very sick from these infections.”

Most human infections also appeared to involve people having direct contact with infected birds. Real-world mink-to-mink transmission now firmly suggests H5N1 is now “poised to emerge in mammals,” Wille said — and while the outbreak in Spain may be the first reported instance of mammalian spread, it may not be the last.

“A virus which has evolved on a mink farm and subsequently infects farm workers exposed to infected animals is a highly plausible route for the emergence of a virus capable of human-to-human transmission to emerge,” she warned.

Louise Moncla, an assistant professor of pathobiology at the University of Pennsylvania school of veterinary medicine, explained that having an “intermediary host” is a common mechanism through which viruses adapt to new host species.

“And so what’s concerning about this is that this is exactly the kind of scenario you would expect to see that could lead to this type of adaptation, that could allow these viruses to replicate better in other mammals — like us.”

Government workers wear protective gear to collect poultry for slaughter during an outbreak of avian influenza on the Ivory Coast. More than 70 countries have reported cases this year, according to the World Organisation for Animal Health.
Government workers wear protective gear to collect poultry for slaughter during an outbreak of avian influenza on the Ivory Coast. More than 70 countries reported cases in 2022, according to the World Organisation for Animal Health. (Legnan Koula/EPA-EFE)

Surveillance, vaccines both needed

What’s more reassuring is the ongoing development of influenza vaccines, giving humanity a head start on the well-known threat posed by bird flu.

Wille noted the earlier spread of H7N9, another avian influenza strain which caused hundreds of human cases in the early 2010s, prompted similar concern that the virus would acquire the mutations needed for ongoing human-to-human transmission.

“However, a very aggressive and successful poultry vaccination campaign ultimately stopped all human cases,” she added.

But while several H5N1 avian influenza vaccines have been produced, including one manufactured in Canada, there’s no option approved for public use in this country.

To ward off the potential threat this strain poses to human health, Bogoch said ongoing surveillance and vaccine production needs to remain top-of-mind for both policy makers and vaccine manufacturers.

Dr. Jan Hajek, an infectious diseases physician at Vancouver General Hospital, also questioned whether it’s time to wind down global mink farming, given the spread of various viruses, from avian influenza to SARS-CoV-2, the virus behind COVID-19.

“We’re closely related to minks and ferrets, in terms of influenza risks … if it’s propagating to minks, and killing minks, it’s worrisome to us,” he said.

In 2021, B.C. officials announced an end to mink farming across the province, saying the farms can be reservoirs for viruses and represent an ongoing danger to public health. All mink farm operations must be shut down, with all of the pelts sold, by April 2025.

However, other provinces — and plenty of countries — do intend to keep their mink farms operating.

“Is it responsible to have these kinds of farming conditions where these types of events can occur?” questioned Moncla. “If we’re going to keep having these types of farms, what can we do to make this safer?”

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6,654 students facing suspension due to out-of-date immunization records

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The Windsor-Essex County Health Unit (WECHU) has issued about 6,654 suspension orders to students who do not meet immunization requirements.

WECHU completed a review of all elementary student immunization records in December and more than 12,000 students received a notice.

These students were either overdue for one or more vaccines required to attend school, or their immunization records were not updated with the health unit.

“While many of these vaccines are normally administered by primary health care providers, parents and guardians of children who received their vaccines from their health care provider still need to report this information to the health unit,” said a WECHU news release.

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The Immunization of School Pupils Act (ISPA) (1990), Section 11, Subsections (1) and (2) requires public health units to maintain and review vaccine records for every student attending school and to enforce a school suspension for incomplete immunization information. As the next step of the ISPA enforcement process, orders were mailed out to students that do not meet this requirement.

WECHU said this is the final notice.

The suspension order notifies parents and guardians that immunization records must be updated to the WECHU by Thursday, March 16, at 6 p.m. or their child will be suspended for up to 20 days from school, starting Monday, March 20, 2023. Once parents and guardians provide the missing immunization information to the WECHU, the student is removed from the suspension list and can attend school again.

Under the ISPA , children can be exempted from immunization for medical reasons or due to conscience or religious belief.

Families can book immunization appointments with their health care provider and are reminded to update their child’s immunization records online at immune.wechu.org.

Catch-up immunization clinics are also being offered at the WECHU Windsor and Leamington offices and will continue until the end of March. Families can book an appointment at a WECHU clinic by visiting wechu.org/getimmunized or by calling the WECHU at 519-960-0231.

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