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The powerful technology behind the Pfizer and Moderna vaccines

Mish Boyka

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The powerful technology behind the Pfizer and Moderna vaccines

Two of the three COVID-19 vaccines that have been authorized so far in the United States use synthetic messenger RNA, or mRNA, to protect against the coronavirus. Though these vaccines – developed by Pfizer and Moderna, respectively – are the first of their kind to be used at this scale, this historic moment would not be possible without the decades of research that came before it.

There are lots of different ways to make a vaccine, but the ultimate goal of any shot is to introduce the body to the biological equivalent of a “most wanted” poster so that if the real enemy ever shows up, our immune systems know how to fight it off.

For some vaccines, that poster is a version of a pathogen that’s been weakened – like the chickenpox shot – or inactivated – like most flu shots – so that it can’t actually cause infection. For others, including the HPV and shingles vaccines, it’s a piece of that pathogen, like the specific protein it uses to infect cells in the first place.

But mRNA vaccines take a different approach. Rather than tinkering with the virus or its parts, this platform harnesses the “beauty of our biology” to deliver protection, said RNA virologist Paul Duprex, who directs the University of Pittsburgh Center for Vaccine Research. These vaccines teach the body to remember one of the coronavirus’ defining features – its spike protein – and prompt the creation of antibodies that can prevent it from infecting cells.

Our DNA resides inside the nucleus of our cells. Every day, mRNA molecules constantly carry genetic information coded in that DNA from the nucleus to the parts of the cells, called ribosomes, that can interpret those messages and then make the proteins that carry out essential biological processes. Without it, life would be impossible.

“Pretty much every single cell in my body at this particular moment is producing billions and billions and billions of messenger RNAs,” Duprex said.

READ MORE: The essential COVID-19 vaccine FAQ

Vaccines that use synthetic mRNA add one more type of mRNA to the legion of other molecules “doing their daily business” within our bodies, and use it “to make a protein which the immune system will see and make antibodies against and protect us from a disease, ”Duprex added.

Around 20 years ago, the work of two researchers – Drew Weissman and Katalin Karikó – helped overcome two primary barriers that had been standing in the way of utilizing mRNA technology: an inflammatory effect on the body that made test animals ill, and the fragile nature of the molecule itself, both of which hindered its utility.

Despite those advancements, and the wealth of research that’s been carried out since, the fact remains that the two mRNA vaccines in use today are the first of their kind. That may be in part because it’s difficult to generate interest and funding to support pursuing “non-mainstream” science outside of a crisis, Duprex said – what he characterized as “a shortsighted way to think about biology.

Only now, amid a devastating pandemic, has this technology reached mainstream prominence. “Given the choice, I would have rather avoided this past year,” Weissman said. “But we didn’t, and now RNA is going to be our future.”

Here’s a look at how, exactly, these vaccines manage to pull off this feat and some of the key research breakthroughs that made this moment possible.

How messenger RNA vaccines work

In order to develop these vaccines, the researchers took the RNA-based genetic sequence of the coronavirus and turned it into DNA. This crucial step allowed them to identify the “instructions” necessary to create the spike protein, engineer corresponding synthetic mRNA and package that into their vaccines.

mRNA, as its moniker implies, is a messenger. This particular type of RNA is tasked with delivering messages to microscopic cellular machines called ribosomes, located in the cytoplasm of our cells, which are responsible for synthesizing proteins. Those ribosomes then interpret that message to make proteins and start executing its instructions, explained Phillip Sharp, a molecular biologist and MIT professor who shared the 1993 Nobel Prize in physiology or medicine for his contribution to our understanding of RNA.

Dendritic cells, the watchdogs of the immune system, play an essential role in responding to pathogens. They patrol the body in search of foreign invaders and, when they find one, start stimulating an immune response. When these cells encounter mRNA that’s been injected via vaccination, their ribosomes decode the message and allow the cells to temporarily display spike proteins identical to the ones found on the coronavirus’ exterior, Weissman said.

“Dendritic cells make the spike protein and then they present it to other immune cells and activate them to start the immune response,” he added.

The proteins allow the dendritic cells to alert two more key players in the immune system – T cells and B cells – that if they see those same spikes on any other cell, they should recognize them as a foreign invaders and either destroy them or generate antibodies. to neutralize them immediately.

“There’s a memory component of those cell populations, and that stays in your body over a long period of time,” Sharp said. “If a similar virus infects you, those memory cells are ready to go. They are all perfected to go out and kill that virus. ”

mRNA naturally degrades rapidly over time, so once it has served its purpose, it simply breaks down. The dendritic cells that expressed the spike protein eventually die and are replaced by new ones that continue to pick up that vaccine-delivered mRNA and repeat the process all over again in the course of about two weeks following immunization.

Some members of the public have expressed concern over unfounded speculation that these vaccines could negatively affect the body. But it is impossible for an mRNA vaccine to alter your DNA because synthetic mRNA operates only in the cytoplasm and is incapable of entering any other parts of our cells, such as the nucleus.

Like virtually all vaccines, those that use mRNA can trigger temporary symptoms like a fever, fatigue and soreness at the injection site that dissipate within a few days. But clinical trials that took place before the vaccines were authorized, as well as those that have followed, all suggest that these vaccines are both safe and effective at preventing serious illness and death.

“It’s always, always much more risky to get the disease than it is to get the vaccine,” Duprex said.

How did we get here?

mRNA was first injected into the muscles of mice in 1990 with the intention to deliver therapeutic proteins. But that effort “didn’t go very far,” according to Weissman, in large part due to the strong inflammatory response it induced, which severely sickened the animals involved.

That’s because in both animals and humans, cells feature a number of different receptors that can recognize mRNA as a foreign substance that must be destroyed. Those receptors help these cells distinguish their fellow cells from invaders like viruses, bacteria or even tumor cells.

Both RNA and DNA are composed of four nucleotides. More than a decade after that first injection in mice, Weissman and Karikó, who now serves as senior vice president at BioNTech, which partnered with Pfizer to manufacture their joint vaccine, figured out a way to insert an modified nucleotide that allows the synthetic mRNA to masquerade as a normal cell and circumvent those receptors, no longer triggering extreme inflammation. It also made the mRNA-spurred protein production more efficient.

“Our big discovery was that we could modify the RNA to make it non-inflammatory. And that had a couple of important features to it, but the first was that it greatly increased the amount of protein made off of the RNA, ”which increased potency, Weissman said.

With the inflammation problem solved, Weissman and Karikó then turned to tweaking how mRNA is delivered so it could actually do its job once injected into the body. mRNA is an inherently “labile,” or unstable, material that can degrade rapidly to the point of being rendered infective.

After testing around 40 different types of delivery systems, the researchers found their golden ticket: lipid nanoparticles. These “droplets of fat” coat the mRNA and allow it to successfully enter our cells, which are also encapsulated in an oily substance.

Traditional vaccines are typically formulated with adjuvants that are designed to stimulate the immune response in their recipients. In what Weissman described as a lucky development, lipid nanoparticles happened to act as an adjuvant that stimulated a specific type of “helper cell” that promotes antibody responses.

“We use the lipid nanoparticles to get over a lot of the fragility [problems] because that protected the [mRNA] after you injected it into people, and it promoted these cells to take up the [mRNA] and start the vaccine process, ”Weissman said.

Where mRNA stands today

In the years since Weissman and Karikó made these breakthroughs, mRNA research has continued to march on. Weissman and his current colleagues have worked on a variety of mRNA vaccines, including a “universal” flu shot that could cover a majority of influenza viruses and has so far proven to be effective in animal trials.

Compared to traditional vaccine platforms that require a series of complex steps, like growing mammalian cells in massive quantities and a viral purification process that looks different depending on the pathogen you’re working with, mRNA is now easy to manufacture at a fairly large scale.

Instead of needing “to reinvent the wheel every time you make a new vaccine,” Weissman said, “with [mRNA,] it’s the same reaction, and the only thing you have to do is plug in the new sequence for any virus, so that makes it very easy to produce a new vaccine. ”

Both Moderna and Pfizer’s vaccines generated above 90 percent protection after two doses during clinical trials that played out before new variants of the virus marginally reduced their efficacy. Even so, the two give recipients remarkably high levels of protection, particularly against severe disease and death.

The CDC recently released new research that found these vaccines reduce a fully vaccinated person’s chance getting infected with the coronavirus by 90 percent in “real-world” settings like the workplace.

Given that no vaccines have ever been approved to immunize people against any kind of coronavirus, and that the FDA’s original hope was to secure one with At least 50 percent efficacy to curb the pandemic, these results represent yet another significant milestone in the annals of RNA technology.

Much more research lies ahead for these vaccines, both of which have been rolled out in the United States and in some other countries over the past few months. In addition to continuing to track safety and efficacy data, researchers need to know how well these vaccines prevent recipients from transmitting COVID-19 and how long the protection they offer lasts. Until we know the answers to those questions, recipients should keep following pandemic precautions like wearing a mask, even after they’ve got their two doses, experts say.

READ MORE: How to stay safe from COVID this summer, according to experts

Johnson & Johnson’s vaccine, a one dose shot that uses a different yet similarly innovative platform to deliver immunity compared to mRNA, has also been authorized for use in the United States. Its strong efficacy and ability to be stored at a less strict temperature range makes experts hopeful that the rollout of this vaccine will help close some gaps in vaccine access both in this country and abroad.

In tackling COVID-19, Pfizer and Moderna’s vaccines have “paved the way,” Duprex said, when it comes to illustrating the utility of synthetic mRNA. And yet, while he anticipates that researchers will “only get better” at making tweaks that allow for better delivery and stability of this technology, he notes that we’re still in the early days of harnessing its utility – we also can’t assume that mRNA is “the next big panacea” that will solve all of our problems.

But, Duprex said, “the beautiful thing about this is this just gives us another brush for the palette of novel therapeutics [and] novel ideas that somebody in the next generation of scientists are going to be able to [use to] paint. ”

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Vermont Health Connect had 10 data breaches last winter

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Vermont Health Connect had 10 data breaches last winter
Vermont Health Connect has set up a special enrollment period in response to the coronavirus outbreak. VHC photo

In mid-December, a Vermont Health Connect user was logging in when the names of two strangers popped up in the newly created account.

The individual, who was trying to sign up for health insurance, deleted the information that had suddenly appeared.

“It was super unsettling to think that someone is filing in my account with my information,” the person, whose name is redacted in records, wrote in a complaint to the Department of Vermont Health Access. “Just seems like the whole thing needs a big overhaul.”

It was one of 10 instances between November and February when Vermont Health Connect users reported logging to find someone else’s information on their account.

The data breaches included names of other applicants and, in some cases, their children’s names, birth dates, citizenship information, annual income, health care plans, and once, the last four digits of a Social Security number, according to nearly 900 pages of public records obtained by VTDigger. On Dec. 22, the department’s staff shut down the site to try to diagnose the problem.

While officials say the glitches have been resolved, it’s the most recent mishap for a system that has historically been plagued by security and technical issues. The breaches could be even more widespread: Administrators of Vermont Health Connect can’t tell if other, similar breaches went unreported.

“We don’t know what we don’t know,” said Jon Rajewski, a managing director at the cybersecurity response company Stroz Friedberg. Regardless of whether there are legal ramifications for the incidents, they should be taken “very seriously,” he said.

“If my data was being stored on a website that was personal, — maybe it contains names or my Social Security number, like my status of insurance… — I would expect that website to secure it and keep it safe,” he said.

“I wouldn’t want someone else to access my personal information.”

Andrea De La Bruere, executive director of the Agency of Human Services, called the data breaches “unfortunate.” But she downplayed the severity of the issues. Between November and December, 75,000 people visited the Vermont Health Connect website for a total of 330,000 page views, she said. The 10 incidents? “It’s a very uncommon thing to have happen,” she said.

De La Bruere said the issue was fixed on Feb. 17, and users had reported no similar problems since. The information that was shared was not protected health information, she added, and the breaches didn’t violate the Health Insurance Portability and Accountability Act, or HIPAA.

“No matter what the law says technically, whether it’s HIPAA-related or just one’s personal information, it’s really concerning,” said Health Care Advocate Mike Fisher.

The timing of the issue is less than ideal, he added. Thousands of Vermonters will be logging into Vermont Health Connect in the coming weeks to take advantage of discounts granted by the American Rescue Plan. “It’s super important that people can access the system, and that it’s safe and secure,” Fisher said.

A ‘major issue

The issues first arose on Nov, 12, when at least two Vermonters logged in and found information about another user, according to records obtained by VTDigger.

Department of Vermont Health Access workers flagged it as a “major issue” for their boss, Kristine Fortier, a business application support specialist for the department.

Similar incidents also occurred on Nov. 17 and 18, and later on multiple days in December.

Department of Vermont Health Access staff members appeared alarmed at the issues, and IT staff escalated the tickets to “URGENT.”

“YIKES,” wrote a staff member Brittney Richardson. While the people affected were notified, the data breaches were never made public.

State workers pressed OptumInsights, a national health care tech company that hosts and manages Vermont Health Connect, for answers. The state has contracted with the company since 2014. It has paid about $11 million a year for the past four years for maintenance and operations, with more added in “discretionary funds.”

Optum appeared unable to figure out the glitch. “It is hard to find root cause of issue,” wrote Yogi Singh, service delivery manager for Optum on Dec. 10. Optum representatives referred comments on the issues to the state.

By Dec. 14, Grant Steffens, IT manager for the department, raised the alarm. “I’m concerned on the growing number of these reports,” he wrote in an email to Optum.

The company halted the creation of new accounts on Dec, 14, and shut down the site entirely on Dec, 22 to install a temporary fix. “It’s a very complex interplay of many many pieces of software on the back end,” said Darin Prail, agency director of digital services. The complexity made it challenging to identify the problem, and to fix it without introducing any new issues, he said.

In spite of the fixes, a caller reported a similar incident on Jan. 13.

On Feb. 8, a mother logged in to find that she could see her daughter’s information. When she logged into her daughter’s account, the insurance information had been replaced by her own.

“Very weird,” the mother wrote in an emailed complaint.

Optum completed a permanent fix on Feb. 17, according to Prail. Vermont Health Connect has not had a problem since, he said.

Prail said the state had reported the issues to the Centers for Medicaid and Medicare Services as required, and had undergone a regular audit in February that had no findings. The state “persistently pressured Optum to determine the root cause and correct the issue expeditiously but at the same time, cautiously, so as to not introduce additional issues/problems,” he wrote in an email to VTDigger.

“We take reported issues like this very seriously,” he said.

A history of glitches

The state’s health exchange has been replete with problems, including significant security issues and privacy violations, since it was built in 2012 at a cost of $200 million.

The state fired its first contractor, CGI Technology Systems, in 2014. A subcontractor, Exeter, went out of business in 2015. Optum took over for CGI, and continued to provide maintenance and tech support for the system.

Don Turner
Don Turner, right, then the House minority leader, speaks in 2016 about the need to fix the state’s glitch-ridden Vermont Health Connect website. With him are Phil Scott, left, then the lieutenant governor, and Sen. Joe Benning. Photo by Erin Mansfield/VTDigger

In 2018, when Vermont Health Connect was less than 6 years old, a report dubbed the exchange outdated and “obsolete.”

Officials reported similar privacy breaches in 2013, when Vermonters saw other people’s information.

An auditor’s report in 2016 found a slew of cybersecurity flaws, and officials raised concerns again during a  2018 email breach.

It wasn’t the first time that Vermont Health Connect users had been able to view other people’s personal information. Three times since October 2019, individuals had logged in to see another individual’s insurance documents. Prail attributed those incidents to human error, not to system glitch; a staff member uploaded documents to the wrong site, he said.

In spite of the issues, Prail said he and other state officials have been happy with Optum. After years of technical challenges with Vermont Health Connect, “Optum has really picked up the ball and improved it and been running it pretty well,” he said.

Glitches are inevitable, he added, and Optum has addressed them quickly. “They took a really difficult-to-manage site and made it work pretty well,” he said. “Optum is generally quite responsive to any issues we have.”

“I find any privacy breach to be concerning,” said Scott Carbee, chief information security officer for the state. He noted that the state uses “hundreds of software systems.” “While the scope of the breaches can be mitigated, true prevention is a difficult task,” he wrote in an email to VTDigger.

Optum spokesperson Gwen Moore Holliday referred comments to the state, but said the company was “honored” to work with Vermont Health Connect “to support the health care needs of Vermont residents.”

Prail said the Agency of Human Services had no plans to halt its contract with the company. “I don’t have a complaint about Optum,” he said. “They took a really difficult-to-manage site and made it work pretty well.”

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Health Care

Tags: data breaches, Optum, Vermont Health Connect

Katie Jickling

About Katie

Katie Jickling covers health care for VTDigger. She previously reported on Burlington city politics for Seven Days. She has freelanced and interned for half a dozen news organizations, including Vermont Public Radio, the Valley News, Northern Woodlands, Eating Well magazine and the Herald of Randolph. She is a graduate of Hamilton College and a native of Brookfield.