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Tag: National Institute of Allergy and Infectious Diseases (NIAID)

  • Virginia Tech awarded grant to study lingering Lyme disease symptoms

    Virginia Tech awarded grant to study lingering Lyme disease symptoms

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    Newswise — An estimated 1,200 Americans, on average, are diagnosed with Lyme disease each day. Some of those patients continue to experience negative effects, even after treatment.

    Lyme disease researcher Brandon Jutras, associate professor in the College of Agriculture and Life Sciences and affiliated faculty of the Fralin Life Sciences Institute, recently received a $2.7 million grant from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, to study what causes the disease to linger long after treatment.

    “Using a series of sophisticated molecular techniques, in combination with both bacterial and host genetics, we’re working to understand why and how some patients respond to therapy, while others do not,” said Jutras, the lead investigator in the Department of Biochemistry and an affiliate faculty member in the Center for Emerging, Zoonotic, and Arthropod-borne Pathogens. “Our two-pronged approach looks at this problem from both sides: What unique chemical features of the bacterium’s cell wall are responsible for causing symptoms and what genetic factors from the host-response side play a role in sustained pathology”.

    Previously, Jutras discovered that:

    This research builds upon the previous discoveries and will determine what about the cell wall makes patients sick and define new strategies, such as monoclonal antibody therapy, to improve Lyme disease patient health when previous treatments have failed.

    “We recognize this is an issue and that patients have these long-term symptoms, but we don’t know why,” said Mecaila McClune, who is a key member of the research team and a graduate student in the Jutras lab. “This is what my research is trying to determine what’s going on and how we can treat the persistent effects of the disease, which will improve quality of life going forward.”

    These new studies were facilitated by earlier support from the Global Lyme Alliance and Bay Area Lyme Foundation and continue an active collaboration with GlycoMIP, and both the University of Virginia and the Medical College of Wisconsin.

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    Virginia Tech

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  • “COVID rebound” is common, even in untreated patients

    “COVID rebound” is common, even in untreated patients

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    Newswise — LA JOLLA, CA—“COVID rebound,” in which evidence of the illness disappears and then returns days or weeks later, is surprisingly common—whether or not patients are given the antiviral Paxlovid.

    The results, reported on February 22 in Clinical Infectious Diseases by scientists at Scripps Research and the digital health company eMed, are a preliminary readout from an ongoing observational study of people who order SARS-CoV-2 antigen test kits online. The researchers found that in an initial group of 170 eMed Test-to-Treat™ kit users, the disappearance and then return of evidence of the virus on antigen tests and in self-reported COVID-19 symptoms occurred in 9.3% and 7.0% of patients who opted not to take antiviral treatment, and in 14.2% and 18.9% of those who opted for Paxlovid.

    Although a higher proportion of the Paxlovid-treated group reported COVID-19 rebound, the difference was not statistically significant in this early snapshot of the ongoing study, which is designed ultimately to enroll a total of 800 patients.

    “These preliminary results suggest that rebound after clearance of SARS-CoV-2 test positivity or COVID-19 symptom resolution is more common than previously reported in both treated and untreated patients,” says study lead author Jay Pandit, MD, an assistant professor and director of Digital Medicine at the Scripps Research Translational Institute. “We’re going to need a larger set of participants and more extended follow-up to better understand this rebound phenomenon.”

    The study, conducted from August to November of last year, was a collaboration with eMed, including epidemiologist and Chief Science Officer Michael Mina, MD, PhD, previously professor at Harvard T.H. Chan School of Public Health, and others at the Test-to-Treat company, which is also implementing the NIH Home Test to Treat COVID-19 program.

    Reports of COVID-19 rebound started appearing in the medical literature in 2022. The cause of rebound has been unclear, although the suggestion in most of these reports has been that rebound occurs more often in patients treated with Paxlovid. The latter, a mix of two antiviral compounds (nirmatrelvir and ritonavir), received emergency use approval in late 2021 from the U.S. Food and Drug Administration (FDA) for treating patients who have mild-to-moderate COVID-19 and are at high risk of developing severe COVID-19.

    To help illuminate the rebound phenomenon and any connection to Paxlovid, Pandit and his colleagues teamed up with eMed to drive a “real-world” study of outcomes among people using the company’s COVID-19 Test-to-Treat antigen test kits with telehealth proctoring and telemedicine.

    “As the COVID-19 landscape continues to evolve, the importance of making timely and effective treatments accessible and thereby helping reduce severe disease outcomes cannot be overstated,” Mina says. “Collaborations such as this with the Scripps Research Translation Institute are a key part of efforts to gather evidence-based data and answer critical questions associated with treatment outcomes. We are also proud that this study not only offers new data surrounding COVID-19 recovery and treatment outcomes, but also highlights the benefits of industry and academic partnerships to accelerate high-quality public health and translational research.”

    The researchers offered Test-to-Treat telehealth kit users participation in the study if they had a verified positive test. If users consented to participate, the researchers sent them more test kits, and asked each participant to take a test and fill out a symptom questionnaire every other day for 16 days. The team then compared the rates of rebound for those who did and didn’t opt to take Paxlovid. Rebound was measured in two ways: a positive test result after a negative test, or a reported recurrence of symptoms after symptom resolution. For this preliminary analysis, there were 127 people in the Paxlovid-treated group, and 43 in the non-Paxlovid group.

    Either way rebounds were measured, the Paxlovid group experienced them at a higher rate: 14.2% vs. 9.3% for antigen test rebounds, and 18.9% vs. 7.0% for symptom rebounds. With the small participant numbers included in this preliminary analysis, these differences were not statistically significant. Moreover, on other measures (such as the time from first positive antigen test to first negative antigen test, and time from symptom onset to first symptom resolution), the two groups had essentially identical outcomes. Age, gender and pre-existing conditions also did not appear to influence rebound.

    Pandit emphasizes that the study is not currently powered to detect statistically significant results, and a final analysis should include up to 800 participants and thus should have much more power to generate conclusive findings. However, he adds, the preliminary findings already make clear that the rebound rates for both treated and untreated groups are higher than the rates reported in prior studies. For example, an analysis of their clinical trial results by Pfizer, the maker of Paxlovid, found rebound rates of only about 2% in both Paxlovid and placebo groups over a two-week period.

    In addition to increasing the number of participants in their ongoing study, Pandit and colleagues plan to start sequencing the virus found in participants and testing participants’ blood samples for antibody levels and other immune markers.

    “We’re hoping to answer key questions about the rebound phenomenon, such as whether it’s enhanced by Paxlovid, how much it depends on the viral variant and what is the role of the patient’s immune system,” Pandit says.

    He and his team also plan to improve the balance of ethnic and racial representation between the treatment and control groups: In the initial group of 170, Whites were much more likely than Blacks and Latinos to opt for Paxlovid treatment.

    “The COVID-19 Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences in Participants Treated with Nirmatrelvir Plus Ritonavir Versus Untreated Controls” was co-authored by Jay Pandit, Jennifer Radin, Danielle Chiang, Emily Spencer, Jeff Pawelek, Mira Diwan, Leila Roumani and Michael Mina.

    Support for the study was provided by eMed, the National Institute of Allergy and Infectious Diseases (3U01AI151812-03S2), and the National Center for Advancing Translational Sciences (NCATS UL1 TR002550).

    About Scripps Research

    Scripps Research is an independent, nonprofit biomedical institute ranked one of the most influential in the world for its impact on innovation by Nature Index. We are advancing human health through profound discoveries that address pressing medical concerns around the globe. Our drug discovery and development division, Calibr, works hand-in-hand with scientists across disciplines to bring new medicines to patients as quickly and efficiently as possible, while teams at Scripps Research Translational Institute harness genomics, digital medicine and cutting-edge informatics to understand individual health and render more effective healthcare. Scripps Research also trains the next generation of leading scientists at our Skaggs Graduate School, consistently named among the top 10 US programs for chemistry and biological sciences. Learn more at www.scripps.edu.

    About eMed

    eMed® is a leader in proctored at-home health diagnostics, using digital technology to bring affordable diagnostic testing, medical screening, and treatment for the most common ailments. With more than 3.7 million customers since its fall 2020 launch, eMed has proven effective and reliable. eMed® Telehealth Kits™ make it easy for consumers to test and screen at home with the guidance of trained Telehealth Proctors and access prescriptions at no additional cost—reducing the time to initiate treatment and improving access to care. The company is revolutionizing the healthcare industry with the first-of-its-kind at-home Test-to-Treat™ solution, an innovative, efficient, and cost-effective way for consumers to have more control over their healthcare at home. Learn more at www.eMed.com.

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    Scripps Research Institute

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  • CHOP Researchers Identify Molecules that Optimize Immune Presentation of Antigens across the Human Population

    CHOP Researchers Identify Molecules that Optimize Immune Presentation of Antigens across the Human Population

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    Newswise — Philadelphia, February 24, 2023—Researchers at Children’s Hospital of Philadelphia (CHOP) have identified variants of a chaperone molecule that optimizes the binding and presentation of foreign antigens across the human population, which could open the door to numerous applications where robust presentation to the immune system is important, including cell therapy and immunization. The findings were published today in Science Advances. 

    Class I major histocompatibility complex (MHC-I) proteins are found on the surface of cells from all jawed vertebrates and play an essential role in the immune system. The MHC-I displays peptide fragments of proteins from within the cell on the cell surface, effectively “presenting” them to the immune system, which is constantly scanning the body for foreign or toxic antigens. When foreign peptides are identified, they trigger a cascade that allows cytotoxic T cells to eliminate intruders.

    For a peptide to be presented to the immune system, it needs to be loaded on a folded MHC-I protein. Several molecules facilitate this process, including proteins known as molecular chaperones, which assist with MHC-I folding. Tapasin and a similar molecule known as TAPBPR are both molecular chaperones that facilitate MHC-I folding and peptide loading. Because TAPBR functions independently outside of the peptide-loading complex, it is well-suited for clinical applications that involve peptide exchange, such as loading immunogenic peptides on MHC-I molecules and generating libraries to detect T-cells that recognize peptides or antigens from infected or cancerous cells.

    However, TAPBPR-mediated peptide exchange has thus far only worked for a limited set of common allotypes of human MHC-I, known as human leukocyte antigen (HLA), which has limited wider use of these technologies in biomedical applications. Over time, HLA subtypes, which include HLA-A, HLA-B, and HLA-C, have evolved such that not all alleles interact equally well with TAPBPR. This has been a roadblock in developing and enhancing novel therapies with the help of molecular chaperones, as some HLA allotypes do not interact with these molecules. 

    To solve this problem, the CHOP researchers analyzed three different TAPBPR proteins: one from humans, one from chickens, and one from mice. They found that unlike human TAPBPR, chicken TAPBPR co-evolved with its class I genes, so that it maintains high affinity across MHC-I allotypes. In their analysis, they found that chicken TAPBPR was able to react with multiple HLA allotypes, many of which were not able to bind to human TAPBPR. They also demonstrated that TAPBPR stabilizes the empty MHC-I groove in an “open” conformation, boosting its affinity for peptide loading.

    Simultaneously, in close collaboration with researchers at the University of Illinois led by Erik Procko, PhD, the research team used deep mutational scanning to characterize the effects from 100s of point mutations on human TAPBPR and found a variant that mimics the chicken sequence. Like the chicken TAPBPR, this variant enhanced peptide exchange across a broad range of HLA types.

    “Although the highly polymorphic nature of MHC-I molecules makes it challenging to engineer ‘universal’ chaperones, our research team demonstrated that both a chicken ortholog of TAPBPR and a human variant with minor adjustments could enhance peptide exchange across multiple disease-relevant HLAs,” said senior author Nikolaos G. Sgourakis, PhD, Associate Professor in the Center for Computational and Genomic Medicine at Children’s Hospital of Philadelphia. “These TAPBPR orthologs could be utilized in various cancer immunotherapeutic settings to narrow the peptide repertoire and increase immunogenicity. The knowledge gained by our studies can guide the design of engineered TAPBPR variants with tailored HLA specificity and catalytic efficiency for peptide exchange applications both in vitroand in vivo.”

    This research was supported by funding from the National Institute of Allergy and Infectious Diseases (5R01AI143997) and National Institute of General Medical Sciences (5R35GM125034). 

    Yi Sun, Georgia F. Papadaki, Christine A. Devlin, Julia N. Danon, Michael C. Young, Trenton J. Winters, George M. Burslem, Erik Procko, and Nikolaos G. Sgourakis. “Xeno-interactions between MHC-I proteins and molecular chaperones enable ligand exchange on a broad repertoire of HLA allotypes,” Science Advances, February 24, 2023, DOI: 10.1126/sciadv.ade7151 

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    About Children’s Hospital of Philadelphia: A non-profit, charitable organization, Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the 595-bed hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as a new inpatient hospital with a dedicated pediatric emergency department in King of Prussia. In addition, its unique family-centered care and public service programs have brought Children’s Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

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    Children’s Hospital of Philadelphia

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  • LJI scientists confirm smallpox vaccine also teaches T cells to fight mpox

    LJI scientists confirm smallpox vaccine also teaches T cells to fight mpox

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    Newswise — LA JOLLA, CA—There’s even more reason to think a vaccine developed against smallpox can help the body fight against mpox (monkeypox virus disease) as well, according to researchers at La Jolla Institute for Immunology (LJI). Their new study, published in Cell Host & Microbe, is the first to provide evidence that the vaccinia vaccine MVA-BN (brand name JYNNEOS) should also train virus-fighting T cells to recognize mpox sequences.

    “This study gives us confidence that T cell response induced by the JYNNEOS vaccine should be able to also recognize mpox virus,” says LJI Professor Alessandro Sette, Dr.Biol.Sci., who co-led the new study with LJI Instructor Alba Grifoni, Ph.D.

    The study comes as more than 100 countries reported unprecedented mpox outbreaks. In the United States, there have been more than 28,000 reported cases and 11 deaths attributed to mpox since May 2022.

    Why we need mpox vaccine data

    Although the JYNNEOS vaccine, based on a non-live attenuated orthopox virus called modified vaccine ankara (MVA), is approved to prevent mpox infection and severe disease, researchers don’t yet have clinical efficacy data from human trials. Still, researchers know that mpox virus is similar enough to other orthopoxviruses that immunization against an orthopoxvirus called vaccinia (VACV) can also train the immune system to fight mpox.

    Mpox (termed “monkeypox” until recently) is a member of the orthopox family of viruses. The deadliest, of course, was variola virus,causing the disease known as smallpox. Smallpox was eradicated worldwide in 1980 thanks to a massive and successful vaccination campaign to administer the Dryvax vaccine, based on VACV.

    VACV and variola virus have a lot of immune system targets (called antigens), in common. This means training the body to recognize VACV also taught immune cells to recognize variola virus. But there was a downside—Dryvax (and a newer version called Acambis 2000) had harmful side effects, especially in immunocompromised people.

    JYNNEOS was designed to have a better safety profile. While the vaccine performed well in pre-clinical tests, the eradication of smallpox meant scientists couldn’t see how JYNNEOS performed in human patients in real-world infection scenarios, such as a smallpox outbreak or possible case of smallpox-based biological warfare (a concern in the early days of the Iraq War).

    How a smallpox vaccine protects against mpox

    For the new study, the LJI team set out to study if the viral proteins known to be targeted by T cells induced by VACV vaccination, would also be conserved in JYNNEOS and in mpox. As Grifoni explains, while antibodies are key for vaccine efficacy and preventing reinfections, T cells are essential for both preventing severe infections and “remembering” past infections.

    “By recognizing infected cells, T cells are able to limit how much viruses can spread inside the body modulate disease severity, and ultimately terminate the infection” says Grifoni. “T cell responses also tend to be long lasting, and resilient to viral mutations to escape immune recognition. What we have seen in the context of SARS-CoV-2 is that even if the virus mutates somewhat, T cells reactivity is still largely preserved.”

    The researchers demonstrated that the known targets of T cell responses seen in the VACV proven -efficacy vaccine, are also found in JYNNEOS and mpox, suggesting that the JYNNEOS vaccine can indeed trigger an effective T cell response against mpox infection.  The initial test of their hypothesis was based on developing viral peptide “megapools,” or reagents designed to detect T cell reactivity to mpox antigens. The experiments further showed that these megapools can be used to accurately detect specific T cells.

    “Vaccines such as JYNNEOS should be able to induce T cells that also recognize mpox and can provide protection from severe disease,” says Grifoni.

    Could the vaccine work in immunocompromised patients?

    “The majority of mpox cases have been in men who have sex with men,” Sette explains. “In that community, a significant fraction of the people that have been infected with mpox also happened to be HIV-positive. So it is important to learn how people who are HIV-positive respond to infection and vaccination compared to HIV-negative individuals. The present study enables future study to establish this key point”

    Sette emphasizes that most HIV-positive individuals are not necessarily at greater risk of mpox infection or severe disease. “We do not expect that HIV-positive individuals will respond differently to infection and vaccination, because in most cases, people who live with HIV live with a controlled HIV because of the available therapies,” he says. “Nevertheless, it’s important to provide these data to the community affected by this outbreak and to the general scientific community.”

    Whether the JYNNEOS vaccine sparks a similar immune response in people with and without HIV—and the role of T cells—will have to be determined in future studies. “We also expect to see no difference in the duration of protection between HIV positive and HIV negative individuals, but that still all needs to be proven and evaluated experimentally. We are actively engaging the community most affected by the outbreak and the scientific community at large ” says Sette.

    Next steps for the LJI team

    The researchers are now working to characterize the T cell response to mpox in more detail. They are especially interested in how T cell responses differ after vaccination versus natural infection. Sette and Grifoni would also like to compare T cell responses following JYNNEOS vaccination with the older Dryvax vaccination.

    Just as they’ve done throughout the COVID-19 pandemic, Sette and his colleagues hope to share their reagents freely to and spur more life-saving studies around the globe. “We want to make these reagents widely available to whoever asks,” says Sette.

    Additional authors of the study, “Defining antigen targets to dissect vaccinia virus (VACV) and Monkeypox virus (MPXV)-specific T cell responses in humans,” include Yun Zhang, Alison Tarke, John Sidney, Paul Rubiro, Maria Reina-Campos, Gilberto Filaci, Jennifer Dan, and Richard H. Scheuermann.

    This research was supported by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (Contract No. 75N93019C00001, 75N9301900065, and HHS75N93019C00076) and through a Ph.D. student fellowship from the Clinical and Experimental Immunology Course at the University of Genoa, Italy, and with support from other private foundations.

    DOI: 10.1016/j.chom.2022.11.003

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    La Jolla Institute for Immunology

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