Methodological Considerations in Evaluating Recombinant Zoster Vaccine Effectiveness in COPD PatientsDear Editor,We read with great interest the article by Tsai et al. addressing the effectiveness of recombinant zoster vaccine (RZV) in chronic obstructive pulmonary disease (COPD) patients[1]. This study highlights the significantly lower risk of herpes zoster among vaccinated COPD patients (HR, 0.62; 95% CI, 0.51–0.75) and importantly draws attention to the concerningly low vaccination rate (<0.5%) in this high-risk population. While these findings provide valuable evidence supporting RZV vaccination in COPD patients, several methodological considerations warrant discussion to strengthen future research in this area.First, there appears to be a discrepancy regarding the study population selection. While the limitations section suggests the inclusion of predominantly U.S. patients, the flow chart indicates data incorporation from five countries. This inconsistency is critical as zoster vaccine implementation and availability varied substantially across countries[2]. For instance, different countries introduced RZV at varying times following its initial U.S. approval in 2017. Additionally, countries have different histories with the live-attenuated zoster vaccine (ZVL); some countries primarily used ZVL, while others transitioned to or directly implemented RZV as their preferred choice[2]. Recent methodological analyses have demonstrated how differential timing of vaccine availability across regions creates systematic selection bias in vaccine effectiveness studies[3]. The composition of vaccinated and unvaccinated groups becomes intrinsically linked to geographical location and timing of vaccine introduction, potentially confounding the effectiveness estimates[3]. In this study, countries with later RZV implementation would contribute proportionally more patients to the unvaccinated group during their pre-implementation period, while early-adopting countries like the U.S. would contribute more to the vaccinated group. A clear breakdown of the temporal and geographical distribution of both vaccinated and unvaccinated groups, along with country-specific vaccination policies, would help assess the impact of this systematic bias.Second, while propensity score matching was employed, several important confounders were not addressed. The study could have benefited from an active comparator design, such as using influenza vaccine recipients as the reference group. This approach would help control for unmeasured confounding factors related to healthcare access and health-seeking behavior, which are known to affect the validity of observational studies[4]. Additionally, important clinical variables such as COPD exacerbation frequency and healthcare utilization patterns were not included in the matching process.Finally, since COPD severity and medication use could potentially influence vaccine effectiveness, we suggest performing stratification analyses. Previous research has demonstrated that COPD patients have varying risks of herpes zoster depending on disease severity and medication regimens, particularly corticosteroid use[5]. Separating analyses based on GOLD stages and medication use patterns would provide more nuanced insights into vaccine effectiveness across different patient subgroups and help identify those who might benefit most from vaccination.These methodological refinements would strengthen the evidence base for RZV use in COPD patients and better inform clinical decision-making. We commend the authors for addressing this important clinical question and hope these suggestions contribute to future research in this area.Bor-Yun Wang, MD1; James Cheng-Chung Wei, MD, PhD1,2*1 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan2 Division of Allergy, Immunology and Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan*Corresponding author: James Cheng-Chung Wei, MD, PhD Division of Allergy, Immunology and Rheumatology Chung Shan Medical University Hospital No. 110, Sec. 1, Jianguo N. Rd., South District Taichung City 402, Taiwan. Email: jccwei@gmail.com ORCID: 0000-0002-1235-0679

Evolutionary Adaptations in H5N1 Influenza: Implications for Human Health and Surveillance StrategiesPrasanta Raghab Mohapatra, MD, FAMS, FRCP(London), FRCP (Glasg), FACP(USA), FCCP(USA), FIDSA(USA), ATSF(USA), Dean (Academic) and Professor & Head of Pulmonary Medicine & Critical Care, 

Epstein-Barr virus (EBV) is the first human cancer-causing viral pathogen to be discovered; it has been epidemiologically associated with a wide range of diseases, including cancers, autoimmunity and hyperinflammatory disorders. Its evolutionary success is underpinned by coordinated expression of viral transcription factors (EBV nuclear antigens), signaling proteins (EBV latent membrane proteins) and non-coding RNAs, which orchestrate cell transformation, immune evasion and dissemination. Each of those activities entail significant metabolic rewiring, which is achieved by viral subversion of key host metabolic regulators such as mammalian target of rapamycin (mTOR), MYC and hypoxia-inducible factor (HIF). In this review, we systemically discuss how EBV-encoded factors regulate metabolism to achieve viral persistence and propagation, as well as potential research questions and directions in EBV-driven metabolism.

In cervical cancer screening, cytology is used as a triage test to refer high-risk human papillomavirus (HR-HPV)-positive women for colposcopy, but its accuracy is inadequate. The present study aimed to demonstrate that the presence of atypical cells with large vacuoles in the cytoplasm of parabasal cells, referred to as vacuolated parabasal cells (VPCs), observed in the Pap smears of HPV-positive women is associated with specific HPV genotypes. Among 2175 patients, 310 with a single HR-HPV infection and cytological diagnosis of high-grade squamous intraepithelial lesions (HSIL) or atypical squamous cells not excluding HSIL (ASC-H) were included, of which 86 were infected with HPV16. Biopsy results revealed that 69 (80.2%) patients had cervical intraepithelial neoplasia Grade 2 or higher (CIN2+). VPCs were found in 47 (54.7%) of HPV16-infected cases, indicating a significant increase of VPCs in HPV16-infected cases ( p < 0.01). Episomal HPV16 load was quantified in 142 VPCs and 156 HSIL (ASC-H) cells using LBC samples from five patients, with a median of 987 copies in VPCs, significantly higher than those in HSIL (ASC-H) cells (176 copies; p < 0.001). VPCs in Pap specimens were identified not only as cells altered by HPV16 infection but also as CIN2+-derived cells and HPV16-producing cells.

Background It is unclear whether iron levels affect BKPyV reactivation after kidney transplantation. Our goal is to analyze the relationship between preoperative iron levels in kidney transplant recipients and postoperative BK virus reactivation. Additionally, we aim to develop and validate a personalized prediction model for BK virus reactivation. Methods We retrospectively analyzed the relationship between preoperative iron levels and BK virus reactivation in 626 kidney transplant recipients. The cohort was randomly divided into a training cohort and a validation cohort in a 2:1 ratio. Independent risk factors associated with BK virus reactivation were identified in the training cohort using COX proportional hazards regression. Based on the analysis results, a nomogram was constructed to develop individualized risk prediction models for BK viremia and BK virus nephropathy. Results Among the 626 kidney transplant recipients, 38 cases (6.1%) of BK viremia and 18 cases (2.9%) of BK virus nephropathy were diagnosed. Univariate analysis revealed that UIBC, TIBC, and TSAT were associated with the occurrence of BK viremia and BKPyVAN. In the training cohort, multivariate analysis showed that preoperative TSAT was an independent risk factor for BK viremia (1.03 [1.01-1.05], P=0.009) and BK virus nephropathy (1.05 [1.01-1.09], P=0.011). The C-index for the nomogram model predicting BK viremia and BK virus nephropathy after kidney transplantation was 0.77 and 0.82 in the training cohort, and 0.88 and 0.92 in the validation cohort, respectively. Conclusions Preoperative transferrin saturation levels in kidney transplant recipients are closely associated with the reactivation and progression of BK virus after transplantation.

Background: Acute-on-chronic liver failure (ACLF) is a disease characterized by systemic inflammatory response with high mortality. Nowadays, there is no prediction model for its long-term prognosis. We aimed to establish and validate a prognostic prediction model incorporating inflammation indexes to forecast the long-term prognosis of patients with hepatitis B-related ACLF (HBV-ACLF). Methods: Retrospective analysis of 986 patients’ clinical data with HBV-ACLF from Third Affiliated Hospital of Sun Yat-sen University between January 2014 and December 2018 were conducted. The patients were randomly divided into the training cohort (690 cases) and the validation cohort (296 cases) according to the ratio of 7:3. LASSO and Cox regression analysis were used to determine the independent risk factors for long-term mortality. Results: The following variables were identified: age, cirrhosis, hepatic encephalopathy, total bilirubin (TBIL), international normalized ratio (INR), Monocyte to lymphocyte ratio (MLR), and Neutrophil to platelet ratio (NPR), and a new nomogram was constructed to predict the survival rate of 1 -month, 3-month, and 12-month by weighting the scores of each variable. The C-index was 0.777 (95%CI 0.752-0.802), and the AUC was 0.829 (95%CI 0.798-0.859) in the training cohort. The predictive value of the nomogram demonstrated a superior ability to predict long-term survival rate compared to MELD score (0.767, 95% CI: 0.730-0.804, P<0.001), and COSSH-ACLF II score (0.807, 95%CI: 0.774-0.840, P=0.028). Evaluation using calibration curves and decision curve analysis (DCA) suggested its practical utility. Conclusions: The novel inflammation scoring system, including MLR and NPR, can well predict long-term mortality in HBV- ACLF patients.

A thorough and precise comprehension understanding of the HIV epidemic is crucial for effective HIV prevention and control. We used Estimation and Projection Package (EPP)/Spectrum software to update the estimates of the overall HIV burden in China in 2018 from the obtained data from more than 1800 HIV sentinel surveillance sites, population-based seroprevalence surveys, and HIV screening of antenatal clinics and pre-marital medical check-ups across the country. In 2018, the total number of PLWH adults in China was estimated to be 1·23 million, corresponding to approximately 106.5/100,000. Over a half PLWH (58·6%) were infected through heterosexual contact, about one-third (30·2%) through male-to-male transmission, 9·0% through IDU, and 2·3% due to former plasma donation. In recent years, the number of new infections through blood donation has been eliminated, and the number of infections through injecting drug use has been kept low. Sexual contact became the predominant transmission route, while casual sexual contact became increasingly common. Overall, HIV mortality has been steadily increasing and has recently begun to decline during 2012-2018. The number of deaths from HIV/AIDS in 2018 was approximately 35 000 (95% UI: 30 000-41 000). The number of estimated PLWH in China has exceeded one million, due to the ongoing occurrence of new infections and longer survival rates. HIV transmission through blood products has been eradicated. Casual sex has become a significant mode of transmission. It is recommended to enhance the implementation of strategies and measures for sexual communication in the general population and to bolster multidisciplinary research.

Background: Human Immunodeficiency Virus (HIV), Human T Lymphotropic Virus (HTLV), Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) coinfection may lead to disease progression or worsen its clinical presentation. Viral coinfections screening during blood donation is critical. Methods: To identify risk factors for coinfection among blood donors, we assessed the blood donations at the Fundação de Hematologia e Hemoterapia da Bahia, from 2008 – 2017. We compared single infection versus coinfection, defined as individuals with two or more blood-borne viruses. A multivariable logistic regression model was performed to evaluate independent associations between characteristics of donors with single infection and multiple infection using “non-infection” category as reference. Results: Among 777,446 collected blood donations, 27,458 (3.5%) were reactive, most (n=26,677, 97.6%) for a single infection and 681 (2.4%) for coinfection. The most frequent coinfections were HBV-HIV (30.6%), HBV-HCV (30.4%), and HBV-HTLV (24.4%). Male sex, lower education, being single, and being a first-time donor were independently associated with both single and coinfection. Nevertheless, the adjusted odds for risk factors of coinfection were notably higher than for single infection. Conclusions: Single and coinfection shared identical risks, but they were significantly higher for coinfection. Preventive strategies addressing the identified risks can decrease transmission of blood-borne viruses via blood transfusion.

Introduction BK polyomavirus-associated nephropathy (BKPyVAN) is a well-known complication of kidney transplantation (KTx).The mainstay of prevention is reduction of immunosuppression upon detection of BK polyomavirus (BKPyV) viremia, which precedes BKPyVAN. However, this reduction may inadvertently increase the risk of alloimmunity particularly in patients with a high BKPyV load, where significant immunosuppression reduction is often necessary. This single-center, retrospective cohort study assesses the risk of de novo donor-specific antibodies (dnDSA) development and biopsy-proven acute rejection (BPAR) following high and low BKPyV viremia. Methods All patients who underwent KTx at Leiden University Medical Center between 2011 and 2020 were included. Patients were grouped according to high (maximum BKPyV serum load >10E4 copies/ml), low (maximum serum BKPyV load <10E4 copies/ml) and absent BKPyV viremia, and analyzed for the development of dnDSA and BPAR, using Cox regression. Results Of 1076 KTx recipients included, 108(10%) developed a BKPyV viremia with a maximum serum load below 10E4 copies/ml, whereas 121(11.2%) developed a BKPyV viremia exceeding 10E4 copies/ml. The risk of dnDSA development was higher in patients with a high BKPyV viremia, compared to patients without viremia (adjusted Hazard Ratio of 1.9(95% CI1.1-3.2, p=0.017). No significant difference in dnDSA risk was observed between patients with low and absent BKPyV viremia. Risk of BPAR did not differ between groups. Conclusion Our study shows that higher BKPyV loads in KTx patients are associated with a higher risk for dnDSA development, highlighting the importance of exploring additional strategies for the prevention and treatment of BKPyV infections in KTx recipients.

Epstein-Barr virus (EBV) is a ubiquitous human ɣ-herpesvirus implicated in various malignancies, including Burkitt’s lymphoma and gastric carcinomas. In most EBV-associated cancers, the viral genome is maintained as an extrachromosomal episome by the EBV nuclear antigen-1 (EBNA1). EBNA1 is considered to be a highly stable protein that interacts with the ubiquitin-specific protease 7 (USP7). Here, we show that pharmacological inhibitors and small interfering RNA (siRNA) targeting USP7 reduce EBNA1 protein levels. The USP7 inhibitor GNE6776 altered EBNA1 protein interactions, including disrupting its ability to bind to USP7. GNE6776 also inhibited EBNA1 binding to EBV oriP DNA and reduced viral episome copy number. GNE6776 selectively inhibited EBV + gastric and lymphoid cell proliferation in cell culture and slowed EBV+ tumor growth in mouse xenograft models. Transcriptomic studies revealed that USP7 inhibition differentially affected EBV + cancer cells compared to EBV - cells with a significant effect on chromosome segregation and mitotic cell division pathways. Our findings indicate that USP7 inhibition perturbs EBNA1 stability and function and can be exploited to target EBV + cancer cells selectively.

A document by Joowon Lee. Click on the document to view its contents.

Objective: A significant increase in Parvovirus B 19 (B19V) infections has been reported in the last months in some European countries. This outbreak could be highly detrimental for pregnant women, considering the capacity of the virus to harm the fetus. However, the magnitude and spread of this outbreak is yet unclear. There is the need for more evidence from other areas and focusing on pregnancy. Methods: Pregnant women with B19V infection who were managed in a referral hospital located in Milan, Northern Italy were reviewed. The primary aim was recording the frequency of ascertained cases of B19V infection in the period January-July 2024 and comparing these data to the frequencies recorded in the previous 9 years (2015-2023). The secondary aim of the study was comparing the severity of the infections in these two periods. Results: The number of B19V infections markedly increased in the first 7 months of 2024. Until 2023, the number of cases per year were below 7, with no cases reported in 2020-2022, while in the period January-July 2024, the number raised to 59 (p<0.001). Maternal characteristics and fetal outcomes before and after January 2024 did not differ. Conclusions: Italy is also involved in the ongoing outbreak of B19V infection and pregnant women are exposed to this threat. Public health authorities must promptly engage to monitor the situation and consider the possibility to introduce universal screening and global preventive measures, at least up to the end of the surge.

Oncolytic viruses are emerging as promising cancer therapeutic agents, with several poxviruses, including vaccinia virus (VACV) and myxoma virus, showing significant potential in preclinical and clinical trials. Modified vaccinia virus Ankara (MVA), a laboratory-derived VACV strain approved by the FDA for mpox and smallpox vaccination, has been shown to be incapable of replicating in human cells unless zinc finger antiviral protein (ZAP) is repressed. Notably, ZAP deficiency is prevalent in various cancer types. We hypothesized that MVA could selectively target and replicate in ZAP-deficient cancer cells. Our study examined MVA’s replication across multiple cancer cell lines with varying ZAP expression levels, revealing that MVA replicates more efficiently in cells with lower ZAP expression. Additionally, we assessed MVA’s oncolytic potential using a xenograft mouse model, where cancer cells were transplanted into immunodeficient mice. The data demonstrated that MVA significantly reduced tumors with lower ZAP expression without causing morbidity in nude mice. These findings suggest that MVA holds promise for further development as a targeted therapy for ZAP-deficient cancers.

Background: Inter-genogroup reassortment of Rotavirus A (RVA) strains has highlighted the spread of unusual RVA strains worldwide. We previously reported the equine-like G3 RVA as predominant strains in Indonesia in 2015-2016. However, since July 2017, typical human genotypes G1 and G3 have replaced these strains completely. To understand how dynamic changes in RVA occur in Indonesia, we performed a detailed epidemiological study. Main body: A total of 356 stool specimens were collected from hospitalized children in Sidoarjo, Indonesia between 2018 and 2022. Whole-genome sequencing was performed for all 26 RVA-positive samples using next-generation sequencing. Twenty-four samples were determined to be the unusual RVA G9P[4], while 2 were G9P[6]. Detailed analysis revealed that seven G9P[4] strains had the typical DS-1-like backbone, while the other strains exhibited a double-reassortant profile (G9-N1) on the DS-1-like backbone. The Bayesian evolutionary analyses suggested that the Indonesian G9P[4] strains share a common ancestor with previously reported G9P[4] strains in the VP7 and VP4 genes. Conclusions: G9P[4] DS-1-like strains were identified as the predominant genotype in Indonesia in 2021 for the first time. These results suggest that the G9P[4] strains were generated from the previous G9P[4] strains that had undergone further intra-reassortments with the other circulating strains.

Torque Teno virus (TTV) load is linked with the functionality of its host’s immune system and has been proposed as a potential monitoring tool for immune-modulating therapy. However, the immunological mechanisms of TTV control are incompletely understood. To assess the effect of the classical complement pathway on TTV, 64 healthy volunteers and 10 kidney transplant recipients treated with the anti-C1s antibody sutimlimab were analyzed for serum TTV copy numbers (c/mL) by qPCR. Overall, a correlation was observed between the decrease in complement activity caused by sutimlimab and the TTV load increase (ρ = −0.367, p < 0.001). Subgroup analysis indicated a trend toward TTV load increase in healthy volunteers following the highest sutimlimab dose compared to baseline (100 mg/kg body weight; median 3.5 log 10 c/mL, interquartile range [IQR] 2.8–4.4 versus 2.9 log 10 c/mL, 0.8–3.5; p = 0.063). Administering multiple lower doses (30 mg/kg) also showed a trend toward TTV load increase in healthy volunteers (1.8 log 10 c/mL, 0–2.3 versus 1.9, 1.3–2.8; p = 0.054) and a significant increase in transplant recipients (3.5 log 10 c/mL, 3.0–6.1 versus 4.1, 3.5–6.4; p = 0.004). This report suggests a role for the classical complement pathway in controlling TTV load.

SARS-CoV-2 continues to mutate, leading to breakthrough infections. The development of new vaccine strategies to combat variant strains is crucial. Protein cyclization can enhance thermal stability and may improve immunogenicity. Here, we designed a cyclic tandem dimeric receptor-binding domain protein (cirRBD2) using the split intein Cth-Ter. Cyclization does not affect the antigen epitopes of the RBD but results in better thermal stability than that of its linear counterpart (linRBD2). Compared with those immunized with linRBD2, mice immunized with two doses of 5 μg of cirRBD2 produced significantly greater levels of broad-spectrum neutralizing antibodies than those immunized with linRBD2 and generated a considerable cellular immune response. In the VEEV-VRP-hACE2-transduced mouse model, two doses of 5 μg of cirRBD2 provided protection against infection with BA.5, XBB.1.9, and partial against EG.5 which has more mutations. This study developed a novel circular RBD dimer subunit vaccine for SARS-CoV-2 that exhibits broad-spectrum neutralizing activity against various variants. A similar strategy can be applied to develop vaccines for other pathogens, especially for thermally stable vaccines.

Tick-borne encephalitis virus (TBEV) can cause life-threatening CNS infection. Changes in cerebrospinal fluid (CSF) metabolites may reflect critical aspects of host responses and end-organ damage in neuro infection and neuroinflammation. In this study, we applied an untargeted metabolomics screen of CSF samples to investigate the metabolites profile and explore biomarkers for TBEV infection. By analyzing CSF samples from 77 patients with TBEV infection and 23 without TBEV infection, tryptophan metabolism and Citrate cycle were found to be the top important metabolic pathways in differentiating the control and case groups; acetoacetate, 5’-deoxy-5’-(methylthio)-adenosine, 3-methyl-2-oxobutanoic acid,etc. were identified to be metabolic biomarkers（| log 2 FC|>1,VIP>1,FDR<0.05）in CSF and clearly separated the TBEV infection from the non-infected samples. Moreover, four metabolites were identified to be associated with fatal outcome, including kynurenic acid, 5-hydroxyindole-3-acetic acid, DL-tryptophan, indole-3-acrylic acid, demonstrating the potential predictive biomarkers for severe TBEV infection. This study explored the metabolic profile of TBEV infection both in CSF samples and identified candidate biomarkers for TBEV infection, which might be useful in target screening for differential diagnosis and therapeutic inter-vention.

Background: Herpes Simplex Virus (HSV) infections, primarily caused by HSV-1 and HSV-2, are prevalent worldwide and carry significant health implications. The impact of tobacco use on HSV infections, however, remains underexplored. Methods: This cross-sectional study utilized the National Health and Nutrition Examination Survey (NHANES) database (2009-2016) to investigate the link between Tobacco use and HSV infections among U.S. adults. Smoking status, volume, and serum cotinine levels were analyzed, alongside demographic and behavioral factors. Propensity score matching (PSM) was employed to adjust for confounders such as sexual behavior. Results: Our study involved 5,693 participants to explore the relationship of tobacco use and HSV infection. We found that smokers, particularly current smokers, have a significantly increased risk of both HSV-1 and HSV-2 infections compared to non-smokers. Specifically, the adjusted odds ratio (OR) for HSV-1 in current smokers was 1.36 (95% CI: 1.16-1.59, p<0.001), and for HSV-2, it was 2.37 (95% CI: 1.88-3, p<0.001). The risk escalates with the intensity of smoking. Elevated serum cotinine levels correlated with an increased risk of HSV infection[HSV-1:1.13 (95% CI:1.09~1.18, p<0.001); HSV-2:1.33 (95% CI:1.25~1.41, p<0.001)]. After propensity score matching (PSM) for factors such as age, gender, sexual behavior, and condom use, these associations remained significant. Conclusion: Tobacco use is significantly associated with an increased risk of HSV infections, highlighting the importance of reducing tobacco exposure in public health strategies against HSV. Further longitudinal studies are warranted to establish causality and explore underlying mechanisms.