Changes In Titers Research Articles

218. Attenuated PreFusion F Antibody Response to RSV Vaccines in Solid Organ Transplant Recipients

Abstract Background RSV causes serious morbidity in solid organ transplant recipients (SOTRs). Novel RSV vaccines are highly protective in the general population, yet immunogenicity among SOTRs is unknown. Demographic and Transplant Characteristics of SOTRs Reporting RSV Vaccination Methods Within a national, prospective cohort study SOTRs submitted whole blood samples at baseline and 2, 4, and 12 weeks post receipt of RSV vaccination (RSVPreF3 [GSK, AREXVY™] or RSVpreF [Pfizer, ABRYSVO™]) between October 2023-March 2024. Plasma prefusion F IgG and IgM (preF Ab) was tested using the Meso Scale Discovery platform and compared between baseline and 4 weeks to assess fold-change (FC); the proportion achieving high-titer Ab (IgG ≥high-titer reference plasma [BEI Resources]) at 4 weeks was also assessed. Ab measures were compared between GSK and Pfizer vaccinees. Change in Prefusion F IgG Titers following RSV Vaccination in SOTRs Blue dots represent Pfizer vaccine recipients and pink dots represent GSK vaccine recipients. Individual titer trajectories are connected by grey lines. High-titer response is denoted by the upper red horizontal line, corresponding to high-titer pooled control plasma. Results Among 27 participants (median [IQR] age 65-73 years, 44% female, 59% GSK and 30% Pfizer vaccinees [11% unspecified]), median [IQR] preF IgG rose from 76,252 [59,116-185,845] to 424,618 [153,503-1,905,705] AU/mL by 4 weeks (median [IQR] FC 5.54 [2.06-13.26]). Overall, 67% demonstrated IgG FC ≥4 at 4 weeks (69% GSK vs 50% Pfizer vaccinees) and 52% demonstrated high-titer Ab at 4 week (62% GSK vs 25% Pfizer vaccinees); clinical and transplant factors were similar between response groups. By 12 weeks, 56% showed high-titer Ab (62% GSK vs 38% Pfizer vaccinees) (Figure). Response patterns varied, including greater IgM change from baseline to 4 weeks in GSK vaccinees (IgM FC ≥4: 31% GSK vs 25% Pfizer) and more pronounced IgG peak-and-wane in GSK vaccinees (median FC from 4 to 12 weeks 1.01 GSK vs 0.49 Pfizer). No participants reported RSV infection during follow up. Prefusion F IgG Titers pre and post RSV Vaccination in SOTRs, by Vaccine Type Blue dots represent Pfizer vaccine recipients and pink dots represent GSK vaccine recipients. High-titer response is denoted by the upper red horizontal line, corresponding to high-titer pooled control plasma. Open circles represent ≥ 4-fold change in titer at 4 weeks. Conclusion RSV preF Ab responses are highly variable and often attenuated in SOTRs following RSV vaccination; 44% did not show high-titer Ab at 4 weeks. Response level and pattern vary by vaccine platform (i.e., adjuvanted versus unadjuvanted), which may imply different risk periods post vaccination and potential role for additional vaccine doses to improve immunoprotection. Prefusion F IgM Titers pre and post RSV Vaccination in SOTRs, by Vaccine Type Blue dots represent Pfizer vaccine recipients and pink dots represent GSK vaccine recipients. Open circles represent ≥ 4-fold change in titer at 4 weeks. Disclosures Andrew H. Karaba, MD PhD, Hologic: Advisor/Consultant William Werbel, MD, AstraZeneca: Advisor/Consultant|AstraZeneca: Honoraria|IDSA: Advisor/Consultant|Novavax: Advisor/Consultant

P-2026. Obeldesivir for the Treatment of COVID-19 in People with Risk Factors for Progression to Severe Disease: the BIRCH Study

Abstract Background COVID-19 remains a serious condition, as the risk of severe outcomes increases with age and comorbid conditions. Early antiviral therapy has been shown to prevent disease progression. Obeldesivir (ODV) is an oral, broad spectrum, nucleoside analog prodrug inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase. Methods BIRCH was a Phase 3, double-blind, placebo-controlled study in adults with risk factors for developing severe COVID-19 who were randomized 1:1 to ODV 350 mg or placebo twice daily for 5 days. The primary endpoint was COVID-19-related hospitalization or all-cause death through Day 29. Other endpoints included time to symptom alleviation and change in viral load and infectious titer. Safety assessments included adverse events (AEs) and laboratory abnormalities. Results Study enrollment was stopped early, reflecting the evolving COVID-19 landscape with low rates of clinical events. Overall, 465 participants were randomized and received ≥1 dose. 56% were female, 4% were Black, 9% were American Indian or Alaska native, and 12% were Asian. Median age was 56 years; 29% were ≥65 years of age. 76% were randomized within 3 days of symptom onset, 42% had never been vaccinated, and 92% were SARS-CoV-2 seropositive. 90% were SARS-CoV-2 positive by nucleic acid amplification test at baseline for efficacy analyses. COVID-19-related hospitalization or all-cause death through Day 29 was reported in 0% for ODV (0/211 participants) and 0.5% for placebo (1/207 participants; P = 0.3161). Among the 162 participants who completed a symptom questionnaire, ODV showed a 2-day improvement in median time to symptom alleviation by Day 15 (ODV: 7.3 days; placebo: 9.3 days; P = 0.0859). ODV demonstrated greater reductions in viral load from baseline to Day 5 (–0.58 log10 copies/mL; P < 0.0001), and a greater proportion with negative infectious titer at Day 5 (ODV: 68/68 [100%]; placebo: 56/69 [81%]; P = 0.0001). The safety profiles of ODV and placebo were comparable, with similar rates of AEs, serious AEs, and AEs leading to discontinuation of study drug. Conclusion ODV treatment resulted in greater decreases in viral load and infectious titer, and a trend in faster time to symptom alleviation. In this population of participants with risk factors for severe COVID-19, ODV was generally safe and well tolerated. Disclosures Anca Streinu-Cercel, MD PhD Prof. Infectious Diseases, Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria Antonella Castagna, MD, Bristol-Myers Squibb: Advisor/Consultant|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Merck Sharp & Dohme: Advisor/Consultant|Merck Sharp & Dohme: Grant/Research Support|Merck Sharp & Dohme: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Honoraria Yiannis Koullias, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Afsaneh Mozaffarian, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Robert H. Hyland, DPhil, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Rita Humeniuk, PhD, Gilead Sciences, Inc.: Former Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Luzelena Caro, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Santosh Davies, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Charlotte Hedskog, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Shuguang Chen, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Kim Etchevers, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Nicole Behenna-Renton, BSc Hons, Gilead Science Europe Ltd: Employee|Gilead Science Europe Ltd: Stocks/Bonds (Public Company) Joe Llewellyn, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Anu Osinusi, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Frank Duff, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Jesus Abraham Simón Campos, MD, AstraZeneca: Advisor/Consultant|AstraZeneca: Honoraria|Lilly: Advisor/Consultant|Lilly: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Roche: Advisor/Consultant|Roche: Honoraria

Exploring the clinical significance of anti-acetylcholine receptor antibody titers, changes, and change rates in Myasthenia Gravis.

Myasthenia Gravis (MG) is a common neuromuscular junction disorder that is primarily mediated by anti-acetylcholine receptor antibodies (AChR-Ab). However, using AChR-Ab titers to predict MG severity and improvement remains controversial. This study aims to explore the relationship between AChR-Ab titers and AChR-Ab rate of change (RR-AChR-Ab, %) and MG scores. We used a prospective study approach, and included 62 patients with generalized MG (GMG) who were positive for AChR-Ab. We measured AChR-Ab titers, MGFA-QMGS, and MG-ADL scores at baseline (before treatment) and at 3 and 6 months into treatment. Pearson and Spearman correlation analyses were used to study the relationships between changes in AChR-Ab titers, rates of change, and MG scores. (1) At baseline, there was no correlation between AChR-Ab titers and age, duration of illness, gender, MGFA classification, or presence of thymic abnormalities. (2) The trend of decreasing AChR-Ab titers matched the trend of reduced QMGS and ADL scores. (3) Six months into treatment,there was a correlation between AChR-Ab titer changes and changes in ADL scores. (4) Three months into treatment, RR-AChRAb showed a correlation with the rate of change in ADL at the same time point. We found the trend of decreased AChR-Ab titers after standardized treatment that was consistent with reductions in QMGS and ADL scores. Additionally, the rate of change in AChR-Ab titers at 3 months and the change in AChR-Ab titers at 6 months into treatment did reflect improvements in activities of daily living for MG patients.

Identifcation of the genes involved in biofilm formation of Avibacterium paragallinarum using random transposon mutagenesis.

Infectious coryza (IC) is a respiratory disease in poultry caused by Avibacterium paragallinarum (Av. paragallinarum). The disease caused growth retardation in broilers and reduced egg production in laying hens, resulting in significant economic losses to the global chicken industry. The biofilm is an important virulence factor for many bacterial pathogens, yet there is a paucity of research on the biofilm of Av. paragallinarum. This study aimed to construct a random mutant library of Av. paragallinarum using the Tn5-Kan transposon to identify genes involved in biofilm formation. A total of approximately 3000 mutants were obtained, and 38 of them demonstrated a reduction in biofilm formation of 70-90 % by crystal violet staining. The transposon insertion sites were further determined by chromosome walking, and 17 functional genes related to biofilm formation were identified. According to the functional analysis of the mutated genes, 14 mutants with mutated genes associated with energy metabolism, cell membrane formation, gene transcription and translation, and material transmembrane transport were screened to further explore their biological characteristics and pathogenicity in vivo and in vitro. The results indicated that the growth performance, resistance to disinfectants, adhesion and invasion ability to DF-1 cells and pathogenicity of the 14 mutants were reduced. The 14 mutants displayed increased sensitivity to antibiotics but did not show significant changes in hemagglutination titer or antiserum bactericidal ability. It is noteworthy that the M-76 mutant exhibited a marked reduction in pathogenicity. Following challenge, the experimental chickens did not present any clinical symptoms or pathological changes for a period of seven days, and the respiratory tract bacterial shedding was also the lowest. This indicates that a deficiency in biofilm formation reduces the pathogenicity of Av. paragallinarum. This study will contribute to our understanding of the molecular mechanism of biofilm formation of Av. paragallinarum and further study the pathogenesis of Av. paragallinarum.

Updated diagnostic and therapeutic management for membranous nephropathy.

Pioneering contributions in membranous nephropathy over the last decade have greatly enhanced our comprehension of its pathogenesis, diagnosis, and treatments, igniting renewed interest in this entity. This review provides an updated perspective on the diagnosis and therapeutic management of membranous nephropathy. The identification of antiphospholipase A2 receptor (PLA2R) antibodies in 50-80% of membranous nephropathy patients was a key breakthrough. High or increasing PLA2R antibody levels are linked to persistent nephrotic syndrome and the need for targeted treatment. Given the high specificity of PLA2R antibodies, a kidney biopsy may not be required for pure nephrotic syndrome cases with no comorbidities. Over the years, various target antigens and associated conditions have been identified in membranous nephropathy patients, leading to a reclassification of membranous nephropathy. Treatment approaches vary based on baseline characteristics and changes in proteinuria and PLA2R titers. Rituximab has emerged as the first-line therapy for most patients without severe risk factors, with other emerging therapies under development. Advances in the diagnosis and treatment of membranous nephropathy have moved the management towards a more precision-based approach, though further studies and new therapies are needed for a comprehensive management strategy.

Original article: Efficacy and safety of single-dose suraxavir marboxil tablet in the treatment of acute uncomplicated influenza in adults: a multi-center, randomized, double-blind, placebo-controlled phase 2 clinical trial.

To evaluate the therapeutic effect of suraxavir marboxil (GP681, abbreviated as suraxavir) in adults with uncomplicated influenza. We conducted a multi-center randomized, double-blind, placebo-controlled phase 2 trial in 18 Chinese centers. Participants had to be aged 18-65years with positive influenza test, presenting with at least one influenza systemic and respiratory symptoms in at least moderate severity within 48hours of onset. Participants were randomly assigned in 1:1:1 to receive suraxavir 40 mg, 20 mg or placebo once. The primary outcome was defined as the time to alleviation of influenza symptoms (TTAS) (from treatment to normal body temperature and resolution of all 7 influenza symptoms for ≥21.5hours) within 15days. Our trial was registered at ClinicalTrials.gov (NCT04736758). From January 8, 2021, to December 18, 2021, 245 participants underwent randomization, and 203 (82.9%) were included in the intention-to-treat infected population, with median age of 29.0 (IQR 11.0) years and the most common virus of influenza B (99.5%, 202/203). The median TTAS was shorter in two suraxavir groups (40 mg: 50.0 [44.1, 71.9] hours; 20 mg: 46.1 [39.6, 58.2] hours) than placebo group (82.3 [67.9, 87.3] hours). The mean (±SD) changes in viral titers from baseline in the suraxavir 40mg group, suraxavir 20mg group and placebo group were -2.14±1.97, -1.48±2.01 and -0.69±1.98 log10 50% tissue culture infectious dose/mL by 1day after administration, respectively. The incidences of adverse events were similar in each group (47.2%, 34/72; 46.6%, 34/73; 53.5%,38/71). The most reported adverse event was diarrhea (7.6%, 11/145). Only one serious adverse event of pulmonary infection occurred in the placebo group. No I38T polymerase acidic protein variants were detected. In this trial, timely single-dose suraxavir was effective in improving clinical symptoms and accelerating viral clearance in adults with uncomplicated influenza B infection safely than placebo.

Predicting the infecting dengue serotype from antibody titre data using machine learning.

The development of a safe and efficacious vaccine that provides immunity against all four dengue virus serotypes is a priority, and a significant challenge for vaccine development has been defining and measuring serotype-specific outcomes and correlates of protection. The plaque reduction neutralisation test (PRNT) is the gold standard assay for measuring serotype-specific antibodies, but this test cannot differentiate homotypic and heterotypic antibodies and characterising the infection history is challenging. To address this, we present an analysis of pre- and post-infection antibody titres measured using the PRNT, collected from a prospective cohort of Thai children. We applied four machine learning classifiers and multinomial logistic regression to the titre data to predict the infecting serotype. The models were validated against the true infecting serotype, identified using RT-PCR. Model performance was calculated using 100 bootstrap samples of the train and out-of-sample test sets. Our analysis showed that, on average, the greatest change in titre was against the infecting serotype. However, in 53.4% (109/204) of the subjects, the highest titre change did not correspond to the infecting serotype, including in 34.3% (11/35) of dengue-naïve individuals (although 8/11 of these seronegative individuals were seropositive to Japanese encephalitis virus prior to their infection). The highest post-infection titres of seropositive cases were more likely to match the serotype of the highest pre-infection titre than the infecting serotype, consistent with antigenic seniority or cross-reactive boosting of pre-infection titres. Despite these challenges, the best performing machine learning algorithm achieved 76.3% (95% CI 57.9-89.5%) accuracy on the out-of-sample test set in predicting the infecting serotype from PRNT data. Incorporating additional spatiotemporal data improved accuracy to 80.6% (95% CI 63.2-94.7%), while using only post-infection titres as predictor variables yielded an accuracy of 71.7% (95% CI 57.9-84.2%). These results show that machine learning classifiers can be used to overcome challenges in interpreting PRNT titres, making them useful tools in investigating dengue immune dynamics, infection history and identifying serotype-specific correlates of protection, which in turn can support the evaluation of clinical trial endpoints and vaccine development.

Rheumatoid Factor Titer as an Indicator of the Risk of Rheumatoid Arthritis Activity: Dose-Effect Analysis with the Restricted Cubic Spline Model.

Rheumatoid factor (RF) titer is known to be correlated to rheumatoid arthritis (RA) activity, but the ideal cut-off titer of RF remains unclear. Here, the relationship between RF titer and RA activity was investigated in order to determine the ideal RF value indicative of the risk of RA activity. Clinical data from 2044 eligible patients were collected from the First Affiliated Hospital of Anhui Medical University from February 2022 to October 2023. A restricted cubic spline (RCS) model was used to evaluate the relationship between RF titer and RA activity. Data from a total of 2044 patients with RA were collected and analyzed. Multivariate logistic regression analysis revealed that higher RF levels were significant predictors of the risk of RA activity calculated according to the disease activity score 28 (DAS28)-erythrocyte sedimentation rate (ESR) (OR = 2.020, 95% CI = 1.457-2.801, P < 0.001) and DAS28-C reactive protein (CRP) (OR = 1.526, 95% CI = 1.092-2.131, P = 0.013), after the results were adjusted for potential covariates. The relationship between log2RF and the risk of RA activity was non‑linear in the RCS model (P < 0.05). The cutoff value of RF titers for determining the risk of RA activity was 65.80 IU/mL. When RF exceeded the cutoff value, the risk of RA activity based on DAS28-ESR increased by 99.2% and the risk of RA activity based on DAS28-CRP increased by 62.8% (P < 0.001). The risk of RA activity increased non-linearly with the continuous change in RF titer.

Vesicular transport-related genes in Diaphorina citri are involved in the process of Candidatus Liberibacter asiaticus infection

Asian citrus psyllid (ACP, Diaphorina citri) is the major vector of Candidatus Liberibacter asiaticus (CLas), which is a bacterial pathogen causing the devastating citrus Huanglongbing (HLB) disease. Diaphorina citri is known to carry CLas in a persistent and propagative manner. Some studies have suggested that CLas may use the vesicular structures of D. citri cells as its propagation organelles. However, the mechanisms by which CLas enters the D. citri cells and how vesicle-mediated trafficking is involved remain unclear. In this study, we monitored the titer change of CLas in D. citri nymphs during the process of CLas acquisition from feeding on infected citrus plants. We found that the titer of CLas increased with the acquisition access period. After infection, there was a significant upregulation in the expression of several vesicular transport-related genes in D. citri. The titer of CLas was significantly reduced in the midgut and whole insect body when endocytosis and the endosome network in D. citri were inhibited. Furthermore, silencing the D. citri clathrin-heavy chain gene also led to a reduction in the CLas titer in D. citri. These results suggest that CLas infection upregulates the genes related to vesicular transport in D. citri, which facilitates the invasion of endocytosis-dependent pathogens.

Different patterns of longitudinal changes in antinuclear antibodies titers in children with systemic lupus erythematosus and Sjögren's syndrome.

to investigate the trend of autoantibody titers during a 2-year follow-up in pediatric systemic lupus erythematosus (pSLE) and pediatric Sjögren's syndrome (pSS). Autoantibodies testing was performed every 3-4 months during 2 years from disease onset in a cohort of children with pSLE and pSS. We enrolled 21 children with pSLE and 22 children with pSS. All pSLE patients at 2 years showed ANA titers significantly lower compared to disease onset. Eleven patients (73%) were still ANA positive at 2 years, while 4 (26%) became ANA negative. At diagnosis, 12 (80%) patients showed a homogeneous pattern, while 3 (20%) patients showed a speckled pattern. The latter remained ANA positive with the same pattern; only 2 patients with a homogenous pattern converted to speckled, 4 patients with a homogeneous pattern became ANA negative. ANA negative pSLE patients showed lower levels of interferon score compared to ANA positive patients. Anti-dsDNA titers declined equally in the two groups. All patients with pSS, at disease onset, were ANA and anti-Ro positive and 14 (66%) were anti-La positive. After 2 years of follow-up, 100% remained ANA positive but showed significant lower titers. During follow-up anti-Ro and anti-La titers remained stable. different patterns in changes of ANA and ENA titers in pSLE and pSS were shown. At 2 years of follow-up, all pSLE patients had a lower ANA titer and 26% became negative; however, all pSS patients remained both ANA and ENA positive. This evidence may be due to different pathogenetic pathways in SLE and pSS.

Age-Dependent Pathogenesis of Influenza A Virus H7N9 Mediated Through PB1-F2-Induced Mitochondrial DNA Release and Activation of cGAS-STING-NF-κB Signaling.

Exactly why human infection of avian influenza A virus H7N9 causes more severe disease in the elderly remains elusive. In this study, we found that H7N9 PB1-F2 is a pathogenic factor in 15-18-month-old BALB/C mice (aged mice) but not in 6-8-week-old young adult mice (young mice). Recombinant influenza A virus with H7N9 PB1-F2-knockout was less pathogenic in aged mice as indicated with delayed weight loss. In contrast, survival of young mice infected with this virus was diminished. Furthermore, tissue damage, inflammation, proinflammatory cytokine and 2'3'-cGAMP production in the lung were less pronounced in infected aged mice despite no change in viral titer. cGAS is known to produce 2'3'-cGAMP to boost proinflammatory cytokine expression through STING-NF-κB signaling. We found that H7N9 PB1-F2 promoted interferon β (IFNβ) and chemokine gene expression in cultured cells through the mitochondrial DNA-cGAS-STING-NF-κB pathway. H7N9 PB1-F2 formed protein aggregate and caused mitochondrial cristae collapse, complex V-dependent electron transport dysfunction, reverse electron transfer-dependent oxidized mitochondrial DNA release to the cytoplasm and activation of cGAS-STING-NF-κB signaling. PB1-F2 N57 truncation, which is frequently observed in human circulating strains, mitigated H7N9 PB1-F2-mediated mitochondrial dysfunction and cGAS activation. In addition, we found that PB1-F2 of pathogenic avian influenza viruses triggered more robust cGAS activation than their human-adapted descendants. Our findings provide one explanation to age-dependent pathogenesis of H7N9 infection.

Protective Impact of Influenza Vaccination on Healthcare Workers.

Influenza vaccine uptake among healthcare workers is crucial for preventing influenza infections, yet its effectiveness needs further investigation. This prospective observational study aimed to assess the protective effect of influenza vaccination among healthcare workers in Shenzhen. We enrolled 100 participants, with 50 receiving the 2023-2024 quadrivalent influenza vaccine (QIV) and 50 serving as unvaccinated controls. Epidemiological data were collected when the participants presented influenza-like illness. Serum samples were collected at three time points (pre-vaccination and 28 and 180 days after vaccination). Hemagglutination inhibition (HI) assay was performed against the strains included in the 2023-2024 QIV (H1N1, H3N2, BV and BY strains) to assess antibody protection levels. Demographics comparisons revealed no significant differences between the vaccinated and control groups (p > 0.05), ensuring group comparability. The incidence of influenza-like illness was significantly lower in the vaccinated (18%) compared to the control group (36%; p = 0.046; OR = 0.39; 95% CI: 0.15 to 0.98). The vaccinated group also exhibited a higher rate of consecutive two-year vaccinations (48% vs. 24% in the control group, p < 0.05). Additionally, the vaccinated healthcare workers were more inclined to recommend vaccination to their families (80% vs. 48%, p < 0.05). HI titers against H1N1 (p < 0.01), H3N2 (p < 0.01), BV (p < 0.001) and BY (p < 0.01) significantly increased in the vaccinated group at 28 days post-vaccination. Moreover, a marked and sustained increase in HI titers against the H3N2 strain (p < 0.001) was observed at 180 days post-vaccination, highlighting the vaccine's enduring impact on the immune response. The fold change in the HI titers, indicative of the magnitude of the immune response, was significantly higher for H1N1 (p < 0.01), H3N2 (p < 0.001), BV (p < 0.01) and BY (p < 0.05) among the vaccinated individuals compared to the control group, underscoring the vaccine's efficacy in eliciting a robust and sustained antibody response. Influenza vaccination significantly reduces the incidence of influenza-like illness among healthcare workers and promotes a sustained immune response. The study supports the importance of annual vaccination for this group to enhance personal and public health.

Bacteriophage P2-71: a promising therapeutic against multidrug-resistant Proteus mirabilis in urinary tract infections.

Proteus mirabilis is a Gram-negative, rod-shaped bacterium widely found in natural environments. It is known for causing a range of severe illnesses in mammals, particularly urinary tract infections (UTIs). This study evaluates the therapeutic efficacy of phage P2-71 against Proteus mirabilis in vivo and in vitro environments. The in vitro therapeutic potential of bacteriophage P2-71 was assessed through the ability of phage to kill Proteus mirabilis by using a plate counting assay, and biofilm inhibition and biofilm lysis assays using a microtitre plate method. Additionally, an in vivo UTI model in C57BL/6Jmice was developed via urethral inoculation of the bacterium. Phage therapy was administered through urethral injection over a period of 5 days. Therapeutic outcomes were measured by analyzing bacterial load, phage titer, inflammatory markers, and histopathological changes in the urine, urogenital tissues, and spleen. In vitro, bacteriophage P2-71 achieved significant reductions in P. mirabilis concentrations, with log reductions of 1.537 and 0.7009 CFU/mL in laboratory and urine environments, respectively (p < 0.001). The phage also decreased biofilm formation by 34-49% and lysed 15-25% of mature biofilms at various multiplicities of infection (MOIs) (p < 0.001). In vivo, phage treatment significantly lowered bacterial concentrations in the urine on Days 1 and 3 (p < 0.0001), achieving a maximum reduction of 4.602 log₁₀ CFU/mL; however, its effectiveness diminished by Day 5 (p > 0.05). Concurrently, phage titers decreased over time. Importantly, phage treatment notably reduced bacterial load in the bladder, kidneys, and spleen (p < 0.001). Inflammatory markers such as IL-6, IL-1β, and TNF-α were significantly lower in the treatment group, especially in the bladder (p < 0.0001), indicating an effective reduction in inflammation. Histopathological analysis showed significant mitigation of tissue damage. The results demonstrated that bacteriophage P2-71 is a promising alternative therapy for UTIs caused by MDR Proteus mirabilis. This bacteriophage therapy offers a viable strategy for managing infections where traditional antimicrobials fail, highlighting its potential in clinical applications.

Association of Hepatitis B Surface Antigen Levels With Long-Term Complications in Chronic Hepatitis B Virus Infection: A Systematic Literature Review.

Chronic hepatitis B virus (HBV) infection is a global issue and can lead to cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B surface antigen (HBsAg) is an important marker of HBV infection and HBsAg quantification could be a useful tool in clinical practice. This systematic literature review aimed to explore the association between HBsAg titres and long-term disease outcomes and evaluate the relationship between HBsAg titres, or changes in HBsAg titres, and clinical and treatment characteristics in patients with chronic HBV infection. Structured searches were performed in MEDLINE and Embase (January 2000 to 31 March 2023). Eighty-two studies were included, comprising 51% retrospective cohort studies, mostly conducted in Asia (85%). HBsAg levels were shown to predict the long-term development of cirrhosis and HCC in patients who were untreated prior to and during follow-up; however, these data were inconclusive in mixed and treated populations. HBsAg titres were significantly associated with various virological markers including serum HBV DNA, HBcrAg, HBeAg, HBV RNA levels, intrahepatic covalently closed circular DNA (cccDNA) and intrahepatic HBsAg expression. HBsAg titres generally declined over time; this decline was more pronounced in early (HBeAg-positive) than later disease phases (HBeAg-negative). Higher decline in HBsAg levels was consistently associated with subsequent HBsAg seroclearance and a greater decline in total intrahepatic HBV DNA and cccDNA levels. In conclusion, this review showed that HBsAg levels and rates of decline could inform assessment, management and prediction of outcomes in chronic HBV infection. Further studies in broader, more diverse populations and treated patients are needed.

Analyses of the association between Helicobacter pylori antibody titre and pathogenicity before and after eradication: results of the Kyushu and Okinawa population study, a retrospective observational cohort study

ObjectivesTo assess the utility of Helicobacter pylori antibody testing, we evaluated the correlation between the H. pylori antibody titre and H. pylori-associated pathogenicity and the changes in antibody titre after...

Antibody levels against respiratory syncytial virus fusion protein conformations and lack of association with life-threatening infection in previously healthy infants

BackgroundHumoral immune response against the pre-fusion (pre-F) conformation of respiratory syncytial virus (RSV) F protein has been proposed to play a protective role against infection. An RSV pre-F maternal vaccine has been recently approved in several countries to protect young infants against RSV. We aimed to assess serum IgG titers against the pre-F and post-F conformations of RSV F protein and their association with life-threatening RSV disease (LTD) in previously healthy infants. MethodsA prospective cohort study including hospitalized infants <12 months with a first RSV infection was conducted during 2017–2019. Patients with LTD required intensive care and mechanical respiratory assistance. RSV pre-F exclusive and post-F antibody responses were determined by post-F competition and non-competition immunoassays, respectively, and neutralizing activity was measured by plaque reduction neutralization test. ResultsFifty-eight patients were included; the median age was 3.5 months and 41 % were females. Fifteen patients developed LTD. RSV F-specific antibody titers positively correlated with neutralizing antibody titers in acute and convalescent phases but, importantly, they did not associate with LTD. Acute RSV pre-F exclusive and post-F IgG titers negatively correlated with patient age (P = 0.0007 and P < 0.0001), while a positive correlation was observed between the fold changes in RSV F-specific antibody titers between convalescent and acute phase and patient age (P = 0.0014 and P < 0.0001). Infants ≤2 months exhibited significantly lower fold-changes in RSV F-specific and neutralizing antibody titers between convalescence and acute phase than older infants. Additionally, acute RSV antibody titers showed no correlation with nasal RSV load and, furthermore, nasal viral load was not associated with the development of LTD. ConclusionsThis study highlights that protection against life-threatening RSV disease is not necessarily antibody-dependent. Further characterization of the immune response against RSV and its role in protection against severe disease is important for the development of the safest possible preventive strategies.

A significant outbreak of respiratory human adenovirus infections among children aged 3-6 years in Hokkaido, Japan, in 2023.

Human adenovirus (HAdV) infections present diverse clinical manifestations upon infecting individuals, with respiratory infections predominating in children. We surveyed pediatric hospitalizations due to respiratory HAdV infections across 18 hospitals in Hokkaido Prefecture, Japan, from July 2019 to March 2024, recording 473 admissions. While hospitalizations remained below five cases per week from July 2019 to September 2023, a notable surge occurred in late October 2023, with weekly admissions peaking at 15-20 cases from November to December. There were dramatic shifts in the age distribution of hospitalized patients: during 2019-2021, 1-year-old infants and children aged 3-6 years represented 51.4%-54.8% and 4.1%-13.3%, respectively; however, in 2023-2024, while 1-year-old infants represented 19.0%-20.1%, the proportion of children aged 3-6 years increased to 46.2%-50.0%. Understanding the emergence of significant outbreaks of respiratory HAdV infections and the substantial changes in the age distribution of hospitalized cases necessitates further investigation into the circulating types of HAdV in Hokkaido Prefecture and changes in children's neutralizing antibody titers against HAdV.

Positive Outcome in a Pregnancy with Anti-kell Alloimmunization Treated with Intravenous Immunglobulin and Therapeutic Plasma Exchange Despite Persistence of High Titre Antibody: A Case Report

Background: Few reports have been published about the current clinical management of anti-Kell alloimmunization in pregnancy; its low frequency of occurrence means that the few long series published have covered an extensive time period in which different treatment approaches have overlapped. The objective of the present paper is to present our experience in the clinical management of a pregnant woman who was positive for the anti-Kell antibody. Materials and Methods: The laboratory follow-up included the weekly measurement of the antibody titre, and identification of the paternal and fetal genotype. The clinical management included TPE and IVIG administration. Obstetric monitoring included ultrasonographic monitoring of the fetus. Case Description: We report a case of anti-Kell alloimmunization with high antibody titre at first observation. Testing for fetal DNA circulating in maternal blood confirmed positivity for KEL1 gene. The patient underwent fifteen sessions of TPE after 18 weeks of gestational age, followed by weekly IVIG infusion, which continued until 27 weeks of pregnancy. Anti-Kell titres were measured before and after each TPE session. The patient had no need for IUBT and delivered by cesarean section at 34 weeks of gestational age. Pregnancy resulted in a live birth with mild HDFN. Discussion: HDFN is a potentially lethal complication of alloimmunization, and IUBT is the standard treatment for severe fetal anemia. TPE and IVIG are two alternative treatment modalities described in the literature to avoid or postpone the need for IUBT transfusion. In the case reported, despite any substantial change in antibody titre, pregnancy resulted in a live birth. This result suggests that the use of TPE and IVIG in alloimmunization during pregnancy could be an effective treatment strategy.

Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial

Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson’s disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 μg or 300/300/300 μg (weeks 1, 5 and 13) intramuscular prime-boost dose groups. Safety was similar across groups; adverse events were mostly mild and transient. Two patients experienced three serious adverse events in total, one possibly treatment related; all resolved without sequalae. Anti-αSyn antibodies in serum from 12/13 and CSF from 5/13 patients who received three UB-312 doses confirmed immunogenicity. Mean serum titers (in log-dilution factor) increased from baseline by 1.398 and 1.354, and peaked at week 29 at 2.520 and 2.133, for 300/100/100 μg and 300/300/300 μg, respectively. CSF titers were 0 at baseline and were 0.182 and 0.032 at week 21, respectively. Exploratory analyses showed no statistical differences in clinical scales but a significant reduction of αSyn seeds in CSF of a subset of UB-312-treated patients. These data support further UB-312 development. ClinicalTrials.gov:NCT04075318.

Longitudinal change of serum NfL as disease activity biomarker candidate in MOGAD: A descriptive cohort study

BackgroundMyelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease (MOGAD) is an autoinflammatory disease of the central nervous system. MOGAD often follows a relapsing course that can lead to severe disability, but monophasic disease is possible as well. Currently, there is an unmet clinical need for disease activity biomarkers in MOGAD. Serum neurofilament light chain (sNfL) is a sensitive biomarker for neuroaxonal damage. However, data on longitudinal change of sNfL as disease activity biomarker for MOGAD are scarce. ObjectiveTo describe the longitudinal course of sNfL in adult patients with MOGAD in an active as well as a stable disease state in relation to clinical parameters and serum MOG-IgG titers. MethodsWe conducted a retrospective, exploratory, monocentric cohort study of adult patients with MOGAD. Cohort 1 consisted of five patients in whom NfL was tested as part of their routine clinical workup, all of which had active disease (maximum 6 months since last attack, median 3 months). Cohort 2 comprised 13 patients, which were tested for NfL in the context of a longitudinal study at predefined time intervals, mostly during remission (median 10 months since last attack). sNfL was measured using single molecule array (Simoa) technology at least at two time points (median 3) within a median observation time of 5 months in cohort 1, and at baseline and after a median duration of 12 months in cohort 2. MOG-IgG titers were measured by a fixed cell-based assay. ResultsChange in sNfL correlated positively with change in MOG-IgG titers (rho=0.59, p = 0.027). The variability of sNfL (difference between highest and lowest level) during the observation period was higher in patients who had an attack within six months before baseline (median 37 [interquartile range [IQR] 10–64] pg/ml vs. 2.3 [IQR 1–5] pg/ml, p = 0.006). sNfL increased in patients with an attack during the observation period. Patients with baseline sNfL measurement within two weeks after attack symptom onset displayed relatively low initial sNfL with an increase afterwards. ConclusionsLongitudinal sNfL change correlates with MOG-IgG titer change and may be a promising biomarker candidate for disease activity in MOGAD. Increasing sNfL levels might be utilized to adjudicate suspected attacks. In acute attacks, sNfL increase may occur with a delay after symptom onset.