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‘The Last of Us’ Come Alive: Fungi Are Adapting to Warmer Temperatures

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Dangerous fungal infections are on the rise, and a growing body of research suggests warmer temperatures might be a culprit.

The human body’s average temperature of 98.6 degrees Fahrenheit has long been too hot for most fungi to thrive, infectious-disease specialists say. But as temperatures have risen globally, some fungi might be adapting to endure more heat stress, including conditions within the human body, research suggests. Climate change might also be creating conditions for some disease-causing fungi to expand their geographical range, research shows. 

“As fungi are exposed to more consistent elevated temperatures, there’s a real possibility that certain fungi that were previously harmless suddenly become potential pathogens,” said

Peter Pappas,

an infectious-disease specialist at the University of Alabama at Birmingham. 

Deaths from fungal infections are increasing, due in part to growing populations of people with weakened immune systems who are more vulnerable to severe fungal disease, public-health experts said. At least 7,000 people died in the U.S. from fungal infections in 2021, the Centers for Disease Control and Prevention said, up from hundreds of people each year around 1970. There are few effective and nontoxic medications to treat such infections, they said. 

Photos: What We Know About Deadly Fungal Infections

In the video game and HBO show “The Last of Us,” a fungus infects people en masse and turns them into monstrous creatures. The fungus is based on a real genus, Ophiocordyceps, that includes species that infect insects, disabling and killing them.

There have been no known Ophiocordyceps infections in people, infectious-disease experts said, but they said the rising temperatures that facilitated the spread of the killer fungi in the show may be pushing other fungi to better adapt to human hosts and expand into new geographical ranges. 

A January study in the journal Proceedings of the National Academy of Sciences showed that higher temperatures may prompt some disease-causing fungi to evolve faster to survive. 

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Researchers at Duke University grew 800 generations of a type of Cryptococcus, a group of fungi that can cause severe disease in people, in conditions of either 86 degrees Fahrenheit or 98.6 degrees Fahrenheit. The researchers used DNA sequencing to track changes in the fungi’s genome with a focus on “jumping genes”—DNA sequences that can move from one location on the genome to another.

Asiya Gusa, a study co-author and postdoctoral researcher in Duke’s Molecular Genetics and Microbiology Department, said movement of such genes can result in mutations and alter gene expression. In fungi, Dr. Gusa said, the movement of the genes could play a role in allowing fungi to adapt to stressors including heat. 

Dr. Gusa and her colleagues found that the rate of movement of “jumping genes” was five times higher in the Cryptococcus raised in the warmer temperature. 

Cryptococcus infections can be deadly, particularly in immunocompromised people. At least 110,000 people die globally each year from brain infections caused by Cryptococcus fungi, the Centers for Disease Control and Prevention said. 

Candida auris, a highly deadly fungus that has been reported in about half of U.S. states, also appears to have adapted to warmer temperatures, infectious-disease specialists said. 

“Fungi isn’t transmitted from person to person, but through fungal spores in the air,” Dr. Gusa said. “They’re in our homes, they’re everywhere.”

An analysis published last year in the journal Clinical Infectious Diseases said some potentially deadly fungi found in the soil, including Coccidioides and Histoplasma, have significantly expanded their geographical range in the U.S. since the 1950s. Andrej Spec, a co-author of the analysis and an associate professor of medicine at Washington University School of Medicine in St. Louis, said warming temperatures, as well as other environmental alterations associated with climate change, could have played a role in this spread. 

Cases of Coccidioidomycosis or Valley fever, a disease caused by Coccidioides, were once mostly limited to the Southwest, Dr. Spec said. Now people are being diagnosed in significant numbers in most states. Histoplasma infections, once common only in the Midwest, have been reported in 94% of states, the analysis said. Histoplasma is also spread through bat droppings and climate change has been linked to changing bat migration patterns, Dr. Spec said.

The World Health Organization has identified Cryptococcus, Coccidioides, Histoplasma and Candida auris as being among the fungal pathogens of greatest threat to people. 

“We keep saying these fungi are rare, but this must be the most common rare disease because they’re now everywhere,” Dr. Spec said.

Write to Dominique Mosbergen at dominique.mosbergen@wsj.com

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Focused ultrasounds: How the noninvasive brain surgery works

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CNN
 — 

Undergoing clinical trials around the world is a brain surgery that doesn’t need an incision or produce any blood yet drastically improves the lives of people with essential tremor, depression and more. The procedure, known as a focused ultrasound, aims sound waves at parts of the brain to disrupt faulty brain circuits causing symptoms.

“Focused ultrasound is a noninvasive therapeutic technology,” said Dr. Neal Kassell, founder and chairman of the Focused Ultrasound Foundation. “We’ve said that focused ultrasound is the most powerful sound you will never hear, but sound that someday could save your life.”

Kassell describes the way it works as “analogous to using a magnifying glass to focus beams of light on a point and burn a hole in a leaf.”

“With focused ultrasound, instead of using an optical lens to focus beams of light,” he added, “an acoustic lens is used to focus multiple beams of ultrasound energy on targets deep in the body with a high degree of precision and accuracy, sparing the adjacent normal tissue.”

The procedure has been significantly beneficial for people with essential tremor, a neurological disorder that causes involuntary and rhythmic shaking. The disorder can affect almost any body part, but the tremors typically occur in hands — even during simple tasks such as eating, drinking or writing.

Essential tremor is usually more prominent on one side of the body and can worsen with movement. It’s most common in people 40 and older, and it affects nearly 25 million worldwide, according to a 2021 study.

Such was the case with Brenda Hric, 80, who recently underwent focused ultrasound at the University of Virginia, a pioneering institution of the procedure.

Hric’s tremors made her uncomfortable in social situations because she was afraid of spilling or knocking something over, she told CNN.

But just 44 seconds of focused ultrasound waves got rid of her tremor.

“I looked at my hand, and I could see that it was not moving, and that was the first time I had been able to see my fingers still in about 20 years,” Hric said. “I think it’s definitely a miracle, and I thank the Lord for it.”

Focused ultrasound is a form of functional neurosurgery, the targeting of precise structures deep in the brain to change it, to restore function or, in this case, to stop a tumor. It’s an alternative treatment for those who, like Hric, don’t respond to or stop being affected by conventional medication treatment, experts said.

“In a simplistic sense, you can imagine that there’s a bunch of abnormal neurons in this one target that are firing away uncontrollably, causing the tremor, the shaking,” Kassell said.

Focused ultrasound technology uses a transducer to force beams of sound waves to converge at one point to raise the temperature and destroy tissue.

Before receiving high-intensity focused ultrasound, the one necessary for treating essential tremor, patients need to have their heads shaved since air can sometimes get trapped in hair follicles.

The patient then undergoes MRI and CT scans so doctors can use the resulting images to map the structure of the brain and the target.

The Insightec Exablate Neuro, a focused ultrasound platform, instructs how many beams should be used to do the treatment, then neurosurgeons might do what Dr. Jeff Elias calls “test shots, just to make sure we’re focused right at the bull’s-eye.”

A UVA Health neurosurgeon who treated Hric, Elias is a pioneer of treating essential tremors using ultrasound waves. In 2011, he led the clinical trials critical for gaining regulatory approval of this procedure in the United States.

“These (test shots) are really low energy, but we want to see if our treatment is exactly where we want it,” he said. “This is our chance to kind of sight the rifle.”

Four 11-second treatment doses significantly improved Hric’s tremor. The entire procedure lasted less than two hours, with most of it spent mapping the brain and testing the target.

Beforehand, Hric had trouble drawing inside the lines of circles. Focused ultrasound helped her color inside the lines.

Generally, anyone with an essential tremor diagnosis not responding to medications would be eligible for focused ultrasound treatment, said Dr. Nir Lipsman, a scientist at Sunnybrook Health Sciences Centre in Toronto and director of Sunnybrook’s Harquail Centre for Neuromodulation.

People who can’t undergo MRI scans due to claustrophobia or having metal inside their body aren’t eligible for focused ultrasound, said Dr. Noah Philip, a professor of psychiatry and human behavior at Brown University’s Alpert Medical School. Philip is also lead for mental health research at the VA RR&D Center for Neurorestoration and Neurotechnology.

Ideally, the benefits of focused ultrasound are permanent, Lipsman said. “If you’re able to destroy the part of the brain responsible for the tremor, it should be a permanent effect,” he said. “At one year, however, some of these patients will have a rebound or recurrence of their tremor, and we don’t know why that is.”

Such a return can happen with medication treatment, too, though — which is why some essential tremor patients turn to focused ultrasound in the first place.

But some patients have experienced the benefits five years after undergoing focused ultrasound, according to a 2022 study by Elias.

Potential side effects of focused ultrasound are why the mapping and testing parts of the procedure are so important. If the wrong area is targeted or treated excessively, a patient’s balance and stability can be harmed long term.

“The most common risks that we encounter in patients is a temporary numbness or tingling that can sometimes happen in the treated arm or in the lip area,” Lipsman said. “The vast majority of the time that goes away with time.”

Other common, but usually temporary, risks include slight unsteadiness on one’s feet after the procedure. But doctors don’t use a general anesthetic or hospitalize patients for this procedure, he added.

Today, focused ultrasound technology is used globally in various stages, including clinical trials and approved regulatory use. There are more than 170 clinical uses — including for neurodegenerative disorders and tumors of the brain, breast, lung, prostate and more — and the field is growing, Kassell said.

“You can watch the effect of the ultrasound treatment in real time while the treatment’s being administered, whereas with radiation, the effect of the treatment is invisible while it’s being administered,” Kassell said. “And it takes weeks or months for the effect of radiation to become apparent.”

Use for depression and obsessive-compulsive disorder is on the table, according to a small 2020 study by Lipsman and a team of researchers. They found focused ultrasound was safe and effective in improving symptoms for people with major depression and OCD. But further studies are needed.

One limitation of focused ultrasound is that not every person’s skull is made equal, Lipsman said.

“The density of the skull has a major impact on the ability of ultrasound to travel through it,” he added. “It’s rare, but there are some patients that, try as we might, we cannot make an effective lesion in the brain. The skull does not allow the passage of ultrasound. So that’s a technical limitation of the technology, something that we’re actively working on.”

Focused ultrasound isn’t available for every condition, but experts said they are hopeful that “medicine’s best-kept secret” will one day become a standard treatment.

“My belief is that in 10 years,” Kassell said, “focused ultrasound will be a mainstream therapy that is affecting millions of patients every year around the world. It’ll be widely accepted.”

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Aging can be reversed in mice. Are people next?

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CNN
 — 

In Boston labs, old, blind mice have regained their eyesight, developed smarter, younger brains and built healthier muscle and kidney tissue. On the flip side, young mice have prematurely aged, with devastating results to nearly every tissue in their bodies.

The experiments show aging is a reversible process, capable of being driven “forwards and backwards at will,” said anti-aging expert David Sinclair, a professor of genetics in the Blavatnik Institute at Harvard Medical School and codirector of the Paul F. Glenn Center for Biology of Aging Research.

Our bodies hold a backup copy of our youth that can be triggered to regenerate, said Sinclair, the senior author of a new paper showcasing the work of his lab and international scientists.

The combined experiments, published for the first time Thursday in the journal Cell, challenge the scientific belief aging is the result of genetic mutations that undermine our DNA, creating a junkyard of damaged cellular tissue that can lead to deterioration, disease and death.

“It’s not junk, it’s not damage that causes us to get old,” said Sinclair, who described the work last year at Life Itself, a health and wellness event presented in partnership with CNN.

“We believe it’s a loss of information — a loss in the cell’s ability to read its original DNA so it forgets how to function — in much the same way an old computer may develop corrupted software. I call it the information theory of aging.”

Jae-Hyun Yang, a genetics research fellow in the Sinclair Lab who coauthored the paper, said he expects the findings “will transform the way we view the process of aging and the way we approach the treatment of diseases associated with aging.”

While DNA can be viewed as the body’s hardware, the epigenome is the software. Epigenes are proteins and chemicals that sit like freckles on each gene, waiting to tell the gene “what to do, where to do it, and when to do it,” according to the National Human Genome Research Institute.

The epigenome literally turns genes on and off. That process can be triggered by pollution, environmental toxins and human behaviors such as smoking, eating an inflammatory diet or suffering a chronic lack of sleep. And just like a computer, the cellular process becomes corrupted as more DNA is broken or damaged, Sinclair said.

“The cell panics, and proteins that normally would control the genes get distracted by having to go and repair the DNA,” he explained. “Then they don’t all find their way back to where they started, so over time it’s like a Ping-Pong match, where the balls end up all over the floor.”

In other words, the cellular pieces lose their way home, much like a person with Alzheimer’s.

“The astonishing finding is that there’s a backup copy of the software in the body that you can reset,” Sinclair said. “We’re showing why that software gets corrupted and how we can reboot the system by tapping into a reset switch that restores the cell’s ability to read the genome correctly again, as if it was young.”

It doesn’t matter if the body is 50 or 75, healthy or wracked with disease, Sinclair said. Once that process has been triggered, “the body will then remember how to regenerate and will be young again, even if you’re already old and have an illness. Now, what that software is, we don’t know yet. At this point, we just know that we can flip the switch.”

The hunt for the switch began when Sinclair was a graduate student, part of a team at the Massachusetts Institute of Technology that discovered the existence of genes to control aging in yeast. That gene exists in all creatures, so there should be a way to do the same in people, he surmised.

To test the theory, he began trying to fast-forward aging in mice without causing mutations or cancer.

“We started making that mouse when I was 39 years old. I’m now 53, and we’ve been studying that mouse ever since,” he said. “If the theory of information aging was wrong, then we would get either a dead mouse, a normal mouse, an aging mouse or a mouse that had cancer. We got aging.”

With the help of other scientists, Sinclair and his Harvard team have been able to age tissues in the brain, eyes, muscle, skin and kidneys of mice.

To do this, Sinclair’s team developed ICE, short for inducible changes to the epigenome. Instead of altering the coding sections of the mice’s DNA that can trigger mutations, ICE alters the way DNA is folded. The temporary, fast-healing cuts made by ICE mimic the daily damage from chemicals, sunlight and the like that contribute to aging.

ICE mice at one year looked and acted twice their age.

Now it was time to reverse the process. Sinclair Lab geneticist Yuancheng Lu created a mixture of three of four “Yamanaka factors,” human adult skin cells that have been reprogrammed to behave like embryonic or pluripotent stem cells, capable of developing into any cell in the body.

The cocktail was injected into damaged retinal ganglion cells at the back of the eyes of blind mice and switched on by feeding mice antibiotics.

“The antibiotic is just a tool. It could be any chemical really, just a way to be sure the three genes are switched on,” Sinclair told CNN previously. “Normally they are only on in very young, developing embryos and then turn off as we age.”

The mice regained most of their eyesight.

Next, the team tackled brain, muscle and kidney cells, and restored those to much younger levels, according to the study.

“One of our breakthroughs was to realize that if you use this particular set of three pluripotent stem cells, the mice don’t go back to age zero, which would cause cancer or worse,” Sinclair said. “Instead, the cells go back to between 50% and 75% of the original age, and they stop and don’t get any younger, which is lucky. How the cells know to do that, we don’t yet understand.”

Today, Sinclair’s team is trying to find a way to deliver the genetic switch evenly to each cell, thus rejuvenating the entire mouse at once.

“Delivery is a technical hurdle, but other groups seem to have done well,” Sinclair said, pointing to two unpublished studies that appear to have overcome the problem.

“One uses the same system we developed to treat very old mice, the equivalent of an 80-year-old human. And they still got the mice to live longer, which is remarkable. So they’ve kind of beaten us to the punch in that experiment,” he said.

“But that says to me the rejuvenation is not just affecting a few organs, it’s able to rejuvenate the whole mouse because they’re living longer,” he added. “The results are a gift and confirmation of what our paper is saying.”

What’s next? Billions of dollars are being poured into anti-aging, funding all sorts of methods to turn back the clock.

In his lab, Sinclair said his team has reset the cells in mice multiple times, showing that aging can be reversed more than once, and he is currently testing the genetic reset in primates. But decades could pass before any anti-aging clinical trials in humans begin, get analyzed and, if safe and successful, scaled to the mass needed for federal approval.

But just as damaging factors can disrupt the epigenome, healthy behaviors can repair it, Sinclair said.

“We know this is probably true because people who have lived a healthy lifestyle have less biological age than those who have done the opposite,” he said.

His top tips? Focus on plants for food, eat less often, get sufficient sleep, lose your breath for 10 minutes three times a week by exercising to maintain your muscle mass, don’t sweat the small stuff and have a good social group.

“The message is every day counts,” Sinclair said. “How you live your life even when you’re in your teens and 20s really matters, even decades later, because every day your clock is ticking.”

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Alzheimer’s drug lecanemab receives accelerated FDA approval amid safety concerns

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CNN
 — 

The US Food and Drug Administration granted accelerated approval Friday for the Alzheimer’s disease drug lecanemab, one of the first experimental dementia drugs to appear to slow the progression of cognitive decline.

“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” Dr. Billy Dunn, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a statement. “This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease.”

Lecanemab will be marketed as Leqembi, the FDA statement said. It has shown “potential” as an Alzheimer’s disease treatment by appearing to slow progression, according to Phase 3 trial results, but it has raised safety concerns due to its association with certain serious adverse events, including brain swelling and bleeding.

In July, the FDA accepted Eisai’s Biologics License Application for lecanemab under the accelerated approval pathway and granted the drug priority review, according to the company. The accelerated approval program allows for earlier approval of medications that treat serious conditions and “fill an unmet medical need” while the drugs continue to be studied in larger and longer trials.

If those trials confirm that the drug provides a clinical benefit, the FDA could grant traditional approval. But if the confirmatory trial does not show benefit, the FDA has the regulatory procedures that could lead to taking the drug off the market.

Lecanemab, a monoclonal antibody, is not a cure but works by binding to amyloid beta, a hallmark of Alzheimer’s disease. In late November, results from an 18-month Phase 3 clinical trial published in The New England Journal of Medicine showed that lecanemab “reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events.”

The results also showed that about 6.9% of the trial participants given lecanemab, as an intravenous infusion, discontinued the trial due to adverse events, compared with 2.9% of those given a placebo. Overall, there were serious adverse events in 14% of the lecanemab group and 11.3% of the placebo group.

The most common adverse events in the lecanemab group were reactions to the intravenous infusions and abnormalities on their MRIs, such as brain swelling and bleeding called amyloid-related imaging abnormalities, or ARIA, which can become life-threatening.

Some people who get ARIA may not have symptoms, but it can occasionally lead to hospitalization or lasting impairment. And the frequency of ARIA appeared to be higher in people who had a gene called APOE4, which can raise the risk of Alzheimer’s disease or other dementias. ARIA “were numerically less common” among APOE4 noncarriers, the study showed.

The drug’s prescribing information carries a warning about ARIA, the FDA says.

The trial results also showed that about 0.7% of participants in the lecanemab group and 0.8% of those in the placebo group died, corresponding to six deaths in the lecanemab group and seven in the placebo group.

The Alzheimer’s Association welcomed Friday’s decision.

“By slowing progression of the disease when taken in the early stages of Alzheimer’s, individuals will have more time to participate in daily life and live independently,” President and CEO Joanne Pike said. “This could mean more months of recognizing their spouse, children and grandchildren. This could also mean more time for a person to drive safely, accurately and promptly take care of family finances, and participate fully in hobbies and interests.”

More than 6.5 million people in the United States live with Alzheimer’s disease, according to the Alzheimer’s Association, and that number is expected to grow to 13.8 million by 2060.

Lecanemab will carry a wholesale price of $26,500 per patient per year, the drug’s manufacturers announced Friday.

Biogen and Eisai have listed the drug slightly below the reduced price of the Alzheimer’s medication Aduhelm, which now costs an average patient about $28,200. The companies had to lower the cost of Aduhelm – originally set at $56,000 per patient per year – after insurers balked at covering it.

In justifying the cost of Leqembi, the companies said in a news release that based on the estimated quality of life gained by people who take it, the value of the medication to society is around $37,000 a year, but they chose to go lower “aiming to promote broader patient access, reduce overall financial burden, and support health system sustainability.”

The wholesale cost of a drug is akin to a car’s sticker price. It isn’t necessarily what patients will pay after insurance or other discounts are factored in.

Insurance coverage for this medication is not a given, however. Medicare restricted its coverage of lecanemab’s sister drug, Aduhelm, after clinical trials showed questionable benefits to patients. The agency agreed to cover the drug only for people enrolled in registered clinical trials, which limited access to the medication.

Center for Medicare and Medicaid Services Administrator Chiquita Brooks-LaSure said after the FDA’s decision Friday that her office would quickly review Leqembi, but for now, because of its accelerated approval, it will be covered the same way Aduhelm is covered.

“At CMS, we will continue to expeditiously review the data on these products as they become available and are committed to timely access to treatments, including drugs, that improve clinically meaningful outcomes,” Brooks-LaSure said in a statement.

Last month, the Alzheimer’s Association filed a formal request asking CMS to provide “full and unrestricted coverage” Alzheimer’s treatments approved by the FDA.

“What the FDA did today in granting accelerated approval to Leqembi was the right decision. But what CMS is doing by severely restricting coverage for approved treatments is unprecedented and wrong,” Pike said in a statement Friday.

“The FDA carefully reviewed the evidence for Leqembi before granting approval. CMS, in sharp contrast, denied coverage for Leqembi months ago before it had even reviewed this drug’s evidence. CMS has never done this before for any drug, and it is clearly harmful and unfair to those with Alzheimer’s. Without access to and coverage of this treatment and others in its class, people are losing days, weeks, months – memories, skills and independence. They’re losing time.”

CMS told CNN that it will review and respond to the association’s request. The agency also noted that it continues to stay informed about ongoing clinical trials, including the most recent lecanemab results published in the New England Journal of Medicine. Also, it has met with drugmakers to learn about their efforts since CMS’s coverage decision was announced.

The FDA approved Aduhelm for early phases of Alzheimer’s disease in 2021 – but that decision has been shrouded in controversy as a congressional investigation found last week that the FDA’s “atypical collaboration” to approve the high-priced drug was “rife with irregularities.”

Before Aduhelm, the FDA had not approved a novel therapy for the condition since 2003.

Aduhelm’s FDA approval and initial hefty price tag hit Medicare’s Part B premiums, driving up the 2022 standard monthly payments by 14.5% to $170.10.

About $10 of the premium spike – or just under half the amount – was due to Aduhelm, a CMS official told CNN in late 2021.

The premium increase was set before Medicare announced its limited coverage of the drug, but its actuaries had to make sure that the program had sufficient funding in case Aduhelm was covered.

Medicare’s decision, as well as Biogen’s slashing of the drug’s cost, prompted a decline in monthly premiums for 2023 to $164.90.

The FDA’s accelerated approval of lecanemab was expected, said Dr. Richard Isaacson, director of the Alzheimer’s Prevention Clinic in the Center for Brain Health at Florida Atlantic University’s Schmidt College of Medicine.

Isaacson said lecanemab can be “another tool” in his toolbox to fight Alzheimer’s disease.

“I will prescribe this drug in the right person, at the right dose and in a very carefully monitored way, but this drug is not for everyone,” he said.

“I would do genetic testing for APOE4 first. I would have a frank discussion with my patients,” he said. “If someone is having side effects, if someone is on a blood-thinning medication, if someone has a problem, they need to discuss this with the treating physician, and they need to seek medical attention immediately.”

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Mystery of Smell Loss After Covid-19 Might Be Solved

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The nose knows why some people still can’t smell long after recovering from Covid-19.

A haywire immune response in the olfactory system was found to explain why some people still can’t smell long after symptoms of the disease have abated, according to a small, peer-reviewed study published Wednesday in the journal Science Translational Medicine. In some cases, the immune or inflammatory response was detected in patients with smell loss up to 16 months after recovery from Covid-19.

Compared with people who can smell normally, patients with long-term smell loss had fewer olfactory sensory neurons, cells in the nose responsible for detecting smells and sending that information to the brain. Patients with lingering loss of smell had an average of 75% fewer of the neurons compared with healthy people, said

Brad Goldstein,

a study co-author and sinus surgeon at Duke University.

“We think the reduction of sensory neurons is almost definitely related to the inflammation,” Dr. Goldstein said.

Loss of smell is a common Covid-19 symptom, though its prevalence varies widely depending on factors including which variant caused the infection, head and neck specialists said.

Most Covid-19 patients who experience smell loss regain the sense within weeks of infection. But the symptom can stick around for a year or longer for up to 7% of patients, a February analysis said.

Dr. Goldstein said he and his colleagues sought to identify what was damaged or altered in people with long-term smell loss. “If we don’t know what’s broken, it’s hard to tell how to fix it,” he said.

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They took samples from the nose tissue of nine patients who couldn’t smell long after Covid-19 infections and compared them with cells from healthy people. Patients with persistent smell loss had more T-cells, a type of white blood cell that plays a critical part in immune response, in their noses, the study said. The T-cells were making interferon-gamma, a substance linked to inflammation, Dr. Goldstein said, and support cells appeared to be reacting to it.

The support cells protect and nourish olfactory sensory neurons. Without them, the olfactory sensory neurons can’t survive. Research has shown that the virus that causes Covid-19 doesn’t infect olfactory sensory neurons directly, but that it can attack such support cells.

Patients with smell loss also had fewer of a certain type of anti-inflammatory cell and more of a particular inflammatory cell than healthy people, said the study of 24 patients. The healthy group included two people who had recovered from Covid-19 but didn’t have long-term smell loss.

Covid-19 researchers said the study bolstered evidence that inflammation could be a culprit in long-Covid symptoms. An April study in the journal JAMA Neurology found inflammation among deceased Covid-19 patients in the olfactory bulb, the part of the brain responsible for receiving and processing information from olfactory sensory neurons in the nose.

Neuroinflammation could be a contributor to loss of smell and other neurological symptoms related to long-Covid such as brain fog, said

Cheng-Ying Ho,

a co-author of the April study and an associate professor of pathology at Johns Hopkins University School of Medicine.

Dr. Ho, who wasn’t involved in the new study, said inflammation that starts in the nasal cavity could extend to the brain. She said that the new study was compelling but that its small sample size necessitated further work in more patients. Because the vaccination status of participants wasn’t collected, she said it wasn’t clear whether getting the shots played a role in the olfactory system’s inflammatory response. 

In a survey published last year of more than 400 patients with smell loss, more than 40% reported depressive symptoms and almost 90% reported enjoying food less.

“People might think smell loss is not really an important Covid symptom compared with severe symptoms such as pneumonia, but it can really bother some patients,” Dr. Ho said. 

Researchers said regions of the brain linked to the sense of smell are closely associated with brain regions that control memory and emotion.  

Sandeep Robert Datta,

a co-author of the new study and a professor of neurobiology at Harvard Medical School, said he and others are conducting more research into the reasons for smell loss following Covid-19 infection smell loss. The research could lead to potential targets for treatment. There are no effective treatments for long-term smell loss, Dr. Datta said.

“Smell gives you a sense of place. It can be very disorienting without it,” Dr. Datta said.

Write to Dominique Mosbergen at dominique.mosbergen@wsj.com

Copyright ©2022 Dow Jones & Company, Inc. All Rights Reserved. 87990cbe856818d5eddac44c7b1cdeb8

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HIV vaccine candidate induces immune response in early clinical trial

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CNN
 — 

An experimental HIV vaccine has been found to induce broadly neutralizing antibodies among a small group of volunteers in a Phase 1 study. The findings suggest that a two-dose regimen of the vaccine, given eight weeks apart, can elicit immune responses against the human immunodeficiency virus.

The clinical trial results, published Thursday on World AIDS Day in the journal Science, establish “clinical proof of concept” in support of developing boosting regimens to induce immune responses against HIV infection, for which there is no cure and which can cause acquired immunodeficiency syndrome, known as AIDS.

The vaccine, called eOD-GT8 60mer, had a “favorable safety profile” and induced broadly neutralizing antibodies in 97%, or all but one, of the 36 recipients, according to the researchers from Scripps Research, the Fred Hutchinson Cancer Center, the National Institutes of Health and other institutions in the United States and Sweden.

Antibodies are proteins made by the immune system to help fight infections, and broadly neutralizing antibodies are known to neutralize many genetic variants of HIV, but they have been difficult to elicit by vaccination.

“Learning how to induce broadly neutralizing antibodies against pathogens with high antigenic diversity, such as HIV, influenza, hepatitis C virus, or the family of betacoronaviruses, represents a grand challenge for rational vaccine design,” the researchers wrote. “Germline-targeting vaccine design offers one potential strategy to meet this challenge.”

The eOD-GT8 60mer vaccine candidate is germline-targeting, meaning it was designed to induce the production of broadly neutralizing antibodies by targeting and stimulating the right antibody-producing cells.

The International AIDS Vaccine Initiative announced the start of this Phase 1 clinical trial in 2018, to evaluate the safety of eOD-GT8 60mer and the immune responses it is able to induce.

The trial included a total of 48 healthy adults, ages 18 to 50, who were enrolled at two sites: George Washington University in Washington and Fred Hutchinson Cancer Center in Seattle.

Among the participants, 18 received a 20-microgram dose of the vaccine and, eight weeks later, a same-size dose of the vaccine with an adjuvant; 18 received a 100-microgram dose of the vaccine and, eight weeks later, a same-size dose of the vaccine with an adjuvant; and 12 received two doses of a saline placebo, eight weeks apart. The adjuvant is called AS01B, developed by the pharmaceutical company GSK. The vaccines and placebo were given into the arm muscle.

The researchers collected and analyzed immune cells from the blood and lymph nodes of participants during the study. They specifically examined how B cells, a type of white blood cell that makes antibodies in the immune system, responded to the vaccine.

The researchers found no serious adverse events reported among the study participants, and no participants acquired HIV infection during the study. About 97% – or all but one – of the 48 study participants reported local or systemic adverse events that were generally mild or moderate, such as pain at the injection site, malaise and headache. In most cases, these events were resolved within a day or two.

After the first immunization, all vaccine recipients but no placebo recipients were found to produce antibodies elicited by the eOD-GT8 60mer vaccine. Those vaccine-induced responses increased after the second vaccination, the researchers wrote.

Another Phase 1 study on this vaccine candidate is underway, said Dr. Julie McElrath, senior vice president and director of the vaccine and infectious disease division at Fred Hutchinson Cancer Center, who was an author of the study.

What is unique about this HIV vaccine candidate is that it was engineered to directly target the production of broadly neutralizing antibodies, said Dr. Timothy Schacker, vice dean for research and program director in HIV medicine at the University of Minnesota Medical School, who was not involved in the research.

“In HIV, when we’ve designed and tested vaccines in the past, they didn’t for whatever reason induce these broadly neutralizing antibodies,” he said. “Call them super antibodies, if you want. The broadly neutralizing antibodies work more efficiently. They’re better at controlling things.”

By showing that broadly neutralizing antibodies can be induced by a vaccine, this new study could help inform the development of other types of immunizations, not just HIV vaccines, Schacker said.

“The hope is that if you can induce this kind of immunity in people, you can protect them from some of these viruses that we’ve had a very hard time designing vaccines for that are effective,” he said. “So this is an important step forward.”

Although this is “exciting science,” much more work needs to be done before this vaccine may be considered for use in the public, said Dr. Carlos del Rio, co-director of the Center for AIDS Research at Emory University and executive associate dean for Emory School of Medicine at Grady Health System, who was not involved in the new study.

“We know that broadly neutralizing antibodies are a potentially effective strategy to prevent HIV,” del Rio said. “We’re far from using this as a vaccine, but this is very exciting science. … Investing in this kind of research is critically important in not only developing a vaccine for HIV, but if this strategy works, it can be used for other vaccines.”

An HIV vaccine will probably need to elicit these broadly neutralizing antibodies, or bnAbs, “which are able to recognize globally diverse HIV strains and can prevent HIV infection. However, triggering bnAbs by vaccination has proven impossible so far. A key challenge is that bnAbs rarely develop, even during infection,” Penny Moore, of the University of the Witwatersrand and the National Institute for Communicable Diseases in South Africa, wrote in an editorial published alongside the new study.

A “key question” that still needs to be answered is how long the elicited antibodies from the first immunization can last.

Also, if the booster shot is too different from the previous vaccine, “antibodies that have been triggered by the first vaccination may not recognize the booster and will not mature further,” Moore wrote. “However, the incorporation of many different shots into an HIV vaccine regimen is unappealing. Getting the balance right between the need for antibody maturation toward bnAbs and feasibility in the real world will be essential.”

Last year, more than 38 million people were living with HIV or AIDS around the globe. More than 20 HIV vaccine clinical trials are ongoing around the world, according to the International AIDS Vaccine Initiative.

Many people in the United States have turned to daily HIV-prevention pills or frequent injections, known as PrEP, to reduce their risk of infection.

“It’s a daily pill or it’s a painful shot. It’s a shot that is uncomfortable at best that you have to get several times a year,” Schacker said of PrEP.

But having an HIV vaccine available would make protection against the virus more accessible, he said. “If you can give a vaccine, you’re going to reach more people and provide, if you have an effective vaccine, more and better coverage to reduce the probability of transmission if you’re exposed.”

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Lab-made blood could have enormous potential for people with rare blood conditions

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CNN
 — 

Scientists have transfused lab-made red blood cells into a human volunteer in a world-first trial that experts say has major potential for people with hard-to-match blood types or conditions such as sickle cell disease. The research could someday mean an end to long searches for compatible donors or dangerous transfusion reactions.

The experimental transfusion was done at Addenbrooke’s Hospital in Cambridge, England, as part of a collaborative effort among UK scientists to understand how lab-made blood transfusions could work.

The scientists took whole blood from donors in a UK database and separated out the stem cells. These are the body’s raw materials – the cells from which all specialized cells, like a red blood cell, can generate.

The researchers grew red blood cells from those stem cells and transfused them into two healthy volunteers.

The transfusions involved only a tiny amount of blood: the equivalent of one or two teaspoons. A standard blood transfusion would involve many hundred times that amount.

This stage of the trial involves two mini transfusions at least four months apart, one with a standard donation of red cells and the other with lab-made cells from the same donor.

The researchers are closely monitoring the volunteers to determine whether the process was safe. They say there have been with “no untoward side effects” so far.

They’re also watching how long the lab-grown cells last compared with an infusion of standard red blood cells. Red blood cells typically last about 120 days, but a transfusion from a standard donation contains cells that are a variety of ages because the bone marrow continuously makes these cells.

Previous tests have shown that manufactured cells function like normal cells and that these lab-made cells are likely to survive longer overall while in circulation. This study will determine for the first time whether that’s true.

Further trials will be necessary to determine whether there could be a clinical use of this lab-grown product.

The research could eventually make a difference for people with sickle cell disease, those who develop antibodies against most donor blood types, or those with genetic disorders in which their body can’t make red blood cells or the blood cells they make don’t work well.

Red blood cells are the helper cells that carry oxygen from the lungs to the body’s tissues, which use this oxygen to produce energy. The process also generates waste in the form of carbon dioxide that the red blood cells take to the lungs to be exhaled out.

With sickle cell disease – also called sickle cell anemia – red blood cells take on a folded shape that can clog tiny blood vessels and cause organ damage and pain. People with sickle cell often need multiple transfusions over the course of their lives.

“This world leading research lays the groundwork for the manufacture of red blood cells that can safely be used to transfuse people with disorders like sickle cell,” Dr. Farrukh Shah, a researcher on the study and medical director of transfusion for NHS Blood and Transplant, said in a news release. “The need for normal blood donations to provide the vast majority of blood will remain. But the potential for this work to benefit hard to transfuse patients is very significant.”

Dr. Glenn Ramsey, medical director of the blood bank at Northwestern Memorial Hospital and a professor of pathology at Northwestern University Feinberg School of Medicine, said he has had many patients over the years who are extremely difficult to transfuse and would have benefited from a therapy like the one in this study.

Often, if there is not a local blood match, he has to turn to the American Rare Blood Donor Program – and even then won’t always find an appropriate donor. In one case a few Thanksgivings ago, it was so difficult to find a match for one patient that they had to turn to a world database and bring in blood from Canada.

“This doesn’t come up very often, and it’s an extreme example, but this would be the kind of problem that these kinds of cells could try to solve,” said Ramsey, who was not involved in the new research.

He found the work “quite exciting” and its potential enormous.

Scientists have been working on this issue for many years, he said.

“Down the road in years to come, this might be a way to replace transfusions as we know it,” Ramsey said. “It’s still a long way from getting to that point, but it certainly starts us down the road to see if this will even be feasible.”

Dr. Cheryl Maier, an assistant professor of pathology and laboratory medicine and a medical director at the Emory Center for Transfusion and Cellular Therapies, said the experiment is a “really exciting advancement.”

She is particularly interested in the possibilities of lab-made red blood cell for people with sickle cell.

“There hasn’t been a lot of attention on some of these diseases, especially sickle cell, which mostly affects African American patients, and it can be really frustrating and disheartening that there isn’t more attention to it,” said Maier, who wasn’t involved in this study.

“For certain patients, especially patients with sickle cell disease or other patients that need some kind of chronic transfusion therapy, if you gave them incompatible blood, they would have oftentimes a very strong bad transfusion reaction,” she said.

The research could lay the groundwork for studies of things like platelets, which are often in critically short supply, she said. If scientists find that lab-made red blood cell products last longer, it may also improve the quality of life for people who wouldn’t have to be transfused as regularly.

“Even in 2022, there are patients that we almost can’t find units for, and they get a delay in their treatment because we can’t find matching units for them,” Maier said. “I think it definitely has the ability to revolutionize how we support some patients that are really difficult to support with blood products currently.”

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New RSV vaccines may soon put an end to rough seasons

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CNN
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It’s shaping up to be a severe season for respiratory syncytial virus infections – one of the worst some doctors say they can remember. But even as babies struggling to breathe fill hospital beds across the United States, there may be a light ahead: After decades of disappointment, four new RSV vaccines may be nearing review by the US Food and Drug Administration, and more than a dozen others are in testing.

There’s also hope around a promising long-acting injection designed to be given right after birth to protect infants from the virus for as long as six months. In a recent clinical trial, the antibody shot was 75% effective at heading off RSV infections that required medical attention.

Experts say the therapies look so promising, they could end bad RSV seasons as we know them.

And the relief could come soon: Dr. Ashish Jha, who leads the White House Covid-19 Response Task Force, told CNN that he’s “hopeful” there will be an RSV vaccine by next fall.

Charlotte Brown jumped at the chance to enroll her own son, a squawky, active 10-month-old named James, in one of the vaccine trials this summer.

“As soon as he qualified, we were like ‘absolutely, we are in,’ ” Brown said.

Babies have to be at least 6 months old to enter the trial, which is testing a vaccine developed at the National Institutes of Health – the result of decades of scientific research.

Brown is a pediatrician who cares for hospitalized children at Vanderbilt University Medical Center in Nashville, and she sees the ravages of RSV firsthand. A recent patient was in the back of her mind when she was signing up James for the study.

“I took care of a baby who was only a few months older than him and had had nine days of fever and was just absolutely pitiful and puny,” she said. Brown said his family felt helpless. “And I was like, ‘this is why we’re doing it. This single patient is why we’re doing this.’ “

Even before this year’s surge, RSV was the leading cause of infant hospitalizations in the US. The virus infects the lower lungs, where it causes a hacking cough and may lead to severe complications like pneumonia and inflammation of the tiny airways in the lungs called bronchiolitis.

Worldwide, RSV causes about 33 million infections in children under the age of 5 and hospitalizes 3.6 million annually. Nearly a quarter-million young children die each year from complications of their infections.

RSV also preys on seniors, leading to an estimated 159,000 hospitalizations and about 10,000 deaths a year in adults 65 and over, a burden roughly on par with influenza.

Despite this heavy toll, doctors haven’t had any new tools to head off RSV for more than two decades. The last therapy approved was in 1998. The monoclonal antibody, Synagis, is given monthly during RSV season to protect preemies and other high-risk babies.

The hunt for an effective way to protect against RSV stalled for decades after two children died in a disastrous vaccine trial in the 1960s.

That study tested a vaccine made with an RSV virus that had been chemically treated to render it inert and mixed with an ingredient called alum, to wake up the immune system and help it respond.

It was tested at clinical trial sites in the US between 1966 and 1968.

At first, everything looked good. The vaccine was tested in animals, who tolerated it well, and then given to children, who also appeared to respond well.

“Unfortunately, that fall, when RSV season started, many of the children that were vaccinated required hospitalization and got more severe RSV disease than what would have normally occurred,” said Steven Varga, a professor of microbiology and immunology at the University of Iowa, who has been studying RSV for more than 20 years and is developing a nanoparticle vaccine against the virus.

A study published on the trial found that 80% of the vaccinated children who caught RSV later required hospitalization, compared with only 5% of the children who got a placebo. Two of the babies who had participated in the trial died.

The outcomes of the trial were a seismic shock to vaccine science. Efforts to develop new vaccines and treatments against RSV halted as researchers tried to untangle what went so wrong.

“The original vaccine studies were so devastatingly bad. They didn’t understand immunology well in those days, so everybody said ‘oh no, this ain’t gonna work.’ And it really was like it stopped things cold for 30, 40 years,” said Dr. Aaron Glatt, an infectious disease specialist at Mount Sinai South Nassau in New York.

Regulators re-evaluated the guardrails around clinical trials, putting new safety measures into place.

“It is in fact, in many ways, why we have some of the things that we have in place today to monitor vaccine safety,” Varga said.

Researchers at the clinical trial sites didn’t communicate with each other, Varga said, and so the US Food and Drug Administration put the publicly accessible Vaccine Adverse Events Reporting System into place. Now, when an adverse event is reported at one clinical trial site, other sites are notified.

Another problem turned out to be how the vaccine was made.

Proteins are three-dimensional structures. They are made of chains of building blocks called amino acids that fold into complex shapes, and their shapes determine how they work.

In the failed RSV vaccine trial, the chemical the researchers used to deactivate the virus denatured its proteins – essentially flattening them.

“Now you have a long sheet of acids but no more beautiful shapes,” said Ulla Buchholz, chief of the RNA Viruses Section at the National Institutes of Allergy and Infectious Diseases.

“Everything that the immune system needs to form neutralizing antibodies that can block and block attachment and entry of this virus to the cell had been destroyed in that vaccine,” said Buchholz, who designed the RSV vaccine for toddlers that’s being tested at Vanderbilt and other US sites.

In the 1960s trial, the kids still made antibodies to the flattened viral proteins, but they were distorted. When the actual virus came along, these antibodies didn’t work as intended. Not only did they fail to recognize or block the virus, they triggered a powerful misdirected immune response that made the children much sicker, a phenomenon called antibody-dependent enhancement of disease.

The investigators hadn’t spotted the enhancement in animal studies, Varga says, because the vaccinated animals weren’t later challenged with the live virus.

“So of course, we require now extensive animal testing of new vaccines before they’re ever put into humans, again, for that very reason of making sure that there aren’t early signs that a vaccine will be problematic,” Varga said.

About 10 years ago, a team of researchers at the NIH – some of the same investigators who developed the first Covid-19 vaccines – reported what would turn out to be a pivotal advance.

They had isolated the structure of the virus’s F-protein, the site that lets it dock onto human cells. Normally, the F-protein flips back and forth, changing shapes after it attaches to a cell. The NIH researchers figured out to how freeze the F-protein into the shape it takes before it fuses with a cell.

This protein, when locked into place, allows the immune system to recognize the virus in the form it’s in when it first enters the body – and develop strong antibodies against it.

“The companies coming forward now, for the most part, are taking advantage of that discovery,” said Dr. Phil Dormitzer, a senior vice president of vaccine development at GlaxoSmithKline. “And now we have this new generation of vaccine candidates that perform far better than the old generation.”

The first vaccines up for FDA review will be given to adults: seniors and pregnant woman. Vaccination in pregnancy is meant to ultimately protect newborns – a group particularly vulnerable to the virus – via antibodies that cross the placenta.

Vaccines for children are a bit farther behind in development but moving through the pipeline, too.

Four companies have RSV vaccines for adults in the final phases of human trials: Pfizer and GSK are testing vaccines for pregnant women as well as seniors. Janssen and Bavarian Nordic are developing shots for seniors.

Pfizer and GSK use protein subunit vaccines, a more traditional kind of vaccine technology. Two other companies build on innovations made during the pandemic: Janssen – the vaccine division of Johnson & Johnson – relies on an adenoviral vector, the same kind of system that’s used in its Covid-19 vaccine, and Moderna has a vaccine for RSV in Phase 2 trials that uses mRNA technology.

So far, early results shared by some companies are promising. Janssen, Pfizer and GSK each appear effective at preventing infections in adults for the first RSV season after the vaccine.

In an August news release, Annaliesa Anderson, Pfizer’s chief scientific officer of Vaccine Research and Development, said she was “delighted” with the results. The company plans to submit its data to the FDA for approval this fall.

GSK has also wrapped up its Phase 3 trial for seniors. It recently presented the results at a medical conference, but full data hasn’t been peer reviewed or published in a medical journal. Early results show that this vaccine is 83% effective at preventing disease in the lower lungs of adults 60 and older. It appears to be even more protective – 94% – for severe RSV disease in those over 70 and those with underlying medical conditions.

“We are very pleased with these results,” Dormitzer told CNN. He said the company was moving “with all due haste” to get its results to the FDA for review.

“We’re confident enough that we’ve started manufacturing the actual commercial launch materials. So we have the bulk vaccine actually in the refrigerator, ready to supply when we are licensed,” he said.

Even as the company applies for licensure, GSK’s trial will continue for two more RSV seasons. Half the group getting the vaccine will be followed with no additional shots, while the other group will get annual boosters. The aim is to see which approach is most protective to guide future vaccination strategies.

Janssen’s vaccine for older adults appears to be about 70% to 80% effective in clinical trials so far, the company announced in December.

In a study on Pfizer’s vaccine for pregnant women published in the New England Journal of Medicine this year, the company reported that the mothers enrolled in the study made antibodies to the vaccine and that these antibodies crossed the placenta and were detected in umbilical cord blood just after birth.

The vaccines for pregnant women are meant to get newborns through their first RSV season. But not all newborns will benefit from those. Most maternal antibodies are passed to baby in the third trimester, so preemies may not be protected, even if mom gets the vaccine.

For vulnerable infants and those whose mothers decline to be vaccinated, Dr. Helen Chu, an infectious disease specialist at the University of Washington, says the long-acting antibody shot for newborns, called nirsevimab, should cover them for the first six months of life. She expects it to be a “game-changer.”

That shot, which has been developed by AstraZeneca, was recently recommended for approval in the European Union. It has not yet been approved in the United States.

The field is so close to a new approval that public health officials say they’ve been asked to study up on the data.

Chu, who is also a member of an RSV study group of the Advisory Committee on Immunization Practices, a panel that advises the US Centers for Disease Control and Prevention on its vaccine recommendations, says her group has started to evaluate the new vaccines – a sign that an FDA review is just around the corner.

No companies have yet announced that process is underway. FDA reviews can take several months, and then there are typically discussions and votes by FDA and CDC advisory groups before vaccines are made available.

“We’ve been working on this for several months now to start reviewing the data,” Chu said. “So I think this is imminent.”

Watching this year’s RSV season unfold, Brown, the pediatrician who enrolled her son in the vaccine trial for toddlers, says progress can’t come fast enough.

“The hospital is surging. We’re not drowning the way some states are. I mean, Connecticut, South Carolina, North Carolina, they’re really drowning. But our numbers are huge, and our services are so busy,” she says.

Brown says her son is mostly healthy. He doesn’t have any of the risks for severe RSV she sees with some of her patients, so she was happy to have a way to help others.

And while it’s far too early to say whether the vaccine James is helping to test will prove to be effective, the trial was unblinded last week, and Brown learned that her son was in the group that got the active vaccine, not the placebo

He has done well through this heavy season of illness, she says. The NIH-sponsored study they participated in is scheduled to be completed next year.

The vaccine, which is made with a live but very weak version of virus, is given through a couple of squirts up the nose, so there are no needles. The hardest part for squirmy James, she said, was being held still.

“If we can do anything to move science forward and help another child, like, sorry, James. You had to have your blood drawn, but it absolutely was worth it.”

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Pig’s Heart Took Longer to Generate a Beat in Transplant Patient

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A genetically modified pig heart transplanted into a severely ill person took longer to generate a heartbeat than those of typical pig or human hearts, research showed, another potential challenge for doctors aiming to conduct clinical trials of pig-organ transplants.

Doctors took daily electrocardiograms of

David Bennett,

a 57-year-old handyman and father of two who received a gene-edited pig heart in an experimental surgery at the University of Maryland Medical Center in Baltimore in January. Mr. Bennett died in March from heart failure, but doctors still aren’t sure why the pig heart thickened and lost its pumping ability.

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Doctors involved in the groundbreaking surgery have been studying data from Mr. Bennett’s case, which is being closely watched in the wider transplant community. Researchers reported in May that a common pig virus was detected in the pig heart transplanted into Mr. Bennett. They said there is no evidence the virus infected Mr. Bennett, but its presence in the pig heart could have caused inflammation that contributed to the cascade of events that led to his death from heart failure.

Researchers analyzed Mr. Bennett’s EKG data as part of efforts to understand his decline after the transplant, direct future research and determine a possible path toward opening clinical trials. Widely used tests that measure electrical signals that cause the heart to beat, EKGs can help diagnose heart attacks, irregular heart rhythms and other possible abnormalities.

Researchers reported unexpected findings in two aspects of Mr. Bennett’s EKG data: the time it takes electricity to travel from the top to the bottom chamber of the heart and across the bottom chambers, which pumps blood through the heart, and the time it takes the lower chambers of the heart to go through a full electrical cycle, which is associated with a heartbeat.



The surfaces of pig cells contain a sugar molecule that triggers the human immune system to attack the organs. Scientists are using the gene editing tool Crispr to overcome this obstacle.

Here’s one approach:

…and then insert the edited DNA into a pig egg cell whose nucleus has been removed. The egg cell is then transferred to the uterus of a sow. The sow gives birth to pigs whose cells—including those in their organs— contain the edited genes.

Crispr acts like scissors cutting DNA at a specific place

scientists edit troublesome genes in pig DNA…

…and sometimes add human genes…

ORGAN OPTIONS

Researchers are trying various techniques that might allow transplantation of gene-edited pig hearts, kidneys and livers into humans. Recent studies on pig organ transplantation in baboons and people have focused mainly on hearts and kidneys.

HEART TO HEART

Pig and human hearts have similarities—but also some differences.

Pigs can be bred to have hearts of similar size as human hearts.

Pig and human hearts each have four pumping chambers—two small ones known as atria and two large ones known as ventricles.

The wall of tissue separating the ventricles is thicker in pig hearts than in human hearts.

Pig and human hearts each are attached to a large artery known as the aorta as well as to a large vein known as the vena cava.

A pig’s inferior (lower) vena cava joins a pig heart’s right atrium at an angle. The vein is longer in pigs than in humans.

EASING ORGAN REJECTION

The surfaces of pig cells contain a sugar molecule that triggers the human immune system to attack the organs. Scientists are using the gene editing tool Crispr to overcome this obstacle. Here’s one approach:

Crispr acts like scissors cutting DNA at a specific place.

Scientists edit troublesome genes in pig DNA…

…and sometimes add human genes…

…and then insert the edited DNA into a pig egg cell whose nucleus has been removed. The egg cell is then transferred to the uterus of a sow. The sow gives birth to pigs whose cells—including those in their organs—contain the edited genes.

ORGAN OPTIONS

Researchers are trying various techniques that might allow transplantation of gene-edited pig

hearts, kidneys and livers into humans. Recent studies on pig organ transplantation in baboons and people have focused mainly on hearts and kidneys.

HEART TO HEART

Pig and human hearts have similarities—but also some differences.

Pigs can be bred to have hearts of similar size as human hearts.

Pig and human hearts each have four pumping chambers—two small ones known as atria and two large ones known as ventricles.

The wall of tissue separating the ventricles is thicker in pig hearts than in human hearts.

Pig and human hearts each are attached to a large artery known as the aorta as well as to a large vein known as the vena cava.

A pig’s inferior (lower) vena cava joins a pig heart’s right atrium at an angle. The vein is longer in pigs than in humans.

EASING ORGAN REJECTION

The surfaces of pig cells contain a sugar molecule that triggers the human immune system to attack the organs. Scientists are using the gene editing tool Crispr to overcome this obstacle. Here’s one approach:

Crispr acts like scissors cutting DNA at a specific place.

Scientists edit troublesome genes in pig DNA…

…and sometimes add human genes…

…and then insert the edited DNA into a pig egg cell whose nucleus has been removed. The egg cell is then transferred to the uterus of a sow. The sow gives birth to pigs whose cells— including those in their organs—contain the edited genes.

ORGAN OPTIONS

Researchers are trying various techniques that might allow transplantation of gene-edited pig

hearts, kidneys and livers into humans. Recent studies on pig organ transplantation in baboons and people have focused mainly on hearts and kidneys.

HEART TO HEART

Pig and human hearts have similarities—but also some differences.

Pigs can be bred to have hearts of similar size as human hearts.

Pig and human hearts each have four pumping chambers—two small ones known as atria and two large ones known as ventricles.

The wall of tissue separating the ventricles is thicker in pig hearts than in human hearts.

Pig and human hearts each are attached to a large artery known as the aorta as well as to a large vein known as the vena cava.

A pig’s inferior (lower) vena cava joins a pig heart’s right atrium at an angle. The vein is longer in pigs than in humans.

The time intervals are typically shorter in pig hearts that are in pigs. But they took longer in the gene-modified pig heart inside a human. The time for the electricity to travel through the heart’s electrical system and generate a heartbeat also took longer than what is typical for human hearts, said

Timm Dickfeld,

a professor of medicine and director of electrophysiology research at the University of Maryland Medical Center, who was the leader of the EKG study.

What that might mean in the future for doctors caring for patients with gene-modified pig heart transplants is uncertain, said

Paul Wang,

director of the Stanford Cardiac Arrhythmia Service and a professor of medicine and bioengineering at Stanford University, who examined the data but wasn’t involved in the study.

“It has only been done once,” Dr. Wang said. “It needs to be done many more times for us to understand what these differences mean.”

The EKG data haven’t been published or undergone an outside vetting process. They are being presented by the Maryland team at an American Heart Association annual meeting starting Nov. 5. The Maryland team said they are studying the significance of the findings and hope to gather more data in future studies.

The fact that the electrical signals traveled through Mr. Bennett’s heart more slowly than expected “did not appear to be associated with a pathological outcome,” said

Bartley Griffith,

co-director of the cardiac xenotransplantation program at the University of Maryland School of Medicine, who performed Mr. Bennett’s transplant surgery.

Dr. Griffith added that if Mr. Bennett had survived longer and the time intervals became even slower, a pacemaker might eventually have become necessary.

Researchers have tried for decades to develop the transplantation of organs between different species, or xenotransplantation, to address a chronic shortage of organs. More than 3,500 people are on the waiting list in the U.S. for a heart transplant, according to a 2022 update from the American Heart Association.

Megan Sykes,

director of the Columbia Center for Translational Immunology in New York, said that although pigs are similar to humans in organ size and physiology, the EKG data illustrate that there are differences that may only emerge after doing transplants into humans.

“We have reached the point where we need human studies as well as animal studies,” Dr. Sykes said.

The Maryland team and other groups have met with the Food and Drug Administration recently to discuss how to start small clinical trials of genetically modified pig organs. The FDA has requested additional data from the Maryland team in baboons, said

Muhammad Mohiuddin,

the scientific program director of cardiac xenotransplantation at the University of Maryland School of Medicine. Dr. Mohiuddin said they plan to gather additional EKG data as part of the research.

Write to Amy Dockser Marcus at amy.marcus@wsj.com

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Epstein-Barr: Researchers speed efforts for vaccine against virus linked with mono, MS

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Maybe you’ve never heard of the Epstein-Barr virus. But it knows all about you.

Chances are, it’s living inside you right now. About 95% of American adults are infected sometime in their lives. And once infected, the virus stays with you.

Most viruses, such as influenza, just come and go. A healthy immune system attacks them, kills them, and prevents them from sickening you again. Epstein-Barr and its cousins, including the viruses that cause chickenpox and herpes, can hibernate inside your cells for decades.

This viral family has “evolved with us for millions of years,” said Blossom Damania, a virologist at the University of North Carolina-Chapel Hill. “They know all your body’s secrets.”

Although childhood Epstein-Barr infections are typically mild, exposure in teens and young adults can lead to infectious mononucleosis, a weeks-long illness that sickens 125,000 Americans a year, causing sore throats, swollen glands, and extreme fatigue. And while Epstein-Barr spends most of its time sleeping, it can reawaken during times of stress or when the immune system is off its game. Those reactivations are linked to a long list of serious health conditions, including several types of cancer and autoimmune diseases.

Scientists have spent years trying to develop vaccines against Epstein-Barr, or EBV. But recently several leaps in medical research have provided more urgency to the quest — and more hope for success. In just the past year, two experimental vaccine efforts have made it to human clinical trials.

What’s changed?

First, the Epstein-Barr virus has been shown to present an even greater threat. New research firmly links it to multiple sclerosis, or MS, a potentially disabling chronic disease that afflicts more than 900,000 Americans and 2.8 million people worldwide.

The journal Science in January published results from a landmark 20-year study of 10 million military personnel that offers the strongest evidence yet that Epstein-Barr can trigger MS. The new study found that people infected with Epstein-Barr are 32 times as likely as people not infected to develop MS.

And shedding new light on the mechanisms that could explain that correlation, a separate group of scientists published a study in Nature describing how the virus can cause an autoimmune reaction that leads to MS. The disease, which usually strikes between ages 20 and 40, disrupts communication between the brain and other parts of the body and is often marked by recurring episodes of extreme fatigue, blurred vision, muscle weakness, and difficulty with balance and coordination. At its worst, MS can lead to impaired speech and paralysis.

Amplifying that newfound urgency, several new studies suggest that reactivation of the Epstein-Barr virus also is involved with some cases of long covid, a little-understood condition in which patients experience lingering symptoms that often resemble mononucleosis.

And just as crucial to the momentum: Advances in vaccine science spurred by the pandemic, including the mRNA technology used in some covid vaccines, could accelerate development of other vaccines, including ones against Epstein-Barr, said Dr. Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine. Hotez co-created a low-cost, patent-free covid vaccine called Corbevax.

Some researchers question the need for a vaccine that targets a disease like MS that, while debilitating, remains relatively rare.

Eliminating Epstein-Barr would require vaccinating all healthy children even though their risk of developing cancer or multiple sclerosis is small, said Dr. Ralph Horwitz, a professor at the Lewis Katz School of Medicine at Temple University.

Before exposing children to the potential risks of a new vaccine, he said, scientists need to answer basic questions about MS. For example, why does a virus that affects nearly everyone cause disease in a small fraction? And what roles do stress and other environmental conditions play in that equation?

The answer appears to be that Epstein-Barr is “necessary but not sufficient” to cause disease, said immunologist Bruce Bebo, executive vice president for research at the National MS Society, adding that the virus “may be the first in a string of dominoes.”

Hotez said researchers could continue to probe the mysteries surrounding Epstein-Barr and MS even as the vaccine efforts proceed. Further study is required to understand which populations might benefit most from a vaccine, and once more is known, Hotez said, such a vaccine possibly could be used in patients found to be at highest risk, such as organ transplant recipients, rather than administered universally to all young people.

“Now that we know that Epstein-Barr is very tightly linked to MS, we could save a lot of lives if we develop the vaccine now,” Damania said, “rather than wait 10 years” until every question is answered.

Moderna and the National Institute of Allergy and Infectious Diseases launched separate clinical trials of Epstein-Barr vaccines over the past year. Epstein-Barr vaccines also are in early stages of testing at Opko Health, a Miami-based biotech company; Seattle’s Fred Hutchinson Cancer Center; and California’s City of Hope National Medical Center.

Scientists have sought to develop vaccines against Epstein-Barr for decades only to be thwarted by the complexities of the virus. Epstein-Barr “is a master of evading the immune system,” said Dr. Jessica Durkee-Shock, a clinical immunologist and principal investigator for NIAID’s trial.

Both MS and the cancers linked to Epstein-Barr develop many years after people are infected. So a trial designed to learn whether a vaccine can prevent these diseases would take decades and a lot of money.

Moderna researchers initially are focusing on a goal more easily measured: the prevention of mononucleosis, which doubles the risk of multiple sclerosis. Mono develops only a month or so after people are infected with Epstein-Barr, so scientists won’t have to wait as long for results.

Mono can be incredibly disruptive on its own, keeping students out of class and military recruits out of training for weeks. In about 10% of cases, the crippling fatigue lasts six months or more. In 1% of cases, patients develop complications, including hepatitis and neurological problems.

For now, the clinical trials for Epstein-Barr immunizations are enrolling only adults. “In the future, the perfect vaccine would be given to a small child,” Durkee-Shock said. “And it would protect them their whole life, and prevent them from getting mono or any other complication from the Epstein-Barr virus.”

The NIAID vaccine, being tested for safety in 40 volunteers, is built around ferritin, an iron-storage protein that can be manipulated to display a key viral protein to the immune system. Like a cartoon Transformer, the ferritin nanoparticle self-assembles into what looks like a “little iron soccer ball,” Durkee-Shock said. “This approach, in which many copies of the EBV protein are displayed on a single particle, has proved successful for other vaccines, including the HPV and hepatitis B vaccine.”

Moderna’s experimental vaccine, being tested in about 270 people, works more like the company’s covid shot. Both deliver snippets of a virus’s genetic information in molecules called mRNA inside a lipid nanoparticle, or tiny bubble of fat. Moderna, which has dozens of mRNA vaccines in development, hopes to learn from each and apply those lessons to Epstein-Barr, said Sumana Chandramouli, senior director and research program leader for infectious diseases at Moderna.

“What the covid vaccine has shown us is that the mRNA technology is well tolerated, very safe, and highly efficacious,” Chandramouli said.

But mRNA vaccines have limitations.

Although they have saved millions of lives during the covid pandemic, the antibody levels generated in response to the mRNA vaccines wane after a few months. It’s possible this rapid loss of antibodies is related specifically to the coronavirus and its rapidly evolving new strains, Hotez said. But if waning immunity is inherent in the mRNA technology, that could seriously limit future vaccines.

Designing vaccines against Epstein-Barr is also more complicated than for covid. The Epstein-Barr virus and other herpesviruses are comparatively huge, four to five times as large as SARS-CoV-2, the coronavirus that causes covid. And while the coronavirus uses just one protein to infect human cells, the Epstein-Barr virus uses many, four of which are included in the Moderna vaccine.

Earlier experimental Epstein-Barr vaccines targeting one viral protein lowered the rate of infectious mononucleosis but failed to prevent viral infection. Targeting multiple viral proteins may be more effective at preventing infection, said Damania, the UNC virologist.

“If you close one door, the other door is still open,” Damania said. “You have to block infection in all cell types to have a successful vaccine that prevents future infections.”

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