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What’s next for mRNA vaccines?

Moderna mRNA vaccines are already in the works to reduce the health risks of latent viruses like Epstein-Barr virus and cytomegalovirus and to tackle additional…

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Robert Langer, ScD, is the David H. Koch Institute professor at MIT and a co-founder of Moderna, the pharmaceutical company behind a COVID-19 mRNA vaccine. In this Q&A, he tells us about the present and future of these versatile vaccines.

Q: The technology behind mRNA vaccines has been available for decades, but it was only with the pandemic that we first saw a publicly available mRNA vaccine. Why didn’t this happen sooner?

RL: While it is true that over the last thirty years hundreds of scientists have worked on developing mRNA vaccines and therapeutics, real breakthroughs in making an effective and commercially viable mRNA vaccine were greatly accelerated by the COVID-19 pandemic. It’s important to realize that Moderna and others like BioNtech and Curevac were in clinical trials for multiple different vaccines and therapeutics at the time the COVID-19 crisis started in late 2019/early 2020.

In fact, Moderna had eight vaccines (including a personalized cancer vaccine, a vaccine against Zika virus, and a dual vaccine against metapneumovirus and a type of parainfluenza) in human clinical trials at that point. Moderna recognized the incredible and unique opportunity to quickly meet the global demand for a COVID-19 vaccine by leveraging our mRNA tools and technologies. All the necessary pieces were in place, such as the correct mRNA chemistry and the development of nanoparticles to protect the messenger RNA (this actually had part of its origins in our MIT lab for which I received the Millennium Technology Prize in 2008). So the organization refocused efforts on bringing a COVID-19 mRNA vaccine to patients as quickly as possible without compromising public safety.

Moderna scientists identified the ideal protein candidate on the coronavirus SARS-CoV-2 virus (the spike protein), determined the mRNA sequence necessary to encode for this protein and, six months later, was given FDA clearance to proceed.

The many advantages of mRNA versus traditional vaccines prompted scientists to use mRNA vaccines to fight SARS-CoV-2. These advantages include the ability to quickly update the vaccine as new variants emerge, the ability to develop combination vaccines to fight several variants (and pathogens) simultaneously, and the ability to rapidly scale to serve a global population.

What’s more, Moderna’s mRNA platform generates antigens with superior biological fidelity and a greater success rate than traditional vaccines—all in record time. mRNA vaccines don’t require a giant manufacturing plant to produce them. All mRNA vaccines and therapeutics can be produced at the same location via the same process.

Q: What are some other diseases or disorders against which mRNA vaccines can provide protection?

RL: Moderna mRNA vaccines are already in the works to reduce the health risks of latent viruses like Epstein-Barr virus (EBV) and cytomegalovirus (CMV) and to tackle additional areas of unmet need, including an all-in-one mRNA vaccine to treat COVID-19, seasonal flu, and respiratory syncytial virus (RSV). Additionally, Moderna plans to develop mRNA vaccines to help patients beat Herpes simplex virus (HSV), MS, cancer, and HIV once and for all.

HSV, CMV, and EBV are large viruses that gain entry into cells via multiple proteins. Identifying which proteins to target remains a challenge, as does the development of adjuvants to fine-tune the body’s immune response. In the case of HIV, the situation is particularly complex.

Simply put, the immune system must be rigorously trained to produce a specific type of antibody (broadly neutralizing antibody or bnAbs), that has been found to be effective at fighting HIV. Further, a truly protective HIV vaccine will likely require a combination of antigens to stimulate the formation of multiple bnAbs classes.

“The many advantages of mRNA versus traditional vaccines prompted scientists to use mRNA vaccines to fight SARS-CoV-2 “ [Crocothery/Getty Images]
Indeed, mRNA vaccines can provide protection against practically any viral or bacterial infection. Unlike traditional vaccines, mRNA vaccines enable the patient’s own cells to “train” the immune system to recognize a pathogen by producing the invader proteins the immune system will need to attack.

Therefore, mRNA vaccines are limited only by the immune system’s own ability to fight the pathogen. Once an ideal protein candidate is identified, it is a relatively simple process to identify the mRNA needed to encode for those proteins.

Q: Can mRNA vaccines provide universal protection against a family of viruses, such as coronaviruses?

RL: Theoretically, yes. AI, machine learning, and robotic process automation (RPA) are technologies that can help us more rapidly catalog common familial viral elements, predict potential variations and mutations, and identify antigen-protein targets—all while eliminating human error.

Further, these technologies can accelerate the process of identifying the ideal, most productive mRNA sequence needed to generate those proteins. Over time, AI/machine learning refinements will continuously improve the range and effectiveness of this approach by providing ever-larger datasets to draw from.

Q: Do mRNA vaccines have the potential to combat antimicrobial/antibiotic resistance?

RL: Yes. Antimicrobial and antibiotic resistance arises as a natural evolutionary process, the result of genetic variation (“errors”) and mutation in the pathogen, giving rise to novel traits. Organisms that develop traits which make them drug-resistant naturally survive and thrive.

First, mRNA vaccines have the potential to help combat antimicrobial and antibiotic resistance by reducing our reliance on traditional antibiotics. Additionally, Moderna’s mRNA platform helps combat resistance by identifying the most desirable and persistent antigens for targeting, by improving the prediction of new strains, and by accelerating the production of vaccines to defeat those strains.

Finally, by training the immune system to look for specific surface proteins on the bacterium, an mRNA vaccine more effectively targets specific pathogens while avoiding the issue of damaging a patient’s “good” bacteria with increasingly toxic antibiotics. For instance, through the selection of a “coat protein” as the target-antigen, an mRNA vaccine against a drug-resistant strain of malaria has already yielded encouraging results.

Q: On the whole, mRNA vaccines are safer, more efficient, and easier to produce than “traditional” vaccines. However, like with all technologies, there is always room to improve its accessibility, affordability, efficacy, and safety. Cold storage requirements and side effects including possible allergic reactions are some of the issues impacting uptake of these vaccines. Are there any solutions to these (or any other) issues that researchers are currently working upon?

RL: Moderna is leveraging AI and machine learning technologies to identify ways to make mRNA vaccines safer and more durable (with simpler refrigeration requirements) by minimizing the length of mRNA strands. Moderna is implementing a multi-pronged approach to ease the substantial global disease burden by making mRNA vaccines more widely accessible, affordable, efficient, and safe.

Moderna’s mRNA Access program aims to accelerate the creation of new mRNA vaccines through collaboration with global partners. mRNA Access lets outside researchers leverage Moderna’s platform to develop mRNA vaccines against emerging and neglected infectious diseases around the world.

This strategy exponentially expands our brain trust, making the discovery of safer and more efficient vaccines an inevitable outcome. To help ensure the success of our mission to combat the top respiratory diseases worldwide, Moderna has entered into ten-year supply agreements with strategic countries.

Finally, Moderna is expanding its COVID-19 vaccine technology patent-free into 92 additional low- and middle-income countries as well as building an mRNA manufacturing facility in Kenya.

In addition, at MIT, we are working on ways of creating self-boosting vaccines that can be given in a single injection that does not require the patient to return for boosters. We are also developing ways to create more stable nanoparticles, as well as microneedle patches that could be shelf stable and shipped around the world.

Q: Recently, there has been discussion about developing vaccines that can be administered as a pill or a nasal spray. Is this method of delivery possible for mRNA vaccines?

RL: The possibilities for vaccine administration are endless so long as an appropriate, effective delivery mechanism can be found that protects the mRNA from the local environments (e.g., mucus, saliva, stomach acid [HCL]) yet facilitates the delivery of mRNA into the cell. While the gold standard for vaccine administration is through an intramuscular shot in the arm, intranasal COVID-19 vaccines have already been shown to elicit strong cellular immune response in humans.

Additionally, at MIT, Gio Traverso and myself recently developed a self-orienting mRNA “milli-injector” capsule that uses a polymer coating to deliver mRNA to the stomach via milli-needle injections in the gastric lining, thereby avoiding damaging acids. The experiments successfully produced proteins in gastric mucosa, as well as systemic uptake though, due to volume restrictions, their effectiveness may be limited to diseases of the gastrointestinal tract.

Where logic meets illusion
“Theoretically, AI, machine learning, and robotic process automation (RPA) are technologies that can help us more rapidly catalog common familial viral elements, predict potential variations and mutations, and identify antigen-protein targets—all while eliminating human error.” [Moyo Studio/Getty Images]
One major roadblock to a nasal mRNA vaccine is nasal clearing. Mucus and nasal cilia act as a protective barrier against pathogens, typically a good thing. Unfortunately, antigen absorption decreases as nasal clearance increases. Another drawback to a nasal mRNA vaccine is cost since a specialized delivery system is required. Unlike an intramuscular injection, an intranasally administered vaccine must survive several biological obstacles to reach the target site and provide long-term protection.

A nasal vaccine’s formulation and delivery method must be precisely tuned and would require amplification via immunostimulants. Despite this, several vaccine companies are experimenting with intranasal delivery by tweaking nasal mucosal toxicity, mucoadhesion, and pH. AstraZeneca and the Chalmers University of Technology have initiated mRNA-based nasal spray vaccine development against SARS-CoV-2, where nasal vaccines make the most sense since viral invasion happens via the nasal mucosa.

Advantages of a pill or nasal spray include reduced patient hesitancy and increased compliance. Specific advantages of an intranasal spray include ease of combining vaccines, simple vaccine swapping to accommodate variants, a combined mucosal and systemic immune response, protection at distant mucosal sites, and a faster onset of a strong immune response.

Q: What are some other ways that mRNA vaccine technology can improve human wellbeing that you believe hasn’t yet had enough attention or curiosity?

RL: An mRNA vaccine enables the patient to produce proteins, but these proteins don’t have to be used to stimulate the immune system to fight disease. mRNA vaccine technology can be used to replace missing proteins in patients suffering from inherited metabolic disorders (of which hundreds exist, such as phenylketonuria). These potentially debilitating diseases are caused by an enzyme deficiency; the body is unable to manufacture or break down certain proteins.

Phenylketonuria (PKU) results in low levels of the enzyme phenylalanine hydroxylase, a protein that breaks down phenylalanine. Without it, phenylalanine builds up in the body, often to toxic levels, even causing brain damage. Current treatment is simply the dietary reduction of foods that contain phenylalanine (which includes much more than you think: all meats, milk, eggs, cheese, nuts, soy, beans, and more). The dietary requirements are so severe as to require supplementing with a special drink to ensure the essential nutrients.

Similarly, an mRNA vaccine may be used to potentially help treat depression by enabling patients to boost their levels of serotonin or dopamine to elevate their mood or reduce anxiety. In short, an mRNA vaccine can be used to express any protein and possibly treat almost any disease.

Q: What advice would you give to budding researchers interested in studying and working on mRNA vaccines?

RL: I think it’s important to realize that there are few limits. Whether it’s mRNA vaccines or anything else, I always tell my students to dream big dreams, dreams that can change the world. But if you do that you may run into obstacles. When I first discovered a way to deliver macromolecules including nucleic acids from small particles, I was ridiculed by the scientific community. My first nine research grants were rejected and no engineering department in the world would hire me for a faculty position. But I didn’t give up and I always tell my students to never give up either.

GEN wishes to thank David Olajide, consultant at CURZONPR in London, for providing the raw material for this article.

The post What’s next for mRNA vaccines? appeared first on GEN - Genetic Engineering and Biotechnology News.

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Decrease in Japanese children’s ability to balance during movement related to COVID-19 activity restrictions

A team of researchers from Nagoya University in central Japan investigated how restrictions on children’s activities during the COVID-19 pandemic affected…

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A team of researchers from Nagoya University in central Japan investigated how restrictions on children’s activities during the COVID-19 pandemic affected their life habits and their abilities to perform physical activities. By comparing medical examination data before and after the onset of the pandemic, they found that physical functions among adolescents deteriorated, including their dynamic balance. They also found that the children had higher body fat levels and worse life habits. Rather than a lack of exercise time, this may have been because of a lack of quality exercise due to activity restrictions.  

Credit: Credit must be given when image is used

A team of researchers from Nagoya University in central Japan investigated how restrictions on children’s activities during the COVID-19 pandemic affected their life habits and their abilities to perform physical activities. By comparing medical examination data before and after the onset of the pandemic, they found that physical functions among adolescents deteriorated, including their dynamic balance. They also found that the children had higher body fat levels and worse life habits. Rather than a lack of exercise time, this may have been because of a lack of quality exercise due to activity restrictions.  

During the COVID-19 pandemic, in Japan, as in other countries, schools and sports clubs tried to prevent the spread of infection by reducing physical education and restricting outdoor physical activities, club activities, and sports. However, children who are denied opportunities for physical activity with social elements may develop bad habits. During the pandemic, children, like adults, increased the time they spent looking at television, smartphone, and computer screens, exercised less, and slept less. Such changes in lifestyle can harm adolescent bodies, leading to weight gain and health problems. 

Visiting Researcher Tadashi Ito and Professor Hideshi Sugiura from the Department of Biological Functional Science at the Nagoya University Graduate School of Medicine, together with Dr. Yuji Ito from the Department of Pediatrics at Nagoya University Hospital, and  Dr. Nobuhiko Ochi and Dr. Koji Noritake from Aichi Prefectural Mikawa Aoitori Medical and Rehabilitation Center for Developmental Disabilities, conducted a study of Japanese children and students in elementary and junior high schools, aged 9-15, by analyzing data from physical examinations before and during the COVID-19 pandemic. They evaluated the children’s muscle strength, dynamic balance functions, walking speed, body fat percentage, screen time, sleep time, quality of life, and physical activity time.  

The researchers found that after the onset of the pandemic, children were more likely to have decreased balance ability when moving, larger body fat percentage, report spending more time looking at TV, computers or smartphones, and sleep less. Since there were no changes in the time spent on physical activity or the number of meals eaten, Sugiura and his colleagues suggest that the worsening of physical functions was related to the quality of exercise of the children. The researchers reported their findings in the International Journal of Environmental Research and Public Health.  

“Since the outbreak of the novel coronavirus in Japan after April 2020, children have not been able to engage in sufficient physical education, sports activities, and outdoor play at school. It became clear that balance ability during movement was easily affected, lifestyle habits were disrupted, and the percentage of body fat was likely to increase,” explained Ito. “This may have been because of shorter outdoor playtime and club activities, which impeded children’s ability to learn the motor skills necessary to balance during movement.” 

“Limitations on children’s opportunities for physical activity because of the outbreak of the novel coronavirus have had a significant impact on the development of physical function and lifestyle and may cause physical deterioration and health problems in the future,” warned Ito. “Especially, the risk of injury to children may increase because of a reduced dynamic balance function.” 

The results suggest that even after the novel coronavirus becomes endemic, it is important to consider the effects of social restrictions on the body composition of adolescents. Since physical activities with a social element may be important for health, authorities should prioritize preventing the reduction of children’s physical inactivity and actively encourage them to play outdoors and exercise. The group has some recommendations for families worried about the effects of school closings and other coronavirus measures on their children. “It is important for children to practice dynamic balance ability, maintaining balance to avoid falling over while performing movements,” Ito advised. “To improve balance function in children, it is important to incorporate enhanced content, such as short-term exercise programs specifically designed to improve balance functions.” 


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These Are The World’s Richest Billionaires Over The Past 10 Years

These Are The World’s Richest Billionaires Over The Past 10 Years

The last decade has seen a number of changes in the world’s richest billionaires…

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These Are The World's Richest Billionaires Over The Past 10 Years

The last decade has seen a number of changes in the world’s richest billionaires list.

For one, there are new faces at the top of the leaderboard that were never there before. But, as Visual Capitalist's Nick Routley details below, one of the most obvious changes though, is that the richest billionaires have accumulated a lot more wealth in recent years.

Using annual data from Forbes on the richest billionaires, Routley has visualized the wealth and ranking of the top 10 billionaires over the past decade.

Who are the World’s Richest Billionaires?

While the pecking order has fluctuated, the leaderboard remains very exclusive. Out of a possible 10 spots, there are only 19 individuals that have made the list over the last decade.

Here’s the current list of richest billionaires in 2022, including when they first made the list (if in the last decade):

 

*Billionaires with “-” first made the list at an earlier date. Example: Mukesh Ambani made the 2008 list.

 

Microsoft co-founder turned philanthropist, Bill Gates, is a perennial presence at the top of these lists. Gates is currently at his lowest rank over this time period, but is still in fourth spot. The billionaire has pledged to give away nearly all of his fortune to the eponymously named Bill & Melinda Gates Foundation.

From 2018 to 2021, Jeff Bezos sat at the top of the world’s richest people ranking, only to be bumped out by Elon Musk. In 2020, Bezos became the first person to amass a $200 billion fortune after Amazon’s stock price surged during the pandemic. In recent months, Bezos’ net worth has taken a hit as Amazon’s share price has fallen back down to Earth.

Today, Elon Musk is the world’s richest person.

The Rich Get Richer

Over time, the median net worth of the richest billionaires has grown significantly.

 

Most fortunes are held in the form of business equity, real estate, and publicly-traded stocks—all asset classes that have benefited from the era of cheap money and ultra-low interest rates.

 

Over the decade period, the median net worth of the top 10 billionaires has nearly tripled from $39 billion to $115 billion.

In fact, the first billionaire to pass the $100 billion threshold was Jeff Bezos in 2018, when he took the top spot on the list from Bill Gates. However, now all but two on the top 10 wealthiest list are centibillionaires.

Tyler Durden Mon, 12/05/2022 - 20:40

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Contradictions, Lies, And “I Don’t Recalls”: The Fauci Deposition

Contradictions, Lies, And "I Don’t Recalls": The Fauci Deposition

Authored by Techno Fog via The Reactionary,

Today, Missouri Attoney General…

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Contradictions, Lies, And "I Don't Recalls": The Fauci Deposition

Authored by Techno Fog via The Reactionary,

Today, Missouri Attoney General Eric Schmitt released the transcript of the testimony of Dr. Anthony Fauci. As you might recall, Fauci was deposed as part of an ongoing federal lawsuit challenging the Biden Administration’s violations of the First Amendment in targeting and suppressing the speech of Americans who challenged the government’s narrative on COVID-19.

Here is the Fauci deposition transcript.

And here are the highlights…

EcoHealth Alliance - the Peter Daszak group - is knee-deep in the Wuhan controversy, having been funded by the Fauci’s NIH for coronavirus and gain of function research in China (and having worked with the Chinese team in Wuhan). What does Fauci say about EcoHealth Alliance? Over two years after the COVID-19 pandemic began, and after millions dead worldwide, he’s “vaguely familiar” with their work.

In early 2020, Fauci was put on notice that his group - NIAID - had funded EcoHealth alliance on bat coronavirus research for the past five years.

This coincided with early reports - directly to Fauci, from Jeremy Ferrar and Christian Anderson - “of the possibility of there being a manipulation of the virus” based on the fact that “it was an unusual virus.”

Fauci conceded that he was specifically made aware by Anderson that “the unusual features of the virus” make it look “potentially engineered.”

Fauci couldn’t recall why he sent an article discussing gain of function research in China to his deputy, Hugh Auchincloss, telling him it was essential that they speak on the phone. He couldn’t recall speaking with Auchincloss via phone that day. But remarkably, Fauci did remember assigning research tasks to Auchincloss

Fauci was evasive on conversations with Francis Collins about whether NIAID may have funded coronavirus-related research in China, eventually stating “I don’t recall.”

The phrase “I don’t recall” was prominent in Fauci’s deposition. He said it a total of 174 times:

For example, Fauci couldn’t remember what anyone said on a call discussing whether the virus originated in a lab:

During that same call, Fauci couldn’t recall whether anyone expressed concern that the lab leak “might discredit scientific funding projects.” He also couldn’t recall whether there was a discussion about a lab leak distracting from the virus response. Fauci did remember, however, that they agreed there needed to be more time to investigate the virus origins - including the lab leak theory.

What else couldn’t Fauci remember? Whether, early into the pandemic, his confidants raised concerns about social media posts about the origins of COVID-19.

Yet Fauci did admit he was concerned about social media posts blaming China for the pandemic. He even admitted the accidental lab leak “certainly is a possibility,” contradicting his prior claims to National Geographic where he said the virus “could not have been artificially or deliberately manipulated.”

Fauci also couldn’t recall whether he had any conversations with Daszak about the origins of COVID-19 in February 2020, but admitted those conversations might have happened: “I told you before that I did not remember any direct conversations with him about the origin, and I said I very well might have had conversations but I don't specifically remember conversations.” And he couldn’t recall telling the media early on during the pandemic that the virus was consistent with a jump “from an animal to a human.”

Fauci said he was in the dark on social media actions to curb speech and suspend accounts that posted COVID-19 information that didn’t fit the mainstream narrative: “I’m not aware of suppression of speech on social media.” Yet it was Fauci’s proclamations of the truth, whether about the origins of COVID-19 to the effectiveness of hydroxychloroquine, that led to social media companies banning discussions of contrary information.

Regarding those removals of content, Fauci had no personal knowledge of a US Government/Social Media effort to curb “misinformation.” But he conceded the possibility numerous times.

Then there’s the issue of masks. In February 2020, Fauci informed an acquaintance that was traveling: “I do not recommend that you wear a mask.” Fauci would later become a vocal proponent of masks only two months later.

I’m near my Substack length limit - posting the excerpts does that - but you can see from Fauci’s testimony that his public statements about COVID-19 origins and the necessity to wear a mask didn’t match his private conversations. This has been known for some time, but it’s finally nice to get him on record.

Again, read it all and subscribe here.

Tyler Durden Mon, 12/05/2022 - 21:40

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