Iwasaki, an immunobiology professor at the School of Medicine, and Krumholz, a cardiology professor at the School of Medicine, founded the project in 2022. The LISTEN Initiative, which stands for Listen to Immune, Symptom and Treatment Experiences Now, works with patients enrolled in Hugo Health, a program founded by Krumholz that allows individuals to centralize their healthcare information — from their medical history to data from their personal wearables, like smartwatches.

Once patients with long-COVID symptoms consent to share their data with the LISTEN initiative, researchers analyze the data to identify common symptoms that are understudied in the medical community. At the same time, patients discuss their symptoms on Kindred, a network where patients and researchers can share their long-COVID stories.

“The LISTEN study created a community of what we call a kindred,” Mitsuaki Sawano, an associate research scientist on the LISTEN team, told the News. “[It] is kind of like a social media group itself.”

Sawano said that Kindred allows researchers to see live documentation of patient symptoms, or “monitored diaries,” where patients discuss with other patients and researchers to better describe their shared symptoms. Many experts have noted that long COVID presents differently in different patients, making treatment complicated.

For Sawano, this active communication is crucial for the LISTEN team. After highlighting common trends, Krumholz and Iwasaki host town halls with patients to discuss their findings and avenues for future research. 

According to Krumholz, LISTEN’s holistic approach — encompassing all patient data from personal wearable devices to medical history — gives researchers a fuller understanding of the patient’s health.

“A one-time office-based blood pressure is not as good as a daily blood pressure measurement that you could get from a patient’s wearable,” Krumholz said. 

For Krumholz, current methods of data collection pose a limitation to research studies. Many doctors struggle to understand the daily and long-term conditions of a patient’s health because they often obtain data during regularly scheduled visits.

Due to long COVID’s varied nature, the LISTEN initiative seeks to use more consistent data to learn how the disease manifests in different people.

“The major choke point is that we’re unable to do enough research studies fast enough to learn quickly enough about what works,” Krumholz said.

In addition to using quantitative healthcare data from patient profiles, the LISTEN study also conducts surveys to evaluate what patients are experiencing. Crucially, the surveys are created with patient symptoms in mind. 

If patients report a new symptom, Krumholz, Iwasaki and others can study its prevalence and mechanisms.

“Then, somebody may say to us, ‘one of the things we’re experiencing is not on any questionnaires,’” Krumholz said.

In fact, one of the LISTEN initiative’s key studies came from patients describing a symptom that was not widely recognized as a sign of long COVID.

Patients told the researchers that they were experiencing “internal tremors,” a symptom that wasn’t listed on any of their evaluative surveys or well-described in medical research.

“We found that the internal tremor is contributing to the loss of quality of life in the patient’s eye in a significant way,” Iwasaki said. “We know of patients who really took their lives because of internal tremors. It’s a debilitating condition.”

Krumholz added that patients also contributed to the research process by describing what alleviates or worsens the tremors. During subsequent town halls, researchers and patients discussed potential research directions to help find adequate treatment options.

Krumholz contrasted patients in the LISTEN initiative with those participating in other studies. Krumholz found that many patients, especially those with long COVID, feel that physicians dismiss their symptoms, suggesting that this could be due to the fundamental way physicians are trained. 

“Doctors are trained in pattern recognition,” Krumholz said. “When doctors are confronted with something that doesn’t fit the pattern that they’ve been taught about, then they often feel that it either doesn’t exist or they don’t know how to process it.”

According to Bornali Bhattacharjee, an associate research scientist who works in Iwasaki’s lab, the LISTEN initiative tries to combat these traditional medical biases by crowdsourcing patient experiences via Kindred and obtaining continuous patient data. The LISTEN researchers organize and highlight the severity of many unofficially-recognized symptoms. 

Bhattacharjee said that without widespread holistic data, many patient symptoms remain under-researched.

“In order to validate an actual symptom of something, there needs to be a mass categorization to prove that something is actually occurring,” Bhattacharjee said.

Still, Sawano and Krumholz both noted that the initiative’s biggest challenge is deciding where they should continue to pursue research.

“The interpretation of science still has subjectivity associated with it,” Krumholz said. “Science needs to drive [research], but you’re still trying to mediate different opinions about what the science means.”

However, they see this disagreement as a necessary process to better understand a patient’s health. 

“It’s a team effort, and it does involve a lot of going back and forth and communication,” Sawano said. “But I think that’s part of the process. And I think that’s going to improve science.”

Patients in the Kindred network who are 18 or older can participate in the LISTEN study

The post Diving into the LISTEN Initiative appeared first on Yale Daily News.

A group of Yale and University of North Carolina at Charlotte researchers compared and modeled COVID-19 with its evolutionary precursors, analyzing the seasonality of COVID-19 surges across the globe. 

“This research showed the average probabilities of COVID-19 infections over a year given the virus is endemic,” Jeffrey Townsend, a biostatistics professor at the School of Public Health, told the News. “This is pretty useful to have.”

Townsend noted that there have been several COVID-19 surges over the past few years.  However, many researchers have struggled to project international COVID-19 cases due to the variability across global health systems.

Towsend added that COVID-19 is still relatively young compared to other respiratory viruses. 

“We’ve only started seeing [COVID-19] human infection a few years ago and it’s all been in the pandemic phase,” Townsend said. “If you just try and look at when people got infected, the season and the climate, it’s very hard to come up with an expectation.”

Inspired by previous research on the longevity of COVID-19 immunity, Townsend and his team observed four other coronaviruses that were evolutionarily related to COVID-19, have been present for decades and caused a common cold. According to Hayley Hassler, a research associate at the School of Public Health and the team’s lead data analyst, the team sifted through various research studies on different coronaviruses to help predict COVID-19 trends.

By comparing the genetic sequences of different coronaviruses to COVID-19, the researchers were able to draw an evolutionary tree of the virus.

According to Hassler, the researchers discovered the numerical proportion of infection for every month in the year, which highlighted how often infection frequency fluctuates throughout the year. Most of the coronaviruses had higher rates of transmission in the winter months, though they each had distinct ranges of months when infection was highest.

“From there, the model leverages the evolutionary relatedness of the coronaviruses to predict the proportion of monthly cases COVID-19,” Hassler wrote in an email to the News. “In this sense, we’d expect more closely related coronaviruses to possess similar trends in seasonality.”

Towsend said they localized the relative frequency of coronavirus transmission to major temperate cities. The researchers can then predict where the COVID-19 surge will be most prevalent based on proximity to major cities.

Towsend and his team incorporated an abundance of data from the Northern Hemisphere, but, due to limited data from the Southern Hemisphere, they were unable to include it in their model.

“Unfortunately, there hasn’t been much research in the past in the Southern Hemisphere, but every location is important,” Towsend said.

The team’s model also had other limitations. The datasets involving older coronaviruses didn’t have a standardized age range. Some datasets were restricted to children while others contained data from multiple age groups. The team is also unsure whether COVID-19 will settle into a consistent seasonal pattern.

Towsend and his team’s research predicts COVID-19 transmission rates once the virus becomes endemic, or when it begins to follow regular immunity patterns and the disease spreads at a low level. 

Still, the team believes their research will benefit public health professionals. Aia Nisho ’21, a co-author of the study who helped write the manuscript, said that knowing when and where the virus will be can help providers reduce and mitigate COVID-19 transmission.

“If we don’t accurately predict outbreaks, we’re at risk of much higher rates of infection,” Nisho wrote in an email to the News. “In ‘at-risk’ communities, such as hospitals and care homes, this translates to an increase in potential fatalities. I hope the findings of this project will be used to efficiently direct funding to public health education in communities we found to be most at risk at different times throughout the year.” 

In Connecticut, there have been 1,375 COVID-19 cases in the past week. 

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Loved ones, medical staff, and the patients themselves doubt the reality of their symptoms. Doctors struggle to offer them explanations.  

At the Yale Multidisciplinary Long Covid Clinic, however, medical workers try to unravel the mystery of long COVID. The center is directed by Lisa Sanders, associate professor of general medicine, who is no stranger to medical mysteries like long COVID. She currently writes the “Diagnosis” and “Think Like a Doctor” columns for the New York Times, and she previously published two medical books,“Every Patient Tells a Story: Medical Mysteries and the Art of Diagnosis” and “Diagnosis: Solving the Most Baffling Medical Mysteries.” 

In her role as director, Sanders is essentially a detective in a white coat. When a patient is referred to the clinic, Sanders first investigates whether the culprit is long COVID. This process involves ruling out other factors that may cause similar symptoms. For example, if a patient reports feeling fatigued, she checks that the patient does not have sleep apnea. According to Sanders, by repeating this process, the researchers remove some uncertainty from a long COVID diagnosis. 

From there, Sanders told the News, she tackles the downstream effects of the disease. Because the symptoms of long COVID are known and treatable, Sanders said she can treat the effects, despite not understanding the root cause.

“If you can’t treat the actual disease, just treat the symptoms that are tormenting people and reassure them that at least some people get better,” Sanders said. “Depending on who you read, 80-plus percent of people don’t have symptoms after a year.”

The Yale Multidisciplinary Long Covid Clinic is on the third floor of Yale New Haven Hospital’s St. Raphael Campus. Patients enter a waiting room adorned with long COVID support group flyers and prints of beach paintings. A narrow hallway connects Sanders’ office, an examination room and a physical therapy room.

Sanders said that next month the Center will move to a larger space.

“Our patients say ‘oh my god, this is such a small room, this is such a small space.’ Like really?” Sanders said. “It’s gonna be so luxurious.”

Despite its small size, the Center provides each patient with help from social workers, physical therapists and Sanders. 

Early in the pandemic, this level of treatment was not available to long-haulers, a colloquial term for people with long COVID. Instead, patients in New Haven with long COVID symptoms had to seek out specialists in separate departments that best aligned with their symptoms, Sanders said. Sanders said that eventually, specialists realized that the best way to help people with long COVID was not with specialty care, rather, it was with a specialized long COVID Center. Sanders was immediately interested in leading the center.

“The thought that I could learn about this, and maybe help people with it seemed appealing,” Sanders told the News.

Part of this learning is trying to define long COVID. 

Characterized by persistent symptoms long after initial infection, long COVID remains a puzzling challenge for patients, healthcare professionals and researchers. However, common symptoms include fatigue, brain fog, cough and shortness of breath after their initial COVID-19 infection, Sanders told the News. For many patients, these symptoms can become physically and emotionally debilitating, Sanders said.

“You had COVID, and then something bad happened,” Sanders said. “But that’s all we can say now because we have no idea what the pathophysiology is.”

Parallels to polio

COVID-19 is not the first epidemic to leave a wake of people experiencing lingering symptoms, said Naomi Rogers, a history professor at Yale who studies 20th and 21st-century medicine and disability. 

In the middle of the 20th century, the United States weathered a series of polio outbreaks, a virus that primarily affects children and can, in rare cases, cause long-term paralysis. One 1955 polio epidemic infected 3,950 people in Massachusetts. Of those infected, 2,771 were paralyzed, some for a few weeks or months and some permanently.

“Polio was seen as a really scary disease because of its disabling effects,” Rogers said. “Everybody feared that if their child got it, they would never be able to work independently or live independently.” 

According to Rogers, some patients with polio also developed “post-polio” syndrome. These people had polio as children and fully recovered, but then, decades after their illness, became paralyzed.

Rogers pointed to similarities between post-polio syndrome and long COVID. Like patients with long COVID, people with post-polio syndrome continued to have symptoms of the disease long after the actual infection had passed, Rogers said. Some patients with post-polio were dismissed by their doctors because the doctors had never heard of the disease, according to Rogers. People with post-polio syndrome, like those with long COVID, Rogers said, had to advocate for themselves in medical settings and seek ways to alleviate their symptoms outside of traditional medicine. 

Rogers also highlighted similarities between long COVID and diseases such as chronic Lyme and Chronic Fatigue Syndrome. For people with these conditions, she said, it is difficult to make friends, family or doctors aware that there is an actual disease behind what she said are relatively vague symptoms. 

“You can’t see pain. You can’t see weakness. There are a lot of chronic responses that are not visible,” Rogers said.

In addition to vague symptoms, Rogers said that long COVID is complicated because nobody knows exactly what it is or how to think about it. 

Unlike other chronic diseases such as cancer or AIDS, she explained, long COVID is too recent for the public to have a clear picture of what it is like. 

“When we say long COVID, we don’t have in our minds what long COVID looks like,” Rogers said. 

Studying Long Covid

A group of interdisciplinary researchers at Yale are working to uncover what long COVID is and how it can be treated. 

During the pandemic, researchers at Yale, including Akiko Iwasaki, Sterling Professor of immunobiology at the School of Medicine, noticed that some patients who had COVID-19 developed chronic symptoms that lasted for a long time after their infection. Iwasaki and her lab also noted that some people who got the COVID-19 vaccine had an immune response.

As the pandemic progressed, Iwasaki established a network of researchers studying COVID-19 who also wanted to understand the unusual immune responses caused by COVID-19. This collaboration became the Center for Infection and Immunity, or CII, which opened in August 2023. 

The center, which Iwasaki directs, seeks to understand how chronic diseases develop and uncover links between infection and chronic disease. It also tries to connect immune responses to factors such as sex, genetics, age and environment, and develop therapies for treating chronic disease.

Iwasaki said that, because post-acute syndromes, such as long COVID, are difficult to understand and quantify, studying them requires an interdisciplinary approach.

Patient-centered approach

In studying chronic disease, the CII seeks to include patients as full participants in their research. CII partners with the Center for Outcomes Research and Evaluation, or CORE, to enhance their patient-centered research approach.

“We’re trying to create a different spirit around the research,” Harlan Krumholz, a professor at the School of Medicine and the director of CORE told the News. Krumholz is also on the CII leadership team. 

Krumholz said patients with post-acute syndromes are “desperate for answers.” 

But because chronic syndromes like long COVID are poorly understood, he said many patients feel “abandoned” by doctors, caregivers and the medical system. 

“There’s not one evidence-based therapy,” Krumholz said. “We even have trouble defining the condition, because there aren’t any diagnostics.”

To combat this feeling of neglect, CORE and CII developed a new model for doing patient research which Krumholz called “highly participant-centric.”

One way the researchers study long COVID is through the Yale LISTEN study, which stands for Listen to Immune, Symptom and Treatment Experiences Now. The LISTEN study follows a pool of participants with long COVID who share health data and specimens like blood or saliva with researchers. 

People participating in the LISTEN study can opt to participate in different research projects. For example, the CII is also conducting a trial on the effect of Paxlovid — an antiviral drug used to treat COVID-19 — on long COVID. 

The trial is being conducted virtually, to make it easy for people to participate in research. Patients involved in the study receive drugs or placebo pills by mail, then fill out surveys online and electronically transmit their data to researchers. 

The trial organizers also hold regular town hall meetings, where study participants can ask questions and suggest changes. When researchers learn new information through their research, they share it with the participants. 

New long COVID study gives hope to researchers, patients 

In September, researchers from the CII and Mount Sinai Hospital published a paper in Nature that identified biological markers associated with long COVID. By analyzing blood samples, the researchers found that hormonal dysfunction, exhaustion of certain immune cells and the reactivation of latent viruses are key factors in long COVID. 

“To us, that means that there is an immunological underpinning to this disease,” Iwasaki said. 

According to Iwasaki, the evidence that long COVID is a biological disease is an important discovery not only to understand the disease but also to validate patients’ struggles. People suffering from long COVID and other chronic diseases are often perceived as inventing or exaggerating their illness, Iwasaki said. 

The idea that patients are making up their symptoms, Iwasaki said, is one of the major misconceptions that the CII seeks to debunk. Iwasaki added that the identification of biological markers helps dispel the belief that long COVID is only a psychiatric illness. 

Sanders said she believes there should have never been a need to prove long COVID patients had an actual disease. 

“I never thought they needed any validation. I thought that people who saw it as psychiatric alone were nuts,” Sanders told the News. “Eleven million people have long COVID in the United States alone, and there’s so many more than that in the world. Over a million people don’t just come up with the same problem.” 

Long COVID is not the CII’s only focus. Researchers at the Center also study diseases such as chronic Lyme disease, which is a disease spread by ticks, and myalgic encephalomyelitis chronic fatigue syndrome, or ME/CFS.

While post-acute syndromes are complex and tricky to study, long COVID provides a unique research opportunity, Iwasaki said. People with the disease became ill around the same time and from the same virus, which allows researchers to simultaneously study a large number of people who have a similar chronic illness. 

Iwasaki said that it is difficult to find this kind of continuity with other post-acute viral syndromes because most chronic diseases occur in small numbers and at different times. 

Research developments often come up in conversation during visits to the Long COVID Clinic. Patients frequently tell Sanders about new research they have encountered, and Sanders will follow up on it. Sanders even has a Google alert that sends her every online publication that has to do with long COVID.

Like Iwasaki, Sanders views long COVID as a unique opportunity to develop our understanding of chronic illness.

“It would be terrible to waste this and not learn anything from it, like we have done with so many other infections,” Sanders said. “We have the technology and the curiosity. God only knows what other factors allowed this to be an active area of research, but I’m so glad it is.”

Adults aged between 35 and 49 exhibited the highest prevalence of experiencing long COVID.

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Researchers at the Yale School of Medicine and Mount Sinai Hospital have identified significant biological markers associated with Long COVID. The team  analyzed blood samples of participants with varying COVID-19 exposure histories and Long COVID statuses. Published in “Nature” on Monday, the study identified hormonal dysfunction, exhaustion of certain cells within the immune system and the reactivation of latent viruses as key factors in Long COVID. 

“I believe the results of this study will help patients in many ways,” Akiko Iwasaki, Sterling Professor of Immunobiology and a lead author of the study, wrote to the News in an email. “We provide evidence that Long COVID is a biological disease, with immune and hormonal dysregulation that underlie its pathogenesis.”

In the study, the researchers divided participants into five distinct groups, each with varying histories of COVID-19 exposure and different Long COVID statuses. The Mount Sinai team, led by David Putrino, recruited participants from Long COVID clinics within the Mount Sinai Healthcare System. Participants experiencing LC underwent thorough medical evaluations, which according to the researchers, was intended to ensure that alternative medical conditions were not causing their persistent symptoms.

According to Putrino, the team excluded roughly half of the participants who applied because the researchers determined that these participants were not suffering from Long COVID. Putrino said these participants had not fully recovered from initial COVID-19 infections.

“They would say ‘Yeah, I’m fully recovered, but I can’t go to the gym anymore,’” Putrino said. “And we would ask, ‘Why can’t you go to the gym?’ ‘Because every time I go to the gym, I crash.’ That’s not fully recovered.”

Once enrolled in the study, all participants provided blood samples and completed symptom surveys on the same day as their sample collection. Additionally, researchers collected self-reported medical histories from all participants in the study. 

According to Putrino, the team discovered three signals associated with LC: hormonal dysfunction, an exhausted immune system and the reactivation of latent viruses.

The study found that people with LC experience significantly lower morning cortisol levels — which help wake the body up — compared to healthy individuals. 

According to Putrino, cortisol levels rise around 3 a.m. and trigger the brain to wake up around 6 a.m. or 7 a.m. LC patients’ extreme fatigue and difficulty starting their day can partially be explained by the lower cortisol levels. Their symptoms tend to improve in the afternoon, only to repeat the cycle after sleep.

The study also found that LC patients have exhausted immune systems. Blood samples showed higher activated B and cytokine-secreting T cells in LC patients. B cells are responsible for generating antibodies that help fight infections. If higher levels of antibodies to a protein associated with COVID-19 are present, the immune system is likely actively fighting an infection, which could suggest persistence of SARS-CoV-2 — the virus that causes COVID-19 — in LC patients.

The researchers also observed elevated levels of cytokine-secreting T cells — cells that help coordinate immune responses — in LC patients. Separately, they identified T cells nearing a state of exhaustion after combating an unknown threat for an extended period.

Finally, the study found evidence of recent reactivation of latent viruses in the body, such as Epstein-Barr Virus and various herpes viruses, in LC patients. While the immune system had previously controlled these viruses, according to the study’s findings, the LC patients’ weakened immune systems may have allowed the viruses to return. 

“These viruses are saying, ‘these T cells are starting to get depleted, the B cells are distracted with something else, let’s party,”  Putrino said. 

One section of the self-reported medical history evaluation assessed whether patients previously suffered from anxiety or depression. Crucially, the researchers found no disparities in the pre-existing history of depression or anxiety between those who have never reported having COVID-19, those with COVID-19 but not Long COVID, and those with Long COVID. Additionally, the study did not find evidence that the three objective biomarkers co-occur with any mental health issues measured in the study, which the researchers argue can help to dispell belief that LC is a purely psychiatric condition.

Still, the researchers noted that the study has certain limitations. Only 273 people took part in the study, and researchers only recruited participants from LC centers.  Additionally, the study focused on peripheral immune factors, even though they claim that LC often presents with organ-specific dysfunctions. 

Putrino said that he and his team hope to conduct further research and deepen their understanding of the study’s key findings, including the significant difference in morning cortisol levels between groups. He noted that they are currently organizing a broader investigation into cortisol patterns throughout the day. 

“The study is a good, broad picture of where are going to be the next best places to look for further studies,”  Dr. Rahul Dhodapkar ’15 MED ’24, one of the study’s first authors, said.

Patients collectively created the phrase “Long COVID” in the early months of the pandemic.

Correction, Oct. 4: Three paragraphs in the article have been updated to more accurately reflect specific scientific terminology derived from the study. 

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Founded by immunology professor Akiko Iwasaki, the new Center for Infection & Immunity, or CII, was established on Aug. 18. CII involves collaboration between over 25 health care experts in fields ranging from epidemiology to vaccine development. Their goal is to enhance current diagnostic methods and treatments, with the long-term objective of developing cures and vaccines for post-acute infection syndromes. 

The Center’s faculty told the News they also hope to cultivate a “patient-partner model” that includes patients’ real-time feedback and symptoms in the process of researching post-acute infection syndromes.

“I’m very excited,” said Iwasaki. “I don’t think any other centers are focusing on these post-acute syndromes, not at all.”

Post-acute infection syndromes refer to a group of chronic health conditions that can develop after the acute phase of a viral, bacterial or parasitic infection. These syndromes generally produce persistent and often debilitating symptoms such as fatigue, unrefreshing sleep, pain and cognitive impairment. 

These conditions gained attention after a spike in the number of people suffering from long COVID symptoms during the pandemic, said Nicole Darricarrere GRD ’14, the Center’s scientific program director. This newfound recognition, she explained, has led to greater research funding and collaborative initiatives around post-acute infection syndromes.

“Long COVID is a great opportunity to crack the mystery that we’ve known was there but has been neglected,” said Darricarrere.

Although they arise from different diseases, post-acute infection syndromes share some common symptoms, Iwasaki explained, suggesting that these illnesses share similar biological underpinnings. As a result, the Center plans to prioritize pathobiology research to explore the biology behind the syndromes and develop targeted, effective therapies.

The Center also has a disease prevention arm that will develop new types of vaccines, Iwasaki added. For instance, her team plans to research mucosal vaccines, which are delivered at the sites where pathogens enter the body — such as the nose, mouth or gastrointestinal tract — instead of via injections. As a result, mucosal vaccines station biological guards against germs at the body’s entrances, redirecting the immune response to the locations where diseases start and potentially creating a more effective immune response.

With a traditional vaccine injection, however, those entrances remain open. After a disease invades the body, the immune system has to detect an attack and can only respond after one begins.

“If you can prevent the entry or the interaction at the mucosal site, that would prevent infection even before it goes to your bloodstream or lower respiratory tract,” said Inci Yildirim, a pediatric infectious disease specialist and a vaccine expert in the Center. 

According to Darricarrere, the Center hopes to bring together experts from a wide variety of fields, from immunobiology to epidemiology to vaccine development. The interdisciplinary approach, she explained, could promote a deeper understanding of post-acute infection syndromes and accelerate the development of effective treatment strategies. 

As a result, Darricarrere and Iwasaki said that they selectively choose scientists from a wide range of backgrounds — including early-career scientists and those from underrepresented groups. 

“The collaborative environment is beneficial to any site, but particularly when we are looking at sort of diseases of unknown sort of etiology or infectious diseases that may come up in the future and cause a pandemic,” Iwasaki told the News.

Iwasaki explained that the new Center’s projects incorporate a “patient-partner model” that uses real-time feedback from patients to shape the progress of ongoing trials. Patients can input feedback and medical records on a phone app and can sign up to provide blood samples on a regular basis. 

By doing so, patients can contribute actively to the research process surrounding their diseases, rather than being passive participants, Iwasaki explained. 

“I think that’s the future of science,” said Iwasaki, “The patients are their own experts, and how they perceive the disease and how they interpret it and tell us about the disease has been incredibly informational and instructive for us.”

By 2025, Darricarre added, the Center will have a physical space. In the interim, researchers leverage available facilities, equipment and training through Iwasaki’s lab. There are already two ongoing clinical trials led by the Center, plus more than seven research projects underway. 

The Yale School of Medicine is located at 333 Cedar St.

Correction 9/24: A previous version of this article incorrectly quoted Dr. Akiko Iwasaki as saying “ideology” instead of “etiology.” Additionally, that version described the CII as having seven clinical trials lined up. The CII has seven research projects lined up, not clinical trials. 

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An updated version of the influenza vaccine is currently available to all Yale students, faculty and staff, while the updated iteration of the COVID-19 vaccine is set to be available on campus by October.

The new COVID-19 vaccines will be available nationwide later this week, following their approval by the Food and Drug Administration and the Centers for Disease Control and Prevention on Monday and Tuesday, respectively. The booster shots’ arrival on campus coincides with an uptick in COVID-19 cases in the Yale and New Haven communities, which has raised concerns among Yale public health experts who spoke with the News.

How do this year’s COVID-19 and flu vaccines work?

While last year’s version of the COVID-19 mRNA vaccine was a bivalent booster that protected against two separate variants, the vaccination’s latest update will be monovalent and focused on providing protection against the XBB.1.5 omicron variant alone.

According to Richard Martinello, medical director of infection prevention at Yale New Haven Hospital and Yale New Haven Health, XBB.1.5 is no longer the most common circulating variant. However, recent data has demonstrated that the updated vaccine still helps the body to generate an effective immune response against the Omicron variants that are circulating.

“We have a very good understanding of the safety of these mRNA vaccines now,” Martinello said in an interview with the News prior to the CDC’s approval of the new COVID-19 vaccines. “So we’re very comfortable anticipating [the vaccines] becoming available.”

The vaccine protecting against the flu, on the other hand, is a quadrivalent vaccine, Martinello explained. It contains components that provide protection against four different types of the flu: the H1N1 and H3N2 strains of influenza A, and the Victoria and Yamagata strains of influenza B.

Additionally, unlike the mRNA-based COVID-19 vaccine, the flu vaccines are made up of a protein called hemagglutinin that is purified away from the four different strains of influenza the vaccine provides protection against.

“It’s been well-known that this hemagglutinin protein is very immunogenic and can help, when vaccinated, to produce a protective response against the virus,” Martinello said. “So when we get a shot of a flu vaccine, it’s actually those proteins that are purified from the virus itself that help to immunize us and protect us.”

Who should get the COVID and flu vaccines?

According to a University-wide email sent by Madeline Wilson, the chief campus health officer and chief quality officer at Yale Health, everyone over the age of six months should receive the flu vaccine.

The CDC also recommends that people in that same age range receive an updated COVID-19 vaccine, according to a news release published Tuesday.

Martinello highlighted additional versions of the flu vaccine that are specifically formulated for different age groups. A half-dose pediatric formulation is available for younger children, while a higher-dose formulation is recommended for individuals over the age of 65.

Depending on their position at Yale, certain individuals will be required to receive the flu vaccine, both Martinello and Wilson said. Yale health care workers and health care students are required to receive the updated flu vaccine by Dec. 1.

However, the University has not yet made a decision as to whether the new version of the COVID-19 vaccine will be mandated for all students, faculty and staff. The primary series and additional booster vaccines are currently required.

Martinello said the University expects to engage in “further discussions” regarding any changes to the mandate after hearing new guidance from the FDA and CDC. 

“Even if we do not mandate the new vaccine, I would really strongly encourage everybody to get out and get vaccinated,” Martinello said, “because we know how beneficial that vaccine is not only in protecting people against COVID, but for those who do get COVID.”

Where and when can I get the COVID and flu vaccines?

Because this iteration of the COVID-19 booster vaccine has just received approval, Yale does not yet have it in stock, Wilson explained.

In an email to the News, Wilson said the University expects supplies by October, “if not sooner.” She added that an email with information about vaccines is scheduled to arrive in students’ inboxes later this week. 

Students, faculty and staff can periodically check for updates on the availability of the vaccine through the Yale Vaccine Program website and, once Yale receives a supply of the vaccine, will be able to make appointments to receive it. Wilson noted that the University made some of these appointments available for October, but that all the October appointments have already been booked.

While the COVID-19 vaccine will not be immediately available on campus, appointments to receive this year’s flu vaccine are readily available. Students, faculty and staff can schedule their vaccinations at any one of a number of locations, including both adult and family flu clinics. An option to receive a flu shot at an already-scheduled appointment with Yale Health, unrelated to getting the vaccination, is available as well.

Why should I get vaccinated?

Martinello and Wilson strongly emphasized the importance of getting vaccinated against both COVID-19 and the flu.

In her University-wide email, Wilson cited the capacity of the flu vaccine to prevent infection or decrease the severity of illness if one contracts the virus. She also emphasized the vaccine’s ability to provide protection to not just the recipient, but to everyone around the recipient as well.

“Vaccine reduces the risk of spreading infection to vulnerable members of your family and community, including infants, pregnant people, older individuals and those with weakened immune systems,” Wilson wrote.

In a college campus setting, where students and staff may interact with dozens of people per day, Wilson said, such community protection is vital to allowing classes, extracurriculars and other activities to move forward without posing any danger to those involved.

Ned Swansey ’25 agreed with Wilson’s sentiment, citing students’ responsibility to not just their own health but to that of their peers and professors.

“As a large and relatively insular community, there’s a lot of potential for illnesses to spread if people don’t get vaccinated,” Swansey wrote to the News. “I believe that as students, we have a responsibility to get vaccinated not just for our own health but also to protect other students, faculty and staff.”

A risk for significant complications and a recent increase in the number of hospitalizations due to COVID-19-related illness also factors into the importance of getting vaccinated, according to Martinello.

As COVID-19 becomes endemic in a similar way to the flu, he explained, the public should take the lessons learned from the pandemic into their wider mindset towards preventing the transmission of respiratory viruses.

“During the years of COVID, we’ve come to learn that the transmission of these respiratory viruses is in large part preventable through what we would call non-pharmaceutical interventions — so, doing things like keeping your distance, staying home when you’re sick and wearing a mask,” Martinello said. “And I think not only should we continue to apply those behaviors when we’re concerned about COVID, but I think we should think more broadly about them to include other respiratory viruses, especially influenza.”

The Campus COVID Resource Line is available at (203) 432-6604 from 8:30 a.m. to 5:00 p.m., Monday through Friday.

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In a paper published in the biomedical journal, Science Translational Medicinal, researchers at the Yale School of Engineering & Applied Science and the School of Medicine developed a method using nanoparticles to deliver an mRNA COVID-19 vaccine in mice. Compared to available COVID-19 shots, the nasal spray opens the door to a less invasive vaccination option.

“There’s been a lot of enthusiasm for different modes of delivery,” said Jason Schwartz ENV ’13, an associate professor of health policy at the Yale School of Public Health who was not involved in the study. “And a lot of enthusiasm for these next generation of COVID vaccines.”

According to Mark Saltzman, professor of biomedical engineering and the paper’s senior author, a nasal approach to vaccines might provide more protection against the virus.

Saltzman’s co-author, Sterling Professor of Immunobiology Akiko Iwasaki, had also previously demonstrated that vaccines delivered nasally — the same way humans encounter the pathogen in the real-world — could be more effective than a shot.

“That more natural exposure to the vaccine can provide an enhanced protective response from the immune system,” Saltzman said. “It’s really her work that has inspired us to figure out how you could administer an mRNA vaccine in this way.”

Saltzman explained that the vaccines work by using PACE, a nanoparticle delivery system. PACE sheaths a spike protein which encodes a SARS-CoV-2 mRNA vaccine so they can be inserted into cells. Inside the cell, they can generate a response that helps individuals develop immunity to COVID-19. 

According to Schwartz, nasal vaccines could be easier to use, since they do not require needles or injections. The spray also allows for the possibility of self-administered vaccines in the future. 

Traditional vaccines also might trigger needle anxiety in some individuals, Schwartz said, to which nasal sprays might offer a solution.

“To the extent that we can remove at least that one issue of needle anxiety or the nature of the injection, we can take that off the table,” Schwartz said. “It’s at least one reason for hesitancy to receive vaccines.”

Still, creating this vaccine was not without challenges. According to Saltzman, the lungs contain a layer of mucus that makes it difficult for the mRNA to reach the target cells. Some nasal vaccines using nanoparticle technology have also been shown to cause inflammation in lung tissue. 

The team overcame those hurdles by coating the nanoparticles with co-polyethylene glycol, a compound that Saltzman describes as a slippery coat which allows the nanoparticle to pass through the mucus and remain intact.

The final step was getting the mRNA into the cell without accidentally killing the cells. 

“That I think is the hardest barrier,” Saltzman said. “It’s easy to get things into cells and kill them. It’s harder to make it effective without causing safety concerns. You are on the line between effectiveness and safety.”

Saltzman said he sees the vaccine technology as promising not only for COVID-19 vaccines, but also for other immunizations against respiratory infections like the flu and respiratory syncytial virus. He said he also hopes to modify the nano-particle design to combat genetic diseases in the lungs like cystic fibrosis.

Schwartz is optimistic that this technology could help “facilitate the broad distribution of vaccines.” Equitable access to vaccinations could become easier with widespread availability of an easy-to-administer nasal spray, he explained.

But Schwartz also raised concerns about the need for education around these potential nasal vaccines.

“Innovation as we saw with mRNA vaccines in general can be both exciting but can also be one more source of concern that the public health community needs to educate and inform about,” Schwartz told the News. “Should technologies like the one that research is happening here at Yale, make its way down the line and actually arrive at a widely used and approved kind of product?”

James Meek, the associate director of the Yale Emerging Infections Program, wrote to the News expressing reservations about the widespread implementation of self-administered nasal vaccines. At-home COVID-19 vaccines, he explained, could make vaccine tracking more difficult for public health officials. 

“A major disadvantage to self-administered vaccines, from a public health perspective, is the lack of ability to reliably track vaccine uptake,” he wrote. 

Currently, when a healthcare provider administers a vaccination they are required to register that event in the state immunization registry, Meek explained. He warned that the public health impact of self-vaccination could end up becoming similar to COVID-19 home testing. Home testing for COVID-19, according to Meek, reduced public health experts’ ability to accurately monitor how much of the COVID-19 virus is circulating.

The license for the team’s patent has already been given to the biotech company Xanadu Bio. But Schwartz explained that nasal COVID-19 vaccines might not be publicly available in the near future.

“I think on the one hand, we say this is promising, but it’s a reminder that there’s a long path, probably measured in years, before a product like this would actually reshape what individuals receive in their pharmacies or their doctor’s offices,” he said. “Lots of things that can go wrong along the way. That’s how medical research works.”

The Yale School of Engineering & Applied Science was founded in 1852.

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The study is being led by Harlan Krumholz, a professor at the School of Medicine, and Akiko Iwasaki, a professor of immunobiology and molecular, cellular and developmental biology. The Yale Paxlovid for Long COVID trial aims to research whether consistent use of the antiviral medication can help improve the lives and symptoms of long COVID patients. 

Krumholz, who primarily researches cardiovascular diseases, said that he was drawn to the project not only because of its potential impact on many patients, but also for its innovative methods in conducting clinical research. 

“It was becoming clear to me that it was an opportunity both to try to make a contribution to those who were suffering, but also to innovate around how we pursued research … in a way that was digital, decentralized, democratized and was breaking new grounds in the ways that we were participating with people in our studies” Krumholz said. “[W]e could set an example to others how we could re-engineer the way we are doing studies.”

Iwasaki emphasized that because the study is decentralized, it is easier for people from across the country to participate. 

“Participants do not have to travel anywhere to get their biospecimen collected or obtain the medicine,” Iwasaki wrote to the News. “Everything is delivered to them. People living in Alabama to Wyoming can participate in the trial … this is particularly important for people with long COVID, who may be too ill to drive to a study site.”

Long COVID is defined in the study as a condition in which participants with prior COVID-19 infection developed symptoms of within four weeks of their initial infection. Those symptoms, according to the study’s definition, have persisted for at least three months. The study aims to test whether long COVID is caused by the persistence of the COVID-19 virus in patients. 

“[D]ifferent mechanisms may be going on in different people,” Erica Spatz, an associate professor of cardiology and one of the early organizers of the study, wrote. “One of these mechanisms is the persistence of coronavirus in the system. In fact, I have had some patients become reinfected with COVID and suddenly their Long COVID symptoms go away, potentially because their body was able to mount an effective immune response to residual virus. This study of Paxlovid is tapping into some of these theories, namely that there is persistent virus leading to symptoms of Long COVID.”

Paxlovid is an antiviral medication typically given to patients for five days during their infectious period. It works to inhibit a key enzyme that the COVID-19 virus uses to replicate itself. The researchers hypothesized that taking this medication for a longer period of time can help clear the remaining virus and alleviate patients of their long COVID symptoms. 

Interested participants take a pre-screening survey online to determine their eligibility. If they meet the qualifications, the patients compile their medical records in a secure cloud-based account and send them to the researchers, who then determine whether the patient should qualify for the study. 

Participants are randomly sorted, either receiving ritonavir-boosted nirmatrelvir — the generic name for Paxlovid — or a placebo to be taken orally for 15 days. The participants will complete a daily diary cataloging their symptoms alongside other surveys that the researchers will use to create an overall “summary score.” According to Krumholz, the summary score standardizes differences in symptoms between patients, since long COVID patients tend to have a large variety of symptoms. The overall score helps the researchers gauge whether the patients’ quality of life was generally improved by taking the medication despite the differences between patients. 

Beyond the questionnaires and summary score, blood and saliva samples will be taken from participants before and after treatment. These samples will go through an immunophenotyping analysis in the Iwasaki lab.

“They are measuring thousands of components of the immune system trying to characterize what is active, what is not, what levels are high and what levels are low, what immune antibodies may exist within the course of treatment and how it correlates with people’s response,” Krumholz said. “Even if the results are negative, it may be that we can identify the signatures of people who are responders and help us understand whether there are subsets of people that might benefit.”

Participants will continue to be followed after the 15 days of treatment to see whether the improvement of symptoms is sustained long term. 

Rohan Khera, assistant professor of medicine and biostatistics, is leading the analytic side of the project. In particular, Khera is working on decentralized data analysis in the trial. While this study is a good start, Khera said that there is still more research to be done regarding long COVID.

“There is a lot being done, and I think the biggest value will come from research that helps better characterize what symptom constellation defines Long COVID and whether there are disease subtypes representing different pathophysiologies,” Khera wrote to the News. “The treatment could then be targeted to the mechanisms causing the symptoms and challenges to patients.”

There are currently patients enrolled from 43 states, and Krumholz said they are aiming to include participants from the 48 contiguous states. As of September, roughly one third of the study is full. The researchers are still screening participants for eligibility. Krumholz hopes to be done enrolling participants by the end of this year and to get results sometime during the spring of 2024, although it would take additional time for the FDA to approve the use of Paxlovid for long COVID.

The School of Public Health is located at 60 College St.

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Completed in collaboration with researchers at Stanford University and the University of Florida, the study used data from the Connecticut Department of Correction that measured the spread of COVID-19 among incarcerated populations. Researchers examined the data to determine how exposure to the COVID-19 virus impacts the efficacy of the vaccine and other forms of immunity. 

“There was a lot of interest both on the part of the DoC to better understand what the data was saying about their own policies and how COVID was spreading between the Connecticut correctional system,” Murilo Dorion ’24, a co-author of the study, told the News. 

The study found that protection against COVID-19, both from the vaccine and through previous infection, is “leaky,” or exposure-dependent. When inmates were housed with others who had COVID-19, vaccines or acquired immunity from previous infections were less likely to protect them from the disease. 

In the months when the delta variant was dominant, researchers found that the vaccine was 68 percent effective in protecting those who had no exposure to infected cellmates. However, the vaccine was only 26 percent effective for those who were exposed to an infected cellmate. Similarly, during the omicron wave, the vaccine was 43 percent effective for those with no exposure but just 4 percent effective for those with exposure. 

“This is something that many of us suspected since the beginning of the epidemic,” Albert Ko, professor of public health at the School of Public Health and a senior author of the study said to the News. “If you are exposed to high levels of the virus, that may overwhelm the protection you may have against being infected.” 

In many COVID-19 studies, researchers must contend with testing-related biases. Margaret Lind, associate research scientist in epidemiology at the School of Public Health and first author of the study, said that despite the team’s efforts to clean and process the data, residual bias is always a risk.

Benjamin Oldfield, an internal medicine specialist at Yale New Haven Hospital, echoed a similar sentiment in an email to the News. “People with exposures tend to get more COVID tests, and this was the case for the study participants. So, this biases the results towards greater COVID positivity in those with exposures.” 

Lind noted that because the correctional facilities were highly controlled and the spread of COVID-19 was well-documented, the study’s findings can be applied to other spaces where the risk of exposure to COVID-19 is heightened. 

“We’ve been able to learn a lot about the general mechanisms of COVID, but also provide back information that’s directly applicable to the [Department of Correction],” Lind said. “This study has direct implications in that it encourages, on an individual level, people within correctional facilities to wear masks when a lot of people around them have COVID.”

Lind and Ko highlighted the importance of the study in emphasizing preventative methods to reduce the spread of COVID-19. For both researchers, being vaccinated, wearing masks, social distancing and quarantining continue to be crucial as people become more aware of the imperfect protections the vaccine offers.

With the recent uptick in COVID-19 cases, this study has possible ramifications for policies pertinent to curbing its spread. 

“In other congregate situations, like a hospital or indoors, there may be some benefit in trying to reduce your level of exposure to the virus so you can actually maximize the effectiveness and the protection you get from being vaccinated or having immunity from prior infection,” Ko said.

The researchers emphasized the importance of collaborating with organizations like the Connecticut Department of Correction in conducting research that not only advances an understanding of science but also has direct implications for protecting vulnerable populations.

According to Lind, the study has allowed the department to identify policies that are working well and “move into policies that may be working better.”

The Connecticut Department of Correction operates 18 correctional facilities across the state.

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Although levels remain low compared to this time last year, cases across Connecticut have been steadily increasing over the past several weeks. The most recent available CDC data indicate that there were 184 new COVID-19 hospitalizations in Connecticut during the week of Aug. 19, up from 80 weekly hospitalizations at the start of July. 

In New Haven County, according to the CDC, there were 89 new hospitalizations during the week of Aug. 19, a nearly 30-percent increase from the week prior.

“We have seen the same general uptick in cases on campus that have been reported elsewhere, as students travel to campus and gatherings bring people together again,” wrote Madeline Wilson, Yale’s chief campus health officer, in an email to the News. 

But experts believe that COVID-19 cases may be even higher than the newest CDC reports suggest. According to Gregg Gonsalves, an associate professor of epidemiology at the Yale School of Public Health, the hospitalization data is a “lagging indicator,” meaning that the rise in hospitalizations is a delayed measurement of a previous spike in COVID-19 cases.

The current COVID-19 caseload, he explained, is difficult to measure accurately.

“Over the past few weeks we have seen a rise in COVID hospitalizations, which … suggests that there has been a rise in cases preceding these admissions,” Gonsalves wrote in an email to the News. “Since many people are not testing or don’t have the resources to do so, how many cases we have locally [is] hard to discern.”

The difficulty in estimating current COVID-19 cases might be exacerbated by lenient reporting requirements for when people test positive.

According to Choukri Ben-Mamoun, a professor of microbial pathogenesis and pathology at the Yale School of Medicine, at-home, over-the-counter rapid antigen tests are increasingly popular tools to screen for COVID-19. Testing at home, he noted, rather than at certified facilities that are required to report new COVID-19 cases, might be causing a potential underreporting of COVID-19 diagnoses.

An Eris wave

Despite difficulties in estimating COVID-19 numbers, Gonsalves believes that the U.S. is in the midst of a “summer surge” likely driven by new variants of the coronavirus. Notable among these, experts say, is the EG.5 variant of the virus, also known as Eris.

A descendant of the Omicron variant responsible for 20.6 percent of all COVID-19 cases in the U.S, Eris is currently the dominant and fastest-circulating variant of the disease in the country. 

According to Michael Cappello, a professor of epidemiology and infectious diseases at YSPH, new variants like Eris may be more contagious or better at dodging immunity acquired from previous vaccination or infection. Such factors could be driving the uptick in symptomatic  cases.

Because the new variants can more easily evade “short-lived” protection from a previous COVID-19 infection or vaccination, Cappello explained, people might be at greater risk of developing the disease as they become “more relaxed” and less likely to take precautions like wearing a mask and washing their hands.

“The new variants … are potentially more transmissible and perhaps less susceptible to vaccine induced antibodies, but it’s a bit early to know for sure whether they will present a greater risk to the Yale community in terms of severe illness leading to hospitalization,” Cappello wrote to the News. “For now, the current CDC and Yale guidelines are appropriate to follow, but as with any fluid situation, students should remain alert to changes in recommendations.”

In response to the uptick, Yale continues to monitor COVID-19 cases on campus and requests that those who test positive report their result to the University, Wilson told the News. Free rapid antigen tests are also available to students at residential colleges and in designated locations, such as the Yale Bookstore.

In January, Yale Health expanded its infrastructure to create a new Campus Health Office, helmed by Wilson, to coordinate the University’s health response, including vaccination registration. She noted that the University also plans to roll out free COVID-19 and flu vaccines in October, with information about accessing them set to be released after Labor Day.

“Overall levels of immunity on campus are high due to prior vaccination and infection, and we hope that most will take the opportunity to get the updated COVID vaccine and boost immunity further,” Wilson wrote. “While we are vigilant, we feel we are well-equipped to manage the inevitable cases on campus this fall.”

Looking ahead

Public health experts told the News that they expect fall and winter to bring a resurgence of COVID-19, particularly since most mitigation measures have been dropped across the country and at institutions of higher learning.

“COVID is likely seasonal similarly to other respiratory diseases,” Jeffrey Townsend, Elihu Professor of Biostatistics at the School of Public Health, wrote to the News. “As the summer comes to an end, it is likely to begin to increase in prevalence in alignment with other respiratory diseases.” 

Townsend noted that because many people will be over six months from their last COVID-19 booster as winter approaches, they will be at increased risk to variants like Eris. Other factors, such as a reduced reliance on protective measures, such as masking, and frequent gathering in closed-air environments will likely also play a role in this season’s transmission.

However, public health faculty whom the News contacted for comment agreed on the key steps needed to reduce the burden of COVID-19 in the coming months.

Both Cappello and Gonsalves recommended staying up-to-date on vaccinations, getting the next vaccine booster in the coming semester, wearing a mask in crowded indoor spaces and testing for COVID-19 if feeling ill.

“You don’t want COVID. Even if you are young and healthy, risks still remain for you, and … while you may not get seriously ill, we are all one or two degrees of separation from those at higher risk,” Gonsalves said. “Getting through this means getting through this together.” 

Connecticut’s COVID-19 public health emergency declaration ended on May 11, 2023.

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