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Nature Communications Feb 2024In the context of continuous emergence of SARS-CoV-2 variants of concern (VOCs), one strategy to prevent the severe outcomes of COVID-19 is developing safe and effective...
In the context of continuous emergence of SARS-CoV-2 variants of concern (VOCs), one strategy to prevent the severe outcomes of COVID-19 is developing safe and effective broad-spectrum vaccines. Here, we present preclinical studies of a RBD vaccine derived from the Gamma SARS-CoV-2 variant adjuvanted with Alum. The Gamma-adapted RBD vaccine is more immunogenic than the Ancestral RBD vaccine in terms of inducing broader neutralizing antibodies. The Gamma RBD presents more immunogenic B-cell restricted epitopes and induces a higher proportion of specific-B cells and plasmablasts than the Ancestral RBD version. The Gamma-adapted vaccine induces antigen specific T cell immune responses and confers protection against Ancestral and Omicron BA.5 SARS-CoV-2 challenge in mice. Moreover, the Gamma RBD vaccine induces higher and broader neutralizing antibody activity than homologous booster vaccination in mice previously primed with different SARS-CoV-2 vaccine platforms. Our study indicates that the adjuvanted Gamma RBD vaccine is highly immunogenic and a broad-spectrum vaccine candidate.
Topics: Animals; Mice; Humans; SARS-CoV-2; Broadly Neutralizing Antibodies; COVID-19 Vaccines; COVID-19; Vaccines, Subunit; Adjuvants, Immunologic; Epitopes, B-Lymphocyte; Antibodies, Viral; Antibodies, Neutralizing; Spike Glycoprotein, Coronavirus
PubMed: 38307851
DOI: 10.1038/s41467-024-45180-8 -
Journal of Clinical Medicine Apr 2024The John Cunningham virus (JCV) is a polyomavirus that usually infects people at a young age and does not cause any symptoms in immunocompetent individuals. However, in... (Review)
Review
The John Cunningham virus (JCV) is a polyomavirus that usually infects people at a young age and does not cause any symptoms in immunocompetent individuals. However, in immunocompromised individuals, such as kidney transplant recipients, JCV can cause severe and potentially fatal disease. Unfortunately, JCV has not been researched as extensively as the BK virus and is not mentioned in relevant kidney transplant guidelines. This lack of attention to JCV can lead to less consideration in kidney transplant patients' care. Surveillance using locally available diagnostic methods is of the utmost importance. The presence of JCV can be diagnosed with urine decoy cells, viruria, or viremia verified by the PCR method. A low threshold for considering JCV as a possible cause of any neurological or renal dysfunction in kidney transplant recipients must be maintained. In such cases, kidney and brain biopsy are indicated. Maintaining the appropriate immunosuppression while avoiding over-immunosuppression to prevent JCV disease is crucial, and the approach should be individual, according to overall immunological risk. We hypothesize that the presence of the JCV can indicate overt immunosuppression and identify kidney transplant recipients more prone to opportunistic infections and diseases, including some malignancies. To explore that, future observational studies are needed.
PubMed: 38673491
DOI: 10.3390/jcm13082217 -
Neurology(R) Neuroimmunology &... May 2024Epstein-Barr virus (EBV) infection is a major risk factor of multiple sclerosis (MS). We examined the presence of EBV DNA in the CSF and blood of patients with MS and...
BACKGROUND AND OBJECTIVES
Epstein-Barr virus (EBV) infection is a major risk factor of multiple sclerosis (MS). We examined the presence of EBV DNA in the CSF and blood of patients with MS and controls. We analyzed whether EBV DNA is more common in the CSF of patients with MS than in controls and estimated the proportions of EBV-positive B cells in the CSF and blood.
METHODS
CSF supernatants and cells were collected at diagnostic lumbar punctures from 45 patients with MS and 45 HLA-DR15 matched controls with other conditions, all participants were EBV seropositive. Cellular DNA was amplified by Phi polymerase targeting both host and viral DNA, and representative samples were obtained in 28 cases and 28 controls. Nonamplified DNA from CSF cells (14 cases, 14 controls) and blood B cells (10 cases, 10 controls) were analyzed in a subset of participants. Multiple droplet digital PCR (ddPCR) runs were performed per sample to assess the cumulative EBV positivity rate. To detect viral RNA as a sign of activation, RNA sequencing was performed in blood CD4-positive, CD8-positive, and CD19-positive cells from 21 patients with MS and 3 controls.
RESULTS
One of the 45 patients with MS and none of the 45 controls were positive for EBV DNA in CSF supernatants (1 mL). CSF cellular DNA was analyzed in 8 independent ddPCRs: EBV DNA was detected at least once in 18 (64%) of the 28 patients with MS and in 15 (54%) of the 28 controls ( = 0.59, Fisher test). The cumulative EBV positivity increased steadily up to 59% in the successive ddPCRs, suggesting that all individuals would have reached EBV positivity in the CSF cells, if more DNA would have been analyzed. The estimated proportion of EBV-positive B cells was >1/10,000 in both the CSF and blood. We did not detect viral RNA, except from endogenous retroviruses, in the blood lymphocyte subpopulations.
DISCUSSION
EBV-DNA is equally detectable in the CSF cells of both patients with MS and controls with ddPCR, and the probabilistic approach indicates that the true positivity rate approaches 100% in EBV-positive individuals. The proportion of EBV-positive B cells seems higher than previously estimated.
Topics: Humans; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Multiple Sclerosis; DNA, Viral; RNA, Viral
PubMed: 38608226
DOI: 10.1212/NXI.0000000000200226 -
Antiviral Research Feb 2024JC polyomavirus (JCPyV) is a nonenveloped, double-stranded DNA virus that infects the majority of the population. Immunocompetent individuals harbor infection in their...
JC polyomavirus (JCPyV) is a nonenveloped, double-stranded DNA virus that infects the majority of the population. Immunocompetent individuals harbor infection in their kidneys, while severe immunosuppression can result in JCPyV spread to the brain, causing the neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Due to a lack of approved therapies to treat JCPyV and PML, the disease results in rapid deterioration, and is often fatal. In order to identify potential antiviral treatments for JCPyV, a high-throughput, large-scale drug screen was performed using the National Institutes of Health Clinical Collection (NCC). Drugs from the NCC were tested for inhibitory effects on JCPyV infection, and drugs from various classes that reduced JCPyV infection were identified, including receptor agonists and antagonists, calcium signaling modulators, and enzyme inhibitors. Given the role of calcium signaling in viral infection including Merkel cell polyomavirus and simian virus 40 polyomavirus (SV40), calcium signaling inhibitors were further explored for the capacity to impact JCPyV infection. Calcium and calmodulin inhibitors trifluoperazine (TFP), W-7, tetrandrine, and nifedipine reduced JCPyV infection, and TFP specifically reduced viral internalization. Additionally, TFP and W-7 reduced infection by BK polyomavirus, SV40, and SARS-CoV-2. These results highlight specific inhibitors, some FDA-approved, for the possible treatment and prevention of JCPyV and several other viruses, and further illuminate the calcium and calmodulin pathway as a potential target for antiviral drug development.
Topics: Humans; Calcium; Calmodulin; Neurodegenerative Diseases; Leukoencephalopathy, Progressive Multifocal; Polyomavirus Infections; JC Virus; Simian virus 40; Antiviral Agents; Sulfonamides
PubMed: 38246207
DOI: 10.1016/j.antiviral.2024.105817 -
Frontiers in Neurology 2024A scoping review found that most studies on women's health in multiple sclerosis (MS) focused on pregnancy, fetal/neonatal outcomes and sexual dysfunction. Few studies...
BACKGROUND
A scoping review found that most studies on women's health in multiple sclerosis (MS) focused on pregnancy, fetal/neonatal outcomes and sexual dysfunction. Few studies addressed menopause, contraception, gynecologic cancers/cancer screening. However, the perceived relative importance of these knowledge gaps to people living with MS and other partners is unknown. We engaged a range of partners, including people living with MS, health care providers, researchers, and patient advocacy groups, to set priorities for future research in women's health in MS.
METHODS
We employed a three-step global engagement process. First, we identified which broad research topics relevant to women's health in MS were of highest priority using two surveys. Second, we developed specific research questions within these topics using focus groups. Finally, we prioritized the research questions with a third survey.
RESULTS
Overall, 5,266 individuals responded to the initial surveys [ = 1,430 global survey, mean (SD) age 50.0 (12.6), all continents; = 3,836 North American Research Committee on Multiple Sclerosis survey, mean (SD) age 64.8 (9.6), United States]. Menopause, sexual dysfunction, pregnancy, gynecologic cancer/cancer screening, hormones and parenthood were identified as the most important topics. Focus groups generated 80 potential research questions related to these topics. In the final survey 712 individuals prioritized these questions. The highest priority questions in each research topic were: (i) How do perimenopause and menopause affect disease activity, course, response to disease-modifying treatment and quality of life in MS; (ii) What are the most effective strategies for managing issues around sexual intimacy, including related to low sexual desire, changes in physical function, and MS symptoms; (iii) Are there long-term effects of disease-modifying therapies on the children of persons with MS; (iv) What are the short and long-term effects of disease-modifying drugs on gynecologic cancer risk, particularly for high efficacy disease-modifying drugs and hematopoietic stem cell transplantation; (v) Are there hormone related treatments that can stabilize fluctuations in MS symptoms; and (vi) How does MS fatigue impact parenting strategies.
CONCLUSION
Priorities for research relating to women's health issues for persons with MS have been delineated using a collaborative process with key partners. Alignment of future research with these priorities should be monitored.
PubMed: 38440114
DOI: 10.3389/fneur.2024.1355817 -
Life (Basel, Switzerland) Jul 2023Decoy cells that can be detected in the urine sediment of immunosuppressed patients are often caused by the uncontrolled replication of polyomaviruses, such as BK-Virus...
Decoy cells that can be detected in the urine sediment of immunosuppressed patients are often caused by the uncontrolled replication of polyomaviruses, such as BK-Virus (BKV) and John Cunningham (JC)-Virus (JCV), within the upper urinary tract. Due to the wide availability of highly sensitive BKV and JCV PCR, the diagnostic utility of screening for decoy cells in urine as an indicator of polyomavirus-associated nephropathy (PyVAN) has been questioned by some institutions. We hypothesize that specific staining of different infection time-dependent BKV-specific antigens in urine sediment could allow cell-specific mapping of antigen expression during decoy cell development. Urine sediment cells from six kidney transplant recipients (five males, one female) were stained for the presence of the early BKV gene transcript lTag and the major viral capsid protein VP1 using monospecific antibodies, monoclonal antibodies and confocal microscopy. For this purpose, cyto-preparations were prepared and the BK polyoma genotype was determined by sequencing the PCR-amplified coding region of the VP1 protein. lTag staining began at specific sites in the nucleus and spread across the nucleus in a cobweb-like pattern as the size of the nucleus increased. It spread into the cytosol as soon as the nuclear membrane was fragmented or dissolved, as in apoptosis or in the metaphase of the cell cycle. In comparison, we observed that VP1 staining started in the nuclear region and accumulated at the nuclear edge in 6-32% of VP1 cells. The staining traveled through the cytosol of the proximal tubule cell and reached high intensities at the cytosol before spreading to the surrounding area in the form of exosome-like particles. The spreading virus-containing particles adhered to surrounding cells, including erythrocytes. VP1-positive proximal tubule cells contain apoptotic bodies, with 68-94% of them losing parts of their DNA and exhibiting membrane damage, appearing as "ghost cells" but still VP1. Specific polyoma staining of urine sediment cells can help determine and enumerate exfoliation of BKV-positive cells based on VP1 staining, which exceeds single-face decoy staining in terms of accuracy. Furthermore, our staining approaches might serve as an early readout in primary diagnostics and for the evaluation of treatment responses in the setting of reduced immunosuppression.
PubMed: 37511901
DOI: 10.3390/life13071526 -
Open Forum Infectious Diseases Nov 2023Data on modified Vaccinia Ankara (MVA) vaccine effectiveness against mpox in real-world settings are limited.
BACKGROUND
Data on modified Vaccinia Ankara (MVA) vaccine effectiveness against mpox in real-world settings are limited.
METHODS
We performed a retrospective cohort analysis using Cox proportional hazards regression to estimate the association between vaccination and laboratory-confirmed mpox incidence. Study subjects included all men who have sex with men seen in a sexual health clinic in Seattle, Washington, between 1 January 2020 and 31 December 2022. Subjects' receipt of vaccine and diagnosis with mpox were ascertained from public health vaccine registry and surveillance data. Analyses were adjusted for demographic factors, human immunodeficiency virus (HIV) status, and sexual risk behaviors.
RESULTS
The incidence of mpox per 100 person-years was 8.83 among patients with 0 doses, 3.32 among patients with 1 dose, and 0.78 among patients with 2 doses of MVA vaccine. Mpox diagnosis was significantly associated with age category 30-39 and 40-51 years, HIV positivity, syphilis diagnosis in the prior year, >10 sex partners in the last year, and having a clinic visit in the last year. In the multivariate model adjusting for these factors, vaccine effectiveness was 81% for 1 dose and 83% for 2 doses.
CONCLUSIONS
These data support the effectiveness of the MVA vaccine-including a single dose of the vaccine-in preventing mpox disease and highlight the appropriateness of risk factor-based prioritization of immunization early in the epidemic. The durability of MVA vaccine-induced immunity is unknown, and at-risk persons should receive 2 doses of MVA.
PubMed: 37942460
DOI: 10.1093/ofid/ofad528 -
Perspectives in Public Health Jul 2023Development and rollout of vaccines offers the best opportunity for population protection against the SARS-CoV-2 (COVID-19) virus. However, hesitancy towards the...
AIMS
Development and rollout of vaccines offers the best opportunity for population protection against the SARS-CoV-2 (COVID-19) virus. However, hesitancy towards the vaccines might impede successful uptake in the United Kingdom, particularly in young adults who demonstrate the highest rates of hesitancy. This prospective study explored COVID-19 vaccine hesitancy in young adults and whether the reasons behind these attitudes changed during the initial stages of the United Kingdom's vaccine rollout.
METHOD
Data on vaccination intention were collected from a British university student cohort at three time points: October 2020, February 2021, and March 2021. This online survey included items on intention to receive a vaccine and a free-text response for the reasons behind this intention. Cochran's Q tests examined changes in rates of hesitancy and acceptance over time and free-text responses were analysed thematically.
RESULTS
At baseline, 893 students provided data, with 476 participants completing all three time points. Hesitancy declined over time, with 29.4% of participants expressing hesitancy at baseline, reducing to 9.1% at wave 2 and 5.9% at wave 3. The most commonly endorsed themes for those willing to accept a vaccine were self-protection against COVID-19 and pro-social reasons, including protecting the population or unspecific others, and ending the pandemic/returning to normal life. The most commonly endorsed hesitancy themes related to 'confidence' in the vaccines and potential personal risk, including insufficient testing/scientific evidence, concern about side effects, and long-term effects. These reasons remained the most commonly endorsed at both waves 2 and 3.
CONCLUSIONS
While a decline in hesitancy was observed over time, the key reasons behind both vaccine acceptance and hesitancy remained consistent. Reasons behind hesitancy aligned with those of the general public, providing support for the use of generalist interventions. Pro-social reasons frequently underpinned vaccine acceptance, so cohort-specific interventions targeting those factors may be of benefit.
Topics: Young Adult; Humans; COVID-19 Vaccines; Prospective Studies; COVID-19; SARS-CoV-2; Vaccines
PubMed: 35575215
DOI: 10.1177/17579139221094750 -
European Journal of Pharmacology Jan 2024Respiratory syncytial virus (RSV) pneumonia is the main cause of acute bronchiolitis in infants. Luteolin-7-O-glucoside (LUT-7G) is a natural flavonoid, which exists in...
Respiratory syncytial virus (RSV) pneumonia is the main cause of acute bronchiolitis in infants. Luteolin-7-O-glucoside (LUT-7G) is a natural flavonoid, which exists in a variety of plants and has the potential to treat viral pneumonia. We established RSV pneumonia mouse models and RSV-infected cell models. Clodronate liposomes were used to deplete macrophages. We used HE staining and immunohistochemistry to determine inflammatory damage and virus replication. We detected the expression levels of inflammatory factors and IFN-β through qPCR and ELISA. JC-1 kit was used for detecting the cell mitochondrial Membrane potential (MMP). ROS, SOD, and MDA kits were used for detecting intracellular oxidative stress damage. Metabolites of TCA in lung tissue and serum of mice were detected by GC-MS. Pharmacodynamic studies have shown that intervention with LUT-7G can alleviate lung tissue damage caused by RSV infection, inhibit RSV replication, and downregulate TNF-α, IL-1β, and IL-6 mRNA expression. LUT-7G upregulated the IFN-β content and the expression of IFN-β, ISG15, and OAS1 mRNA. In vitro, LUT-7G inhibited RSV-induced cell death, reversed the RSV-induced decrease of MMP and decreased intracellular oxidative stress. Target metabonomics showed that RSV infection upregulated the levels of glycolysis and TCA metabolites in lung tissue and serum, while LUT-7G could improve the disorder of glucose metabolism. The results indicate that LUT-7G can promote the release of IFN-β in the lung, alleviate inflammatory damage, and inhibit RSV replication during RSV infection. These effects may be achieved by protecting the mitochondrial function of alveolar macrophages and correcting the disorder of glucose metabolism.
Topics: Animals; Humans; Mice; Glucose; Macrophages; Pneumonia; Respiratory Syncytial Virus Infections; RNA, Messenger; Luteolin; Interferon-beta; Mitochondria
PubMed: 38113965
DOI: 10.1016/j.ejphar.2023.176271 -
Annals of Internal Medicine Feb 2024The efficacy of the BNT162b2 vaccine in pediatrics was assessed by randomized trials before the Omicron variant's emergence. The long-term durability of vaccine... (Observational Study)
Observational Study
BACKGROUND
The efficacy of the BNT162b2 vaccine in pediatrics was assessed by randomized trials before the Omicron variant's emergence. The long-term durability of vaccine protection in this population during the Omicron period remains limited.
OBJECTIVE
To assess the effectiveness of BNT162b2 in preventing infection and severe diseases with various strains of the SARS-CoV-2 virus in previously uninfected children and adolescents.
DESIGN
Comparative effectiveness research accounting for underreported vaccination in 3 study cohorts: adolescents (12 to 20 years) during the Delta phase and children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase.
SETTING
A national collaboration of pediatric health systems (PEDSnet).
PARTICIPANTS
77 392 adolescents (45 007 vaccinated) during the Delta phase and 111 539 children (50 398 vaccinated) and 56 080 adolescents (21 180 vaccinated) during the Omicron phase.
INTERVENTION
First dose of the BNT162b2 vaccine versus no receipt of COVID-19 vaccine.
MEASUREMENTS
Outcomes of interest include documented infection, COVID-19 illness severity, admission to an intensive care unit (ICU), and cardiac complications. The effectiveness was reported as (1-relative risk)*100, with confounders balanced via propensity score stratification.
RESULTS
During the Delta period, the estimated effectiveness of the BNT162b2 vaccine was 98.4% (95% CI, 98.1% to 98.7%) against documented infection among adolescents, with no statistically significant waning after receipt of the first dose. An analysis of cardiac complications did not suggest a statistically significant difference between vaccinated and unvaccinated groups. During the Omicron period, the effectiveness against documented infection among children was estimated to be 74.3% (CI, 72.2% to 76.2%). Higher levels of effectiveness were seen against moderate or severe COVID-19 (75.5% [CI, 69.0% to 81.0%]) and ICU admission with COVID-19 (84.9% [CI, 64.8% to 93.5%]). Among adolescents, the effectiveness against documented Omicron infection was 85.5% (CI, 83.8% to 87.1%), with 84.8% (CI, 77.3% to 89.9%) against moderate or severe COVID-19, and 91.5% (CI, 69.5% to 97.6%) against ICU admission with COVID-19. The effectiveness of the BNT162b2 vaccine against the Omicron variant declined 4 months after the first dose and then stabilized. The analysis showed a lower risk for cardiac complications in the vaccinated group during the Omicron variant period.
LIMITATION
Observational study design and potentially undocumented infection.
CONCLUSION
This study suggests that BNT162b2 was effective for various COVID-19-related outcomes in children and adolescents during the Delta and Omicron periods, and there is some evidence of waning effectiveness over time.
PRIMARY FUNDING SOURCE
National Institutes of Health.
Topics: United States; Humans; Adolescent; Child; BNT162 Vaccine; COVID-19 Vaccines; COVID-19; Comparative Effectiveness Research; Hospitalization
PubMed: 38190711
DOI: 10.7326/M23-1754