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Tripledemic Rouses Vaccine Developers and Variant Trackers

Some things that come in threes are seen in a positive light. But threes also have their dark side, as evidenced by the so-called tripledemic—the unprecedented…

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Some things that come in threes are seen in a positive light: the Triple Crown of horse racing, the Three Musketeers, and hockey’s “hat trick.” But threes also have their dark side, as evidenced by the so-called tripledemic—the unprecedented concurrence this winter of three major respiratory viruses: respiratory syncytial virus (RSV), seasonal influenza, and COVID-19. At times, the tripledemic has threatened to overwhelm the healthcare system.

By early winter, RSV, flu, and COVID-19 were surging more or less simultaneously. Might such multipronged attacks become the norm? “Most certainly COVID-19 is not going away,” says Steven J. Lawrence, MD, professor of medicine, Division of Infectious Diseases, Washington University School of Medicine. “However, many believe that once the variants settle down, there will be a more seasonal pattern. The problem is that when a new variant appears, it begins to infect a lot of people no matter what time of year it is. However, we do see some seasonality with COVID-19.”

Lawrence also suggests that the tripledemic pattern may be here to stay: “It is likely that this is going to be the new normal with each year seeing the co-circulation and seasonality of RSV, flu, and COVID-19.”

Surveillance and testing

Identifying which virus is causing an infection is not only critical to appropriate medical management, but also necessary for properly tracking outbreaks. A global network has already been established for tracking influenza. “There are reference sites that have been around a long time, such as doctors’ offices and clinics,” Lawrence notes. “Each year, members send their flu isolates into a central repository for analysis. Thus, we are tracking not only flu numbers but also strains and the mutations that are occurring.” An updated weekly U.S. influenza surveillance report (FluView) is available from the Centers for Disease Control and Prevention (CDC).

Influenza A and B viruses cause seasonal epidemics of flu disease almost every winter in the United States, but only influenza A viruses are known to cause global epidemics. Both A and B viruses receive special attention from the CDC, which supplied this image of an A virus. The week this article went to press, the CDC reported that of the A viruses known to be circulating, 72% were A(H3N2) and 28% were A(H1N1). H: hemagglutinin; N; neuraminidase; M2: matrix-2 protein; RNP: ribonucleoprotein.

Lawrence indicates that COVID-19 surveillance lags behind but is becoming more robust in tracking numbers of cases and in using sophisticated genomic analyses of SARS-CoV-2 to identify which variants are circulating. He points out, “However, RSV hasn’t caught up in surveillance with the others. There are pockets around the country performing RSV surveillance. They don’t have quite the robustness that has been established for flu and COVID-19, but they still provide insights.”

As for testing to diagnose viruses, PCR testing remains the gold standard for identifying and differentiating each virus. “During flu season, multiplex tests performed by healthcare providers are valuable to distinguish each virus,” Lawrence elaborates. “While home COVID-19 tests are widely available, they are not as available for other viruses. But since there is overlap among symptoms, and since there are specific treatments for COVID-19 and flu, it is important to determine which virus is causing infections.”

According to Lawrence, there are two major forms of therapy for COVID-19. The first form involves the administration of drugs that stop viral replication. These drugs include Paxlovid (nirmatrelvir/ritonavir), Veklury (remdesivir), and Lagevrio (molnupiravir). The second form involves monoclonal antibodies such as Evusheld (tixagevimab/cilgavimab).

For pre-exposure prophylaxis, Evusheld is becoming less effective against the newer COVID-19 variants. Bebtelovimab, another monoclonal antibody, no longer works against the current dominant strain (Omicron variant BQ1.1). Accordingly, the Food and Drug Administration has pulled bebtelovimab’s emergency use authorization.

Lawrence stresses that it is important for patients to seek flu treatment, especially if they are high-risk individuals. The CDC reports that all viruses evaluated were susceptible to the influenza antivirals Tamiflu (oseltamivir), Rapivab (peramivir), Relenza (zanamivir), and Xofluza (baloxavir).

Faster and more potent flu vaccines

Keeping up with fast-mutating viruses is no easy feat. For example, the rapid emergence of a veritable smorgasbord of SARS-CoV-2 variants has challenged vaccine developers. Fortunately, these developers have been able to take advantage of mRNA technology, which continues to improve and expedite the appearance of COVID-19 vaccines. And now mRNA technology is being used to engineer improved flu vaccines.

Scientists at the Washington School of Medicine are conducting a Phase II study to assess a new mRNA flu vaccine developed by Moderna (mRNA-1010). “Our study is designed to examine in detail the immunologic response of this mRNA vaccine as compared to the standard flu vaccine,” reports Rachel Presti, MD, PhD, associate professor of medicine and medical director of the institution’s Infectious Diseases Clinical Research Unit.

According to Presti, one major challenge of the current flu vaccines is that they sometimes target the wrong strains. “Every year, the CDC has data for how well the flu vaccine strains chosen matched the strains that actually circulated,” she notes. “Because traditional flu vaccines take longer to prepare, we have to choose strains very early in the year. Even when the best available data is used, incorrect strains are sometimes chosen to be in the vaccine.

“What is exciting about mRNA vaccines is that the speed of preparing them allows us to wait, for example, until late summer to see what is circulating in the world. Those few extra months provide better current data to select more accurately the best strains to use.”

Although the technology to produce mRNA vaccines is still new, Presti feels that it could be the wave of the future, especially against viruses. “For viruses where we know what antigens we need to target, it may be of more use,” she points out. “For bacterial pathogens that may require targeting of sugar structures, for example, mRNA vaccines may not be the solution. But I do think more and more mRNA vaccines will be developed—especially against epidemic-like viruses, where we need to respond rapidly.”

RSV immunity gap?

One reason RSV has surged this year may relate to an “immunity gap,” according to Dan Rocca, PhD, a research leader at Charles River Laboratories. “During the pandemic, the safety measures such as lockdowns, mask wearing, and social distancing which kept us protected from catching COVID-19 also protected us from the large variety of other respiratory viruses such as influenza and RSV,” he says. “It is likely that many of these preventative COVID-19 measures led to a lack of exposure to the virus and an ‘immunity gap’ where the usual immune response to existing RSV strains that populations build over time was subsequently greatly diminished.”

Several therapies are being used to help the most susceptible or most at-risk patients avoid hospitalization. “Palivizumab [sold under the brand name Synagis], for example, is a monoclonal antibody therapy directed specifically at RSV,” details Sandy Kimber, PhD, group leader of the Portishead UK Infection Team at Charles River. “Ribavirin [sold under brand names such as Moderiba, Virazole, and Ribasphere] is another antiviral inhibitor therapy that is effective against RSV, but it isn’t used in children due to long-term safety concerns.

“More RSV antiviral inhibitors that prevent viral entry and replication are in development, as well as therapeutic antibodies to limit infection. One such example is the recently approved nersivemab from AstraZeneca/Sanofi [sold under the brand name Beyfortus]—a long-lived monoclonal antibody of demonstrated superiority that has cost benefits over current acute therapies.”

RSV maternal vaccine

Although the development of vaccines against RSV has lagged behind the development of vaccines against flu and COVID-19, a new maternal vaccine candidate against RSV is undergoing clinical trials. One of the scientists working on these trials is Carol Kao, MD, assistant professor of pediatrics, Washington University School of Medicine.

respiratory syncytial virus (RSV)
The surveillance of respiratory syncytial virus (RSV) is not as robust as the surveillance of influenza and COVID-19. At present, this surveillance gap is a source of consternation. RSV is surging, possibly because of an “immunity gap,” a population-level vulnerability that may be due to anti-COVID-19 safety measures reducing exposure to RSV. (This image shows RSV under a fluorescence microscope.)

“RSV is the number one cause of infant hospitalizations in the United States,” she says. “Worldwide, it causes over 30 million infections in children less than five years of age and is a leading cause of death in infants. RSV prevention in infants is a huge unmet need; there are no widely available preventative measures or treatments for RSV illness. All we can really do is support babies with intravenous fluids or supplemental oxygen until they get better.”

She adds, however, that the new RSV vaccine candidate looks promising. “This would be the first RSV vaccine approved,” she remarks. “So, this is a very exciting time.”

The new vaccine candidate is called RSVpreF, and it is being developed by Pfizer. The company says that RSVpreF is a bivalent vaccine candidate that is composed of equal amounts of recombinant RSV prefusion F from subgroups A and B.

“Given that young infants are the most severely affected by RSV, a maternal vaccine given during pregnancy would allow for infants to be protected right off the bat, during their most vulnerable early months of life,” Kao explains. “This is similar to why we give influenza, COVID-19, and Tdap (pertussis) vaccines to women during pregnancy.”

Kerstin Pohl
Kerstin Pohl, SCIEX

Pfizer recently announced positive top-line data from MATISSE (MATernal Immunization Study for Safety and Efficacy), a Phase III, randomized, double-blinded, placebo-controlled trial that started in June 2020 and that has spanned multiple RSV seasons in both the northern and southern hemispheres. Pregnant women were vaccinated in their late second to third trimester of pregnancy, followed for six months after delivery, and their infants were followed for at least one to two years. Kao reports, “Preliminary study results, which included 7,400 pregnant people and infants, showed that the vaccine was well tolerated and 82% effective at preventing severe lower respiratory tract infections in babies for the first three months of life and 70% effective for the first six months of life.”

Advancing analytics and surveillance

Even amid the tripledemic, scientists continue to improve the analysis of vaccines as well as the surveillance of viral variants. For example, scientists at Sciex and Precision NanoSystems are collaborating to develop highly analytical tests to support the development of mRNA vaccines and other products.

 

Adam Crowe
Adam Crowe, PhD
Precision NanoSystems

“The established and ideal carriers for mRNA-based medicines, including certain COVID-19 vaccines and mRNA therapeutics, are lipid nanoparticles (LNPs),” asserts Kerstin Pohl, senior manager of cell and gene therapy and nucleic acids, SCIEX. Recent studies, however, have identified an impurity that originates from ionizable lipids, a key component of LNPs. “Ionizable lipids are susceptible to chemical alterations—predominantly oxidation,” Pohl notes. “Site-specific oxidation can lead to the formation of reactive lipid species that bind to mRNA to form mRNA-lipid adducts. These adducts, even in tiny amounts, can prevent mRNA-triggered protein expression, reducing drug efficacy.”

Ramin Khaksa

Sciex has developed a new electron-activated dissociation (EAD) mass spectrometry approach that can analyze LNPs and lipid raw materials at very low abundance, revealing exact oxidation sites. According to Adam Crowe, PhD, manager of analytical development, Precision NanoSystems, advanced analytics can help biopharmaceutical companies manage the challenges of mRNA lipidation. He adds that these companies are increasingly requiring support from contract development and manufacturing organizations.

“Direct monitoring of adduct formation on mRNA via ion-pair reversed-phase high-performance liquid chromatography with ultraviolet spectroscopy detection and mass spectrometry has proven effective,” Crowe states. “However, significant expertise is required to optimize methods, generate controls, and ensure assay robustness.”

electron-activated dissociation (EAD)
Besides improving the surveillance of virus variants, scientists are improving the analysis of vaccines. The latter activity is aided by the use of electron-activated dissociation (EAD) mass spectrometers such as the ZenoTOF 7600, an instrument developed by SCIEX. By enabling the tunable fragmentation of all molecule types, the ZenoTOF can detect and quantify impurities such as ionizable lipids, which may originate from the lipid nanoparticles that carry mRNA-based vaccines and medicines.

Improvements in next-generation sequencing are also tightening the surveillance of variants. Ramin Khaksar, PhD, COO and CSO at Clear Labs, says that such improvements are evident in his company’s surveillance solution: “It is a uniquely complete end-to-end, near-real-time solution that integrates software, hardware, bioinformatics, analytics, and reporting with a single touch point. This integrated solution enables NGS applications to be more adaptable to a variety of laboratories without barriers from lab and computer infrastructure or access to skilled scientists and bioinformaticians.”

The tally

At the end of 2022, the CDC released estimates that it had gathered for the flu season up to that point: 20 million illnesses, 210,000 hospitalizations, and 13,000 deaths. The good news was that the CDC also indicated that the majority of flu viruses tested were antigenically similar to those included in the current year’s vaccine. At the time, 44% of U.S. counties were experiencing medium to high COVID-19 levels in each community. (To see current results, visit the CDC’s COVID Data Tracker, an online resource.)

Although experts warn that the tripledemic trend will likely continue in subsequent seasons, scientists continue fighting back by developing improved antiviral vaccines and treatments as well as more sophisticated and accurate analytical and surveillance technologies.

 

The post Tripledemic Rouses Vaccine Developers and Variant Trackers appeared first on GEN - Genetic Engineering and Biotechnology News.

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Glimpse Of Sanity: Dartmouth Returns Standardized Testing For Admission After Failed Experiment

Glimpse Of Sanity: Dartmouth Returns Standardized Testing For Admission After Failed Experiment

In response to the virus pandemic and nationwide…

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Glimpse Of Sanity: Dartmouth Returns Standardized Testing For Admission After Failed Experiment

In response to the virus pandemic and nationwide Black Lives Matter riots in the summer of 2020, some elite colleges and universities shredded testing requirements for admission. Several years later, the test-optional admission has yet to produce the promising results for racial and class-based equity that many woke academic institutions wished.

The failure of test-optional admission policies has forced Dartmouth College to reinstate standardized test scores for admission starting next year. This should never have been eliminated, as merit will always prevail. 

"Nearly four years later, having studied the role of testing in our admissions process as well as its value as a predictor of student success at Dartmouth, we are removing the extended pause and reactivating the standardized testing requirement for undergraduate admission, effective with the Class of 2029," Dartmouth wrote in a press release Monday morning. 

"For Dartmouth, the evidence supporting our reactivation of a required testing policy is clear. Our bottom line is simple: we believe a standardized testing requirement will improve—not detract from—our ability to bring the most promising and diverse students to our campus," the elite college said. 

Who would've thought eliminating standardized tests for admission because a fringe minority said they were instruments of racism and a biased system was ever a good idea? 

Also, it doesn't take a rocket scientist to figure this out. More from Dartmouth, who commissioned the research: 

They also found that test scores represent an especially valuable tool to identify high-achieving applicants from low and middle-income backgrounds; who are first-generation college-bound; as well as students from urban and rural backgrounds.

All the colleges and universities that quickly adopted test-optional admissions in 2020 experienced a surge in applications. Perhaps the push for test-optional was under the guise of woke equality but was nothing more than protecting the bottom line for these institutions. 

A glimpse of sanity returns to woke schools: Admit qualified kids. Next up is corporate America and all tiers of the US government. 

Tyler Durden Mon, 02/05/2024 - 17:20

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Four burning questions about the future of the $16.5B Novo-Catalent deal

To build or to buy? That’s a classic question for pharma boardrooms, and Novo Nordisk is going with both.
Beyond spending billions of dollars to expand…

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To build or to buy? That’s a classic question for pharma boardrooms, and Novo Nordisk is going with both.

Beyond spending billions of dollars to expand its own production capacity for its weight loss drugs, the Danish drugmaker said Monday it will pay $11 billion to acquire three manufacturing plants from Catalent. It’s part of a broader $16.5 billion deal with Novo Holdings, the investment arm of the pharma’s parent group, which agreed to acquire the contract manufacturer and take it private.

It’s a big deal for all parties, with potential ripple effects across the biotech ecosystem. Here’s a look at some of the most pressing questions to watch after Monday’s announcement.

Why did Novo do this?

Novo Holdings isn’t the most obvious buyer for Catalent, particularly after last year’s on-and-off M&A interest from the serial acquirer Danaher. But the deal could benefit both Novo Holdings and Novo Nordisk.

Novo Nordisk’s biggest challenge has been simply making enough of the weight loss drug Wegovy and diabetes therapy Ozempic. On last week’s earnings call, Novo Nordisk CEO Lars Fruergaard Jørgensen said the company isn’t constrained by capital in its efforts to boost manufacturing. Rather, the main challenge is the limited amount of capabilities out there, he said.

“Most pharmaceutical companies in the world would be shopping among the same manufacturers,” he said. “There’s not an unlimited amount of machinery and people to build it.”

While Novo was already one of Catalent’s major customers, the manufacturer has been hamstrung by its own balance sheet. With roughly $5 billion in debt on its books, it’s had to juggle paying down debt with sufficiently investing in its facilities. That’s been particularly challenging in keeping pace with soaring demand for GLP-1 drugs.

Novo, on the other hand, has the balance sheet to funnel as much money as needed into the plants in Italy, Belgium, and Indiana. It’s also struggled to make enough of its popular GLP-1 drugs to meet their soaring demand, with documented shortages of both Ozempic and Wegovy.

The impact won’t be immediate. The parties expect the deal to close near the end of 2024. Novo Nordisk said it expects the three new sites to “gradually increase Novo Nordisk’s filling capacity from 2026 and onwards.”

As for the rest of Catalent — nearly 50 other sites employing thousands of workers — Novo Holdings will take control. The group previously acquired Altasciences in 2021 and Ritedose in 2022, so the Catalent deal builds on a core investing interest in biopharma services, Novo Holdings CEO Kasim Kutay told Endpoints News.

Kasim Kutay

When asked about possible site closures or layoffs, Kutay said the team hasn’t thought about that.

“That’s not our track record. Our track record is to invest in quality businesses and help them grow,” he said. “There’s always stuff to do with any asset you own, but we haven’t bought this company to do some of the stuff you’re talking about.”

What does it mean for Catalent’s customers? 

Until the deal closes, Catalent will operate as a standalone business. After it closes, Novo Nordisk said it will honor its customer obligations at the three sites, a spokesperson said. But they didn’t answer a question about what happens when those contracts expire.

The wrinkle is the long-term future of the three plants that Novo Nordisk is paying for. Those sites don’t exclusively pump out Wegovy, but that could be the logical long-term aim for the Danish drugmaker.

The ideal scenario is that pricing and timelines remain the same for customers, said Nicole Paulk, CEO of the gene therapy startup Siren Biotechnology.

Nicole Paulk

“The name of the group that you’re going to send your check to is now going to be Novo Holdings instead of Catalent, but otherwise everything remains the same,” Paulk told Endpoints. “That’s the best-case scenario.”

In a worst case, Paulk said she feared the new owners could wind up closing sites or laying off Catalent groups. That could create some uncertainty for customers looking for a long-term manufacturing partner.

Are shareholders and regulators happy? 

The pandemic was a wild ride for Catalent’s stock, with shares surging from about $40 to $140 and then crashing back to earth. The $63.50 share price for the takeover is a happy ending depending on the investor.

On that point, the investing giant Elliott Investment Management is satisfied. Marc Steinberg, a partner at Elliott, called the agreement “an outstanding outcome” that “clearly maximizes value for Catalent stockholders” in a statement.

Elliott helped kick off a strategic review last August that culminated in the sale agreement. Compared to Catalent’s stock price before that review started, the deal pays a nearly 40% premium.

Alessandro Maselli

But this is hardly a victory lap for CEO Alessandro Maselli, who took over in July 2022 when Catalent’s stock price was north of $100. Novo’s takeover is a tacit acknowledgment that Maselli could never fully right the ship, as operational problems plagued the company throughout 2023 while it was limited by its debt.

Additional regulatory filings in the next few weeks could give insight into just how competitive the sale process was. William Blair analysts said they don’t expect a competing bidder “given the organic investments already being pursued at other leading CDMOs and the breadth and scale of Catalent’s operations.”

The Blair analysts also noted the companies likely “expect to spend some time educating relevant government agencies” about the deal, given the lengthy closing timeline. Given Novo Nordisk’s ascent — it’s now one of Europe’s most valuable companies — paired with the limited number of large contract manufacturers, antitrust regulators could be interested in taking a close look.

Are Catalent’s problems finally a thing of the past?

Catalent ran into a mix of financial and operational problems over the past year that played no small part in attracting the interest of an activist like Elliott.

Now with a deal in place, how quickly can Novo rectify those problems? Some of the challenges were driven by the demands of being a publicly traded company, like failing to meet investors’ revenue expectations or even filing earnings reports on time.

But Catalent also struggled with its business at times, with a range of manufacturing delays, inspection reports and occasionally writing down acquisitions that didn’t pan out. Novo’s deep pockets will go a long way to a turnaround, but only the future will tell if all these issues are fixed.

Kutay said his team is excited by the opportunity and was satisfied with the due diligence it did on the company.

“We believe we’re buying a strong company with a good management team and good prospects,” Kutay said. “If that wasn’t the case, I don’t think we’d be here.”

Amber Tong and Reynald Castañeda contributed reporting.

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Petrina Kamya, Ph.D., Head of AI Platforms at Insilico Medicine, presents at BIO CEO & Investor Conference

Petrina Kamya, PhD, Head of AI Platforms and President of Insilico Medicine Canada, will present at the BIO CEO & Investor Conference happening Feb….

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Petrina Kamya, PhD, Head of AI Platforms and President of Insilico Medicine Canada, will present at the BIO CEO & Investor Conference happening Feb. 26-27 at the New York Marriott Marquis in New York City. Dr. Kamya will speak as part of the panel “AI within Biopharma: Separating Value from Hype,” on Feb. 27, 1pm ET along with Michael Nally, CEO of Generate: Biomedicines and Liz Schwarzbach, PhD, CBO of BigHat Biosciences.

Credit: Insilico Medicine

Petrina Kamya, PhD, Head of AI Platforms and President of Insilico Medicine Canada, will present at the BIO CEO & Investor Conference happening Feb. 26-27 at the New York Marriott Marquis in New York City. Dr. Kamya will speak as part of the panel “AI within Biopharma: Separating Value from Hype,” on Feb. 27, 1pm ET along with Michael Nally, CEO of Generate: Biomedicines and Liz Schwarzbach, PhD, CBO of BigHat Biosciences.

The session will look at how the latest artificial intelligence (AI) tools – including generative AI and large language models – are currently being used to advance the discovery and design of new drugs, and which technologies are still in development. 

The BIO CEO & Investor Conference brings together over 1,000 attendees and more than 700 companies across industry and institutional investment to discuss the future investment landscape of biotechnology. Sessions focus on topics such as therapeutic advancements, market outlook, and policy priorities.

Insilico Medicine is a leading, clinical stage AI-driven drug discovery company that has raised over $400m in investments since it was founded in 2014. Dr. Kamya leads the development of the Company’s end-to-end generative AI platform, Pharma.AI from Insilico’s AI R&D Center in Montreal. Using modern machine learning techniques in the context of chemistry and biology, the platform has driven the discovery and design of 30+ new therapies, with five in clinical stages – for cancer, fibrosis, inflammatory bowel disease (IBD), and COVID-19. The Company’s lead drug, for the chronic, rare lung condition idiopathic pulmonary fibrosis, is the first AI-designed drug for an AI-discovered target to reach Phase II clinical trials with patients. Nine of the top 20 pharmaceutical companies have used Insilico’s AI platform to advance their programs, and the Company has a number of major strategic licensing deals around its AI-designed therapeutic assets, including with Sanofi, Exelixis and Menarini. 

 

About Insilico Medicine

Insilico Medicine, a global clinical stage biotechnology company powered by generative AI, is connecting biology, chemistry, and clinical trials analysis using next-generation AI systems. The company has developed AI platforms that utilize deep generative models, reinforcement learning, transformers, and other modern machine learning techniques for novel target discovery and the generation of novel molecular structures with desired properties. Insilico Medicine is developing breakthrough solutions to discover and develop innovative drugs for cancer, fibrosis, immunity, central nervous system diseases, infectious diseases, autoimmune diseases, and aging-related diseases. www.insilico.com 


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