Neutralizing antibodies during treatment of secondary progressive MS with interferon beta-1b.

Long-term effectiveness of natalizumab in secondary progressive multiple sclerosis: A propensity-matched study

Interferon beta-1b (IFNβ-1b; Betaferon®/Betaseron®) is an effective treatment for relapsing forms of multiple sclerosis (MS). It was the first immunomodulatory therapy to receive approval for this indication in 1993 in the USA and in 1995 in Europe. It remains the only high-dose, high-frequency treatment with proven efficacy in patients with a clinical demyelinating event, RRMS and SPMS. Several large controlled studies have been performed, including 16 years follow-up of patients, providing a unique data set to evaluate long-term safety and efficacy. Results obtained from several studies have shown an inconsistent impact of neutralizing antibodies (NAb) to IFNβ-1b, unlike NAb to other IFNβ therapies. Although patient heterogeneity and the use of different NAb assays are involved, this reflects intrinsic differences between the respective IFNβ-1b versus IFNβ-1a molecules as well as their sensitivity to NAb effects. When evaluating the occurrence and the impact of NAb during different IFNβ therapies, standardization is a necessity. Three phase III trials of IFNβ-1b, in which the same assay methodology was applied, suggest that NAb to IFNβ-1b are transient, mostly of low to moderate titre and have no effect on disability progression with only limited effect on relapse rate. Two controlled studies showed better efficacy of high dose, high frequency beta-interferon treatment even in NAb-positive patients over low dose, low frequency beta-interferon treatment in NAb-negative individuals. Given the overall clinical efficacy of IFNβ-1b, the inconsistent data regarding the effect of NAb to IFNβ-1b on treatment outcome, and the unpredictable course of disease in a given patient, treatment decisions should be based on patient response to therapy, not on NAb status. This position is endorsed by current regulatory and neurology association guidelines and is reflected in the package insert information. Multiple Sclerosis 2007; 13: S21—S27 http://msj.sagepub.com

97 sera collected during a 10-year period from 10 HIV-1 infected individuals were tested for neutralizing capacity against a virus isolate FICPH-22 obtained from a Danish AIDS patient, and the laboratory strain HTLV-IIIB. Three patterns of serum neutralizing activity were demonstrated: (a) patients developing high neutralizing activity against both HIV strains; (b) patients developing high neutralizing activity against the Danish virus isolate; and (c) patients developing only low titers of neutralizing antibodies (NA) against both HIV strains. The HTLV-IIIB strain was less sensitive to serum neutralization than the FICPH-22 isolate and the appearance of NA against HTLV-IIIB was typically lacking several years behind that against FICPH-22 indicating a broadening of the NA response over time. No difference in clinical outcome was observed comparing patients reaching high titers of NA and patients with low titers. Development of AIDS among patients reaching high titers of NA was preceded by a decline in NA titers, indicating an association of high titers of NA with the healthy carrier state and of declining or low titers of NA with disease progression. The majority of the neutralizing activity was mediated by IgG, but some neutralizing activity was demonstrated in the IgG depleted serum, indicating the presence of additional neutralizing substances in serum.

Introduction: Secondary progressive multiple sclerosis (SPMS) represents a disabling stage of multiple sclerosis (MS) with limited treatment options. The evidence regarding the effectiveness of disease-modifying therapies (DMTs) in SPMS remains uncertain. This study evaluated the comparative efficacy and safety of DMTs in SPMS using a network meta-analysis (NMA). Methods: A systematic search of PubMed, Embase, Web of Science, and Cochrane databases was conducted from January 2000 to May 2025 to identify randomized controlled trials (RCTs) involving adults with SPMS. The outcomes of interest were confirmed disability progression (CDP) and serious adverse events (SAEs). A frequentist random-effects NMA was performed to estimate odds ratios (ORs) and rank treatments using surface under the cumulative ranking (SUCRA) values. Results: Seven RCTs involving 5,872 patients with SPMS were included in the final analysis. Approximately 60% of participants were women, with a mean age ranging from 39.9 to 48.9 years and a baseline Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5. Tolebrutinib (OR 0.66, 95% confidence interval [CI] 0.50–0.87; SUCRA 0.713) and siponimod (OR 0.72, 95% CI 0.57–0.92; SUCRA 0.606) significantly reduced 6-month CDP compared with placebo. At 3 months, interferon beta-1b (OR 0.64, 95% CI 0.43–0.97; SUCRA 0.663), tolebrutinib (OR 0.73, 95% CI 0.56–0.96; SUCRA 0.554), and siponimod (OR 0.76, 95% CI 0.61–0.96; SUCRA 0.497) showed significant benefits. In terms of safety, tolebrutinib was associated with a higher risk of SAEs (OR 1.53, 95% CI 1.04–2.25), whereas the other agents had safety profiles comparable to placebo. Conclusion: This NMA found that tolebrutinib, IFN-β-1b, and siponimod delay disability progression in SPMS, with IFN-β-1b and siponimod remaining the most practical options. The conclusions should be interpreted cautiously given bias risk, moderate evidence certainty, limited safety data, and clinical heterogeneity.

Economic evaluations of treatments for multiple sclerosis have focused either on relapsing-remitting or secondary progressive disease. None has addressed specifically the question of how treatments affect disease progression from diagnoses to severe disability; however, in both clinical and economic terms this is one of the key questions. This study therefore created a disease model that includes both relapsing and progressive multiple sclerosis and covers the full range of disease severity. In addition, the issue of covariates influencing the cost per QALY and the uncertainty in the estimates is addressed. The model is based on our earlier approach using a Markov model, where disease progression is measured as functional disability (EDSS), costs and utilities associated with different disability levels, and outcome expressed as QALY. Treatment is based on a subgroup of patients with active disease in two placebo-controlled clinical trials and open-label extensions with interferon-beta(1b) in relapsing-remitting or secondary progressive multiple sclerosis, and natural history data are used for the extrapolation beyond the trials. Disease progression (transition probabilities) was estimated using a probit model controlling for differences in patient and disease characteristics, and costs and utilities for different disability levels are taken from large population-based observational studies. Results are presented for Sweden and compared to the United Kingdom. When treatment is given for 36 months (adjusted for compliance) and no further effect is included, the cost per QALY is EURO 7800 (direct, indirect, and informal care costs included, discounted at 3%) over 10 years. The total number of QALYs increases from 3.45 in the no-treatment group to 3.64 in the treatment group. When treatment is prolonged to 54 months, the cost per QALY is EURO 38,700. Using the full range of costs and utilities, the probability that the cost per QALY over a 20-year time-frame is below EURO 50,000 for patients starting treatment at EDSS 3.0 is 80%. In view of the progression of MS over many years models are required to estimate the cost-effectiveness of new treatments. The model proposed here allows estimating disease progression, costs, and QALYs for patients with different characteristics and types of MS, and it can be adapted to different countries. It can hence be used to assess the cost-effectiveness of a defined intervention, such as interferon-beta(1b).

Reply from the Authors: It is impossible to compare the neutralizing antibody (NAB) response in the interferon beta-1b (IFNB-1b, Betaseron) trial1 with the NAB data in the Ares Serono trial or the trial by Jacobs et al.4 using interferon beta-1a (Rebif, Avonex), since neither of the two studies give sufficient details of assay methodology, assay sensitivity, or criteria of NAB positivity. In the Betaseron trial 11% of patients receiving placebo had NABs in at least one specimen, compared with 4% in …

BackgroundCurrently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising option and can be readily obtained using minimally invasive procedures.Patients and methodsIn this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high-dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded.ResultsThirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy.ConclusionInfusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique.

Dysregulation of humoral immunity, iron homeostasis, and lipid metabolism is associated with multiple sclerosis progression

The high genetic and antigenic variability of influenza virus and the repeated exposures of individuals to the virus over time account for the human immune responses toward this pathogen to continuously evolve during the lifespan of an individual. Influenza-specific immune memory to past strains has been shown to affect the immune responses to subsequent influenza strains and in turn to be changed itself through the new virus encounter. However, exactly how and to what extent this happens remains unclear. Here we studied pre-existing immunity against influenza A virus (IAV) by assessing IAV binding (IgG), neutralizing, and neuraminidase-specific antibodies to 5 different IAV strains in 180 subjects from 3 different age cohorts, adolescents, adults, and elderly, over a 5-year time span. In each age cohort, the highest neutralizing antibody titers were seen for a virus strain that circulated early in their life but the highest increase in titer was found for the most recent virus strains. In contrast, the highest IgG titers were seen against recent virus strains but the biggest increase in titer occurred against older strains. Significant increases in neutralizing antibody titers against a newly encountered virus strain were observed in all age cohorts demonstrating that pre-existing immunity did not hamper antibody induction. Our results indicate that the evolution of influenza-specific humoral immunity differs for rather cross-reactive virus-binding antibodies and more strain-specific neutralizing antibodies. Nevertheless, in general, our observations lend support to the antigenic seniority theory according to which the antibody response to influenza is broadened with each virus encounter, with the earliest encountered strain taking in the most senior and thus dominant position.

Neutralization and complement-fixation tests to detect rubella antibody are described. Results of such tests show that between 80 and 95% of adults in England and Wales have neutralizing antibody. The presence of complement-fixing antibody indicates recent infection with rubella virus.Results are presented showing the development of neutralizing and complement-fixing antibody after rubella.Antibody tests on children with congenital rubella and their mothers are detailed. It is noted that higher neutralizing antibody titres are found in this group than in the general population.

A prophylactic vaccine to prevent the congenital transmission of human cytomegalovirus (HCMV) in newborns and to reduce life-threatening disease in immunosuppressed recipients of HCMV-infected solid organ transplants is highly desirable. Neutralizing antibodies against HCMV confer significant protection against infection, and glycoprotein B (gB) is a major target of such neutralizing antibodies. However, one shortcoming of past HCMV vaccines may have been their failure to induce high-titer persistent neutralizing antibody responses that prevent the infection of epithelial cells. We used enveloped virus-like particles (eVLPs), in which particles were produced in cells after the expression of murine leukemia virus (MLV) viral matrix protein Gag, to express either full-length CMV gB (gB eVLPs) or the full extracellular domain of CMV gB fused with the transmembrane and cytoplasmic domains from vesicular stomatitis virus (VSV)-G protein (gB-G eVLPs). gB-G-expressing eVLPs induced potent neutralizing antibodies in mice with a much greater propensity toward epithelial cell-neutralizing activity than that induced with soluble recombinant gB protein. An analysis of gB antibody binding titers and T-helper cell responses demonstrated that high neutralizing antibody titers were not simply due to enhanced immunogenicity of the gB-G eVLPs. The cells transiently transfected with gB-G but not gB plasmid formed syncytia, consistent with a prefusion gB conformation like those of infected cells and viral particles. Two of the five gB-G eVLP-induced monoclonal antibodies we examined in detail had neutralizing activities, one of which possessed particularly potent epithelial cell-neutralizing activity. These data differentiate gB-G eVLPs from gB antigens used in the past and support their use in a CMV vaccine candidate with improved neutralizing activity against epithelial cell infection.

The identification and management of Multiple Sclerosis (MS) patients who are at risk of disease progression and/or conversion to Secondary Progressive MS (SPMS) is a significant unmet clinical need. This study aimed to develop machine and deep learning (ML/DL) models to predict disability progression and/or conversion to SPMS at least 6 months before progression, determined by Expanded Disability Status Scale (EDSS) score. Three traditional ML algorithms were trained on brain parcellation volume measurements derived from T1 weighted magnetic resonance images (MRI) and convolutional neural networks (CNNs) were trained directly on MRI images. The results showed that the three ML models performed slightly better than a random classifier, with the Support Vector Classifier achieving the best results in terms of area under the receiver operating characteristic curve (AUROC) with a score of 0.62. The CNN approach yielded the most promising results, with an AUROC score of 0.75. This suggests that the ability to identify MS patients at high risk of future disability progression directly from MRI scans is a promising research direction. Further development of these algorithms could enable timely interventions, potentially preventing or delaying the onset of disability progression and/or SPMS.

Prevalence of neutralizing antibodies to 9 rotavirus strains representing 7 G-serotypes in sheep sera

Background Dengue infection is still rising globally despite the implementation of preventive efforts in many endemic countries. Monitoring the circulation of dengue virus (DENV) serotypes is not performed routinely in the Indonesian national surveillance program, primarily due to high cost and effort. Objective To evaluate the distribution of DENV serotypes based on serological profile and neutralizing antibody level against all four DENV serotypes in Jakarta, Indonesia. Methods This cross-sectional study was performed as part of a dengue vaccine effectiveness study, 10 years after a dengue vaccination program was initiated. It was conducted in five community public health centers in Jakarta in subjects aged 12 years and above who had not received the dengue vaccine. We collected serum samples and DENV neutralizing antibody titers were measured using a plaque reduction neutralization test (PRNT). Results Eighty healthy subjects with a median age of 15 (range 12-27) years were enrolled. The highest median antibody titer was that to DENV-2 [898 (range 29-91558) 1/dil], followed by that to DENV-3 [297.5 (range 10-36091); 1/dil], DENV-1 [288 (range 0-68237) 1/dil], and DENV-4 [164 (range 0-35812) 1/dil]. Neutralizing antibodies against the four DENV serotypes were found in all the 5 districts studied in Jakarta. A multitypic neutralizing antibody profile was observed in the majority (74/80 subjects; 92.5%). Three subjects were naïve. Conclusion All four dengue serotypes are widely circulating in Jakarta based on neutralizing antibody detection in the community, with the highest neutralizing antibody titer being against DENV-2, followed by DENV-3, DENV-1 and DENV-4.

Therapy with either recombinant beta-1a or beta-1b interferons (IFNs) is worldwide approved for Relapsing Remitting Multiple Sclerosis (RRMS). A major unanswered question is whether this treatment is able to safely reverse or retard the progressive phase of the disease. The main objective was to verify whether IFNs treatment in Secondary Progressive Multiple Sclerosis (SPMS) is more effective than placebo in reducing the number of patients who experience disability progression. We searched the Cochrane Multiple Sclerosis Group's Trials Register (1995 to 15 February 2011), the reference lists of relevant articles and conference proceedings. Regulatory agencies were used as additional sources of information. We included all randomised, double or single blind, placebo-controlled trials (RCTs) evaluating the efficacy of IFNs versus placebo in SPMS patients. Two review authors independently assessed all reports retrieved from the search. They independently extracted clinical, safety and MRI data, using a predefined data extraction form, resolving disagreements after discussion with a third reviewer. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using Risk Ratio (RR) with 95% confidence intervals (CI) for the binary outcomes and Standard Mean Difference with 95% CI for the continuous outcomes. Five RCTs met the inclusion criteria, from which 3122 (1829 IFN and 1293 placebo) treated patients contributed to the analysis. Included population was heterogeneous in terms of baseline clinical characteristics of the disease, in particular the percentage of patients affected by secondary progression with superimposed relapse ranging from 72% to 44%. IFN beta 1a and 1b did not decrease the risk of progression sustained at 6 months (RR, 95% CI: 0.98, [0.82-1.16]) after three years of treatment. A significant decrease of the risk of progression sustained at 3 months (RR, 95% CI: 0.88 [0.80, 0.97]) and of the risk of developing new relapses at three years (RR 0.91, [0.84-0.97]) were found. The risk of developing new active brain lesions decreased over time but this data was obtained from single studies on Magnetic Resonance Imaging (MRI), performed in subgroups of patients; in spite of no effect on progression, the radiological data supported an effect on MRI parameters. The safety profile reflects what is commonly reported in MS IFN-treated patients. Well designed RCTs, evaluating a high number of patients were included in the review. Recombinant IFN beta does not prevent the development of permanent physical disability in SPMS. We were unable to verify the effect on cognitive function for the lack of comparable data. This treatment significantly reduces the risk of relapse and of short -term relapse-related disability.Overall, these results show that IFNs' anti-inflammatory effect is unable to retard progression, when established. In the future, no new RCTs for IFNs versus placebo in SPMS will probably be undertaken, because research is now focusing on innovative drugs. We believe that this review gives conclusive evidence on the clinical efficacy of IFNs versus placebo in SPMS.