Carbon Chemist

Tag: SARS-CoV-2

  • Long COVID manifests as a post-viral syndrome indistinguishable from other respiratory illnesses

    Long COVID manifests as a post-viral syndrome indistinguishable from other respiratory illnesses

    [ad_1]

    Long COVID appears to manifest as a post-viral syndrome indistinguishable from seasonal influenza and other respiratory illnesses, with no evidence of increased moderate-to-severe functional limitations a year after infection, according to new research being presented at this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024) in Barcelona, Spain (27-30 April).

    The study by Queensland Health researchers suggests that in the highly vaccinated population of Queensland exposed to the Omicron variant, long COVID’s impact on the health system is likely to stem from the sheer number of people infected with SARS-CoV-2 within a short period of time, rather than the severity of long COVID symptoms or functional impairment.

    The findings add to previous research by the same authors and published in BMJ Public Health which found no difference in ongoing symptoms and functional impairment when COVID-19 was compared with influenza,12 weeks post infection.

    Rates of long COVID in Australia are low due to high vaccination rates upon easing of COVID restrictions and the population’s subsequent exposure to the Omicron variant. Symptoms reported with the illness include fatigue, brain fog, cough, shortness of breath, change to smell and taste, dizziness, and rapid or irregular heartbeat.

    To understand more about the impact of long COVID on the Australian state of Queensland, researchers surveyed 5,112 symptomatic individuals aged 18 years and older, comprising those with PCR-confirmed infection for COVID-19 (2,399 adults) and those who were PCR negative for COVID-19 (2,713 adults: 995 influenza positive and 1,718 PCR negative for both but symptomatic with a respiratory illness) between 29 May and 25 June 2022.

    Laboratory reporting for COVID-19 and influenza is mandated upon PCR test request under Queensland’s public health legislation, with the results recorded in the Queensland Department of Health’s Notifiable Conditions System.

    A year after their PCR test, in May and June 2023, participants were asked about ongoing symptoms and the degree of functional impairment using a questionnaire delivered by SMS link.

    Overall, 16% (834/5,112) of all respondents reported ongoing symptoms a year later, and 3.6% (184) reported moderate-to-severe functional impairment in their activities of daily life.

    After controlling for influential factors including age, sex, and First Nation status, the analysis found no evidence that COVID-19 positive adults were more likely to have moderate-to-severe functional limitations a year after their diagnosis than symptomatic adults who were negative for COVID-19 (3.0% vs 4.1%).

    Moreover, results were similar when compared with the 995 symptomatic adults who had influenza (3.0% vs 3.4%).

    Interestingly, the analysis also found that those who were more likely to report moderate-to-severe functional impairment were those aged 50 years or older, and those who had symptoms of dizziness, muscle pain, shortness of breath, post-exertional malaise, and fatigue.

    In health systems with highly vaccinated populations, long COVID may have appeared to be a distinct and severe illness because of high volumes of COVID-19 cases during the pandemic. However, we found that the rates of ongoing symptoms and functional impairment are indistinguishable from other post-viral illnesses. These findings underscore the importance of comparing post-COVID-19 outcomes with those following other respiratory infections, and of further research into post-viral syndromes.”


    Dr. John Gerrard, Queensland’s Chief Health Officer

    He adds, “Furthermore, we believe it is time to stop using terms like ‘long COVID’. They wrongly imply there is something unique and exceptional about longer term symptoms associated with this virus. This terminology can cause unnecessary fear, and in some cases, hypervigilance to longer symptoms that can impede recovery.”

    The authors caution that the findings are associations and do not represent prevalence. They point to several limitations, including that participants who were hospitalised or had pre-existing illness were not identifiable within the cohort. They also note that the risk of long COVID has been lower during the Omicron wave compared with other SARS-CoV-2 variants, and because 90% of people in Queensland were vaccinated when Omicron emerged, the lower severity of long COVID could be due to vaccination and/or the variant.

    Source:

    European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024)

    [ad_2]

    Source link

  • New drug candidate designed at the atomic level could help halt emerging SARS-CoV-2 variants

    New drug candidate designed at the atomic level could help halt emerging SARS-CoV-2 variants

    [ad_1]

    Although COVID-19 has faded from the headlines, SARS-CoV-2 – the coronavirus behind the pandemic – is still rampantly infecting people around the world. Public health officials fear as the virus continues to evolve, it will eventually hit upon a diabolical mutation that renders current treatments ineffective, triggering a new wave of severe infection and social disruption.

    In pursuit of new therapies to avoid this dark fate, researchers at Stanford have now unveiled a compound that measures up as a potentially powerful anti-coronavirus drug, detailed in a paper published March 13 in Science Translational Medicine. Dubbed ML2006a4, the compound works in the same way as Paxlovid – the most effective oral drug available to date – by binding to coronavirus particles and preventing the virus from making copies of itself. Compared to Paxlovid, though, ML2006a4 binds more tightly and durably, courtesy of the Stanford team custom-crafting the compound atom-by-atom.

    In preclinical experiments, the compound prevented deadly infections in mice at a superior rate compared to Paxlovid. In addition, the new compound is potent enough that it could likely be formulated without an additional component present in Paxlovid that poses severe drug interaction concerns. Importantly, ML2006a4 also performed well against coronavirus variants that have already evolved degrees of resistance to Paxlovid, suggesting the compound’s honed affinity makes it less vulnerable to mutant virus strains.

    At this point entering the fifth year of the pandemic, Paxlovid is our only really good drug against SARS-CoV-2, but it’s proven fairly easy for the virus to evolve resistance to it. As new waves of coronavirus keep crashing down, we need to have alternative drugs that are more tolerant of mutations and not as easy for the virus to defeat.”


    Michael Lin, senior author of the study, associate professor of neurobiology and of bioengineering in the schools of Medicine and Engineering and a member of Stanford Bio-X

    For the study, Lin worked closely with lead author Michael Westberg, now an assistant professor at Aarhus University in Denmark. From 2018 until 2022, Westberg worked in Lin’s lab as a visiting scholar at Stanford Bio-X, funded by the Novo Nordisk Foundation, through a joint program designed to strengthen international collaborations and the exchange of scientific expertise between Stanford and Denmark.

    Atomic-level precision

    Before the pandemic outbreak in 2020, Lin’s lab had already been investigating the broad class of drugs known as viral protease inhibitors. These drugs target protease enzymes that viruses need for disassembling bulky viral proteins as part of their replication cycle. Like a key fitting into a lock, protease inhibitors occupy the spaces, or active sites, where proteases normally link up with those bulky proteins, thus nipping replication in the bud.

    Specifically, the Stanford researchers had gained familiarity with hepatitis C virus protease, which has similarities to coronavirus versions. Although Westberg had come to Stanford to work on other projects, the global emergency prompted a pivot. “When the pandemic hit, we asked if we could put our expertise to good use,” said Lin.

    Their early research, posted online in September 2020, demonstrated that a hepatitis C drug, boceprevir, slotted reasonably well into the coronavirus protease site. Other scientists built off those findings, including at the pharmaceutical company Pfizer, which ultimately created Paxlovid and received regulatory approval for its use in December 2021. “We knew then that we were on the right track,” said Lin, “and we were motivated to keep going and make an even more effective drug.”

    The Lin lab pooled its collective chemical knowledge to design improvements to their iterative boceprevir-based compounds. Much of the work involved modifying the compound on the atomic scale in intricately detailed computer models to fit more snugly in the coronavirus protease active site.

    “Basically, you put your drug in the active site and you look for gaps where it doesn’t tightly fit. Then you fill those gaps,” said Lin.

    The Stanford researchers approached this challenge in a rational way by adding different configurations of atoms of carbon, nitrogen, and oxygen to the compounds as permitted by the laws of biochemistry.

    “There’s a lot of creativity and intuition involved because everyone is working with the same three atoms, but there are essentially infinite ways to arrange them,” said Lin. “Making these modifications, it’s like playing atomic Tetris.”

    The resulting compounds were then tested against actual coronavirus particles at the Stanford In Vitro Biosafety Level 3 Service Center. After multiple rounds of honing, Lin’s team arrived at the compound designated ML2006a4.

    A promising drug candidate

    In studies with SARS-CoV-2-infected mice, ML2006a4 worked as well as Paxlovid in promoting survival, while offering better protection of the rodents’ lungs and lowering overall virus load in the body.

    The researchers attribute this success to ML2006a4’s extremely refined fit inside coronavirus protease, where the compound boasted a 20-fold higher binding affinity than Paxlovid. That better fit equates to stronger chemical bonds, meaning the drug can stay bound to the protease for a longer time. In this temporal regard, ML2006a4 indeed proved quite sticky: The inhibitor remained attached for approximately 330 minutes, or greater than five hours, whereas the corresponding Paxlovid inhibitor typically fell off its target in just about two minutes.

    From a medication perspective, such staying power translates to spaced-out, smaller doses that can still prevent disease from worsening while giving the immune system a chance to kill off the invaders. “The long-lived drug-enzyme complex helps ensure that the virus doesn’t escape and replicate before your next medication dose,” said Lin.

    In this way, ML2006a4 offers other advantages compared to Paxlovid. Technically, Paxlovid is two drugs packaged together: nirmatrelvir, the actual protease inhibitor, and ritonavir, a drug that prevents the liver from quickly breaking down nirmatrelvir, boosting nirmatrelvir’s performance. Yet the slowing of the liver’s metabolism by ritonavir means that other drugs can toxically build up, forcing patients to take the risk of temporarily stopping their normal medications.

    According to Lin, an oral pill based on ML2006a4 might not require ritonavir to prop up drug levels enough between typical 12-hour administrations to effectively keep coronavirus in check, but “this would need to be tested to make sure,” said Lin. “We also continue to make improved versions of ML2006a4 with better potency and duration of activity,” he added.

    For the promising compounds to move forward, Lin and colleagues are seeking additional investment. So far, their funding has mostly consisted of small grants geared toward early-stage drug discovery. The group now feels their compounds are ready for expanded preclinical testing with an eye toward clinical trials in human patients.

    “We’re very excited how far we’ve come and how successful our drug discovery has been on a shoestring budget,” said Lin. “We hope to see this promising compound developed further to stay ready for what SARS-CoV-2 throws at us next.”

    Source:

    Journal reference:

    Park, T., et al. (2024) Single-mode squeezed-light generation and tomography with an integrated optical parametric oscillator. Science Advances. doi.org/10.1126/sciadv.adl1814.

    [ad_2]

    Source link

  • Anti-inflammatory gene variant shields men under 75 from severe COVID-19

    Anti-inflammatory gene variant shields men under 75 from severe COVID-19

    [ad_1]

    A certain variant of a key anti-inflammatory gene protects men under age 75 from severe illness and death when hospitalized from COVID-19, a genetic analysis of their blood shows.

    According to the study authors, the protective gene in question, an interleukin-1 receptor antagonist (IL1RN) variant, appears to tamp down inflammation. Inflammation is the body’s normal reaction to infection, but when unchecked, inflammation can go too far and damage tissues as part of many diseases, including in severe cases of infection with the pandemic virus SARS-CoV-2.

    Published as a “major article” in The Journal of Infectious Diseases online March 13, the study showed that 124 men between the ages of 19 and 74 who possessed the IL1RN variant, called rs419598, were less likely to become severely ill after hospitalization for COVID-19 and 80 percent less likely to die from the disease.

    IL1RN is expressed naturally in the body. Different types of interleukin genes are known to dial inflammation up or down in the context of arthritis, and researchers say the results of the current study suggest that a similar dynamic influences the interleukin-1-related inflammation seen in patients with COVID-19.

    The findings, from researchers at NYU Grossman School of Medicine, stand out because historically more men than women are known to die from COVID-19, and the IL1RN rs419598 variant appears to selectively protect only men up to age 74, but not beyond that, as age-related chronic illnesses unfold.

    The research team used sequencing technologies for the study to determine the presence of specific genes or variations in the letter code that makes up genes in blood samples from 2,589 men and women hospitalized for COVID-19 at NYU Langone’s Tisch Hospital in Manhattan from March 2020 to March 2021.

    More than half of the men and women in the study were older than age 60 and had obesity, factors that are known to increase the risk of death from the viral infection. Overall, more men than women (240 men, at 60.5 percent, and 157 women, at 39.5 percent) died from their disease, with women 20 percent less likely to die than men.

    Our study results show that among hospitalized patients, while women are still overall less likely than men to die from COVID-19, those men age 74 and younger who possess the IL1RN gene variant rs419598 are much less likely to suffer the severe inflammation tied to SARS-CoV-2 infection and less likely to die from the disease.”


    Mukundan G. Attur, PhD., study co-lead investigator and molecular biologist

    Dr. Attur is an associate professor in the Department of Medicine at NYU Langone Health.

    Among the study’s other findings was that average blood levels of the anti-inflammatory protein IL-1Ra, coded by IL1RN, were 14 times higher in 181 hospitalized men than in healthy male study controls from the general population, and 10 times as high in 178 hospitalized women than in healthy females. However, researchers say the increased levels of IL-1Ra in women did not result in any statistically significant reductions in death.

    Our analysis offers substantial evidence of the biological link between the severe inflammation seen in SARS-CoV-2 and that which occurs in rheumatoid arthritis.”


    Steven Abramson, MD, study senior investigator, the Frederick H. King Professor of Internal Medicine at NYU Langone

    Dr. Abramson, a rheumatologist who also serves as chair of the Department of Medicine and chief academic officer at NYU Langone, says previous research has shown that such rheumatoid inflammation is lower in people who possessed one of the three IL1RN variants analyzed in the study.

    More importantly, Dr. Abramson says, the new research suggests that restraining the interleukin-1 biological pathway, which is in part tamped down by the anti-inflammatory protein IL-1Ra, could help prevent the severe inflammation seen in SARS-CoV-2 infection. Further research, he says, is warranted into whether IL1-inhibiting therapies, such as the IL1 receptor antagonists anakinra, canakinumab, and rilonacept, are effective against COVID-19 infection.

    Dr. Abramson already has plans to investigate if the IL-1 pathway plays a role in long COVID, when people experience new or lingering symptoms, such as fatigue and brain fog, months after recuperating from their initial infection.

    Dr. Abramson points out that the new study adds to the growing scientific evidence about the biological factors that contribute to the differences between the sexes seen in deaths from COVID-19, which are known to vary widely across the United States.

    Funding support for this study was provided by National Institutes of Health grants P30CA016087 and R21AR078466.

    Besides Dr. Abramson and Dr. Attur, other NYU Langone researchers involved in this study are co-lead investigators Christopher M. Petrilli, MD, and Samrachana Adhikari, PhD, and study co-investigators Eduardo Iturrate, MD; Xiyue Li, MS; Stephanie Tuminello, MPH; Nan Hu, MS; Aravinda Chakravarti, PhD; and David B. Beck, MD, PhD.

    Source:

    Journal reference:

    Attur, M., et al. (2024) Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19. The Journal of Infectious Diseases. doi.org/10.1093/infdis/jiae031.

    [ad_2]

    Source link

  • Mobile delivery of COVID-19 vaccines improved uptake in rural Sierra Leone

    Mobile delivery of COVID-19 vaccines improved uptake in rural Sierra Leone

    [ad_1]

    Nature, Published online: 13 March 2024; doi:10.1038/d41586-023-03186-0

    A trial that took mobile health services to rural Sierra Leone finds that this initiative increased COVID-19 vaccine uptake. But more must be done to expand the coverage of health services in low-income countries.

    [ad_2]

    Source link

  • Massive public-health experiment sends vaccination rates soaring

    Massive public-health experiment sends vaccination rates soaring

    [ad_1]

    Vaccination team member Baison Salone (left) facilitates a vaccination clinic in Kafugumbah village, Karene district.

    A vaccination clinic in Kafugumbah village, northwest Sierra Leone.Credit: Conor O’Donovan/Concern Worldwide

    Deploying mobile COVID-19 vaccination clinics in rural areas of Sierra Leone increased vaccination rates sharply, according to an ambitious experiment involving 150 villages1. The effort is an outlier: many more studies examine vaccine hesitancy and misinformation than focus on vaccine access.

    “The investigators made a great effort to bring vaccines to remote communities,” says Jean Nachega, an infectious-disease epidemiologist at the University of Pittsburgh in Pennsylvania, who has highlighted challenges in COVID-19 vaccine access in Africa2. The model could be transferred easily to other countries, he adds, calling the campaign “very laudable”.

    The results, published on 13 March in Nature, highlight the importance of delivering vaccines, as well as other essential medical treatments and supplies, to rural, less affluent areas, says study co-author Ahmed Mushfiq Mobarak, an economist at Yale University in New Haven, Connecticut.

    Vaccine disparity

    By November 2023, more than 80% of people in high-income countries had received at least one dose of a COVID-19 vaccine, compared with roughly one-third of the population of Africa.

    COVID-19: talk of ‘vaccine hesitancy’ lets governments off the hook

    In addition to vaccine supply issues, another possible reason for this disparity is that nearly 60% of people in sub-Saharan Africa live in rural areas, where medical care can be inaccessible. For example, when COVID-19 vaccines first became available, people in rural Sierra Leone, in western Africa, needed to make, on average, a seven-hour round trip to receive the jab, at a total cost that could exceed a week’s wages, Mobarak says.

    To address this problem, Mobarak and his colleagues designed a system to make vaccines accessible to these rural communities. They selected 150 villages in Sierra Leone and randomly assigned 100 of them to host a two- or three-day vaccination clinic; the remaining 50 served as a control group. By the end of the clinics, 30% of people in the communities that had hosted one had been vaccinated against COVID-19, compared with about 6% of people in control villages.

    Last-mile delivery

    The researchers found that the clinics’ success varied by region; after the clinics were held, the vaccination rate was at least 65% in some communities and as low as 0% in others. Mobarak says that future research will need to identify the source of this variation, and the extent to which vaccine hesitancy might have played a part.

    Hesitancy is important to understand, but it shouldn’t preclude vaccination campaigns or more research on vaccine supply and access, Mobarak says. “When you’re starting with a baseline vaccination rate of essentially zero, our research shows that the most cost-effective thing to do is just to show up,” he says.

    The clinics cost about US$33 per person vaccinated. The researchers now plan to test the same strategy in other countries, and to deliver routine childhood vaccines and medical supplies, such as oral rehydration packets, that would further reduce costs per person treated.

    [ad_2]

    Source link

  • Research highlights the need for continued surveillance of emerging SARS-CoV-2 variants and vaccines

    Research highlights the need for continued surveillance of emerging SARS-CoV-2 variants and vaccines

    [ad_1]

    Researchers at the Francis Crick Institute and the National Institute for Health and Care Research Biomedical Research Centre at UCLH have highlighted the importance of continued surveillance of emerging SARS-CoV-2 variants and vaccine performance as the virus continues to evolve.

    Published today as a research letter in The Lancet, their study compared the newer monovalent COVID vaccine, which specifically targets the XBB variant of Omicron (as recommended by the World Health Organisation), with older bivalent vaccines containing a mix of an Omicron variant and the original strain of COVID-19, which the UK deployed in Autumn 2023 before turning to monovalent vaccines1. 

    The researchers found that both vaccines generated neutralizing antibodies against the most recent strain of Omicron, BA.2.86. However, the new monovalent vaccine generated higher levels of antibodies against a range of other Omicron variants.

    The team collected blood and nasal mucosal samples both before and after a fifth dose vaccination from 71 participants of the Legacy study, a research collaboration between the Crick and the NIHR University College London Hospitals Biomedical Research Centre. They compared the antibody levels before and after vaccination.

    All 36 participants who received the bivalent vaccine and 17 who received the monovalent vaccine had boosted levels of antibodies against all variants tested, including the newest strain BA.2.86, which caused a wave of infection this winter. But those with the newer monovalent vaccine had 3.5x higher levels of antibodies against the XBB and BQ.1.1 strains after their booster vaccination.

    Since the Omicron virus is highly transmissible and the virus replicates in the nose and throat, the researchers tested the levels of antibodies in the participants’ nasal cavity.

    They found that the monovalent vaccine increased their ability to produce mucosal antibodies against most of the tested variants, whereas the bivalent vaccine didn’t provide a significant boost.

    Neither vaccine increased neutralizing antibody levels in the nasal cavity against the newest variant, BA.2.86, suggesting that current vaccines may be less likely to stop transmission or prevent asymptomatic or mild illness, while still protecting against severe disease.

    This highlights the importance of careful vaccine updates and continuing to complement a vaccination program with the development of antibody drugs that work against all variants, as some more vulnerable people don’t respond well to vaccines.

    The UK’s strategy to deploy stocks of older vaccines paid off last year, as both vaccines provided equal protection against the newest strain. However, ongoing monitoring is needed, as the virus is continuing to evolve, so vaccine-induced antibodies might not work so well in the future. In the long run, vaccines that are effective against all new variants and can block COVID-19 being transmitted from person to person are needed.”


    Emma Wall, Senior Clinical Research Fellow at the Crick and Consultant in Infectious Diseases at UCLH

    David LV Bauer, Group Leader of the RNA Virus Replication Laboratory at the Crick, said: “The situation this winter could have been different if the newly emerged BA.2.86 and JN.1 variants were substantially distinct from older Omicron variants, but fortunately this wasn’t the case.

    “Most new variants arise quicker than most clinical trials can produce data. But laboratory analysis can provide a detailed picture very quickly. Continued surveillance will help us stay on top of viral evolution.”

    Source:

    The Francis Crick Institute

    Journal reference:

    Shawe-Taylor, M., et al. (2024) Divergent performance of vaccines in the UK autumn 2023 COVID-19 booster campaign. The Lancet. doi.org/10.1016/S0140-6736(24)00316-7.

    [ad_2]

    Source link

  • mRNA vaccines train T cells in waves, study shows

    mRNA vaccines train T cells in waves, study shows

    [ad_1]

    mRNA vaccines developed against the spike glycoprotein of severe acute respiratory syndrome type 2 coronavirus (SARS-CoV-2), displayed remarkable efficiency in combating coronavirus 19 (COVID-19). These vaccines work by triggering both cellular and humoral immune responses against the spike protein of the virus. Cellular immunity may play a more protective role than humoral immunity to variants of concerns (VOC) against SARS-CoV-2, as it targets the conserved regions of spike protein and possibly cross-reacts with other variants.

    Since a single spike epitope is recognized by multiple T-cell clones, the mRNA vaccination-induced T-cell response may consist of multiple spike-reactive clones. Thus, it is important to understand the mechanism of mRNA vaccination-induced cellular immune response. However, to address this clonal-resolution analysis on T-cell responses to mRNA vaccination has not been performed yet.

    To bridge this gap, a team of researchers, led by Associate Professor Satoshi Ueha, including Professor Kouji Matsushima from the Tokyo University of Science (TUS), Japan, Mr. Hiroyasu Aoki from the University of Tokyo, and Professor Toshihiro Ito from Nara Medical University, aimed to develop a kinetic profile of spike-reactive T-cell clones during repetitive mRNA vaccination. For this, they performed a longitudinal TCR sequencing on peripheral T cells of 38 participants who had received the Pfizer vaccine from before the vaccine to after the third vaccination and then analyzed the single-cell gene expression and epitope specificity of the clonotypes.

    Their findings, published in Cell Reports on March 7, 2024, revealed that while the primary T-cell response of naïve T cells generally peaked 10-18 days after the first shot, expansion of “early responders” was detected on day 7 after the first shot, suggesting that these early responders contain memory T cells against common cold coronaviruses. They also found a “main responder” that expanded after the second shot and did not expand early after the first shot and a “third responder” that appeared and expanded only after the third shot.

    By longitudinally tracking the total frequency of each response pattern, it was observed that, after the second shot, a shift among the clonotypes occurred, wherein the major population changed from early responders to main responders, suggestive of a shift in clonal dominance. A similar shift of responding clones was also observed in CD4+ T cells.

    We next analyzed the phenotype of main responders after the second and the third vaccination. The results showed that the main responders after the second and third shots mostly consist of effector-memory T cells (TEM), with more terminally differentiated effector memory-like phenotype after the third shot.”

    Satoshi Ueha, Associate Professor, Tokyo University of Science

    The researchers then examined the repertoire changes of main responders, revealing that the expansion of main responders, which occurred after the second shot, diminished following the third shot, and the clonal diversity decreased and was partially replaced by the third responders. This may potentially mean that the third vaccination selected better-responding clones.

    Due to the vaccination-induced shift in immunodominance of spike epitopes, the study supports the inter-epitope shift model. In addition, there were intra-epitope shifts of vaccine-responding clonotypes within spike epitopes.

    Prof. Ueha explains the significance of these results, “Our analysis suggests that T cells can “re-write” themselves and reshape their memory populations after successive vaccinations. This re-writability not only maintains the number of memory T cells but also maintains diversity that can respond to different variants of pathogens. Moreover, by tuning the replacement of memory cells, more effective vaccines can be developed that can also be tailored to an individual’s unique immune response.”

    Overall, this study provides important insights into mRNA vaccine-induced T-cell responses, which will be crucial for developing next-generation vaccines for more effective and broad protection against viruses.

    Source:

    Tokyo University of Science

    Journal reference:

    Aoki, H., et al. (2024) CD8+ T cell memory induced by successive SARS-CoV-2 mRNA vaccinations is characterized by shifts in clonal dominance. Cell Reports. doi.org/10.1016/j.celrep.2024.113887.

    [ad_2]

    Source link

  • Researchers forge new path to combat viruses and cancers with helicase inhibitors

    Researchers forge new path to combat viruses and cancers with helicase inhibitors

    [ad_1]

    Helicases are enzymes that unwind DNA and RNA. They’re central to cellular life, implicated in a number of cancers and infections-;and, alas, extraordinarily difficult to target with drugs. 

    Now, new research provides a powerful platform for designing covalent inhibitors tailored to target helicases. The paper, published in the Journal of the American Chemical Society, describes how researchers used this innovative new platform to design molecules that take aim at helicases involved in COVID and certain cancers.

    “High-resolution structural and biochemical data alone are not sufficient for finding druggable sites in conformationaly dynamic enzymes such as helicases. Our approach can identify these sites and also provide chemical starting points for developing drugs that target helicases.”

    Tarun Kapoor,  The Rockefeller University

    Mechanical difficulties 

    Complex molecular machines that traverse DNA and RNA strands, helicases must kickstart the unraveling process that prepares genetic information for processes such as replication or transcription. But when helicases go rogue, they can promote the growth of some cancers. At the same time, helicases are also crucial for viral replication and bacterial proliferation. It follows that different drugs targeting these enzymes could treat certain cancers, or stop infections in their tracks.

    “Helicases are very hot targets right now,” says lead author Jared Ramsey, a graduate student in the Kapoor lab. “Drugs that inhibit helicases are of great interest to the scientific community, and could be leveraged as new and effective treatments.” 

    Helicase inhibitors, however, are hard to come by. By testing thousands of small molecules, drug companies have occasionally happened upon methods for grinding one helicase or another to a halt, but these occurences have proven rare. “The same was true in our lab,” Ramsey says. “We were unable to identifiy helicase inhibitors using typical approaches such as high-throughput screening.” 

    Ramsey, Kapoor, and colleagues wondered whether electrophilic small molecules could be used to scout out the weak points in a helicase, quietly prodding the enzyme for potential binding sites susceptible to drugs. Central to this idea is the concept of covalency, where inhibitor candidates irreversibly bind the helicase target, possibly circumventing complications from the dynamic and fluid nature of these enzymes. To that end, the team selected two innocuous molecules and directed the so-called scout fragments toward a helicase of SARS-CoV-2.

    Once they found likely binding sites on the helicase, they promoted the scouts to soldiers. “We just had to take a minimally elaborated electrophilic molecule, identify where it binds with mass spectrometry, and then use medicinal chemistry to modify it and screen a few versions of to achieve a potent, specific inhibitor,” Ramsey says. 

    The team also demonstrated that scout fragments could be tuned to shut down two specific helicases, BLM and WRN, which are implicated in Bloom Syndrome and Werner Syndrome, respectively, as well as a number of cancers. While the published findings aren’t expected to immediately translate into drugs that treat COVID or cancer, they do serve as a valuable starting point for drug developers to make bespoke helicase targets. 

    “Our findings show how the platform we developed could accelerate work in other labs,” Ramsey says. “We take a basic science approach, and that’s how many useful findings are uncovered. This takes a challenging problem and gives us a solid place to start.”

    Source:

    The Rockefeller University

    Journal reference:

    Ramsey, J. J., et al. (2023). Using a Function-First “Scout Fragment”-Based Approach to Develop Allosteric Covalent Inhibitors of Conformationally Dynamic Helicase Mechanoenzymes. Journal of the American Chemical Society. doi.org/10.1021/jacs.3c10581.

    [ad_2]

    Source link

  • Man takes 217 COVID vaccines with no ill effects, shows immune boost

    Man takes 217 COVID vaccines with no ill effects, shows immune boost

    [ad_1]

    In a recent case report published in The Lancet Infectious Diseases, researchers described a case of a 62-year-old male who received 217 vaccinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 29 months and examined his immunological responses. They found that hyper-vaccination did not cause adverse events or significantly affect the quality of adaptive immune responses while resulting in increased T-cells and spike-specific antibodies.

    Study: Adaptive immune responses are larger and functionally preserved in a hypervaccinated individual. Image Credit: Douglas Sacha / ShutterstockStudy: Adaptive immune responses are larger and functionally preserved in a hypervaccinated individual. Image Credit: Douglas Sacha / Shutterstock

    Background

    Booster vaccinations may potentially amplify immune responses, while persistent antigen exposure may induce immune tolerance. However, the advantages, constraints, and risks of recurrent vaccination in humans remain to be thoroughly investigated. In the present study, researchers investigated the immunological responses in an older man hyper-vaccinated against SARS-CoV-2.

    The case

    In this case study, a 62-year-old male from Magdeburg, Germany (referred to as HIM), engaged in deliberate hyper-vaccination against SARS-CoV-2, receiving 217 vaccinations over 29 months for personal reasons. This occurred outside a clinical study context and contrary to national recommendations. Despite an investigation by a public prosecutor for potential fraud, no criminal charges were filed. Notably, HIM’s immunological evaluation, initiated during the public prosecutor’s investigation, received active and voluntary cooperation from HIM and was ethically approved. Throughout the extensive hyper-vaccination, HIM reported no vaccine-related side effects, and routine clinical chemistry parameters displayed no abnormalities between November 2019 and October 2023. In the repeated negative SARS-CoV-2 tests, including antigen tests, polymerase chain reaction (PCR) test, and nucleocapsid serology, HIM showed no signs of past SARS-CoV-2 infection.

    Starting from the 214th vaccination, HIM’s anti-spike SARS-CoV-2 immunoglobulin G (IgG) levels were measured before and after vaccinations. The antibody peak occurred at the 214th vaccination, and there was a slight increase after the 217th vaccination. Additionally, HIM showed IgG4 subclass switching after the 215th vaccination, which is uncommon in regimens with adenoviral-based vaccines as the first dose.

    A total of 29 individuals who received three doses of a messenger ribonucleic acid (mRNA) vaccine formed the control group. As compared to controls, HIM exhibited mildly elevated levels of anti-spike IgM and IgA in the serum. However, in saliva samples, HIM showed detectable levels of anti-spike IgG, contrary to the control participants. HIM’s serum neutralization capacity was higher (5.4-fold for wildtype and 11.5-fold for Omicron B1.1.529 spike proteins) than the controls, indicating elevated quantities of spike-specific IgG. This observed difference was not attributed to antibody avidity as it remained comparable among the groups.

    HIM showed a slightly increased number of spike-specific B-cells, with the same phenotype as seen in single-cell RNA sequencing (scRNA-seq). No significant differences were observed in the rates of somatic hypermutation or clonal expansion. CD8+ T-cells specific to the spike epitope were about six-fold more frequent in HIM, with a preference for effector memory T-cells. Further, scRNA-seq of LTD-specific T-cells showed a more differentiated phenotype and increased clonal expansion compared to controls. Flow-cytometric analysis and metabolic profiling showed no significant abnormalities in 14 protein markers.

    LTD-specific CD8+ T-cells in HIM showed a proliferative capacity similar to control individuals, aligned with conserved numbers of T-cells with a phenotype like early differentiated stem cells. After epitope-specific stimulation, HIM displayed higher cytokine-positive cells, but the cytokine release per cell remained roughly equal. Cytokine analysis in the supernatant revealed the typical pattern of virus-specific CD8+ T-cells. Additionally, HIM’s CD8+ T-cells showed higher peptide sensitivity than the control group. Examination of spike-reactive CD4+ T-cells revealed a dearth of nucleocapsid-specific immunity, with similar cytokine-producing CD4+ T-cell amounts in HIM compared to the control group while retaining peptide sensitivity.

    Conclusion

    In conclusion, the present case report showed that hyper-vaccination against SARS-CoV-2 yielded no adverse events and elevated T-cell levels and spike-specific antibodies. Notably, the implicit quality of adaptive immune responses showed no significant effects. Although breakthrough SARS-CoV-2 infections were not observed in the individual, any causal link with the hyper-vaccination regimen remains unclear. The researchers emphasize that they do not advocate for hyper-vaccination as an approach to improve adaptive immunity.

    [ad_2]

    Source link

  • A call for better diagnosis and treatment

    A call for better diagnosis and treatment

    [ad_1]

    In a recent review published in the journal Nature Reviews Microbiology, a group of authors summarized recent advancements in understanding long coronavirus disease (COVID) ‘s mechanisms, impacts, and research needs for better diagnostics and treatments.

    Review: Long COVID: major findings, mechanisms and recommendationsReview: Long COVID: major findings, mechanisms and recommendations

    Background

    Long COVID, affecting over 65 million globally, manifests through diverse, systemic symptoms regardless of initial infection severity. This condition leads to various health issues like cardiovascular diseases and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), causing widespread disability and workforce impacts. Pathogenesis theories include persistent viral presence and immune dysregulation, but no effective treatments have been established. Research has identified risk factors such as gender and socioeconomic status, although many patients had no prior conditions. Long COVID’s resemblance to other post-viral syndromes underscores the urgent need for research into its mechanisms, risk factors, and treatments to enhance patient outcomes.

    Immunological and virological discoveries in Long COVID

    Long COVID triggers significant immune changes, particularly post-mild COVID, marked by T cell exhaustion, reduced effector memory Cluster of Differentiation (CD)4+ and CD8+ T cells, elevated Programmed Death-1 (PD1) expression, and activated innate immune responses. The scarcity of naive T and B cells, alongside sustained high type I and III interferon levels, indicates continued immune dysregulation. An altered immune cell balance, including increased non-classical monocytes, reduced dendritic cells, and low cortisol, highlights a distinct immune profile in long COVID.

    Research points to autoimmunity in long COVID, highlighted by raised autoantibodies against key receptors like Angiotensin-Converting Enzyme 2 (ACE2). Viral reactivations, notably of Epstein-Barr Virus (EBV) and Human Herpesvirus 6 (HHV-6), which impact mitochondrial function and energy metabolism, play a significant role. The condition’s development is initially linked to inadequate immune responses, including poor antibody and T-cell response. Signs of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persistence across multiple body tissues suggest a potential mechanism for the enduring nature of long COVID symptoms.

    Systemic impact and organ damage

    SARS-CoV-2 causes widespread organ damage beyond the respiratory system, affecting the circulatory system through endothelial dysfunction and increased thrombosis risks. Long-term alterations in blood properties and vascular density contribute to the heightened prevalence of cardiovascular diseases post-COVID, demonstrating the virus’s systemic and lasting effects.

    Neurological impact

    Long COVID induces neurological and cognitive issues, such as memory loss and cognitive impairment, with effects comparable to significant aging. Potential underlying mechanisms like neuroinflammation and neuronal damage link these symptoms to Alzheimer’s-like pathology, highlighting severe brain impacts.

    ME/CFS and related conditions

    There is a notable overlap between long COVID and ME/CFS, with many patients meeting the criteria for the latter. This relationship underscores commonalities like immune alterations and mitochondrial dysfunction, with dysautonomia commonly co-occurring, suggesting shared pathophysiological mechanisms.

    Reproductive and respiratory concerns

    Long COVID’s reproductive effects call for focused research on sex-specific impacts, while persistent respiratory symptoms underscore lasting lung damage. These aspects illustrate the condition’s broad spectrum of effects.

    Gastrointestinal symptoms and chronicity

    Persistent gastrointestinal issues and altered gut microbiota in long COVID patients emphasize its systemic nature. The diverse onset and duration of symptoms across patients highlight the condition’s complexity and the challenge of predicting individual outcomes.

    Diagnostic advances and challenges

    Diagnostic approaches for long COVID are under development, with existing techniques like tilt table tests and Magnetic Resonance Imaging (MRI) scans often failing to detect the condition effectively. Emerging diagnostics, including microclot imaging, corneal microscopy, and novel Electrocardiogram (ECG) markers, offer hope for more precise identification. Research into biomarkers and unconventional methods, such as scent detection by dogs, highlights the innovative directions being explored to improve long COVID diagnosis.

    Treatment landscape and future directions

    Current treatment strategies for long COVID are primarily symptom-focused, with some success using methods adapted from ME/CFS management. Innovations such as low-dose naltrexone and anticoagulant therapy show promise, while experimental treatments like Paxlovid and probiotics are beginning to demonstrate potential benefits. Nonetheless, the need for rigorous clinical trials to establish effective treatments remains critical, underscoring the initial stage of long COVID care and the importance of ongoing research.

    Vaccine impact and the role of variants

    Vaccination’s impact on long COVID varies, showing both minimal and reduced risk. Variants and vaccine doses may affect long COVID chances, with early studies hinting at variant-dependent risks and vaccine efficacy. Reinfections, particularly multiple ones, could heighten long COVID risks, stressing the importance of continuous research and monitoring.

    Diagnosing Long COVID: obstacles and solutions

    The early pandemic’s diagnostic challenges, such as limited polymerase chain reaction (PCR) test availability and high false-negative rates, led to widespread underdiagnosis, affecting mainly non-hospitalized individuals. Compounded by unreliable antibody tests, particularly among specific groups like women, children, and those with mild infections, these issues have significantly hindered long COVID research and patient care. Misclassification and study exclusion have clouded our understanding of the condition. A comprehensive approach incorporating insights from ME/CFS and dysautonomia is essential to improve long COVID research. Emphasizing clinical trials, diverse participant inclusion, and engaging patient communities, alongside updated healthcare training, will enhance patient outcomes and advance our knowledge of long COVID.

    [ad_2]

    Source link