How owners can make buildings healthier post pandemic

 During this pandemic, the simple act of walking into a building can feel like entering a biohazard area. With a virus that’s primarily transmitted through the air, being inside almost any space is a risk. But not all spaces are equally risky. A new verification system lets building owners quickly convey the safety of their indoor spaces to occupants.

Global safety science company UL has created a Verified Healthy Buildings verification, offering building owners and operators the chance to prove to people that they’ve done as much as they can to reduce the potential risk of contracting the virus indoors. About 400 buildings and spaces have received the mark so far, and a total of 175 million square feet of buildings have either been verified or are in the process of being verified. That includes properties owned and operated by some of the biggest commercial real estate holders, including Brookfield Properties and Brandywine Realty Trust, as well as entertainment venues like the Walt Disney Concert Hall in Los Angeles.

The verification focuses primarily on air, according to Sean McCrady, director of assets and sustainability for real estate and properties at UL. “In many respects air quality is the bedrock of optimizing the indoor environment overall,” he says. “Because that’s how people get sick; it’s a lack of ventilation in crowded spaces. We didn’t need to reinvent the wheel, we just need to have that much more focus on what’s always been important.”

Building certification systems are nothing new but most, like the U.S. Green Building Council’s LEED rating system, tend to focus more on design and environmental metrics.

McCrady says UL’s verification system is not just a response to the pandemic but it also has created an opening for building owners and operators to pay more attention to the internal systems that may be making their buildings unhealthy environments.

The verification system looks specifically at ventilation, air quality, water quality, building janitorial practices, lighting, and acoustic quality. To evaluate buildings, UL performs a detailed examination of building systems and policies, looking at everything from the number of air changes that happen in a given room to how snugly filters are fitted to HVAC units.

After creating a comprehensive report on the ways a building is falling short of various health and environmental guidelines from the Environmental Protection Agency, the Occupational Safety and Health Administration, and other governmental bodies, UL works with building owners to identify improvements. Once those improvements have been put in place, the building is verified, and UL performs two checkups within a year to ensure the building is still performing. UL’s marketing team offers digital and physical placards to indicate that a building has qualified for the verification.

“Most buildings could achieve this mark if they’re willing to really focus on the fundamentals that quite frankly should be done anyway,” McCrady says. “It doesn’t need to be just the class A office building or the state-of-the-art enterprise building that can achieve the mark.”

McCrady says buildings often don’t need major upgrades to meet the healthy building standard, but rather that small adjustments to HVAC settings or replacing outdated vents can do the trick. Most buildings benefit, even from small changes. “We’ve been doing these top-down holistic inspections for decades in literally thousands of buildings a year,” McCrady says. “It’s very rare that we go into a building and we don’t find things where we’re going to have action items or recommendations.”

It’s important to note that the verification isn’t intended to give people the impression that buildings are totally safe. “You don’t want to say something you can’t back up. You don’t want to say the things that we’re doing are killing 99% of germs. You can’t prove that, and that’s what’s going to get you in trouble,” McCrady says. “You can never remove risk altogether. Hopefully most people know that.”

There’s clearly a limit to what such a verification can accomplish. For the COVID-19 pandemic, it’s well understood that the spread of the virus is reduced not just through better engineering systems or design elements but also through behavioral changes like wearing masks and social distancing. All the filtered air conditioning and natural ventilation won’t do much if an unmasked person carrying the virus comes coughing into your building lobby.

But McCrady says that the verification can at least provide one level of assurance that risks are being reduced. It’s meant to be a clear indication that, other risk vectors notwithstanding, building owners are doing everything in their power to reduce the transmission of disease. He says that as buildings and venues gradually begin repopulating, this kind of information will be increasingly important.

“People know a lot more now than before we had a pandemic hit,” he says. “There are going to be new expectations for how buildings are managed.”

https://www.fastcompany.com/90632814/leed-for-the-covid-era-is-here

Biomarker detects severe COVID-19 early on

 Severe cases of COVID-19 can now be detected at an early stage. Researchers at the University of Zurich have identified the first biomarker that can reliably predict which patients will develop severe symptoms. This can help to improve the treatment of severe cases of COVID-19.

Most people who are infected with SARS-CoV-2 develop no or only mild symptoms. However, some patients suffer severe life-threatening cases of COVID-19 and require intensive medical care and a ventilator to help them breathe. Many of these patients eventually succumb to the disease or suffer significant long-term health consequences. To identify and treat these patients at an early stage, a kind of "measuring stick" is needed—predictive biomarkers that can recognize those who are at risk of developing severe COVID-19.

First biomarker to predict severity of disease

A team led by Professor Burkhard Becher at the Institute of Experimental Immunology at the University of Zurich, working with researchers from Tübingen, Toulouse and Nantes, has now discovered such a biomarker—the number of natural killer T cells in the blood. These cells are a type of white blood cell and part of the early immune response. "The number of natural killer T cells in the blood can be used to predict severe cases of COVID-19 with a high degree of certainty—even on a patient's first day in hospital," says Burkhard Becher.

Targeted therapy thanks to precise immunopathogenesis

The new biomarker test helps clinicians decide which organizational and treatment measures need to be taken for patients with COVID-19, such as transfer to the ICU, frequency of oxygen measurements, type of therapy and treatment start. "Predictive biomarkers are very useful for making these decisions. They help clinicians provide patients suffering severe symptoms with the best care possible," says Stefanie Kreutmair, first author of the study. "Our findings also make it possible to investigate new therapies against COVID-19."

With the help of high-tech

The rapid deterioration in the health of COVID-19 patients is caused by an overreaction of the body's immune system. "The body produces small proteins called cytokines at a much higher rate, which leads to a 'cytokine storm' and triggers massive inflammation. Immune cells invade the lungs, where they disrupt gas exchange," explains Becher. To detect the immune cells and cytokines in patient samples, the UZH researchers used high-dimensional cytometry. This technology enables researchers to characterize many surface and intracellular proteins in millions of individual cells and process them using computer algorithms.

SARS-CoV-2-specific immune signature deciphered

Many other pathogens besides SARS-CoV-2 can cause pneumonia—and thus spark an immune response. The immune response triggered by COVID-19 has been studied extensively, but the exact nature of the immune response to SARS-CoV-2 has, to date, been unclear. To characterize this response, the researchers also analyzed blood samples of patients with severe pneumonia driven by a pathogen other than the novel coronavirus. By comparing the immune responses in COVID-19 patients with those of the control group, the researchers were able to determine the unique characteristics of the SARS-CoV-2 immune response.

"The immune responses to the various pneumonias are very similar and part of the body's general inflammatory response, as often observed in patients in intensive care. When it comes to COVID-19, however, T cells and natural killer cells display a unique behavior and describe a kind of pattern in the immune system—the immune signature specific to COVID-19," explains Becher.

More information: Unique immunological signatures distinguish severe COVID-19 from non-SARS-CoV-2-driven critical pneumonia. Immunity. DOI:10.17632/ffkvft27ds.1

https://medicalxpress.com/news/2021-05-biomarker-severe-covid-early.html

In fight against COVID variants some firms target T cell jabs

 Getting COVID vaccines into the arms of the world's population is an international priority—but will today's jabs stay effective against virus variants that are spreading across the globe?

It is one of the big questions about the pandemic, with Pfizer chief Albert Bourla recently acknowledging that it is likely a booster will be needed to help extend the protection conferred by its vaccine and ward off new variants.

A recent study presented a mixed picture.

It found that the antibody response of current vaccines could fail against variants. However, a second immune response in the form of killer T cells—which attack already infected cells and not the virus itself—remained largely intact.

Several startups are working on developing shots centred on T cells in hopes of producing a jab that would not only provide protection against new virus strains already on the loose, but also variants that don't yet exist.

Alexis Peyroles heads up French biotech firm OSE Immunotherapeutics, which is developing a vaccine that targets T cells that has just begun clinical trials.

"It could offer several years of protection," he told AFP.

Another French firm, Lyon-based Osivax, is also working on a T cell shot, promising a "universal" vaccine that would be effective against any potential variant.

The government of France, which has yet to develop its own vaccine, is supporting the effort with millions in funding.

Such projects are far from widespread. Among the 400 vaccines under development counted by the World Health Organization only a few are aimed at universal use.

The most advanced shot of its kind is the ImmunityBio vaccine under development in the United States. Very preliminary results released last month were mostly encouraging.

'Complement and broaden'

No lab foresees a final product before next year and many scientists are sceptical about the usefulness of trying to develop a shot to protect against a virus strain that doesn't yet exist.

"Mass vaccination itself is a form of evolutionary 'selection' pressure," British virologist Julian Tang told AFP, "and this pressure may push the virus to evolve to escape any vaccine protection—so it can be a double-edged sword."

Other questions involve the extent to which the body will be able to fight the virus with a T cell-based response.

T cells and antibodies work together to form an immune response in the body.

French virologist Yves Gaudin pointed out that if an antibody response fails, "T cells don't serve much purpose".

He said he is "doubtful about the effectiveness of such a vaccine," emphasising that an ideal vaccine would be effective in both areas.

In Europe and the United States the plan for T cell jabs, should they see the light of day, would be to give them to people who had already received the current antibody vaccines.

Peyroles confirmed that OSE's vaccine, should it prove effective in trials, is indeed meant as a way to strengthen current inoculations.

"You would complement and broaden the response created by the first vaccines in terms of scope and time."

He added that T cell vaccines could offer protection to people who have difficulties developing antibodies due to other ailments such as diabetes or cancer.

https://medicalxpress.com/news/2021-05-covid-variants-firms-cell-jabs.html

Inovio going after 'impossible tumor' left behind by new cancer meds

 Patients with difficult cancers have seen a massive influx of new treatment options and hope for prolonged survival in recent years—except for those with the aggressive brain cancer glioblastoma.

Inovio is hoping to change that with a new DNA medicine combination of INO-5401, INO-9012 and Regeneron-Sanofi’s PD-1 inhibitor Libtayo. The Plymouth Meeting, Pennsylvania-based biotech is conducting a phase 1 clinical trial called GBM-001 that will provide early data in a quest to extend the lives of newly-diagnosed patients beyond the three to five years that is currently the norm.

“This is still such an impossible tumor to treat,” said Jeff Skolnik, M.D, Inovio’s senior vice president of clinical development. While immune checkpoint inhibitors have taken off in metastatic lung cancer and other indications, boosting survival and prolonging progression, “GBM has seen none of those benefits.”

Globlastoma has long stymied the pharmaceutical world, even as breakthrough therapies changed the landscape in other cancers. Skolnik, who is still a practicing physician at the Children’s Hospital of Philadelphia despite his role at Inovio, said this type of brain cancer has typically spread throughout the brain by the time it’s diagnosed.

Treatment options are surgery, chemotherapy and radiation, but they can only go so far for obvious, if not sobering, reasons: “You can go for breast cancer, you can go for a prophylactic mastectomy and completely avoid recurrence of breast cancer by simply removing 100% of the breast tissue. You can't do that with the brain. That's incompatible with life,” Skolnik said.

Once surgery is done, oncologists have to treat what’s left, and in glioblastoma, it’s an uphill battle. The tumor has a notoriously hostile micro-environment that loves to bat away immune cells.

Inovio certainly is not alone in trying to finally break the code on glioblastoma, but the pipeline is not as rich as some other cancers that have become intense targets of immunology research. And Inovio has never had a therapy cross the finish line and become a marketed drug. The company—classified as a late-stage biotech—has a COVID-19 vaccine product that’s probably furthest along, but that program recently hit a wall when the FDA shut down a government-sponsored study because of the proliferation of vaccines in the U.S. Inovio has several other cancer hopefuls, including a program with AstraZeneca in head and neck cancer and HPV.

So why Inovio? Skolnik said the glioblastoma program "builds on the totality of data we have specifically in the immune space," and is expected to one day be part of a much larger oncology portfolio. 

Bright sides are hard to find in the ongoing pandemic—but for a company like Inovio, the approval of mRNA vaccines has boosted the technology to the forefront.

“For better or worse, since the COVID pandemic that concept of nucleic acid therapeutics and the validation of those therapeutics has sort of become household terminology,” Skolnik said. “We're really building and utilizing that exact same type of technology.”

Inovio’s technology uses synthetic DNA to build antigen specific T cells inside the body. But instead of attacking a virus like in the vaccine programs, Inovio’s combo is designed to attack common tumor-associated antigens that are over expressed in glioblastoma.

“The idea is … Inovio builds a T cell army that's antigen specific. It goes after the tumor cell, the PD-1 inhibitor revs those cells up, gets them activated and allows that combination, potentially, to benefit the patient,” Skolnik explained.

Some genetic differences exist in glioblastoma patients. Skolnik explained that patients are split by a biomarker called MGMT promoter methylation status. Patients whose tumors are not methylated tend to have a worse prognosis. Inovio’s treatment could potentially be used for both types of patients, but the clinical trial may provide some clues about who might benefit the most.

“Ultimately, the question is, why are some patients doing better than others? Who are the patients that could benefit the best from this? Will it be everybody at the end of the story?” Skolnik said.

At the one year data cut off in the trial, 85% of patients were still alive, which Skolnik called very encouraging. At 18 months, 70% of methylated and 55% of non-methylated patients were alive. Inovio will release two-year data later this summer after the June cut off. The trial is now yielding different data beyond the survival rates that can help in future trials, according to Skolnik.

Inovio, which has fully sponsored the glioblastoma study, is currently having conversations about the next clinical step for the INO-5401 and INO-9012 combination. While the company has not formally partnered with Regeneron, Skolnik said the two companies have collaborated well on the trial, with Regeneron offering up Libtayo. He hopes that will continue as the combination moves into later development.

As for when the combo might be put to regulators, Skolnik said the FDA wants to see randomized data for trials like this, which Inovio has not done yet. The company’s next step is likely to try to compare the combo with standard of care.

https://www.fiercebiotech.com/biotech/inovio-going-after-impossible-tumor-left-dust-new-cancer-meds

COVID testing turned to windfall for hospitals and other providers

 Pamela Valfer needed multiple COVID tests after repeatedly visiting the hospital last fall to see her mother, who was being treated for cancer. Beds there were filling with COVID patients. Valfer heard the tests would be free.

So, she was surprised when the testing company billed her insurer $250 for each swab. She feared she might receive a bill herself. And that amount is toward the low end of what some hospitals and doctors have collected.

Hospitals are charging up to $650 for a simple, molecular COVID test that costs $50 or less to run, according to Medicare claims analyzed for KHN by Hospital Pricing Specialists (HPS). Charges by large health systems range from $20 to $1,419 per test, a new national survey by KFF shows. And some free-standing emergency rooms are charging more than $1,000 per test.

Authorities were saying “get tested, no one’s going to be charged, and it turns out that’s not true,” said Valfer, a professor of visual arts who lives in Pasadena, California. “Now on the back end it’s being passed onto the consumer” through high charges to insurers, she said. The insurance company passes on its higher costs to consumers in higher premiums.

As the pandemic enters its second year, no procedure has been more frequent than tests for the virus causing it. Gargantuan volume—400 million tests and counting, for one type—combined with loose rules on prices have made the service a bonanza for hospitals and clinics, new data show.

Lab companies have been booking record profits by charging $100 per test. Even in-network prices negotiated and paid by insurance companies often run much more than that and, according to one measure, have been rising on average in recent months.

Insurers and other payers “have no bargaining power in this game” because there is no price cap in some situations, said Ge Bai, an associate professor at Johns Hopkins Bloomberg School of Public Health who has studied test economics. When charges run far beyond the cost of the tests “it’s predatory,” she said. “It’s price gouging.”

The data show that COVID tests continue to generate high charges from hospitals and clinics despite alarms raised by insurers, anecdotal reports of high prices and pushback from state regulators.

The listed charge for a basic PCR COVID test at Cedars-Sinai Medical Center in Los Angeles is $480. NewYork-Presbyterian Hospital lists $440 as the gross charge as well as the cash price. Those amounts are far above the $159 national average for the diagnostic test, which predominated during the first year of the pandemic, at more than 3,000 hospitals checked by HPS.

That’s the amount billed to insurance companies, not what patients pay, Cedars spokesperson Cara Martinez said in an email.

“Patients themselves do not face any costs” for the tests, she said. “The amounts we charge [insurers] for medical care are set to cover our operating costs,” capital needs and other items, she said.

Likewise at NewYork-Presbyterian, charges not covered by insurance “are not passed along to patients,” the hospital said.

Many hospitals and labs follow the Medicare reimbursement rate, $100 for results within two days from high-volume tests. But there are outliers. Insurers oftentimes negotiate lower prices within their networks, although not for labs and testing options outside their purview.

Billing by hospitals and clinics from outside insurance company networks can be especially lucrative because the government requires insurers to pay their posted COVID-test price with no limit. Regulation for out-of-network vaccine charges, by contrast, is stricter. Charges for vaccines must be “reasonable,” according to federal regulations, with relatively low Medicare prices as a possible guideline.

“There’s a problem with the federal law” on test prices, said Sabrina Corlette, co-director of the Center on Health Insurance Reforms at Georgetown University. “The CARES Act requires insurers to pay the full billed charge to the provider. Unless they’ve negotiated, their hands are tied.”

But even in-network payments can be highly profitable.

Optim Medical Center in Tattnall, Georgia, part of a chain of orthopedic practices and medical centers, collects $308 per COVID test from two insurers, its price list shows. Yale New Haven Hospital collects $182 from one insurer and $173 from another.

Yale New Haven’s prices resulted from existing insurer agreements addressing unspecified new procedures such as the COVID test, said Patrick McCabe, senior vice president of finance for Yale New Haven Health.

“We didn’t negotiate” specifically on COVID tests, he said. “We’re not trying to take advantage of a crisis here.”

Officials from Optim Medical Center did not respond to queries from KHN.

Castlight Health, which provides benefits and health care guidance to more than 60 Fortune 500 companies, analyzed for KHN the costs of 1.1 million COVID tests billed to insurers from March 2020 through this February. The analysis found an average charge of $90, with less than 1% of bills passing any cost along to the patient. Since last March, the average cost has gone up from $63 to as high as $97 per test in December before declining to $89 in February, the most recent results available.

In some cases, hospitals and clinics have supplemented revenue from COVID tests with extra charges that go far beyond those for a simple swab.

Warren Goldstein was surprised when Austin Emergency Center, in Texas, charged him and his wife $494 upfront for two COVID tests. He was shocked when the center billed insurance $1,978 for his test, which he expected would cost $100. His insurer paid $325 for “emergency services” for him, even though there was no emergency.

“It seemed like highway robbery,” said Goldstein, a New York professor who was visiting his daughter and grandchild in Texas at the time.

Austin Emergency Center has been the subject of previous reports of high COVID-test prices.

The center provides “high-quality health care emergency services” and “our charges are set at the price that we believe reflects this quality of care,” said Heather Neale, AEC’s chief operating officer. The law requires the center to examine every patient “to determine whether or not an emergency medical condition exists,” she said.

Curative, the lab company that billed $250 for Valfer’s PCR tests, said through a spokesperson that its operating costs are higher than those of other providers and that consumers will never be billed for charges insurance doesn’t cover. Valfer’s insurer paid $125 for each test, claims documents show.

Even at relatively low prices, testing companies are reaping high profits. COVID PCR tests sold for $100 apiece helped Quest Diagnostics increase revenue by 49% in the first quarter of 2021 and quadruple its profits compared with the same period a year ago.

“We are expecting … to still do quite well in terms of reimbursement in the near term,” Quest CFO Mark Guinan said during a recent earnings call.

Hospitals and clinics do pay tens of thousands of dollars upfront when purchasing analyzer machines, plus costs for chemical reagents, swabs and other collection materials, maintenance, and training and compensating staff members. But the more tests completed, the more cost-effective they are, said Marlene Sautter, director of laboratory services at Premier Inc., a group purchasing organization that works with 4,000 U.S. hospitals and health systems.

A World Health Organization cost assessment of running 5,000 COVID tests on Roche and Abbott analyzers—not including that initial equipment price, labor or shipping costs—came to $17 and $21 per test, respectively.

Unlike earlier in the pandemic, lab-based PCR tests no longer dominate the market. Cheaper, rapid options can now be purchased online or in stores. In mid-April, some CVS, Walmart and Walgreens stores began selling a two-pack of Abbott Laboratories’ BinaxNOW antigen test for $23.99.

Regulations require insurers to cover COVID testing administered or referred by a health care provider at no cost to the patient. But exceptions are made for public health surveillance and work- or school-related testing.

Claire Lemcke, who works for a Flagstaff, Arizona, nonprofit, was tested at a mall in January and received a statement from an out-of-state lab company saying that the price was $737, that it was performed out-of-network and that she would be responsible for paying. She’s working with her insurer, which has already paid $400, to try to get it settled.

Sticker shock from COVID tests has gotten bad enough that Medicare set up a hotline for insurance companies to report bad actors, and states across the country are taking action.

Free-standing emergency centers across Texas, like the one Goldstein visited, have charged particularly exorbitant prices, propelling the Texas Association of Health Plans to write a formal complaint in late January. The 19-page letter details how many of these operations violate state disclosure requirements, charge over $1,000 per COVID test and add thousands more in facility fees associated with the visit.

These free-standing ERs are “among the worst offenders when it comes to price gouging, egregious billing, and providing unnecessary care and tests,” the letter says.

In December, the Kansas Insurance Department investigated a lab whose cash price was listed at nearly $1,000. State legislatures in both Minnesota and Connecticut have introduced bills to crack down on price gouging since the pandemic began.

"If these astronomical costs charged by unscrupulous providers are borne by the health plans and insurers without recompense, consumers will ultimately pay more for their health care as health insurance costs will rise,” Justin McFarland, Kansas Insurance Department’s general counsel, wrote in a Dec. 16 letter.

https://www.fiercebiotech.com/medtech/covid-testing-has-turned-into-a-financial-windfall-for-hospitals-and-other-providers

Unexpected tumor reduction in metastatic colorectal cancer during SARS-Cov-2 infection

 

Alessandro Ottaiano, Stefania Scala, Crescenzo D’Alterio, ...

https://doi.org/10.1177/17588359211011455

PDF: https://scholar.google.com/scholar_url?url=https://journals.sagepub.com/doi/pdf/10.1177/17588359211011455&hl=en&sa=T&oi=ucasa&ct=ufr&ei=d5mWYKS2Do3nmQGH3ofYDQ&scisig=AAGBfm2hgZVKofqNEcOI2qE8SLrwIBZTQA

Abstract

Herein, we describe three patients affected by metastatic colorectal cancer (mCRC) experiencing infection by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) and reduction of disease burden during coronavirus disease 2019 (COVID-19) course. Insights into tumor-associated angiotensin-converting enzyme (ACE)-2 expression and lymphocyte function suggest a correlation between host/SARS-Cov-2 infection and tumor burden reduction. This may shed new light into (a) the infection mechanism of SARS-CoV-2 virus and (b) the multiple aspects of a composite antiviral immune response with potential paradoxical and unexpected applications.

https://journals.sagepub.com/doi/full/10.1177/17588359211011455

Covid-19: Spike Protein Behavior

 By Derek Lowe

I’ve been getting a lot of questions in the last few days about several Spike-protein-related (and vaccine-related) topics, so I thought this would be a good time to go into them. There’s been a recent report about the vascular effects of the Spike protein alone (not coronavirus infection per se), and another presentation on similar effects in lung tissue. These are almost certainly looking at the same phenomena – the lungs are of course full of vascular tissue, and what’s being seen in both cases is very likely mediated by effects on the vascular endothelium.

In the first study, hamsters were injected with a pseudovirus was created that expressed surface Spike protein, while in the second the researchers just injected the protein directly into mice. The pseudovirus team went on to compare endothelial cells with different mutational forms of the ACE2 surface protein (S680D, with increased stability and S680L, with decreased stability). The response to the pseudovirus was quite different in these two, suggesting that it is indeed the binding of the Spike protein to ACE2 that’s a key part of this process. That happens as the coronvirus infects vascular tissue, of course, but this work shows that it’s not the whole process of viral infection that’s responsible for all the trouble: it starts with the initial binding event.

So I’ve been getting questions about what this means for vaccination: if we’re causing people to express Spike protein via mRNA or adenovirus vectors, are we damaging them just as if they’d been infected with coronavirus? Fortunately, the answer definitely seems to be “no” – in fact, the pseudovirus paper notes near the end that the antibody response generated by vaccination against the Spike protein will be beneficial in two ways, against infection and against the Spike-mediated endothelial damage as well. There are several reasons why the situation is different.

Consider what happens when you’re infected by the actual coronavirus. We know now that the huge majority of such infections are spread by inhalation of virus-laden droplets from other infected people, so the route of administration is via the nose and/or lungs, and the cells lining your airway are thus the first ones to get infected. The viral infection process leads at the end to lysis of the the host cell and subsequent dumping of a load of new viral particles – and these get dumped into the cellular neighborhood and into the bloodstream. They then have a clear shot at the endothelial cells lining the airway vasculature, which are the very focus of these two new papers.

Compare this, though, to what happens in vaccination. The injection is intramuscular, not into the bloodstream. That’s why a muscle like the deltoid is preferred, because it’s a good target of thicker muscle tissue without any easily hit veins or arteries at the site of injection. The big surface vein in that region is the cephalic vein, and it’s down along where the deltoid and pectoral muscles meet, not high up in the shoulder. In earlier animal model studies of mRNA vaccines, such administration was clearly preferred over a straight i.v. injection; the effects were much stronger. So the muscle cells around the injection are hit by the vaccine (whether mRNA-containing lipid nanoparticles or adenovirus vectors) while a good portion of the remaining dose is in the intercellular fluid and thus drains through the lymphatic system, not the bloodstream. That’s what you want, since the lymph nodes are a major site of immune response. The draining lymph nodes for the deltoid are going to be the deltoid/pectoral ones where those two muscles meet, and the larger axillary lymph nodes down in the armpit on that side.

Now we get to a key difference: when a cell gets the effect of an mRNA nanoparticle or an adenovirus vector, it of course starts to express the Spike protein. But instead of that being assembled into more infectious viral particles, as would happen in a real coronavirus infection, this protein gets moved up to the surface of the cell, where it stays. That’s where it’s presented to the immune system, as an abnormal intruding protein on a cell surface. The Spike protein is not released to wander freely through the bloodstream by itself, because it has a transmembrane anchor region that (as the name implies) leaves it stuck. That’s how it sits in the virus itself, and it does the same in human cells. See the discussion in this paper on the development of the Moderna vaccine, and the same applies to all the mRNA and vector vaccines that produce the Spike. You certainly don’t have the real-infection situation of Spike-covered viruses washing along everywhere through the circulation. The Spike protein produced by vaccination is not released in a way that it gets to encounter the ACE2 proteins on the surface of other human cells at all: it’s sitting on the surface of muscle and lymphatic cells up in your shoulder, not wandering through your lungs causing trouble.

Some of the vaccine dose is going to make it into the bloodstream, of course. But keep in mind, when the mRNA or adenovirus particles do hit cells outside of the liver or the site of injection, they’re still causing them to express Spike protein anchored on their surfaces, not dumping it into the circulation. Here’s the EMA briefing document for the Pfizer/BioNTech vaccine – on pages 46 and 47, you can read the results of distribution studies. These were done two ways – by using an mRNA for luciferase (and thus looking at the resulting light emission from the various rodent regions!) and by using a radioactive label (which is a more sensitive technique). The great majority of the radioactivty stays in and around the injection site. In the first hours, there’s also some circulating in the plasma. But almost all of that ended up in the liver, and no other tissue was much over 1% of the total. That’s exactly what you’d expect, and what you see with drug dosing in general: your entire blood volume goes sluicing through the liver again and again, because that’s what the liver is for. But when things like this hit the hepatic tissue, they stay there and eventually get chewed up by various destructive enzymes (that’s also a big part of what the liver is for). It’s a one-way ticket.

So the reports of Spike protein trouble are interesting and important for coronavirus infection, but they do not mean that the vaccines themselves are going to cause similar problems. In fact, as mentioned above, the fact that these vaccines are aimed at the Spike means that they’re protective in more ways than we even realized.

Update: there’s another level of difference that I didn’t mention. In the Moderna, Pfizer/BioNTech, J&J, and Novavax vaccines, the Spike protein has some proline mutations introduced to try to hold it in its “prefusion” conformation, rather than the shape it adopts when it binds to ACE2. So that should cut down even more on the ability of the Spike protein produced by these vaccines to bind and produce the effects noted in the recent papers. That comes in particularly handy for the Novavax one, since it’s an injection of Spike protein itself, rather than a vaccine that has it produced inside the cells. Notably, the AstraZeneca/Oxford vaccine is producing wild-type Spike (although that’s still going to be membrane-anchored as discussed above!)

https://blogs.sciencemag.org/pipeline/archives/2021/05/04/spike-protein-behavior