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A 360-Degree View of AAV Production

In this roundtable discussion, four experts from academia and industry met to discuss challenges in refining and scaling up AAV production pipelines to meet the increasing demand for these indispensable viral vector delivery systems.
The post A 360-Degree

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Sponsored content brought to you be Cytiva

Adeno-associated virus (AAV) has emerged as the most flexible and useful vector for gene therapy. With hundreds of gene therapy trials ongoing, safe and efficient production of AAV is absolutely critical.

In this roundtable discussion, four experts from academia and industry met to discuss challenges in refining and scaling up AAV production pipelines to meet the increasing demand for these indispensable viral vector delivery systems.

We thank Nicole Paulk, PhD, Assistant Professor, Biochemistry and Biophysics at the University of California, San Francisco, Mats Lundgren, PhD, Customer Applications Director at Cytiva, Uppsala, Sweden, Magnus Gustafsson, PhD, Head of Global Business Development at Biovian, Stockholm, Sweden, and Daozhan Yu, PhD, President and CEO at AAVnerGene, Maryland, for participating in this important conversation.

 

Q1. AAV has emerged as a leading vehicle for gene delivery. What are the opportunities and challenges that come with this viral vector?

Nicole Paulk, PhD
Assistant Professor, Biochemistry and Biophysics
UC San Francisco

Paulk: The biggest opportunities are to expand beyond what we are currently doing, using AAV as a genomic medicine delivery tool in rare and ultra-orphan monogenic indications. I’m beginning to hear more about expanding into polygenic disorders and disorders with more complex etiology. Expanding our treatment world to reach more patients and the challenges that come with it—that’s where the greatest opportunity lies. We still need to learn more about things like safe dosing at high doses when we’re trying to get to tissues throughout the body. Then there’s the ever-present problem—manufacturing: can we make enough to treat every patient on the planet if we were to go after something like diabetes or congestive heart failure?

Lundgren: The whole field is evolving. There are new serotypes being discovered or synthetic variants. There are more opportunities coming up, but manufacturing is difficult, especially at high doses.

Gustafsson: If we look at the approval of the first antibody 40 years ago, we were talking about mouse antibodies made from hybridoma cells. Today, we have transgenic mice expressing human antibodies. And somewhere in between, we have chimeric and humanized antibodies. With time, the mAb titers have gone up, and you can do so much more with these drugs. They have revolutionized the world. AAV has just started to make an impact. Today, transfection is probably the fastest way to make AAV, but it’s not the cheapest, the most robust, or the safest. There will be more technologies making an impact on manufacturing. Technology innovation will be the driver for this, not the drugs themselves.

Yu: We have so many opportunities, not only treating rare diseases with AAV but also many common diseases like diabetes, Alzheimer’s, aging, and even COVID-19. Replacing the gene of interest and the capsid, you can make a new drug. The potential is unlimited. Manufacturing will be a problem for a long time as so many gene therapy companies are emerging that need a lot of AAV. However, some gene therapy companies think that AAV is so safe that you can arbitrarily increase the dose. Last year, the FDA put a hold on several clinical trials, mostly related to manufacturing problems. Many are using very high doses. Several patients have died from high-dose AAV treatments. That poses a great challenge that may delay or even ruin the field. High-dose risk is a major problem. Our focus is not just to increase the production mass but to increase production efficiency.

 

Q2. Manufacturing large quantities of viral vectors remains a challenge. We hear of long wait times to get AAV. How is this manufacturing gap being addressed? What recent innovations in the AAV production pipeline help reduce production timelines?

Paulk: Right now, we largely address this by thinking in the short term because we’re desperate! We have patients waiting and folks who have programs to start. In the short term, you build more facilities with more bioreactors so that you can meet the demand. But folks are starting to think more in the long term. We’ve put the BAND-AID over the wound, but now what do we need to do in the long term? That’s going to require a wholesale reimagining of what it means to make AAV. That will likely require us to stop producing it like it’s a monoclonal antibody (mAb).

Lundgren: Every CMO and CDMO is trying to build up capacity, but that doesn’t mean all companies have the expertise and experience. It is important to select CDMOs that are credible and have the right expertise. We have a good example from Biovian here today. When it comes to the process, there will be tremendous improvements: producer cell lines where you will have constitutive expression, improvements in how you grow the cells, and in how you increase the amount of virus. Everyone is trying to increase the proportion of full capsids. Downstream, there will be improvements in purification—how can you purify the full capsids, formulate the material, stabilize it?

Gustafsson: This massive increase in demand is because there are more clinical trials. And that’s because AAV vectors work. We have higher dosing because companies choose systemic delivery over local administration and study larger patient populations. Different applications require vastly different amounts of vector. We need to have something to adjust for that massive difference. We also have a capacity crunch that is addressed by scaling up or scaling out—more reactors or bigger reactors. There is a financial crunch because someone has to pay for that. Massive bioreactors are just not feasible. You have a technology crunch. You need higher titer and more efficient vectors that are more specific for different tissues. And you have a time crunch. Cytiva has been instrumental for years in equipment for both mAbs and viral vectors. In technology development, academics are instrumental in giving us better tools.

Daozhan Yu, PhD
Daozhan Yu, PhD
President and CEO
AAVnerGene, Maryland

Yu: A lot of technology is being developed. Take the AAV manufacturing developed by my partner Dr. Wang. It gives very high yield of AAV and can be easily scaled up. We have borrowed a lot of technology from the antibody manufacturer. However, AAV manufacturing is more complex than small- and large-molecule manufacturing. As former FDA Commissioner Scott Gottlieb said, in AAV gene therapy we will focus more on product manufacture and quality itself. That is different from traditional drug development. You can always run more bioreactors and increase the volume, but scalability is not that easy. Many companies don’t have adequate expertise. We are still using plasmid transfection protocols where cells tend to aggregate. Some companies are developing new transfection reagents that work well.

 

Q3. What are the challenges to a scalable start-to-finish workflow?

Lundgren: Transient transfection is still very good, and it gives you high-quality material, but the problem is scaling up. Other systems are easier to scale up. The adenovirus system, for example, is brilliant when you can work with suspension cells. You can infect them with the adenovirus, and the adenovirus can then be removed in the downstream process. Producer cell lines will be coming, although it’s not as easy as it sounds. Since a lot of innovation is coming from academia, the technologies are inherently small scale. And some steps can be difficult to scale. For example, ultracentrifugation is difficult to scale up because you need to have enormous centrifuges, and it’s difficult to clean them. So, the trend now is to move away from ultracentrifugation and more into filtration and chromatography technologies. And there’s another reason for that—the safety aspects—to ensure that you can have a closed system, so you don’t have any cross-contamination. The way forward is closed and scalable systems and trying to increase titers, the purity, and the potency of the material.

Magnus Gustafsson, PhD
Magnus Gustafsson, PhD Head of Global Business Development, Biovian, Stockholm, Sweden

Gustafsson: We face this problem at Biovian. We have clients who start small scale and then want to go up to larger scale. As a CMO, we do what our clients tell us to do, but if we have a chance to develop a process, we try to go for suspension cultivation because it’s more scalable. We have selected Cytiva to be our provider. We have their scalable Xcellerex system, and we use their ÄKTA system for purification, which is also scalable. If you go for triple transfection, then you also must scale up plasmid manufacture. That becomes the bottleneck. You need huge quantities of plasmids to make virus. You could scale up with stable cell lines and use viral vectors to transduct your AAV. Purification is very important. It would be nice to have a disposable ultracentrifugation system that is serotype nonspecific. But it doesn’t exist yet. So, we go for chromatography, which is scalable.

 

Q4. Cost remains a pain point, particularly from the industrial point of view. How can AAV production be made more cost effective while maintaining rigorous safety standards?

Paulk: One of the main reasons AAV costs so much is because we dose so much. The best way to reduce price in the short term is to just reduce doses. To enable that, you’re going to need innovations around how to make these more potent so that you can give a lower dose. Beyond that, is the need to make an entirely new tissue culture media that costs 1/10,000th of what it costs now. This is the realm of much larger innovations that might take many years. In the short term, we can do things around finding capsids that produce slightly higher titers, finding methods to recover and retain more so as not to lose so much during the purification process, finding ways to have more full capsids from the beginning. In the long term, we will need a wholesale reimagining around how you can make AAV in a cell-free system, without plasmids, bioreactors, cells, or tissue culture media. Can you make this in a veritable test tube?

Mats Lundgren, PhD
Mats Lundgren, PhD Customer Applications Director Cytiva, Uppsala, Sweden

Lundgren: The biology will have a great impact if you can find something that is more potent. Then the costs come down. But in terms of processing, we can look at process intensification. For example, you can grow cells with perfusion systems, so you have more cells in the reactor and higher productivity per volume. We can try to develop platform-type purification processes that will not need to be adapted every time you switch to another virus. Supplies—how can we make cheaper media, better bioreactors? Trying to find scalable platform processes that are easy to implement while maintaining safety and efficacy is important. In the long term, you could go for cell-free production. Even though they are very small, these viruses are still much more complex than mAbs.

Gustafsson: We need to look at the platform with a holistic approach. There will not be one answer to fix everything. You have probably five things to address: the vector itself, the plasmids, cell lines, purification, and manufacturing systems. Today, we use plasmids as they are, but you can use nanoplasmids, minicircles, or rolling circle amplification. The plasmid has to be tailor-made both for the E. coli where it’s expressed and for the cell where it’s used. Or you can skip the plasmids and use transduction by a virus, such as baculovirus. You can use seed stocks. When it comes to cell lines, there are some 160 different HEK293 cell lines. You have to select one that is better than others. You have other cell lines too: CAP cell lines, PER.C6®, HeLa. There are stable cell lines and cell lines that claim they can export or secrete AAV out of the cell. If that technology is developed, you can have continuous production of AAV. We’re looking into suspension and adherent manufacturing systems, but a system for a continuous process that does not lyse cells is most important. Better, more, and serotype-nonspecific ligands or ion-exchange chromatography that can fish out full from empty capsids would be wonderful. Analytical tools to look at your process development and analyze the outcome are important. High-throughput electron microscopy with AI to make conclusions from your analysis would be wonderful.

Paulk: We assume that the list price for an AAV is based off production and process development. But there are also other costs. As an AAV gene therapy company, you have staff and clinical trial costs that get baked into what you choose to list. To reduce your list price, you can bring those costs down. All the work you put in up front matters. If you end up getting a clinical or preclinical hold—that’s time and cost you have to recoup. The more time you invest up front, either while you’re still in academia or right as you’re spinning it out, into determining the backbone, promoter, and inverted terminal repeats (ITRs) you want to use, the better.

 

Q5. How do you see academia and industry continuing to develop their communication and collaboration with regard to AAV production?

Paulk: We’re seeing more industry money coming into academia. But the danger is when you get money from industry there are often strings attached, where you either implicitly or explicitly feel the need to produce for that company with that money. To ensure that academics still have the freedom to research in any way they wish, to publish the results whether they’re positive or negative for your company, and to present that data—to make sure that we remove those conflicts of interest from it so that we don’t poison our own drinking water supply—is important.

Lundgren: It’s not good if you get money from us and we ask you to do contract research. Collaborations around scientific discussions about your pain points, what you foresee, could be good. Funding from industry is dangerous if you rely too much on it. We have collaborations with research institutes on manufacturing technologies—that works because we are not funding them but are working together. We can perhaps do large-scale productions for them to show their molecule works. As an industry, we can never solve biology questions. Analytics is an area where industry and academia could collaborate, but it is important to have the free academic spirit for innovations.

Gustafsson: It would be wonderful to have an academic/commercial initiative with open-source viral vector platform process development. Something like Linux, developed as an open-source student project. We have seen such collaborations in sequencing of the human genome. We are all fighting initial costs. It would be wonderful to have something to build on that is available for everyone.

 

Learn about Cytiva solutions for scalable AAV manufacturing info.cytivalifesciences.com/viralvector

The post A 360-Degree View of AAV Production appeared first on GEN - Genetic Engineering and Biotechnology News.

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International

Weekly Digest – December 16, 2022

Friday, December 16, 2022Volume 3, Issue 59 Quote of the Week “Remember that you must behave as at a banquet. Is anything brought round to you? Put…

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Friday, December 16, 2022
Volume 3, Issue 59


Quote of the Week

“Remember that you must behave as at a banquet. Is anything brought round to you? Put out your hand and take a moderate share. Does it pass by you? Do not stop it. Is it not yet come? Do not yearn in desire toward it, but wait till it reaches you. So with regard to children, wife, office, riches; and you will some time or other be worthy to feast with the gods. And if you do not so much as take the things which are set before you, but are able even to forego them, then you will not only be worthy to feast with the gods, but to rule with them also. For, by thus doing, Diogenes and Heraclitus, and others like them, deservedly became divine, and were so recognized.”

— Epictetus, The Enchiridion, 15


Fortune Cookies

Fortune cookies are entertaining because they come with a vague statement that can often be interpreted positively. But they are usually not to be taken seriously. This is why I find myself annoyed when I read “fortune cookies” on Twitter that provide vapid advice claiming to make inherently difficult things easy to accomplish. 

Since we are approaching the end of the year when many people start thinking about New Year’s resolutions, I thought that I would provide eight (hopefully) higher quality “fortune cookies” of my own that took many years to figure out. 

  • Almost nothing worthwhile can be achieved without considerable effort. If you want something, be prepared to work very hard to get it.
  • If you hate your job, find a different one or switch to a different career. If you are still young, “retirement” is almost certainly a mistake. Find something that you are good at and enjoy doing and then commit to it wholeheartedly. 
  • Commit to reading 25 pages per day. That is over 9,000 pages per year and will put you at the very top in terms of attainment of wisdom, provided that you read with purpose. While difficult at first, it will get easier in time. Eventually, it will be very difficult to not read on a daily basis. Such days will feel incomplete.
  • Start a journal. Writing for fifteen minutes every morning can make a big difference in setting the tone for the day and keeping your goals on track.
  • Avoid hatred at all costsHatred leads to disaster and harms the person doing the hating more than the target of hatred. Instead of falling into hatred, disassociate from toxic people, especially in cases of lies and deception.
  • Be kind to others, especially those who through no fault of their own have been dealt a bad hand. But never allow someone to take advantage of your kindness. Provide a helping hand, not a handout, and never facilitate dysfunctional behavior. Cut people out of your life who are only interested in money.
  • Avoid envy. The people you see on social media who appear to have “perfect lives” almost certainly do not. Many are secretly miserable and hide behind beautiful fictions posted on social media to fool themselves as well as others.
  • Do not confuse frugality with cheapness. Default to generosity when it makes sense. Being cheap when it comes to health and well-being is stupid, and the same is true for intellectual pursuits. Books distill thousands of hours of the author’s time for the cost of a restaurant meal or less. Never budget for books.

These might be “fortune cookies”, but they could actually make a positive impact even though none are necessarily easy to implement. I can say that all of these concepts have helped me despite taking years or, in some cases decades, to really figure out.


Articles

Consoles and Competition by Ben Thompson, December 12, 2022. This article provides over forty years of history of the video game industry before analyzing the FTC’s attempt to block Microsoft’s acquisition of Activision. As someone who is not familiar with the intricacies of this case, I found the lengthy discussion of the industry’s history very valuable since it provides necessary context. “For the record, I do believe this acquisition demands careful overview, and it’s completely appropriate to insist that Microsoft continue to deliver Activision titles to other platforms, even if it wouldn’t make economic sense to do anything but. It’s increasingly difficult, though, to grasp any sort of coherent theory to the FTC’s antitrust decisions beyond ‘big tech bad’.” (Stratechery)

Sea Change by Howard Marks, December 13, 2022. In this memo, Howard Marks points out that forty years of declining interest rates represented a major tailwind for investors. He likens falling interest rates to a moving walkway in an airport. Just as moving walkways make life easier for weary travelers, falling interest rates act as an assist for investors. However, this secular decline in interest rates appears to be at an end which represents a sea change in the investment landscape. Investors need to be aware that the strategies that worked well over the past forty years may not lead to outperformance in the future. (Oaktree Capital)

The California Effect by Mr. Money Mustache, December 10, 2022. The cost of living is famously high in the San Francisco Bay Area where Mr. Money Mustache recently spent a few days observing the attitudes of people with very different approaches to spending money. The reality is that even in the most expensive regions, spending excessively is always a choice, not an inevitable mandate. “San Francisco professionals live in a place where 25-year-old tech workers enjoy $200,000 starting salaries, yet still have credit card debt and car loans, and they think that is normal.” (Mr. Money Mustache)

The College Essay Is Dead by Stephen Marche, December 6, 2022. Will artificial intelligence kill the college essay? Anyone who has played with ChatGPT, a new AI tool that recently opened to the public, might be asking the question which this article explores. I admit to being a little baffled about the handwringing. After all, when I was in college three decades ago, we took exams using technology no more advanced than blue books and a pen or pencil. AI might help students cheat on work done outside the classroom, but you cannot fake your way through an exam where there is no technology other than paper and a writing implement. (The Atlantic)

Ideas That Changed My Life by Morgan Housel, December 7, 2022. Among other topics, Morgan Housel makes an excellent case for reading. Otherwise, your personal experiences will excessively influence your perception of how the world works. “Your personal experiences make up maybe 0.00000001% of what’s happened in the world but maybe 80% of how you think the world works. People believe what they’ve seen happen exponentially more than what they read about has happened to other people, if they read about other people at all. We’re all biased to our own personal history.” (Collaborative Fund)

Thankfully, Life Is Full of Problems by Lawrence Yeo, December 7, 2022. I was reminded of Viktor Frankl when I read this article. Frankl held that people gain a sense of purpose not through a tensionless state but by struggling and striving toward a personally meaningful goal. Lawrence Yeo makes a similar case. What we must do is to “upgrade” from dealing with meaningless problems to a focus on addressing “heavyweight” problems. (More to That)

The Gift of Time by Nick Maggiulli, December 13, 2022. Almost everyone thinks about money in terms of goods or services it can buy. But money is really the gift of time: “Because everything I write isn’t really about money, it’s about time. Time with your loved ones. Time to enjoy yourself. Time to live the life you want. In the end, all of your money will be converted back to time anyways. If not now, then later. And if not by you, then by someone else. Possibly after you’re gone.” (Of Dollars and Data)

Be Wary of Imitating High-Status People Who Can Afford to Countersignal by Rob Henderson, December 11, 2022. This article argues that we should avoid emulating people who have achieved status far above ours, and instead look to those who are just somewhat ahead of us. People with very high status can afford to exhibit unusual behavior. For example, a famous author doesn’t need to use Twitter personally to surface his writing because his fans will do this for him. That’s not the case for most authors seeking wider distribution of their work. (Rob Henderson’s Newsletter)

How Neuroscience Confirms the Most Ancient Myths About Music by Ted Gioia, December 12, 2022. Music has a tremendous capacity to influence our lives as listeners, often putting us into flow states conducive to productivity. For example, I often listen to The Dave Brubeck Quartet’s performance at Carnegie Hall in 1963 when I want to get serious work done. For musicians, performing can induce an even deeper flow state, as Ted Gioia describes: “In the midst of an intense performance, the music seemed to be playing itself.” This article on music and neuroscience is part of a book being published in installments on Substack. (The Honest Broker)


Podcasts

Tom Gayner Discusses the Evolution of Markel, December 14, 2022. 56 minutes. This is a wide-ranging interview covering topics including Berkshire Hathaway’s recent investment in Markel, the growth of Markel Ventures in the context of the company’s overall capital allocation strategy, the use of leverage, and how investing during the pandemic was more challenging than the financial crisis. (Boyar Value Group)

The Essays of Warren Buffett, January 20, 2022. 1 hour, 58 minutes. According to Lawrence Cunningham’s newsletter, which you can sign up for here, the sixth edition of his compilation of Warren Buffett’s shareholder letters will be released early next year. I have the first and second editions and highly recommend the book. While all of the letters are available on Berkshire’s website, the compilation is organized by topic and adds significant value. In this podcast, David Senra provides his enthusiastic commentary about what he took away from this book. (Founder’s Podcast)

Master of Precision: Henry Leland Founder of Cadillac, May 31, 2020. 1 hour, 10 minutes. I think Steve Jobs and Henry Leland had much in common in terms of insisting on high quality and viewing their role as craftsmen, paying obsessive attention to details. “There always was and there always will be conflict between Good and Good Enough. In opening up a new business one can count on meeting resistance to a high standard of workmanship. It is easy to get cooperation for mediocre work, but one must sweat blood for a chance to produce a superior product. —Henry Leland” (Founders Podcast)

DoorDash: Looking for Profitable Routes, December 14, 2022. “DoorDash was founded in 2013 by four Stanford students, who saw an opportunity to make it easier for people to get the food they love delivered to them. Today, DoorDash’s three-sided marketplace serves as one of the largest local delivery companies in the world, serving millions of customers and partnering with hundreds of thousands of restaurants across 27 countries, run rating at over $50 billion of gross merchandise value.” (Business Breakdowns)


Twitter Threads

This is a brief thread on the importance of reading. It is based on The Use of Letters, a journal entry I wrote early last year. Why would anyone voluntarily limit their understanding of the world to just their own direct experiences?

Checking quotes frequently is counterproductive. There is too much noise in quotes when checked on a daily basis and doing so is likely to make most investors miserable.

The origin story of the Eiffel Tower:


A Shepherd and His Flock in Winter

From Wikipedia:

Frederick Ferdinand Schafer (August 16, 1839 – July 18, 1927) was a German-born American painter. He was born in Braunschweig, Germany and he emigrated to the United States in 1876, at age 37. 

Schafer’s paintings, which mostly depict landscape scenes in California and other western states, are dated between 1873 and 1911. There are many scenes of Yosemite National Park included in a catalog of his paintings. As the weather turns colder, I thought that this scene of an unknown location captures the season quite well.

A Shepherd and His Flock in Winter, Frederick Ferdinand Schafer (public domain)

Here is a description of this painting by Jerome H. Saltzer, Professor of Computer Science Emeritus at the Massachusetts Institute of Technology:

“This painting might be described as luminist in style. Paintings such as this one may be the basis for the suggestion that Schafer’s later work was lighter, but the shortage of dated paintings makes it difficult to confirm that suggestion.”


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Government

FDA advisory committee votes unanimously in favor of a one-shot COVID-19 vaccine approach – 5 questions answered

Many questions remain about next steps for US vaccine policy. But the FDA advisory panel’s hearty endorsement of a single-composition COVID-19 vaccine…

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The FDA advisory committee discussed vaccine safety, effectiveness of the current shots, potential seasonality of COVID-19 and more. wildpixel/iStock via Getty Images Plus

The U.S. Food and Drug Administration’s key science advisory panel, the Vaccines and Related Biological Products Advisory Committee, met on Jan. 26, 2023, to chart a path forward for COVID-19 vaccine policy. During the all-day meeting, the 21-member committee discussed an array of weighty issues including the efficacy of existing vaccines, the composition of future vaccine strains and the need to match them to the circulating variants of SARS-CoV-2, the possibility of moving to an annual-shot model, the potential seasonality of the virus and much more.

But the key question at hand, and the only formal question that was voted on, following a proposal from the FDA earlier in the week, had to do with how to simplify the path to getting people vaccinated.

The Conversation asked immunologist Matthew Woodruff, who has been on the front lines of studying immune responses to COVID-19 since the early days of the pandemic, to walk us through the big questions of the day and what they mean for future COVID-19 vaccine strategies.

What exactly did the advisory committee vote on?

The question put before the committee for a vote was whether to move to one COVID-19 vaccine consisting of a single composition for all people – whether currently vaccinated or not – and away from the current model that includes one formulation given as a primary series and a separate formulation administered as a booster. Importantly, approved formulations could come from any number of vaccine manufacturers, not just those that have currently authorized vaccines.

The U.S. Centers for Disease Control and Prevention currently requires that the primary series of shots, or the first two doses of the vaccine that a patient receives, consist of the first generation of vaccine against the original strain of SARS-CoV-2, known as the “Wuhan” strain of the virus. These shots are given weeks apart, followed months later by a booster shot that was updated in August 2022 to contain a bivalent formulation of vaccine that targets both the original viral strain and newer subvariants of omicron.

The committee’s endorsement simplifies those recommendations. In a 21-to-0 vote, the advisory board recommended fully replacing, or “harmonizing,” the original formulation of the vaccine with a single shot that would consist of – at least for now – the current bivalent vaccine.

In doing so, it has signaled its belief that these new second-generation vaccines are an upgrade over their predecessors in protecting from infection and severe illness at this point in the pandemic.

If the FDA panel’s recommendation is endorsed by the CDC, only a single composition of vaccine – in this case, the updated bivalent shot – will be used for both vaccinated and unvaccinated people.

Will the single shot remain a mixed-strain, or bivalent, vaccine?

For now, the single shot will be bivalent. But this may not always be the case.

There was a general agreement that the current bivalent shot is preferable to the original vaccine targeted at the Wuhan strain of the virus by itself. But committee members debated whether that original Wuhan vaccine strain should continue to be a part of updated vaccine formulations.

There is no current data comparing a monovalent, or single-strain, vaccine that targets omicron and its subvariants against the current bivalent shot. As a result, it’s unclear how a monovalent shot against recent omicron subvariants would perform in comparison to the bivalent version.

What is immune imprinting, and how does it apply here?

A main reason for the debate over monovalent versus bivalent – or, for that matter, trivalent or tetravalent – vaccines is a lack of understanding around how best to sharpen an immune response to a slightly altered threat. This has long been a debate surrounding annual influenza vaccination strategies, where studies have shown that the immune “memory” that forms in response to a prior vaccine can actively repress a robust immune response to the next.

This phenomenon of immune imprinting, originally coined in 1960 as “original antigenic sin,” has been a topic of debate both within the advisory committee and within the broader immunological community.

Although innovative strategies are being developed to overcome potential problems with routinely updated vaccines, they are not yet ready to be tested in humans. In the meantime, it is unclear how bivalent versus monovalent vaccine choices might alter this phenomenon, and it is very clear that more study is needed.

Is the committee considering only mRNA vaccines?

While a significant portion of the discussion focused on the mRNA vaccine platform used by both Pfizer and Moderna, several committee members emphasized the need for new technologies that could provide broader immunological protection. Dr. Pamela McInnes, a now-retired longtime deputy director of the National Center for Advancing Translational Sciences, highlighted this point, saying, “I would make a plea for ongoing research on broader protection, maybe different platforms, maybe a different approach.”

A good deal of attention was also directed toward Novavax, a protein-based formulation that relies on a more traditional approach to vaccination than the mRNA-based vaccines. Although the Novavax vaccine has been authorized by the FDA for use since July 2022, it has received much less national attention – largely because of its latecomer status. Nonetheless, Novavax has boasted efficacy rates on par with its mRNA cousins, with good safety profiles and less demanding long-term storage requirements than the mRNA shots.

By simplifying the vaccine schedule to include only a single vaccine formulation, the committee reasoned, it might be easier for competing vaccination platforms to break into the market. In other words, newer vaccine contenders would not have to rely on patients’ having already received their primary series before using their products. Companies seemed ready to take advantage of that future flexibility, with researchers from Pfizer, Moderna and Novavax all revealing their companies’ exploration of a hybrid COVID-19 and flu shot at various stages of clinical trials and testing.

Would the single shot resemble flu vaccine development?

Not necessarily. Currently, the influenza vaccine is decided by committee through the World Health Organization. Because of its seasonal nature, the strains to be included in each season’s flu vaccine strain for the Southern and Northern hemispheres, with their opposing winters, are selected independently. The Northern Hemisphere’s selection is made in February for the following winter based on a vast network of flu monitoring stations around the globe.

Although there was broad consensus among panelists that the shots against SARS-CoV-2 should be updated regularly to more closely match the most current circulating viral strain, there was less agreement on how frequent that would be.

For instance, rapidly mutating strains of the virus in both summer and winter surges might necessitate two updated shots a year instead of just one. As Dr. Eric Rubin, an infectious disease expert from the Harvard T.H. Chan School of Public Health, noted, “It’s hard to say that it’s going to be annual at this point.”

Matthew Woodruff receives funding from the National Institute of Health and the US Department of Defense to support his academic research.

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International

Measles virus ‘cooperates’ with itself to cause fatal encephalitis

Fukuoka, Japan—Researchers in Japan have uncovered the mechanism for how the measles virus can cause subacute sclerosing panencephalitis, or SSPE, a…

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Fukuoka, Japan—Researchers in Japan have uncovered the mechanism for how the measles virus can cause subacute sclerosing panencephalitis, or SSPE, a rare but fatal neurological disorder that can occur several years after a measles infection.

Credit: Kyushu University/Hidetaka Harada/Yuta Shirogane

Fukuoka, Japan—Researchers in Japan have uncovered the mechanism for how the measles virus can cause subacute sclerosing panencephalitis, or SSPE, a rare but fatal neurological disorder that can occur several years after a measles infection.

Although the normal form of the measles virus cannot infect the nervous system, the team found that viruses that persist in the body can develop mutations in a key protein that controls how they infect cells. The mutated proteins can interact with its normal form, making it capable of infecting the brain. Their findings were reported in the journal Science Advances.

If you are of a certain age, you may have gotten the measles as a child. Many born after the 1970s have never gotten it thanks to vaccines. The condition is caused by the virus of the same name, which is one of the most contagious pathogens to this day. The World Health Organization estimates that nearly nine million people worldwide were infected with measles in 2021, with the number of deaths reaching 128,000.

“Despite its availability, the recent COVID-19 pandemic has set back vaccinations, especially in the Global South,” explains Yuta Shirogane, Assistant Professor at Kyushu University’s Faculty of Medical Sciences. “SSPE is a rare but fatal condition caused by the measles virus. However, the normal measles virus does not have the ability to propagate in the brain, and thus it is unclear how it causes encephalitis.”

A virus infects cells through a series of proteins that protrude from its surface. Usually, one protein will first facilitate the virus to attach to a cell’s surface, then another surface protein will cause a reaction that lets the virus into the cell, leading to an infection. Therefore, what a virus can or cannot infect can depend heavily on the type of cell.

“Usually, the measles virus only infects your immune and epithelial cells, causing the fever and rash,” continues Shirogane. “Therefore, in patients with SSPE, the measles virus must have remained in their body and mutated, then gained the ability to infect nerve cells. RNA viruses like measles mutate and evolve at very high rates, but the mechanism of how it evolved to infect neurons has been a mystery.”

The key player in allowing the measles virus to infect a cell is a protein called fusion protein, or F protein. In the team’s previous studies, they showed that certain mutations in the F protein puts it in a ‘hyperfusongenic’ state, allowing it to fuse onto neural synapses and infect the brain.

In their latest study, the team analyzed the genome of the measles virus from SSPE patients and found that various mutations had accumulated in their F protein. Interestingly, certain mutations would increase infection activity while others actually decreased it.

“This was surprising to see, but we found an explanation. When the virus infects a neuron, it infects it through ‘en bloc transmission,’ where multiple copies of the viral genome enter the cell,” continues Shirogane. “In this case, the genome encoding the mutant F protein is transmitted simultaneously with the genome of the normal F protein, and both proteins are likely to coexist in the infected cell.”

Based on this hypothesis, the team analyzed the fusion activity of mutant F proteins when normal F proteins were present. Their results showed that fusion activity of a mutant F protein is suppressed due to interference from the normal F proteins, but that interference is overcome by the accumulation of mutations in the F protein.

In another case, the team found that a different set of mutations in the F protein results in a completely opposite result: a reduction in fusion activity. However, to their surprise, this mutation can actually cooperate with normal F proteins to increase fusion activity. Thus, even mutant F proteins that appear to be unable to infect neurons can still infect the brain.

“It is almost counter to the ‘survival of the fittest’ model for viral propagation. In fact, this phenomenon where mutations interfere and/or cooperate with each other is called ‘Sociovirology.’ It’s still a new concept, but viruses have been observed to interact with each other like a group. It’s an exciting prospect” explains Shirogane.

The team hopes that their results will help develop therapeutics for SSPE, as well as elucidate the evolutionary mechanisms common to viruses that have similar infection mechanisms to measles such as novel coronaviruses and herpesviruses.

“There are many mysteries in the mechanisms by which viruses cause diseases. Since I was a medical student, I was interested in how the measles virus caused SSPE. I am happy that we were able to elucidate the mechanism of this disease,” concludes Shirogane.

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For more information about this research, see “Collective fusion activity determines neurotropism of an en bloc transmitted enveloped virus” Yuta Shirogane, Hidetaka Harada, Yuichi Hirai, Ryuichi Takemoto, Tateki Suzuki, Takao Hashiguchi, Yusuke Yanagi, https://doi.org/10.1126/sciadv.adf3731

About Kyushu University
Kyushu University is one of Japan’s leading research-oriented institutes of higher education since its founding in 1911. Home to around 19,000 students and 8,000 faculty and staff, Kyushu U’s world-class research centers cover a wide range of study areas and research fields, from the humanities and arts to engineering and medical sciences. Its multiple campuses—including the largest in Japan—are located around Fukuoka City, a coastal metropolis on the southwestern Japanese island of Kyushu that is frequently ranked among the world’s most livable cities and historically known as a gateway to Asia.


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