What We Know About Why Some People Never Get Covid 19

Americans who haven’t had covid-19 are now officially in the minority. A study published this week from the US Centers for Disease Control and Prevention (CDC) found that 58% of randomly selected blood samples from adults contained antibodies indicating that they had previously been infected with the virus; among children, that rate was 75%.

What is different about that minority of people that hasn’t yet gotten infected? Stories abound of close calls, of situations where people are sure they could have (or should have) gotten sick, but somehow dodged infection. Not all the questions are answered yet, but the question of what distinguishes the never-covid cohort is a growing area of research even as the US moves “out of the full-blown” pandemic. Here are the possibilities that scientists are considering to explain why some people haven’t contracted the virus.

They behave differently

We’ve seen it play out time and time again—some people adhere more strictly to protocols known to reduce transmission of the virus, including wearing a mask and getting vaccinated. Some people avoid large public settings and may have even been doing so before the pandemic, says Nicholas Pullen, a biology professor at the University of Northern Colorado. Then again, that doesn’t tell the whole story; as Pullen himself notes: “Ironically, I happen to be one of those ‘never COVIDers’ and I teach in huge classrooms!”

They’ve trained their immune systems

The immune system, as any immunologist or allergist can tell you, is complicated. Though vaccination against covid-19 can make symptoms more mild for some people, it can prevent others from contracting the illness altogether.

Growing evidence suggests that there may be other ways that people are protected against the virus even without specific vaccines against it. Some could have previously been infected with other coronaviruses, which may allow their immune systems to remember and fight similarly shaped viruses. Another study suggests that strong defenses in the innate immune system, barriers and other processes that prevent pathogens from infecting a person’s body, may also prevent infection.

An innate immune system that’s already not functioning as well due to other medical conditions or lifestyle factors such as sleep or diet may put a person at higher risk of getting sick from a pathogen. There’s not single answer here yet, but initial studies are intriguing and may offer avenues for future treatments for covid-19 and other conditions.

They’re genetically different

In the past, studies have found interesting associations between certain genetic variants and people’s susceptibility to communicable diseases such as HIV, tuberculosis, and the flu. Naturally, researchers wondered if such a variant could exist for covid-19. One June 2021 study that was not peer reviewed found an association between a genetic variant and lower risk of contracting covid-19; another large-scale study, focused on couples in which one person got sick while the other didn’t, kicked off in Oct. 2021.

“My speculation is that something will be borne out there, because it has been well observed that resistance embedded in genetic variation is selected in pandemics,” Pullen says. But most experts suspect that even if they are able to identify such a variant with some certainty, it’s likely to be rare. For now, it’s best for those who haven’t gotten covid to assume they’re as susceptible as anyone else. Whatever the reasons some people haven’t yet gotten sick, the best defense remains staying up to date with vaccinations and avoiding contact with the virus.

Source: What we know about why some people never get covid-19 — Quartz

“Being exposed to the SARS-CoV-2 virus doesn’t always result in infection, and we’ve been keen to understand why,” study author Rhia Kundu said in a statement, using the scientific name for the coronavirus. “We found that high levels of pre-existing T cells, created by the body when infected with other human coronaviruses like the common cold, can protect against COVID-19 infection.”

The study, which examined 52 people who lived with someone who contracted the coronavirus, found that those who didn’t get infected had significantly higher levels of T cells from previous common cold coronavirus infections. T cells are part of the immune system and believed to protect the body from infection. “Our study provides the clearest evidence to date that T cells induced by common cold coronaviruses play a protective role against SARS-CoV-2 infection,” study author Ajit Lalvani said in a statement.

Researchers cautioned that the findings should not be relied upon as a protection strategy. “While this is an important discovery, it is only one form of protection, and I would stress that no one should rely on this alone,” Kundu said. “Instead, the best way to protect yourself against COVID-19 is to be fully vaccinated, including getting your booster dose.” And the findings on the subject have been inconsistent, with other studies actually suggesting that previous infection with some coronaviruses have the opposite effect.

A major question that has come from the so-called ‘never COVID’ group is whether genetics plays a role in preventing infection. In fact, the question has spurred a team of international researchers to look for people who are genetically resistant to COVID-19 in the hopes that their findings could improve therapeutics. “What we are doing essentially is that we are testing the hypothesis that some people might not be able to get infected because of their genetic and inborn makeup, meaning that they might be genetically resistant to COVID,” says Spaan, who is a member of the COVID Human Genetic Effort.

The effort has sequenced genetic data from about 700 individuals so far, but enrollment is ongoing and researchers have received thousands of inquiries, according to Spaan. The study has several criteria, including laboratory test confirmation that the person has not had previous COVID-19 infection, intense exposure to the virus without access to personal protective equipment like masks and an unvaccinated status at the time of exposure, among others. So far, the group doesn’t know what the genetic difference could be – or if it even exists at all, though they believe it does.

“We do not know how frequent it is actually occurring,” Spaan says. “Is it like a super rare individual with a very, very rare mutation? Or is that something more common?” But the hypothesis is “embedded in human history,” according to Spaan. “COVID is not quite the first pandemic that we are dealing with,” Spaan says. “Humans have been exposed to viruses and other pathogens across time from the early beginning, and these infections have left an imprint on our genetic makeup.”

Those who haven’t gotten the coronavirus are “very much at risk,” says Murphy of Northwestern University. “I think every unvaccinated person is going to get it before this is over.” Experts stressed that research to determine why some people get COVID-19 while others don’t is still very much underway, and no one should rely on any of the hypotheses for protection. Instead, those who haven’t gotten the coronavirus should continue mitigation measures that have been proven to work, like vaccination and mask-wearing.

“You don’t ever want to have COVID,” Murphy says. “You just don’t know which people are going to get really sick from this and die or who’s going to get long COVID, which is hard to diagnose and difficult to treat and very real.” But with coronavirus cases on the rise and mitigation measures like mask mandates dropping left and right, it’s not an easy task.

COVID19: Face masks could return as cases spike Financial Mirror

06:48 Tue, 21 Jun
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As Climate Change Worsens Allergy Season, Tips On How To Cope

Climate change is prompting longer pollen seasons and higher pollen counts, which spells trouble for people with seasonal allergies, allergists warn.

“Allergy seasons have been changing in North America and across the globe, and we see greater changes the further you get from the equator,” explained Dr. Kara Wada, an allergist immunologist at Ohio State’s Wexner Medical Center. “In the U.S., the time between our thaw and our freeze is much longer, so plants have longer to reproduce and produce more pollen.”

Along with more severe and longer-lasting symptoms for allergy sufferers, longer pollen seasons have led to an increase in the number of people diagnosed with seasonal allergies for the first time.

There were 19.2 million American adults diagnosed with seasonal allergies in 2018, according to the U.S. Centers for Disease Control and Prevention. But seasonal allergies affect up to 60 million people in the United States and are the sixth leading cause of chronic illness.

Seasonal allergy sufferers first need to identify their allergens and then take steps to avoid them, Wada said.

  • Monitor pollen levels and avoid spending time outdoors when pollen counts are high.
  • Keep windows closed in the car and at home.
  • Use high-efficiency filters in your heating and cooling system, and change them regularly.
  • If you do go outside, change your clothes and bathe when you return home, to remove pollen from your skin and hair.
  • If possible, begin taking antihistamines recommended by your doctor a few weeks before spring allergy season begins.
  • Consider immunotherapy, which can desensitize the immune system to allergens. Once immunotherapy is complete, patients may need little to no allergy medication.

“There are incredibly helpful, really effective treatments and an allergist immunologist can help you figure out the perfect combination to help treat your symptoms and get you feeling better,” Wada said in a university news release.

“If allergies go untreated, not only are your symptoms going to worsen with stuffy nose, sneezing, but that also can sometimes progress into sinus infections, and recurrent sinus infections can sometimes require surgery,” Wada added.

By: Robert Preidt

Robert Preidt is an award-winning journalist and photographer who began his career 40 years ago. The first 15 years were spent as a newspaper reporter, followed by freelancing for various publications, including the Toronto Star, Family Practice and the Medical Post. He’s been writing for HealthDay since 1999.

Source: As Climate Change Worsens Allergy Season, Tips on How to Cope – Consumer Health News | HealthDay

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 Critics:

Pollen season could start 10-40 days earlier and last 5-20 days longer, with pollen levels that could triple in some places if carbon emissions aren’t curbed, researchers found.

Warmer weather allows plants to start blooming earlier and continue to bloom later in the season, while carbon dioxide in the air from burning fuels such as coal, gasoline, and natural gas helps plants produce more pollen, Allison Steiner, PhD, one of the study co-authors and a climate scientist at the University of Michigan, told The Associated Press.

The research team looked at 15 plant pollens in the U.S. and historical pollen data collected from 100 sites across North America. They used computer simulations to calculate how long the allergy season will get and how pollen emissions will change as temperatures rise during the next 80 years.

They found that temperature and precipitation will affect daily pollen emissions based on the region and type of pollen. The annual total pollen emission could increase 15% to 40% due to seasonal change and temperature-driven pollen production. What’s more, rising carbon dioxide in the atmosphere could increase pollen production by 200% by 2100.

Allergy season has already grown worse in recent decades, the AP reported. Allergists say that pollen season in the U.S. used to start in mid-March around St. Patrick’s Day and now often starts in mid-February around Valentine’s Day.

More contents:

A Good Spring Clean Can Help Tame Seasonal Allergies … ›

Allergy Season Is Near: Be Prepared – Consumer Health News … ›

Is It Allergies or COVID? Expert Shows How to Tell the Difference … ›

Seasonal Allergies in Children – HealthyChildren.org ›

Seasonal Allergies (Hay Fever) (for Parents) – Nemours KidsHealth ›

Seasonal allergies: Nip them in the bud – Mayo Clinic ›

How Omicron Upended What We Thought We Knew About Natural Immunity

After dizzily swelling for weeks, COVID-19 cases seem to be leveling off in New York and Chicago. In the greater Boston area, the amount of SARS-CoV-2 found in wastewater is going down as quickly as it had gone up. The hard part isn’t over yet, but the omicron wave is starting to break and roll back out to sea. Soon we’ll see if any treasures are left behind in the tide pool.

Between Dec. 1 and Jan. 17, at least 18 million Americans contracted COVID. Data suggests that the vast majority of those cases were in unvaccinated people, but plenty of people who got their primary series of the vaccine also caught the immunity-evading omicron variant. By the time this wave is over, American bodies will know this virus like never before. But will the survivors gain anything from having had the disease? After all, there will be more variants in the future. Could the hard-earned immunity we’ve gained from omicron help fight them off? Could this wave be the last?

On Monday, White House chief medical adviser Anthony Fauci said it’s too soon to answer these questions. Scientists we spoke to agreed. But they also said the reason these questions were so difficult to answer was because of an issue that hasn’t always gotten much attention in the public sphere:

The immunity provided by a COVID infection itself. Scientists have learned a lot about this “natural immunity” since the pandemic began. But omicron has upended many of those expectations, and the more we learn about this variant, the less clear it is what we should expect for the future of the virus and our immunity to it.

Scientists have been studying infection-induced immunity since COVID first emerged. In fact, it was the only kind of immunity anyone could really study at that point, said John Moore, a professor of microbiology and immunology at Cornell University’s Weill Cornell Medical College. And while there are now many more studies on vaccine-induced immunity thanks to clinical trials and easily trackable vaccinated populations like medical staff, there’s a lot that can be said about natural immunity, pre-omicron, with a reasonable amount of certainty.

One important takeaway from all that pre-omicron research: Infection-induced immunity and vaccine-induced immunity are pretty similar. On the whole, studies found that the efficacy of infection-induced immunity was about the same as what you’d get from a two-dose mRNA vaccine, and sometimes higher.

For example, research from the U.K., in which a few hundred thousand participants were followed in a large-scale longitudinal survey, found that prior to May 16, having had two doses of the vaccine (regardless of the type) reduced the risk of testing positive by 79 percent, while being unvaccinated and having had a previous infection reduced the risk by 65 percent. After the delta variant became dominant,1 vaccination became less effective, reducing the risk by 67 percent, while a previous infection reduced the risk by 71 percent.

Likewise, both kinds of immunity seemed to wane over time — though Moore said infection-induced immunity might take longer to decline because a vaccination happens nearly all at once, while an infection takes longer to go through a process of growing, declining and finally being cleared from the body. “But it’s also not radically different [from antibody titers to vaccination]. It’s not measured in years, but months,” he said.

This is why some countries, including the member states of the European Union, treat documented recovery from COVID-19 as functionally the same as vaccination in their “vaccine passport” systems.

Still, vaccine-induced immunity is a better choice, not because it produces a stronger immunity, but because it enables you to get the immunity without the side effects and risks that come along with illness — like a greater risk of stillbirth if you’re pregnant, or long COVID, hospitalization and death in general.

The pre-omicron research also indicated another downside to natural immunity: namely, that it can be more variable. All immunity differs from person to person and holds up better against some variants than others. But infection-induced immunity can also be more or less effective depending on how severe your case of COVID was, explained John Dennehy, a professor of biology at the City University of New York’s Graduate Center.

Since the earliest studies, scientists have found evidence that more severe illnesses produce a higher antibody response, while mild cases end up producing much less.

Then came omicron. The public desire for information on omicron is moving faster than science can produce, but we do know that this variant escapes natural immunity as easily as it does vaccine immunity. Omicron carries a lot of mutations that make it able to evade antibodies — and it doesn’t really matter how you got those antibodies in the first place, said Jeffrey Klausner, a professor of medicine in the Division of Infectious Diseases at UCLA’s David Geffen School of Medicine.

Beyond that, the picture is murky. For example, we know milder infections have, with past strains, produced less effective immunity. If a hallmark of omicron is milder infections — and that’s the main reason why there’s so much chatter that it might just be better to get this variant and get some natural immunity — how much immunity can anyone really expect to come out of those mild infections with?

“We’re going to know for sure in a few weeks because a ton of preprint is coming out about it, but I don’t know the answer today,” Moore said. It’s information journalists can come back and update you on later, but it makes informed speculation hard now. (Meanwhile, keep an eye on our COVID-19 research tracker.)

The same holds true when you start trying to parse out what vaccinated people can expect from a breakthrough case of omicron. The combination of vaccine and infection-induced immunity has been shown to produce a hybrid that is probably more effective than either type alone — but, again, that research came from pre-omicron studies. Is a breakthrough case as good as a booster?

If you’re going to get a booster after you’ve had a breakthrough case, how long should you wait? Those are questions scientists don’t have the answers to yet, partly because there’s no clear through line of what to expect once you’re dealing with omicron.

“Maybe your readers are right in being confused, because we don’t really know how long-lasting the immunity you get from omicron will be,” said David Thomas, the director of the Division of Infectious Diseases at Johns Hopkins Medicine.

Which brings us to the biggest question of all: Will the many infections, reinfections and breakthrough infections associated with omicron maybe — finally — put us in a better position for a well-protected, safer society? Maybe even a society that doesn’t have any more big waves crashing on its head?

Theoretically, yes, Klausner told me. And he’s optimistic that it will. Thomas and Dennehy, on the other hand, were more cautious. After all, Dennehy pointed out, there’s no guarantee that future strains will be related to omicron. If omicron is different enough from delta that it evades immunity from that previous variant, what happens if a future variant comes along that’s evolved from delta and not omicron? It’s not unreasonable to expect a whole new wave.

And what does Moore think? He was just ready to take a pause from speculation and get some data before anyone starts making decisions for themselves or for society. “I’m fed up with winging answers to reporters like yourself, because I don’t know the answer,” he said. “None of us know for sure.”

Maggie Koerth

By:

Maggie Koerth is a senior science writer for FiveThirtyEight.

Source: How Omicron Upended What We Thought We Knew About Natural Immunity | FiveThirtyEight

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More contents:

Covid’s Forgotten Hero: The Untold Story Of The Scientist Whose Breakthrough Made The Vaccines Possible

In the summer of 2020, as the pandemic raged, infecting more than 200,000 people a day across the globe, Pfizer CEO Albert Bourla and BioNTech CEO Uğur Şahin boarded an executive jet en route to the hilly countryside of Klosterneuburg, Austria. Their destination: a small manufacturing facility located on the west bank of the Danube River called Polymun Scientific Immunbiologische Forschung.
Bourla and Şahin were on a mission to get the company to manufacture as many lipid nanoparticles as possible for their new Covid-19 vaccine, which was on a fast track to receive emergency authorization from the U.S. Food and Drug Administration.

The Pfizer-BioNTech vaccine had been engineered with messenger RNA technology that instructs the body’s immune system to combat the coronavirus. But to get it safely into human cells, the mRNA needed to be wrapped in microscopic fragments of fat known as lipids. The Austrian manufacturing plant was one of the few places on earth that made the required lipid nanoparticles, and Bourla insisted Şahin go with him personally to press their case.

“The whole mRNA platform is not how to build an mRNA molecule; that’s the easy thing,” Bourla says. “It is how to make sure the mRNA molecule will go into your cells and give the instructions.”

Yet the story of how Moderna, BioNTech and Pfizer managed to create that vital delivery system has never been told. It’s a complicated saga involving 15 years of legal battles and accusations of betrayal and deceit. What is clear is that when humanity needed a way to deliver mRNA to human cells to arrest the pandemic, there was only one reliable method available—and it wasn’t one originated in-house by Pfizer, Moderna, BioNTech or any of the other major vaccine companies.

A months-long investigation by Forbes reveals that the scientist most responsible for this critical delivery method is a little-known 57-year-old Canadian biochemist named Ian MacLachlan. As chief scientific officer of two small companies, Protiva Biotherapeutics and Tekmira Pharmaceuticals, MacLachlan led the team that developed this crucial technology. Today, though, few people—and none of the big pharmaceutical companies—openly acknowledge his groundbreaking work, and MacLachlan earns nothing from the technology he pioneered.


“I look at the news, and 50% of it is vaccines—it’s everywhere—and I have no doubt the vaccines are using the technology we developed.”


“I just wasn’t going to spend the rest of my life dealing with it, but I can’t escape it,” MacLachlan says. “I open my browser in the morning and look at the news, and 50% of it is vaccines—it’s everywhere—and I have no doubt the vaccines are using the technology we developed.”

Moderna Therapeutics vigorously disputes the idea that its mRNA vaccine uses MacLachlan’s delivery system, and BioNTech, the vaccine maker partnered with Pfizer, talks about it carefully. Legal proceedings are pending, and big money is at stake.

Moderna, BioNTech and Pfizer are on their way to selling $45 billion worth of vaccines in 2021. They don’t pay a dime to MacLachlan. Other coronavirus vaccine makers, such as Gritstone Oncology, have recently licensed MacLachlan’s Protiva-Tekmira delivery technology for between 5% and 15% of product sales. MacLachlan no longer has a financial stake in the technology, but a similar royalty on the Moderna and Pfizer-BioNTech vaccines could yield as much as $6.75 billion in 2021 alone. In an ironic twist of fate, though, President Biden’s proposal to waive Covid-19 vaccine patents would make it unlikely that the intellectual property related to MacLachlan’s advances could be a source of riches.

Despite their denials, scientific papers and regulatory documents filed with the FDA show that both Moderna and Pfizer-BioNTech’s vaccines use a delivery system strikingly similar to what MacLachlan and his team created—a carefully formulated four-lipid component that encapsulates mRNA in a dense particle through a mixing process involving ethanol and a T-connector apparatus.

For years, Moderna claimed it was using its own proprietary delivery system, but when it came time for the company to test its Covid-19 vaccine in mice, it used the same four kinds of lipids as MacLachlan’s technology, in identical ratios.

Moderna insists the preclinical formulation of the vaccine was not the same as the vaccine itself. Subsequent regulatory filings by Moderna show its vaccine uses the same four types of lipids as MacLachlan’s delivery system but with a proprietary version of one of the lipids and the ratios “slightly modified” in a still undisclosed manner.

It’s a similar story for Pfizer and BioNTech. FDA documents show their vaccine uses the same four kinds of lipids in nearly the exact ratios that MacLachlan and his team patented years ago, albeit with one of those lipids being a new proprietary variation.

Not everyone ignores MacLachlan. “A lot of credit goes to Ian MacLachlan for the LNP [lipid nanoparticle],” says Katalin Karikó, the scientist who laid the groundwork for mRNA therapies before joining BioNTech in 2013. But Karikó, now a frontrunner for a Nobel Prize, is angry that MacLachlan didn’t do more to help her use his delivery system to build her own mRNA company years ago. “[MacLachlan] might be a great scientist, but he lacked vision,” she says.

Seven years ago, MacLachlan quit his position at Tekmira, walking away from his brilliant discovery and any potential financial rewards. Messy legal battles and political infighting within the biopharma industry over the delivery system had taken a toll on him. His emotions are complex. He may be overlooked, but he knows that he helped save the world.

“There’s a team of people who gave a great deal of their lives to the development of this technology. They gave their heart and soul,” MacLachlan says. “These people worked like dogs and gave the best part of themselves to develop it.”

Perched on a hilltop, Hohentübingen Castle towers above the town of Tübingen, Germany. In October 2013, MacLachlan, then the chief scientific officer of Tekmira Pharmaceuticals, trudged up the hill to the castle to attend a cocktail party at the first International mRNA Health Conference. During the evening, MacLachlan struck up a conversation with Stéphane Bancel, the CEO of an upstart mRNA company called Moderna Therapeutics. MacLachlan suggested Tekmira and Moderna collaborate using his innovative drug delivery system. “You are too expensive,” Bancel told him.

The exchange gave MacLachlan a bad feeling. So did the presence of a former colleague, Thomas Madden, who had been fired by Tekmira five years earlier. By this point MacLachlan had spent more than a decade working on his delivery system, yet people like Bancel seemed more interested in working with the London-born Madden.

The rivalry between these two scientists is the root of the controversy over the delivery technology that today’s Covid-19 vaccines rely on. MacLachlan and Madden met 25 years ago, when they worked together at a small Vancouver-based biotech called Inex Pharmaceuticals. With a Ph.D. in biochemistry, MacLachlan joined Inex in 1996, his first job after completing a postdoctoral fellowship in a gene lab at the University of Michigan.

Inex was cofounded by its chief scientific officer, Pieter Cullis, now 75, a long-haired physicist who taught at the University of British Columbia. From his perch there Cullis started several biotechs, cultivating an elite community of scientists that made Vancouver a hotbed of lipid chemistry.

Inex had a small-molecule chemotherapy drug candidate, but Cullis was also interested in gene therapy. His goal was to deliver large-molecule genetic material, like DNA or RNA, inside a lipid bubble so it could be safely ferried as medicine to the inside of a cell—something biochemists had dreamed about for decades but had been unable to accomplish.

Using a new method that mixed detergent with liquid, Cullis and his team at Inex successfully encapsulated small pieces of DNA in microscopic bubbles called liposomes. Unfortunately, the system could not consistently deliver bigger molecules, the type needed for gene therapy, in medically useful ways. They tried other approaches, including using ethanol, but didn’t succeed.

“We assembled all the LNP [lipid nanoparticle] pieces at Inex, but we didn’t get it to work” for genetic material, Cullis says.

Inex was a business, not a research lab, so it shifted its emphasis to the more promising chemotherapy drug. The gene therapy group was largely disbanded. MacLachlan ran what was left of it until, in 2000, he too decided to quit. Rather than let him completely walk away, Cullis persuaded MacLachlan to take the firm’s delivery assets and spin them out in a new company. Thus was born Protiva Biotherapeutics (MacLachlan became chief scientific officer), in which Inex retained a minority stake. MacLachlan recruited Mark Murray, now 73, a longtime American biotech executive with a Ph.D. in biochemistry, to be CEO.

It wasn’t long before two Protiva chemists, Lorne Palmer and Lloyd Jeffs, made a crucial discovery that led to a new mixing method. They put lipids dissolved in ethanol on one side of a physical T-connector apparatus, and, on the opposite side, genetic material dissolved in saltwater, then shot streams of the two solutions at each other. It was the moment they had been hoping for. The collision resulted in lipids forming a dense nanoparticle that instantly encapsulated the genetic material. The method was elegantly simple, and it worked.


In the midst of all this furious legal fighting, Hungarian biochemist Katalin Karikó showed up at MacLachlan’s door. Karikó was early to grasp that MacLachlan’s delivery system was key to mRNA therapies.


“The various methods that had been used previously were all highly variable and ineffective,” MacLachlan says. “Completely unsuitable for manufacturing.

The team he led quickly went on to develop a new lipid nanoparticle made of four specific kinds of lipids. Though these were among the lipids Inex had also been using in its experiments, MacLachlan’s LNP had a dense core that differed significantly from the sac-like liposome bubbles developed by Inex. MacLachlan’s team had figured out the specific ratios of the four kinds of lipids that worked best relative to one another. Everything was dutifully patented.

Moderna and Pfizer’s Covid vaccines use a type of gene therapy based on the messenger RNA molecule. Protiva’s scientists, though, initially gravitated toward a different type of gene therapy using RNA interference, or RNAi. While mRNA instructs the body to create therapeutic proteins, RNAi aims to silence bad genes before they cause disease. With MacLachlan’s delivery system in hand, Protiva started collaborating with Alnylam, a Cambridge, Massachusetts–based biotech, to make RNAi therapy viable.

Meanwhile, MacLachlan’s old company, Inex, was imploding after the FDA denied accelerated approval to its chemotherapy drug. Inex fired most of its staff and then—despite having spun off Protiva only a few years earlier—looped back to drug delivery. It, too, started working in partnership with Alnylam. In 2005 Cullis quit, leaving none other than MacLachlan’s archrival Thomas Madden to run Inex’s delivery efforts.

In 2006, Protiva and Alnylam published a landmark study in Nature demonstrating the first effective gene silencing in monkeys. The study used the delivery system MacLachlan’s team had developed.

Alnylam went on to develop Onpattro, an RNAi drug used to treat nerve damage in adults with a certain hereditary condition. The drug would become the first RNAi medicine ever approved by the FDA. Regulatory filings show Alnylam used MacLachlan’s delivery system for Onpattro—with one exception. For one of the four kinds of lipids, Alnylam used a modified version it developed with Thomas Madden.

In October 2008, Mark Murray, the CEO MacLachlan had recruited to run Protiva, stood in a room at Tekmira Pharmaceuticals, a small publicly traded shell company he had just taken over. Like Protiva, Tekmira had been created by Inex, which had finally burned out a year earlier, but not before transferring all its remaining assets to Tekmira. Assembled before Murray were some 15 former Inex scientists who had come along in the deal, including Thomas Madden.

“Unfortunately, we are not going to be able to keep you guys any longer,” Murray told them.

Madden’s firing was one result of a massive legal brawl sparked by the fact that both Inex and Protiva had been working separately with Alnylam on drug delivery. The dispute would continue for years. In each iteration, Murray and MacLachlan would accuse Madden and Cullis of having improperly taken their ideas. Cullis and Madden, offended by the accusations, denied them. Sometimes they sued back, claiming Murray and MacLachlan had acted wrongly.

The first round of litigation resulted in a 2008 settlement that saw Protiva take over Tekmira, with Murray as CEO, MacLachlan as chief scientific officer and Madden soon fired. Despite the bruising, Madden and Cullis founded a new company in 2009 to continue working with Alnylam.

Tekmira responded by suing Alnylam, claiming the Massachusetts biotech conspired with Madden and Cullis to cheaply gain ownership of the delivery system developed by MacLachlan. Alnylam denied wrongdoing and—of course—filed counterclaims, saying it simply wanted to work with Madden and Cullis, who had created an improved variation of one of the four kinds of delivery-system lipids.

That round of the legal brawl was settled in 2012, with Alnylam paying Tekmira $65 million and agreeing to assign dozens of its patents back to Tekmira. Those patents included ones for the improved lipid that Madden had developed for Onpattro. Under the deal, Cullis and Madden’s new company was granted a narrow license to use the MacLachlan delivery system to create new mRNA products from scratch.


Feeling defeated, MacLachlan quit Tekmira. He sold his stock, purchased a used Winnebago Adventurer for $60,000 and set off with his wife, two kids and their dog for a 5,200-mile road trip. “I was exhausted and demoralized.”


It was in the midst of all this furious legal fighting that Hungarian biochemist Katalin Karikó first showed up at MacLachlan’s door. Karikó was early to grasp that MacLachlan’s delivery system held the key to unlocking the potential of mRNA therapies. As early as 2006, she began sending letters to MacLachlan urging him to encase her groundbreaking chemically altered mRNA in his four-lipid delivery system. Embroiled in litigation, MacLachlan passed on her offer.

Karikó didn’t give up easily. In 2013, she flew to meet with Tekmira’s executives, offering to relocate to Vancouver and work directly under MacLachlan. Tekmira passed. “Moderna, BioNTech and CureVac all wanted me to work for them, but my number one choice, Tekmira, didn’t,” says Karikó, who took a job at BioNTech in 2013.

By this time, Moderna CEO Stéphane Bancel was also trying to solve the delivery puzzle. Bancel held discussions with Tekmira about collaborating, but talks stalled. At one point, Tekmira indicated it wanted at least $100 million up front, plus royalties, to strike a deal. Instead, Moderna partnered with Madden, who was still working with Cullis at their drug delivery company, Acuitas Therapeutics.

In February 2014, MacLachlan turned 50. His life partner, Karley Seabrook, lured him to Vancouver’s Imperial theater, which was packed with friends and family. She surprised him in a wedding dress, and their two children greeted MacLachlan with cards that read WILL YOU MARRY MOMMY? Seabrook had never thought it important that they get married, but a brush with cancer had altered her perspective—and the wedding would alter his.

For the workaholic scientist, dealing with lawyers and endless corporate maneuvering had taken its toll. Feeling defeated, MacLachlan quit Tekmira in 2014. He sold his stock in the company, purchased a used Winnebago Adventurer for $60,000 and set off with his new wife, two kids and their dog for a 5,200-mile road trip across Canada.

“I was exhausted and demoralized,” he says. With MacLachlan gone, CEO Murray renamed Tekmira, calling it Arbutus BioPharma, and decided the company should focus on creating hepatitis B treatments with New York drug development company Roivant Sciences. Yet he held on to the patents for the four-lipid drug delivery system.

Then Madden’s company, Acuitas, sublicensed the delivery technology to Moderna for the development of an mRNA flu vaccine. Murray was confident Madden had no right to do so, and in 2016 he gave notice that he intended to terminate Acuitas’ licensing agreement. Per custom, two months later, Acuitas sued in Vancouver, denying that it had violated any deal. On cue, Murray countersued, initiating a fresh round of legal combat. Importantly, though, this batch of lawsuits directly involved mRNA.

After battling for two more years, the parties settled. Murray terminated Thomas Madden’s license to MacLachlan’s delivery technology for any future medicines other than four products Moderna had already begun to develop (Murray also lost the rights to some of Madden’s technology). Murray and Roivant then created another company, Genevant Sciences, specifically to house the intellectual property related to the four-lipid delivery system and commercialize it.

Some companies were quick to come on board. Within a few months BioNTech CEO Şahin struck a deal with Genevant to use the delivery system for five of BioNTech’s existing mRNA cancer programs. The companies also agreed to work together on five other mRNA programs targeting rare diseases. There was no provision in the agreement about using the delivery technology for something completely unforeseen—something like Covid-19.

Moderna pursued a different strategy. It filed lawsuits with the U.S. Patent and Trademark Office seeking to nullify a series of patents related to MacLachlan’s delivery system, now controlled by Genevant. But in July 2020, as Moderna was pushing its vaccine through clinical trials, an adjudicative body largely upheld the most important patent claims. (Moderna is appealing.)

After the Moderna and Pfizer-BioNTech vaccines were authorized, Drew Weissman, a prominent mRNA researcher at the University of Pennsylvania, concluded in a peer-reviewed journal that both use delivery systems that are “similar to the Alnylam Onpattro product” but with a proprietary version of one of the lipids. Weissman noted both companies were using T-junction mixing.

Thomas Madden worked on the Pfizer-BioNTech vaccine delivery system and says he used enhanced versions of two of the four kinds of lipids. Madden says neither Onpattro nor the Pfizer-BioNTech vaccine would have been green-lighted by the FDA without his team’s improvements to the lipids.

MacLachlan dismisses the new variations as “iterative innovation.”

In a written statement to Forbes, Ray Jordan, Moderna’s corporate affairs chief, stated, “I can confirm that we did take a license to Tekmira’s IP for certain of our older products. But our newer products (including the Covid vaccine) have moved on with new technology.”

BioNTech declined to comment. Mikael Dolsten, Pfizer’s chief scientific officer, says the Pfizer-BioNTech vaccine is fully covered by patents and that in creating the first authorized mRNA product, Pfizer modified the delivery system to produce 3 billion doses annually.

“It’s different to have a process that may work for a very small scale than a large scale, and some of the assumptions that may look similar are based on how the scientific field evolved and [on] contributions from many different sources,” Dolsten says. “One needs to be careful in assuming that [if] things have similar names and similar molar ratios, it means it’s the same thing.”

Genevant declined to comment, but it could be fighting an uphill battle. In May, the Biden Administration backed waiving intellectual property protection on Covid-19 vaccines. Ironically, such a move might benefit, not hurt, Moderna, BioNTech and Pfizer by preventing Genevant from making any claims on their gigantic vaccine cash pile.

That’s just as well for Ian MacLachlan, whose role in what may be the most important medical advance in a century has been all but erased by the biotech industry.

“I definitely feel I made a contribution,” he says. “I have mixed feelings because of the way it’s being characterized, and I know the genesis of the technology.”

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Why Pfizer May Be The Best Bet to Deliver A Vaccine By The Fall

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In the middle of March, Pfizer chief Albert Bourla beamed into a WebEx video call with the leaders of the American pharmaceutical giant’s vaccine research and manufacturing groups. The two teams had worked late into the night on a robust development plan for Pfizer’s experimental Covid-19 vaccine and told Bourla that they aimed to make it available lightning-fast. It could be ready sometime in 2021.

“Not good enough,” Bourla said. The faces of the researchers tensed up, and conscious of the Herculean effort that had taken place, Bourla made sure to thank them. But he also kept pushing. He asked if people on the call thought the virus might come back in the fall, and what they expected would happen if a vaccine were not available when a new flu season hit at the same time, an issue the federal Centers for Disease Control raised weeks later.

“Think in different terms,” Bourla told them. “Think you have an open checkbook, you don’t need to worry about such things. Think that we will do things in parallel, not sequential. Think you need to build manufacturing of a vaccine before you know what’s working. If it doesn’t, let me worry about it and we will write it off and throw it out.”

Says Mikael Dolsten, Pfizer’s chief scientific officer: “He challenged the team to aim for a moon shot–like goal—to have millions of doses of vaccine in the hands of vulnerable populations before the end of the year.”

On the first Monday of May, Pfizer dosed the initial batch of healthy American volunteers in Baltimore with an experimental Covid-19 vaccine it developed with Germany’s Bio-NTech. Bourla was informed immediately. The following day, in an interview from his home in suburban Scarsdale, New York, he pointed out that it normally takes years to accomplish what Pfizer had just done in weeks. “How fast we moved is not something you could expect from the big, powerful pharma,” he said. “This is speed that you would envy in an entrepreneurial founder-based biotech.”

A Greek veterinarian who worked his way up the Pfizer corporate ladder for 25 years before becoming CEO in 2019, Bourla says nothing in his career could have prepared him for this moment. But he does believe the massive corporate transformation he has led—steering a behemoth conglomerate (2019 sales: $51.8 billion) deeper into the high-risk, high-reward game of developing new patented medicines and away from generic drugs and consumer products like Advil and Chapstick—has prepared Pfizer.

For Bourla, 58, the last four months have been a rollercoaster, an unending series of setbacks and victories. Pfizer is not alone in the race. Most of the world’s biggest pharmaceutical companies, including Johnson & Johnson, Sanofi, AstraZeneca and Roche, are throwing everything they can at Covid-19.

Some experts feel Bourla’s timeline—a viable vaccine in a matter of a few months—is simply unrealistic. Undeterred, Bourla has tasked hundreds of researchers to scour Pfizer’s trove of experimental and existing medicines to look for potential therapies. Early on, he openly authorized having discussions and sharing proprietary information with rival firms, moves unheard of in the secretive world of big pharma. Bourla has made Pfizer’s manufacturing capabilities available to small biotech concerns and is in talks as well to make large quantities of other companies’ Covid-19 drug candidates.

Pfizer’s most prominent effort is its work with Mainz, Germany–based BioNTech, an innovative $120 million (2019 sales) outfit that is mostly known for making cancer medications. The resulting experimental Covid-19 vaccine works with messenger RNA, a bleeding-edge technology that has never resulted in a successful treatment. Pfizer is hoping to get emergency-use authorization from the U.S. government for the vaccine by October. Its unique strategy is to rapidly pit four different mRNA vaccine candidates against one another and double down on the most likely winner.

In preparation, the company is shifting production at four manufacturing plants to make 20 million vaccine doses by the end of the year and hundreds of millions more in 2021. Bourla says Pfizer is willing to spend $1 billion in 2020 to develop and manufacture the vaccine before they know if it will work: “Speed is of paramount importance.”

While the vaccine effort is getting most of the public’s attention, Pfizer is also rushing to start a clinical trial this summer for a new antiviral drug to treat Covid-19. Additionally, it’s involved in a human study that seeks to repurpose Pfizer’s big arthritis drug, Xeljanz, for later-stage Covid-19 patients.

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“Being the CEO of a pharma company that can make a difference or not in a crisis like this is a very heavy weight,” Bourla says. “Even the way my daughter or son ask me, ‘Do you have something or not?’ Every person who knows me does the same. You feel if you get it right, you can save the world. And if you don’t get it right, you will not.”

In January, Uğur Şahin, the brilliant immunologist who founded BioNTech, read an article about Covid-19 in The Lancet. Şahin built BioNTech to hack human cells to go after diseases, particularly cancer, and he thought similar tech might work against the coronavirus. Soon after, Şahin spoke to Thomas Strüngmann, the German pharma billionaire who for years has backed Şahin and his wife, immunologist Özlem Türeci, in their ventures. “He said, ‘This is a big disaster.’ He said the schools will be closed, that this will be a pandemic,” Strüngmann says, referring to Şahin. “He switched most of his team to the vaccine.”

In February, Şahin (who is also now a billionaire, as BioNTech’s stock has soared) called up Kathrin Jansen, who heads vaccine research and development for Pfizer. Şahin told Jansen BioNTech had come up with vaccine candidates for Covid-19 and asked if Pfizer would be interested in working with him. “Uğur, you are asking?” Jansen replied. “Of course we are interested.”

Over the last few years, scientists have become intrigued by the idea of using messenger RNA, the genetic molecule that gives cells protein-making instructions, to develop medicines for cancer, heart disease and even infectious viruses by transforming human cells into drug factories. Because SARS-CoV-2, as the coronavirus is formally known, is an RNA virus, researchers like Şahin focused on the idea of giving mRNA the cellular machinery to make proteins that would create virus-protecting antibodies.

An mRNA vaccine has huge advantages over a traditional one. Because it can be made directly from the genetic code of the virus, it can be invented and entered into clinical trials in a matter of weeks, rather than months or years. But there’s a big downside: No one has ever successfully made one.

BioNTech is not alone in pursuing an mRNA vaccine. Moderna Therapeutics, a biotech in Cambridge, Massachusetts, also got going in January and has launched a big human trial for its mRNA vaccine, backed by $483 million from the federal government. Moderna is likewise aiming to produce millions of doses per month by the end of the year.

Pfizer was already comfortable with BioNTech. Two years ago, the two companies inked a $425 million deal to develop an mRNA flu vaccine. Pfizer was intrigued by the potential of an mRNA approach to short-circuit the process of developing a vaccine for a new strain of the flu every year. That same flexibility and speed appealed to Bourla when it came to working with a partner on a potential vaccine for Covid-19.

On March 16, Bourla convened Pfizer’s top executives and informed them that return on investment would not play a role in the company’s Covid-19 work. “This is not business as usual,” Bourla told them. “Financial returns should not drive any decisions.”

Pfizer signed a letter of intent with BioNTech the next day. The contract they finalized in April makes no mention of commercialization. Pfizer is bringing its enormous manufacturing, regulatory and research capabilities to the effort. BioNTech is bringing the basic science.

At the same time, Bourla made the decision to spend $1 billion on the project, so if the vaccine works, it can be made available this autumn. Pfizer will also be on the hook to pay BioNTech an additional $563 million if everything goes according to plan. “A billion dollars is not going to break us. And, by the way, I don’t plan to lose it. I plan to make sure we use this product,” Bourla says. “You never know until you see the data. So yes, we are going to lose a billion if” the vaccine doesn’t work.

What makes Pfizer’s approach unique is that it’s testing four distinctive vaccines—different mRNA platforms that are supposed to induce a safe immune response. The complex trial will start by testing different dosing levels of the four vaccines in 360 U.S. volunteers and 200 in Germany, eventually expanding to around 8,000 participants.

The U.S. trial was designed to evolve so the company could quickly stop testing any one of the vaccines if immunogenicity data show it is not producing enough antibodies to confer virus protection. The companies are making adjustments on the fly. BioNTech recently realized one of the vaccine candidates should be dosed at a lower level to be safe—an early fling of a monkey wrench into the plans.

There is considerable skepticism among experts that Pfizer’s goal of providing millions of doses to vulnerable populations by the fall is possible. Drew Weissmann, whose University of Pennsylvania laboratory has worked with BioNTech on mRNA vaccines for infectious diseases, recently told Forbes it is simply not known if an mRNA vaccine can prevent infectious disease.

Jansen, Pfizer’s vaccine research chief, expects that Pfizer and BioNTech will have a better idea around the beginning of July as to which of the four vaccine candidates is the most promising and whether their hyper-accelerated timeframe is feasible. The company will likely move just one or two of the most promising vaccines to more advanced trials.

“It’s not easy. As a matter of fact, it has never been done before—I can’t give you a probability,” Jansen says. “An unprecedented crisis, such as the ongoing pandemic, requires unprecedented action. Albert was the first to see that and act on it, and to provide the support and the environment for us to think and act boldly.”

When Albert Bourla started his run at the top of Pfizer in January 2019, he removed the bulky brown table from the CEO’s conference room and did not replace it, re-arranged the chairs in a circle and put up photographs of patients on the wall. The idea was to promote open discussion and remind people about the real purpose of a pharmaceutical company. Soon after, other Pfizer employees began to put pictures on their desks of patients they know or love.

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The unorthodox way Bourla took to the pinnacle of corporate power started in Greece’s second-biggest city, Thessaloniki, a northern port city on the Aegean Sea. He grew up middle-class—his father and uncle owned a liquor store—as part of a tiny Jewish minority that survived the German occupation and the Holocaust.

A love of animals and science drove Bourla to become a veterinarian. At Thessaloniki’s Aristotle University, he was known for playing the guitar and singing, and during the summers worked as a European tour guide. He joined Pfizer’s Greece office in 1993, working in its animal-health division, beginning an ascent that saw him move his family to eight cities in five countries, including Poland and Belgium.

By 2014, Bourla was a high-level executive at Pfizer’s Manhattan headquarters on 42nd Street, where, among other things, he ran Pfizer’s vaccine and cancer divisions. He brought a Mediterranean flair to the buttoned-up conglomerate. His group meetings were boisterous, echoing through the otherwise largely silent corridors. He forced company units to express their metrics in terms of how many patients they were helping, not merely in terms of dollars and cents.

Ian Read, Pfizer’s Scottish-born CEO at the time, had reversed the company’s fortunes on Wall Street, where its stock had been badly underperforming, by repurchasing lots of shares and divesting businesses that sold baby formula and animal medicines. Less visibly, Read reinvigorated Pfizer’s drug pipeline in its core vaccine business and empowered Pfizer’s researchers to develop targeted therapies, particularly for cancer, as some of its mass-marketed drugs, like the cholesterol-lowering blockbuster Lipitor, went off-patent.

Bourla’s last job before ascending to the C-suite was as head of Pfizer’s innovation group. He approached the position as though he was running a life-sciences venture capital firm. He forced each of his six business units, which included oncology, vaccines and rare diseases, to compete for financing. “I was telling all of them, ‘I’m your boss, I am private equity, the one who has the better ideas will get the money,’ ” he says. “A company that has the scale of Pfizer and the mindset of a small biotech was always my dream.”

“Albert has a sense of urgency, and that is coming out in the way he is marshaling the company’s resources behind trying to develop a vaccine or treatment for Covid-19,” says Read, his former boss. “He is a charismatic people person, energizing groups of people to get the job done.”

Bourla’s urgency was evident after a difficult weekend in February when he realized that Covid-19 was not going to be just a problem for China. On a call the following Monday morning, Bourla fired off instructions to Pfizer’s top brass. He told the science executives to make sure the company’s labs remained open, and that Pfizer needed to contribute to a medical solution to the pandemic. “If not us, then who?” Bourla said. He instructed the manufacturing group to make a list of Pfizer’s drugs—including those that treat heart failure and opportunistic bacterial infections—that would be in high demand in a pandemic and make sure they wouldn’t be hampered by production bottlenecks. He then officially informed the board that he was pivoting the company toward Covid-19.

One day in the midst of this retooling, Pfizer director Scott Gottlieb, who used run the FDA, left the company’s Manhattan headquarters, and within hours his fears were coming to pass: Reports were emerging from California indicating community spread in America. That evening Gottlieb posted a Twitter thread: A long fight could be ahead, one requiring shared sacrifice, he said—but partly because of Bourla’s efforts at Pfizer, he could also say that development of vaccines and therapeutics was already underway.

“Albert laid out early why it was so important to put up the enormous resources of Pfizer without an eye toward the business bottom line,” Gottlieb says. “Coming up with a vaccine could change the course of human history. That is literally what’s at stake, and big companies have the ability to scale up manufacturing and run big trials in a way not available to small product developers.”

In the middle of March, Bourla decided to publicly release Pfizer’s plan to share data from its Covid-19 research with rival pharmaceutical companies. He promised to use any excess manufacturing capacity and even shift production at Pfizer’s facilities away from its own products to make Covid-19 treatments from other companies. “You know the saying,” Bourla says. “Beware [of] what you wish for.”

Since then, Pfizer has heard from 340 companies. It has already given technical support to some of them and is on the brink of signing large manufacturing agreements with others. It is also in discussions with additional firms that need financing for their own Covid-19 therapies.

“Will my kids go to school next fall?” Bourla wonders. “I’m also part of society. You cannot stay silent.”

At a video meeting of Pfizer’s board of directors in late April, Bourla was asked what would happen if multiple vaccine makers were successful. That would be the best possible outcome, he replied, because enormous amounts of vaccine could be quickly produced.

Beyond the holy grail of a vaccine, Pfizer is also trying to come up with therapeutic solutions. The researchers tasked with combing through Pfizer’s molecular database became intrigued by several of its antiviral compounds that might attack the virus by stopping it from reproducing. After Pfi-zer got the DNA sequence of the coronavirus in January, researchers figured out which could work best.

Conducting preclinical work on the selected compounds, however, was difficult. Pfizer had trouble finding a lab that could perform the proper assays. The company had scaled down its antiviral research a decade ago and no longer owned a suitable biosafety lab to work with the live virus. At one point, Bourla feared the lack of a lab would delay the clinical-trial process. But a separate government medical agency helped Pfizer find a good one in the Netherlands.

There have been “multiple moments of bad news coming to spoil the good news you had three hours earlier,” Bourla says. Pfizer’s laboratory work has since shown one of its protease inhibitors, initially developed to battle SARS, to exhibit antiviral activity against SARS-CoV-2. Pfizer is now aiming to start a human trial for that antiviral, which is administered intravenously, by the end of the summer.

Another Pfizer drug getting attention is Xeljanz, a rheumatoid arthritis pill generating $2.2 billion annually. It is seen as a potential way to tamp down the massive immune response to Covid-19 that overwhelms some infected patients. Pfizer is supporting a Xeljanz trial in Italian Covid-19 patients, as well as another U.S. trial that will test a different arthritis medicine, an experimental drug that targets the Irak-4 protein, against the virus.

While all this is going on, of course, Bourla still needs to run the rest of Pfizer. He recently planned a symbolic visit to a Pfizer plant—none has closed—but after making the arrangements, he was informed that he would not be allowed to enter because he was not deemed essential.

“I don’t know if I was ever prepared for something like this,” Bourla says. “But you feel that you need to suck it up and rise to the occasion because that’s what you have to do.”

I am a senior editor at Forbes who likes digging into Wall Street, hedge funds and private equity firms, looking for both the good and the bad.

Source: https://www.forbes.com

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Dr. Mikael Dolsten, Pfizer chief scientific officer, joins ‘Closing Bell’ to discuss Pfizer’s new partnership. The company plans to start COVID-19 trials by April. The race is on to develop an immunization against COVID-19. Dozens of companies and public labs around the world are working to develop a vaccine to prevent the spread of the flu-like virus. Over the last 48 hours, three biotech companies, in particular, have been thrust into the spotlight for their promise: BioNTech, CureVac and Moderna. All three of these firms specialize in messenger RNA (mRNA) therapeutics. These mRNA molecules are used to instruct the body to produce its own immune response to fight a range of different diseases. This type of vaccine can potentially be developed and produced more quickly than traditional vaccines. Moderna is a Massachusetts-based biotech company working with the U.S. National Institutes of Health (NIH). It kicked off its first trial Monday in Seattle, Washington. This is called a “phase one” study and is being conducted by the NIH. Moderna is also preparing for a potential “phase two” study that it would conduct itself. Moderna shares rose 27% in Monday’s trading session. For access to live and exclusive video from CNBC subscribe to CNBC PRO: https://www.cnbc.com/pro/?__source=yo… » Subscribe to CNBC TV: https://cnb.cx/SubscribeCNBCtelevision » Subscribe to CNBC: https://cnb.cx/SubscribeCNBC » Subscribe to CNBC Classic: https://cnb.cx/SubscribeCNBCclassic
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