Tag Archives: National Institutes of Health

NIH Scientists Discover Protein Behind Rare Genetic Skin Disorder

Genome sequencing reveals genetic basis for disabling pansclerotic morphea, a severe inflammatory disease.

Researchers at the National Institutes of Health (NIH) and their colleagues have identified genomic variants that cause a rare and severe inflammatory skin disorder, known as disabling pansclerotic morphea, and have found a potential treatment. Scientists discovered that people with the disorder have an overactive version of a protein called STAT4, which regulates inflammation and wound healing. The work also identified a drug that targets an important feedback loop controlled by the STAT4 protein and significantly improves symptoms in these patients. The results were published in the New England Journal of Medicine.

The study was led by researchers at the National Human Genome Research Institute (NHGRI), part of NIH, in collaboration with researchers from the University of California, San Diego (UCSD) and the University of Pittsburgh. Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases, both part of NIH, also participated in the study.

Only a handful of patients have been diagnosed with disabling pansclerotic morphea, a disorder first described in the medical literature around 100 years ago. The disorder causes severe skin lesions and poor wound healing, leading to deep scarring of all layers of the skin and muscles. The muscles eventually harden and break down while the joints stiffen, leading to reduced mobility. Because the disorder is so rare, its genetic cause had not been identified until now.

“Researchers previously thought that this disorder was caused by the immune system attacking the skin,” said Sarah Blackstone, a predoctoral fellow within NHGRI’s Inflammatory Disease Section, a medical student at the University of South Dakota and co-first author of the study. “However, we found that this is an oversimplification, and that both skin and the immune system play an active role in disabling pansclerotic morphea.”

The researchers used genome sequencing to study four individuals with disabling pansclerotic morphea and found that all four have genomic variants in the STAT4 gene. The STAT4 gene encodes a type of protein that helps turn genes on and off, known as a transcription factor. The STAT4 protein not only plays a role in fighting infections but also controls important aspects of wound healing in the skin.

The scientists found that the STAT4 genomic variants result in an overactive STAT4 protein in these four patients, creating a positive feedback loop of inflammation and impaired wound healing that worsens over time. To stop this harmful feedback loop, they targeted another protein in the inflammatory pathway that interacts with the STAT4 molecule and is called Janus kinase, also known as JAK. When the researchers treated the patients with a JAK-inhibiting drug called ruxolitinib, the patients’ rashes and ulcers dramatically improved.

“So far, there has not been a standard treatment for this disorder because it’s so rare and not well-understood. However, our study gives an important new treatment option for these patients,” said Blackstone.

Existing treatments for disabling pansclerotic morphea are designed to halt the progression of the disorder, but previous therapies have been mostly ineffective, often with severe side effects. People with the disorder typically don’t live more than 10 years after their diagnosis.

The study suggests that ruxolitinib could be an effective treatment for patients with this disorder. Ruxolitinib is part of a broader class of drugs called JAK inhibitors, which are commonly used to treat arthritis, eczema, ulcerative colitis, and other chronic inflammatory diseases.

“The findings of this study open doors for JAK inhibitors to be a potential treatment for other inflammatory skin disorders or disorders related to tissue scarring, whether it is scarring of the lungs, liver, or bone marrow,” said Dan Kastner, M.D., Ph.D., an NIH distinguished investigator, head of NHGRI’s Inflammatory Disease Section and a senior author of the paper.

“We hope to continue studying other molecules in this pathway and how they are altered in patients with disabling pansclerotic morphea and related conditions to find clues to understanding a broader array of more common diseases,” said Lori Broderick, M.D., Ph.D., a senior author of the paper and an associate professor at UCSD.

Reference: “Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome” by Hratch Baghdassarian, B.S., Sarah A. Blackstone, B.S., Owen S. Clay, M.D., Ph.D., Rachael Philips, Ph.D., Brynja Matthiasardottir, M.Sc., Michele Nehrebecky, N.P., Vivian K. Hua, B.S., Rachael McVicar, B.S., Yang Liu, Ph.D., Suzanne M. Tucker, M.D., Davide Randazzo, Ph.D., Natalie Deuitch, M.S., Sofia Rosenzweig, B.S., Adam Mark, M.S., Roman Sasik, Ph.D., Kathleen M. Fisch, Ph.D., Pallavi Pimpale Chavan, M.D., Elif Eren, Ph.D., Norman R. Watts, Ph.D., Chi A. Ma, Ph.D., Massimo Gadina, Ph.D., Daniella M. Schwartz, M.D., Anwesha Sanyal, Ph.D., Giffin Werner, B.S., David R. Murdock, M.D., Nobuyuki Horita, M.D., Ph.D., Shimul Chowdhury, Ph.D., David Dimmock, M.D., Kristen Jepsen, Ph.D., Elaine F. Remmers, Ph.D., Raphaela Goldbach-Mansky, M.D., M.H.S., William A. Gahl, M.D., Ph.D., John J. O’Shea, M.D., Joshua D. Milner, M.D., Nathan E. Lewis, Ph.D., Johanna Chang, M.D., Daniel L. Kastner, M.D., Ph.D., Kathryn Torok, M.D., Hirotsugu Oda, M.D., Ph.D., Christopher D. Putnam, Ph.D. and Lori Broderick, M.D., Ph.D., 31 May 2023, New England Journal of Medicine.
DOI: 10.1056/NEJMoa2202318

COVID-19’s Ripple Effect: The Youth Suicide Surge

A recent study found that suicide rates among US youth aged 5-24 years increased during the COVID-19 pandemic, particularly among males, preteens, young adults, and specific racial and ethnic groups. This highlights disparities that have likely been worsened by the pandemic and underscores the need for targeted suicide prevention efforts.

Suicide is a leading cause of death among young people in the United States. Rates of youth suicide deaths were rising before the coronavirus (COVID-19) pandemic began, so it is critical to understand how the pandemic impacted this public health crisis. In a new study supported by the National Institute of Mental Health, researchers examined national youth suicide trends and characteristics in the United States before and during the COVID-19 pandemic.

A research team led by Jeffrey Bridge, Ph.D., Donna Ruch, Ph.D., and Lisa Horowitz, Ph.D., MPH, analyzed national suicide data from the Centers for Disease Control and Prevention. The researchers first identified all U.S. youth aged 5 to 24 years with suicide listed as the cause of death over the first 10 months of the pandemic (March 1, 2020–December 31, 2020). They calculated the total and monthly suicide deaths overall and by sex, age, race and ethnicity, and suicide method. Then, they examined how many young people died by suicide during the first 10 months of the pandemic and compared it to an estimated number of suicide deaths during that same period had the pandemic not occurred (calculated using data from the previous 5 years).

The researchers identified 5,568 youth who died by suicide during the first 10 months of the pandemic, which was higher than the expected number of deaths had the pandemic not occurred. Higher than expected suicide rates were found a few months into the pandemic, starting in July 2020.

The increase in suicide deaths varied significantly by sex, age, race and ethnicity, and suicide method. During the pandemic, there were higher than expected suicide deaths among males, preteens aged 5–12 years, young adults aged 18–24 years, non-Hispanic American Indian or Alaskan Native youth, and non-Hispanic Black youth as compared to before the pandemic. Suicide deaths involving firearms were also higher than expected.

The significantly higher number of suicide deaths reported for certain racial and ethnic groups, specifically non-Hispanic American Indian or Alaskan Native and non-Hispanic Black youth, highlights ongoing disparities in rates of suicide that the pandemic may have exacerbated. The increase in suicide deaths among preteens also suggests that more attention may need to be paid to this age group, who tend to be understudied in suicide prevention research and have different developmental needs than older adolescents and young adults.

This research is only a first step in examining the pandemic’s impact on youth mental health and points to several areas for further investigation. First, it is possible that other events or factors unrelated to the pandemic that occurred during the study’s time frame contributed to the rise in youth suicide deaths but were unmeasured. Second, research is still needed to identify the underlying causes of the increase in youth suicide deaths, both overall and for specific groups. Third, the COVID-19 pandemic period analyzed in this study was limited to 10 months in 2020 and does not reflect longer-term trends in youth suicide that may have changed as the pandemic wore on. Last, suicide deaths for some groups may have been underreported due to inaccurate or misclassified data; ongoing monitoring of suicide rates will help clarify the suicide risk faced by young people in the United States.

This study shows that the pandemic impacted youth suicide rates, but the impact was not the same for everyone and varied based on sex, age, and race and ethnicity. As such, the authors suggest that it may be helpful to broadly implement suicide prevention efforts in settings that serve young people, while also tailoring those efforts to address the disparities faced by specific groups. Moreover, given the extended duration of the pandemic and its ongoing impact on young people in the United States, it will be important to monitor long-term trends in suicide rates associated with COVID-19 and identify factors driving the increased risk for suicide among some people.

For more on this study, see Youth Suicide Rates Surged During COVID-19 Pandemic.

Reference: “Youth Suicide During the First Year of the COVID-19 Pandemic” by Jeffrey A. Bridge, PhD; Donna A. Ruch, PhD; Arielle H. Sheftall, PhD; Hyeouk Chris Hahm, PhD, LCSW; Victoria M. O’Keefe, PhD; Cynthia A. Fontanella, PhD; Guy Brock, PhD; John V. Campo, MD and Lisa M. Horowitz, PhD, MPH, 15 February 2023, Pediatrics.
DOI: 10.1542/peds.2022-058375

Revolutionizing Pancreatic Cancer Treatment With Personalized mRNA Vaccines

An NIH-funded team from Memorial Sloan Kettering Cancer Center has developed a personalized mRNA cancer vaccine for pancreatic ductal adenocarcinoma (PDAC), in collaboration with BioNTech. The experimental treatment, aimed at triggering T cell activation to fight the specific cancer, showed promising results in preventing cancer recurrence among patients with a strong immune response, paving the way for a larger clinical trial.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is one of the deadliest cancer types. Despite modern therapies, only about 12% of people diagnosed with this cancer will be alive five years after treatment.

Immunotherapies—drugs that help the body’s immune system attack tumors—have revolutionized the treatment of many tumor types. But to date, they have proven ineffective in PDAC. Whether pancreatic cancer cells produce neoantigens—proteins that can be effectively targeted by the immune system—hasn’t been clear.

An NIH-funded research team led by Dr. Vinod Balachandran from Memorial Sloan Kettering Cancer Center (MSKCC) have been developing a personalized mRNA cancer-treatment vaccine approach. It is designed to help immune cells recognize specific neoantigens on patients’ pancreatic cancer cells. Results from a small clinical trial of their experimental treatment were published on May 10, 2023, in Nature.

After surgery to remove PDAC, the team sent tumor samples from 19 people to partners at BioNTech, the company that produced one of the COVID-19 mRNA vaccines. BioNTech performed gene sequencing on the tumors to find proteins that might trigger an immune response. They then used that information to create a personalized mRNA vaccine for each patient. Each vaccine targeted up to 20 neoantigens.

Customized vaccines were successfully created for 18 of the 19 study participants. The process, from surgery to delivery of the first dose of the vaccine, took an average of about nine weeks.

All patients received a drug called atezolizumab before vaccination. This drug, called an immune checkpoint inhibitor, prevents cancer cells from suppressing the immune system. The vaccine was then given in nine doses over several months. After the first eight doses, study participants also started standard chemotherapy drugs for PDAC, followed by a ninth booster dose.

Sixteen volunteers stayed healthy enough to receive at least some of the vaccine doses. In half these patients, the vaccines activated powerful immune cells, called T cells, that could recognize the pancreatic cancer specific to the patient. To track the T cells made after vaccination, the research team developed a novel computational strategy with the lab of Dr. Benjamin Greenbaum at MSKCC. Their analysis showed that T cells that recognized the neoantigens were not found in the blood before vaccination. Among the eight patients with strong immune responses, half had T cells target more than one vaccine neoantigen.

By a year and a half after treatment, the cancer had not returned in any of the people who had a strong T cell response to the vaccine. In contrast, among those whose immune systems didn’t respond to the vaccine, the cancer recurred within an average of just over a year. In one patient with a strong response, T cells produced by the vaccine even appeared to eliminate a small tumor that had spread to the liver. These results suggest that the T cells activated by the vaccines kept the pancreatic cancers in check.

“It’s exciting to see that a personalized vaccine could enlist the immune system to fight pancreatic cancer—which urgently needs better treatments,” Balachandran says. “It’s also motivating as we may be able to use such personalized vaccines to treat other deadly cancers.”

More work is needed to understand why half the people did not have a strong immune response to their personalized vaccines. The researchers are currently planning to launch a larger clinical trial of the vaccine.

Reference: “Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer” by Luis A. Rojas, Zachary Sethna, Kevin C. Soares, Cristina Olcese, Nan Pang, Erin Patterson, Jayon Lihm, Nicholas Ceglia, Pablo Guasp, Alexander Chu, Rebecca Yu, Adrienne Kaya Chandra, Theresa Waters, Jennifer Ruan, Masataka Amisaki, Abderezak Zebboudj, Zagaa Odgerel, George Payne, Evelyna Derhovanessian, Felicitas Müller, Ina Rhee, Mahesh Yadav, Anton Dobrin, Michel Sadelain, Marta Łuksza, Noah Cohen, Laura Tang, Olca Basturk, Mithat Gönen, Seth Katz, Richard Kinh Do, Andrew S. Epstein, Parisa Momtaz, Wungki Park, Ryan Sugarman, Anna M. Varghese, Elizabeth Won, Avni Desai, Alice C. Wei, Michael I. D’Angelica, T. Peter Kingham, Ira Mellman, Taha Merghoub, Jedd D. Wolchok, Ugur Sahin, Özlem Türeci, Benjamin D. Greenbaum, William R. Jarnagin, Jeffrey Drebin, Eileen M. O’Reilly and Vinod P. Balachandran, 10 May 2023, Nature.
DOI: 10.1038/s41586-023-06063-y

Increased Long COVID Risk in Adults With Obstructive Sleep Apnea

Study suggests adults with both the sleep disorder and COVID may benefit from clinical monitoring.

A NIH-backed study reveals a higher risk of developing long COVID among adults with obstructive sleep apnea. The research used data from over 2.2 million COVID-19 patients, showing that sleep apnea patients have up to a 75% higher chance of experiencing long COVID, with the risk being greater among women. Despite controlling for various factors, the association remains significant. The reasons for this link are still uncertain.

Among people who have had COVID-19, adults with obstructive sleep apnea were more likely to experience long-term symptoms suggestive of long COVID than those without the sleep disorder, according to a large study supported by the National Institutes of Health (NIH). In fact, multiple analyses of electronic health records (EHR) identified adults with sleep apnea may have up to a 75% higher risk of developing long COVID. The findings, part of the NIH’s Researching COVID to Enhance Recovery (RECOVER) Initiative, published in the journal SLEEP.

The research, which came from EHR data of more than 2.2 million Americans with COVID-19, suggests close monitoring after a COVID-19 infection may help adults with sleep apnea. The findings may also strengthen understanding of why some people are more likely to develop long COVID after acute infection.

“We still have a lot to learn about the long-term effects of this virus, but this study could inform clinical care by identifying patients who may benefit from closer monitoring,” said Marishka K. Brown, Ph.D., director of the National Center on Sleep Disorders Research at the National Heart, Lung, and Blood Institute (NHLBI).

“People with obstructive sleep apnea should also keep up with their vaccinations to minimize the risk of infection,” said Lorna E. Thorpe, Ph.D., M.P.H., the study’s senior author and director of the Division of Epidemiology in the Department of Population Health at New York University’s Grossman School of Medicine, New York City.

The data for this analysis came from three RECOVER EHR research networks: the National COVID Cohort Collaborative (N3C), which included 1.7 million adults; PCORnet®, which included 330,000 adults; and PEDSnet, a pediatric-focused research network participating in PCORnet, which included 102,000 children. All participants included in this analysis had tested positive for COVID-19 between March 2020 and February 2022.

Within each network, researchers used diagnostic codes from EHRs to identify participants who had obstructive sleep apnea, which occurred among 5% of adults and less than 2% of children. They also used machine learning to assess follow-up symptoms and medical visits to determine which people likely had long COVID. About 5% of adults in the N3C study, 17% of adults in PCORnet, and less than 5% of children in PEDSnet were suspected to have developed long COVID.

After controlling for similarities among patients, including COVID-19 severity, age, sex, race and ethnicity, and underlying medical conditions, researchers found adults with obstructive sleep apnea in N3C, the largest study, were 75% more likely to experience long COVID. For adults in PCORnet, the increased odds of having long COVID was 12%. No significant links between sleep apnea and long COVID in children were found after researchers controlled for other medical conditions, including obesity.

A follow-up analysis with additional patients confirmed these associations – showing a link between obstructive sleep apnea and increased odds for long COVID in adults.

“Part of the challenge is that many of the risk factors for sleep apnea are also risk factors for COVID-19 outcomes,” said Thorpe. “We don’t know entirely why we are seeing this association.”

The researchers also found women in the N3C study had an 89% increased likelihood of having long COVID if they had obstructive sleep apnea, compared to a 59% increased chance for men. The underlying associations aren’t clear. However, women diagnosed with obstructive sleep apnea included in this study may have had more severe conditions than men. Severity of obstructive sleep apnea was not controlled for, but sleep apnea is more likely to be undiagnosed in women – which could create a sample with women who have more severe cases. Other studies have also found that women may be more likely to be diagnosed with long COVID and seek health care for the condition.

Long COVID is an umbrella term for one or more symptoms that people can experience for weeks, months, or years after a COVID-19 infection. Multiple definitions were included in this review. The Centers for Disease Control and Prevention defines long COVID as symptoms that last for at least four weeks after infection, while the World Health Organization defines long COVID as symptoms that persist for at least three months.

Obstructive sleep apnea occurs when the upper airway becomes blocked during sleep, which interrupts breathing. The condition affects about 1 in 8 adults but is often underdiagnosed.

For more on this research, see Sleep Apnea Linked With Increased Long COVID Risks.

Reference: “Risk of post-acute sequelae of SARS-CoV-2 infection associated with pre-coronavirus disease obstructive sleep apnea diagnoses: an electronic health recordbased analysis from the researching coronavirus disease to enhance recovery initiative” by Hannah L Mandel, Gunnar Colleen, Sajjad Abedian, Nariman Ammar, L Charles Bailey, Tellen D Bennett, M Daniel Brannock, Shari B Brosnahan, Yu Chen, Christopher G Chute, Jasmin Divers, Michael D Evans, Melissa Haendel, Margaret A Hall, Kathryn Hirabayashi, Mady Hornig, Stuart D Katz, Ana C Krieger, Johanna Loomba, Vitaly Lorman, Diego R Mazzotti, Julie McMurry, Richard A Moffitt, Nathan M Pajor, Emily Pfaff, Jeff Radwell, Hanieh Razzaghi, Susan Redline, Elle Seibert, Anisha Sekar, Suchetha Sharma, Tanayott Thaweethai, Mark G Weiner, Yun Jae Yoo, Andrea Zhou and Lorna E Thorpe on behalf of the RECOVER Consortium, 11 May 2023, Sleep.
DOI: 10.1093/sleep/zsad126

The study was funded by RECOVER (OT2HL161847) and received additional support from the National Center for Advancing Translational Sciences (UL1TR002494).

The National Institutes of Health Researching COVID to Enhance Recovery (NIH RECOVER) Initiative is a $1.15 billion effort, including support through the American Rescue Plan Act of 2021, that seeks to identify how people recuperate from a COVID-19 infection, and who are at risk for developing post-acute sequelae of SARS-CoV-2 (PASC). Researchers are also working with patients, clinicians, and communities across the United States to identify strategies to prevent and treat the long-term effects of COVID – including long COVID.

Decoding Long COVID: NIH Study Exposes the Inner Workings of Neurological Symptoms

Findings offer insight into biological mechanisms, pointing to possible treatments.

An NIH study on twelve Long COVID patients found differences in immune cell profiles and autonomic dysfunction, contributing to the understanding of the condition and potentially leading to better diagnoses and new treatments.

Twelve people with persistent neurological symptoms after SARS-CoV-2 infection were intensely studied at the National Institutes of Health (NIH) and were found to have differences in their immune cell profiles and autonomic dysfunction. These data inform future studies to help explain persistent neurological symptoms in Long COVID. The findings, published in Neurology: Neuroimmunology & Neuroinflammation, may lead to better diagnoses and new treatments.

People with post-acute sequelae of COVID-19 (PASC), which includes Long COVID, have a wide range of symptoms, including fatigue, shortness of breath, fever, headaches, sleep disturbances, and “brain fog,” or cognitive impairment. Such symptoms can last for months or longer after an initial SARS-CoV-2 infection. Fatigue and “brain fog” are among the most common and debilitating symptoms, and likely stem from nervous system dysfunction.

Researchers used an approach called deep phenotyping to closely examine the clinical and biological features of Long COVID in 12 people who had long-lasting, disabling neurological symptoms after COVID-19. Most participants had mild symptoms during their acute infection. At the NIH Clinical Center, participants underwent comprehensive testing, which included a clinical exam, questionnaires, advanced brain imaging, blood and cerebrospinal fluid tests, and autonomic function tests.

The results showed that people with Long COVID had lower levels of CD4+ and CD8+ T cells—immune cells involved in coordinating the immune system’s response to viruses—compared to healthy controls. Researchers also found increases in the numbers of B cells and other types of immune cells, suggesting that immune dysregulation may play a role in mediating Long COVID.

Consistent with recent studies, people with Long COVID also had problems with their autonomic nervous system, which controls unconscious functions of the body such as breathing, heart rate, and blood pressure. Autonomic testing showed abnormalities in control of vascular tone, heart rate, and blood pressure with a change in posture. More research is needed to determine if these changes are related to fatigue, cognitive difficulties, and other lingering symptoms.

Taken together, the findings add to growing evidence that widespread immunological and autonomic nervous system changes may contribute to Long COVID. The results may help researchers better characterize the condition and explore possible therapeutic strategies, such as immunotherapy.

Reference: “Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection” by Yair Mina, Yoshimi Enose-Akahata, Dima A. Hammoud, Anthony J. Videckis, Sandeep R. Narpala, Sarah E. O’Connell, Robin Carroll, Bob C. Lin, Cynthia Chen McMahan, Govind Nair, Lauren B. Reoma, Adrian B. McDermott, Brian Walitt, Steven Jacobson, David S. Goldstein, Bryan R. Smith and Avindra Nath, 5 May 2023, Neurology: Neuroimmunology & Neuroinflammation.
DOI: 10.1212/NXI.0000000000200097

The study was supported by the Intramural Research Program at the National Institute of Neurological Disorders and Stroke (NINDS) and is part of an observational study taking place at the NIH Clinical Center designed to characterize changes in the brain and nervous system after COVID-19 (NCT04564287).

This work is a part of the National Research Action Plan, a broader government-wide effort in response to the Presidential Memorandum directing the Secretary for the Department of Health and Human Services to mount a full and effective response to Long COVID. Led by Assistant Secretary for Health Admiral Rachel Levine, the Plan and its companion Services and Supports for Longer-term Impacts of COVID-19 report lay the groundwork to advance progress in prevention, diagnosis, treatment, and provision of services for individuals experiencing Long COVID.

New Details on Rare Immune Disease Uncovered by NIH Researchers in 11-Year Study

NIH researchers characterize ICL, a rare immune deficiency, linking severe cases to higher risk of infections and cancers.

In an 11-year study, researchers at the National Institutes of Health (NIH) have further characterized idiopathic CD4 lymphocytopenia (ICL), a rare immune deficiency that leaves people vulnerable to infectious diseases, autoimmune diseases, and cancers. Researchers observed that people with the most severe cases of ICL had the highest risk of acquiring or developing several of the diseases associated with this immune deficiency. This study, published on May 4 in the New England Journal of Medicine, was led by Irini Sereti M.D., M.H.S. and Andrea Lisco, M.D., Ph.D. of the HIV Pathogenesis Section in the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious diseases (NIAID), part of NIH, and conducted at the NIH Clinical Center.

ICL is a condition marked by too few CD4+ T-cells, which are a type of white blood cell. The clinical definition of ICL is a CD4+ T-cell count of less than 300 cells per cubic millimeter (mm³) of blood for at least six weeks, in the absence of any disease or therapy associated with reduced white blood cells. Unlike HIV, a virus that suppresses the immune system if left untreated, there is no evidence that ICL is transmitted from person to person, and it has no known cause. There are limited therapeutic options for ICL.

In this observational study, the NIAID researchers quantified immune cells and noted the presence of opportunistic infections—infections that typically only affect people with suppressed immune systems—and other clinical conditions among 91 participant volunteers with ICL. The most prevalent opportunistic infections were human papillomavirus-related diseases (in 29% of participants), cryptococcosis (24%), molluscum contagiosum (9%), and mycobacterial diseases other than tuberculosis (5%). Participants with CD4+ T-cell counts below 100 cells per mm³ had a more than five-fold higher risk of opportunistic infections than those with CD4+ T-cell counts above 100 cells. Cancer risk was also higher in individuals with the lowest CD4+ T-cell counts, but the risk of autoimmune disease was lower.

These findings further support the inverse correlation between CD4+ T-cell count and susceptibility to viral, fungal, and mycobacterial infections, as well as certain cancers, according to the authors. NIAID continues to pursue research on the natural history of rare conditions such as ICL to understand disease progression, as well as potential therapeutic interventions.

“Reappraisal of Idiopathic CD4 Lymphocytopenia at 30 Years” by Andrea Lisco, M.D., Ph.D., Ana M. Ortega-Villa, Ph.D., Harry Mystakelis, M.D., M.H.S., Megan V. Anderson, R.N., B.A., Allyson Mateja, M.S.P.H., Elizabeth Laidlaw, P.A.-C., Maura Manion, M.D., Gregg Roby, R.N., B.S., Jeanette Higgins, Ph.D., Safia Kuriakose, Pharm.D., Magdalena A. Walkiewicz, Ph.D., Morgan Similuk, Sc.M., Jennifer W. Leiding, M.D., Alexandra F. Freeman, M.D., Virginia Sheikh, M.D. and Irini Sereti, M.D., M.H.S., 4 May 2023. New England Journal of Medicine.
DOI: 10.1056/NEJMoa2202348

Andrea Lisco, M.D., Ph.D. is an assistant clinical investigator in the HIV Pathogenesis Section of NIAID’s Laboratory of Immunoregulation, and Irini Sereti, M.D., M.H.S. is chief of the HIV Pathogenesis section. 

NIH Research: Antibiotic Can Help Prevent Common Sexually Transmitted Diseases

A study by scientists at UCSF and the University of Washington reveals that doxycycline post-exposure prophylaxis (doxy-PEP) can reduce the incidence of certain sexually transmitted infections (STIs) by two-thirds in high-risk individuals. However, the study also found a slight increase in antibiotic-resistant bacteria in the doxy-PEP group, indicating a need to weigh the benefits of STI reduction against potential antibiotic resistance.

Sexually transmitted infections (STIs), such as chlamydia, syphilis, and gonorrhea, have been on the rise nationwide. They disproportionally affect men who have sex with men and transgender women. Left untreated, they can lead to serious health issues, such as blindness, brain and nerve problems, and infertility in women. Condoms can block many STIs. But condoms are not always used consistently or correctly. So researchers have been exploring other options for preventing STIs, especially among those at elevated risk for repeated infections.

Previous studies found evidence that the antibiotic doxycycline, taken shortly after sex, might reduce the risk of bacterial STIs among men who have sex with men. This approach is called doxycycline postexposure prophylaxis, or doxy-PEP. But some experts have been concerned that preventive use of antibiotics could lead to antibiotic resistance. This might reduce future options for treating STIs and other bacterial infections.

To learn more, a team led by scientists at the University of California, San Francisco (UCSF) and the University of Washington, Seattle, set out to measure the safety and effectiveness of doxy-PEP. They also looked for evidence of antibiotic resistance. Results were published in the New England Journal of Medicine on April 6, 2023.

The study enrolled 501 adults considered at high risk for bacterial STIs, either men who had sex with men or transgender women. All had been diagnosed with a bacterial STI in the past year and reported having sex without using a condom in the past year. They were either living with HIV or were taking or planning to take medication to prevent HIV infection.

Participants were randomly assigned to receive either doxy-PEP or standard care. Those in the doxy-PEP group were told to take a 200 mg doxycycline tablet as soon as possible within 72 hours after condomless sex. Participants were tested for STIs every three months and followed for one year.

The researchers found that the doxy-PEP group had a two-thirds lower incidence of syphilis, gonorrhea, and chlamydia compared to the standard-care group during each three-month time period. STIs were detected in about 10% of the quarterly tests administered to those in the doxy-PEP group, compared to about 30% of those in the standard-care group.

Gonorrhea was the most often diagnosed STI. The incidence of gonorrhea per quarter in the doxy-PEP group was about 55% lower than in the standard-care group. Chlamydia and syphilis were each reduced by more than 80% per quarter.

The researchers found that the doxy-PEP group had a modestly higher proportion of doxycycline-resistant Staphylococcus aureus living in the nose after 12 months. And the incidence of gonorrhea strains resistant to the antibiotic tetracycline, which is in the same antibiotic class as doxycycline, was 38.5% in the doxy-PEP group compared to 12.5% in the group with standard care. This finding suggests doxy-PEP could be less effective in preventing gonorrhea with existing tetracycline resistance; however, the number of available gonorrhea cultures was low.

“It will be important to monitor the impact of doxy-PEP on antimicrobial resistance patterns over time, and weigh this against the demonstrated benefit of reduced STIs and associated decreased antibiotic use for STI treatment in men at elevated risk for recurrent STIs,” says Dr. Annie Luetkemeyer of UCSF, a co-leader of the study. “Given its demonstrated efficacy in several trials, doxy-PEP should be considered as part of a sexual health package for men who have sex with men and transwomen if they have an increased risk of STIs.”

Reference: “Postexposure Doxycycline to Prevent Bacterial Sexually Transmitted Infections” by Anne F. Luetkemeyer, M.D., Deborah Donnell, Ph.D., Julia C. Dombrowski, M.D., M.P.H., Stephanie Cohen, M.D., M.P.H., Cole Grabow, M.P.H., Clare E. Brown, Ph.D., Cheryl Malinski, B.S., Rodney Perkins, R.N., M.P.H., Melody Nasser, B.A., Carolina Lopez, B.A., Eric Vittinghoff, Ph.D., Susan P. Buchbinder, M.D., Hyman Scott, M.D., M.P.H., Edwin D. Charlebois, Ph.D., M.P.H., Diane V. Havlir, M.D., Olusegun O. Soge, Ph.D. and Connie Celum, M.D., M.P.H. for the DoxyPEP Study Team, 6 April 2023, New England Journal of Medicine.
DOI: 10.1056/NEJMoa2211934

Funding: NIH’s National Institute of Allergy and Infectious Diseases (NIAID).

The Mucus Miracle: How Mucosal Vaccines Could Revolutionize COVID-19 Fight

A virtual workshop in November 2022 highlighted the importance of developing mucosal vaccines for SARS-CoV-2 that could reduce transmission and infection. Participants discussed challenges and priorities, such as identifying protection correlates, improving animal models, and determining delivery methods. Though no COVID-19 mucosal vaccines have been authorized in the US or Europe, the workshop concluded that research in this area could yield benefits for both COVID-19 and other diseases.

In November 2022, the National Institute of Allergy and Infectious Diseases (NIAID) co-hosted a virtual workshop on the importance and challenges of developing mucosal vaccines for SARS-COV-2. The highlights of this workshop have now been published as a report in npj Vaccines.

Although vaccines currently available for COVID-19 are usually effective at preventing severe disease, hospitalizations and death, researchers recognize the need for improvement. A vaccine more effective at preventing transmission or infection with SARS-CoV-2 could reduce overall replication of the virus and associated disease burden. Because SARS-CoV-2 enters the body and is transmitted via the respiratory tract, a vaccine to promote a mucosal immune response in the respiratory tract could be better at blocking transmission and infection. Although at least 44 mucosal vaccines are currently in preclinical development, and several more are in clinical development or authorized for use in other countries, no COVID-19 mucosal vaccines have been authorized for use by regulatory agencies in the United States or Europe. 

NIAID partnered with the Coalition for Epidemic Preparedness Innovation, the Bill and Melinda Gates Foundation, the Biomedical Advanced Research and Development Authority, and the Wellcome Trust to develop the workshop. Over the course of the two-day event (November 7-8 2022), vaccine researchers and developers met virtually in eight sessions and discussed challenges and priorities in mucosal vaccine development. 

For instance, new correlates of protection must be identified and verified to evaluate whether a vaccine improves recipients’ mucosal immune responses to SARS-CoV-2, and to facilitate clinical testing and regulatory approval. Improved animal models are needed to help researchers develop potential mucosal vaccines, according to the report. Careful clinical design is needed to assess the unique safety concerns related to mucosal vaccines and to appropriately evaluate whether a vaccine can block transmission of the virus. Trial design also needs to account for how vaccines will be used. Since most people have either received a SARS-CoV-2 vaccine or had a natural infection, mucosal vaccines likely will be used as boosters, and researchers will need to know how well vaccines function in people who have some prior immunity. The means of delivery also must be considered: nasal sprays, pills, liquids taken by mouth, and even nebulizers could deliver a vaccine more directly to the respiratory system, but each of these poses unique challenges to manufacture, test and deliver. 

Despite these and other challenges, attendees of the workshop were optimistic about the future of mucosal vaccines for COVID-19. Considering the potential benefits that a successful candidate could bring, they concluded that research needed to further mucosal vaccine development is a priority. Such research also could even lead to improved vaccines for other diseases, such as influenza, respiratory syncytial virus (RSV) or tuberculosis, in addition to advancing COVID-19 vaccinology.

Reference: “Mucosal vaccines for SARS-CoV-2: scientific gaps and opportunities—workshop report” by Jane M. Knisely, Lucas E. Buyon, Rebecca Mandt, Rebecca Farkas, Shobana Balasingam, Karin Bok, Ursula J. Buchholz, M. Patricia D’Souza, Jennifer L. Gordon, Deborah F. L. King, Tung T. Le, Wolfgang W. Leitner, Robert A. Seder, Alkis Togias, Stig Tollefsen, David W. Vaughn, Daniel N. Wolfe, Kimberly L. Taylor and Anthony S. Fauci, 12 April 2023, npj Vaccines.
DOI: 10.1038/s41541-023-00654-6

New Clinical Trial Reveals: Cutting Just One Food Can Treat Eosinophilic Esophagitis

A clinical trial funded by the National Institutes of Health has found that eliminating just animal milk from the diet of adults with eosinophilic esophagitis (EoE) is as effective in treating the condition as eliminating animal milk and five other common foods. The researchers noted that for individuals with EoE whose disease persists even after avoiding animal milk, a stricter diet may assist them in achieving remission. These results were recently published in the journal The Lancet Gastroenterology & Hepatology.

“Diet-based therapy for eosinophilic esophagitis will be much easier to follow for many people if it involves cutting just one food from the diet rather than six,” said Hugh Auchincloss, M.D., acting director of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH.

EoE is a chronic disease characterized by an overabundance of white blood cells called eosinophils in the esophagus. Allergic inflammation due to food drives the disease by damaging the esophagus and preventing it from working properly. For people with EoE, swallowing even small amounts of food can be a painful and stressful choking experience. About 160,000 people in the United States are living with EoE.

Excluding certain foods from the diet has been a cornerstone of EoE treatment. During the early 2000s, researchers found that eliminating six common food triggers of esophageal injury—milk, egg, wheat, soy, fish, and nuts—substantially reduced signs and symptoms of EoE. This six-food elimination diet (6FED) became a common approach to managing the disease.

In recent years, scientists have conducted small, non-randomized studies of removing one to four of the most common food antigens from the diet to treat EoE, with some success. However, the relative risks and benefits of eliminating many foods versus a few foods at the start of diet-based therapy remained unclear.

The new findings come from the first multi-site, randomized trial comparing the 6FED with a one-food elimination diet (1FED) in adults with EoE. The trial was co-funded by NIAID, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases, all part of NIH. Marc E. Rothenberg, M.D., Ph.D., the senior author of the published study, is director of both the Division of Allergy and Immunology and the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s.

The trial involved 129 adults ages 18 to 60 years with a confirmed EoE diagnosis, active EoE symptoms, and a high number of eosinophils in esophageal tissue. Volunteers enrolled in the trial at one of 10 U.S. medical centers that participate in the Consortium of Eosinophilic Gastrointestinal Disease Researchers, part of the NIH-funded Rare Diseases Clinical Research Network. Participants were assigned at random to either the 1FED, which eliminated only animal milk from the diet, or the 6FED.

They followed their assigned diet for six weeks, then underwent an upper endoscopy exam and an esophageal tissue biopsy. If the number of eosinophils in the tissue indicated that EoE was in remission, the participant exited the study. If EoE was not in remission, people who had been on 1FED could advance to 6FED, and people who had been on 6FED could take topical swallowed steroids, both for six weeks, followed by a repeat exam with tissue biopsy.

The investigators found that 34% of participants on 6FED and 40% of participants on 1FED achieved remission after six weeks of diet therapy, a difference that was not statistically significant. The two diets also had a similar impact across several other measures, including a reduction in EoE symptoms and an effect on quality of life. Thus, 1FED and 6FED were equally effective at treating EoE, an unexpected finding.

The researchers also discovered that nearly half of the people who did not respond to 1FED attained remission after treatment with the more restrictive 6FED, while more than 80% of the non-responders to 6FED achieved remission with oral steroids.

Taken together, the investigators conclude that 1FED is a reasonable first-line diet therapy option in adults with EoE, and that effective therapies are available for people who do not achieve remission after 1FED or 6FED.

Reference: “One-food versus six-food elimination diet therapy for the treatment of eosinophilic oesophagitis: a multicentre, randomised, open-label trial” by Kara L Kliewer, Nirmala Gonsalves, Evan S Dellon, David A Katzka, Juan P Abonia, Seema S Aceves, Nicoleta C Arva, John A Besse, Peter A Bonis, Julie M Caldwell, Kelley E Capocelli, Mirna Chehade, Antonella Cianferoni, Margaret H Collins, Gary W Falk, Sandeep K Gupta, Ikuo Hirano, Jeffrey P Krischer, John Leung, Lisa J Martin and Marc E Rothenberg, 28 February 2023, The Lancet Gastroenterology & Hepatology.
DOI: 10.1016/S2468-1253(23)00012-2

The study was funded by the National Institute of Allergy and Infectious Diseases.

Study Finds Temperature-Stable Tuberculosis (TB) Vaccine Safe and Effective

A clinical trial testing a freeze-dried, temperature-stable experimental tuberculosis (TB) vaccine in healthy adults found that it was safe and stimulated both antibodies and responses from the cellular arm of the immune system. The Phase 1 trial was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. A non-temperature stable form of the candidate previously had been tested in several clinical trials. However, this was the first clinical trial of any subunit TB vaccine candidate in a temperature-stable (thermostable) form. Results will be published today (March 6, 2023) in the journal Nature Communications.

The experimental vaccine, ID93+GLA-SE, was developed by Christopher B. Fox, Ph.D., and scientists at the Access to Advanced Health Institute (formerly the Infectious Disease Research Institute) in Seattle. It is a recombinant subunit vaccine made from four proteins of Mycobacterium tuberculosis bacteria combined with GLA-SE, an immune-stimulating adjuvant. The freeze-dried formulation does not require refrigeration and is mixed with sterile water just prior to injection. Thermostable vaccines are desirable in settings where maintaining cold or frozen vaccines for long periods can be costly and difficult. 

The current trial investigated whether administering temperature-stable vaccine containing both ID93 and GLA-SE in a single vial would be as effective at inducing an immune response as a regimen in which non-thermostable ID93 and liquid GLA-SE are held in two vials and combined prior to injection. A single-vial presentation of a thermostable vaccine would have clear advantages in ease of storage, transport and administration, the investigators note.

Daniel F. Hoft, M.D., Ph.D., director of the Saint Louis University Center for Vaccine Development, led the single-site trial at the university’s School of Medicine. Twenty-three participants received the thermostable single-vial regimen, while 22 participants received the two-vial, non-thermostable regimen. Both vaccine presentations were safe and well-tolerated. Recipients of the single-vialled thermostable vaccine had robust T-cell responses and produced higher levels of antibodies in the blood than those receiving the non-thermostable two-vial presentation. 

The investigators note some limitations in this small trial. For example, no established correlates of protection define what immune responses are required for vaccine-induced protection from TB disease. Therefore, it is not possible to say whether the enhanced immune responses seen in the thermostable vaccine formulation would translate to improved protective vaccine efficacy. Nevertheless, they conclude, results of this trial demonstrate “a proof-of-concept that adjuvant-containing vaccines can be formulated in a freeze-dried single-vial presentation without detrimentally impacting clinical immunogenicity or safety characteristics.” 

Reference: “Safety and immunogenicity of a thermostable formulation of the ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults” by ZK Sagawa et al., 6 March 2023, Nature Communications.
DOI: 10.1038/s41467-023-36789-2