Meningococcal Research Articles

Vaccine-preventable Pediatric Acute Bacterial Meningitis in France: A Time Series Analysis of a 19-Year Prospective National Surveillance Network.

In France, vaccination has been implemented against Hi serotype b (Hib), pneumococcus with pneumococcal conjugate vaccines (PCV), and Neisseria meningitidis serogroup C (MenC). These interventions with different coverage and uptake have disrupted the epidemiology of vaccine-preventable acute bacterial meningitis (ABM). We analyzed data from a French prospective surveillance network of ABM in children ≤15 years old enrolled by 259 pediatric wards (estimated national coverage: 61%). From 2001 to 2020, the effect of vaccine implementation was estimated with segmented linear regression. We analyzed 7,186 cases, mainly due to meningococcus (35.0%), pneumococcus (29.8%), and Hi (3.7%). MenC ABM incidence decreased (-0.12%/month, 95% CI: -0.17 to -0.07, P < 0.001) with no change for the overall meningococcal ABM when comparing the pre-MenC vaccination and the post-MenC vaccination trends. Despite a decreasing MenB ABM incidence without a vaccination program (-0.43%/month, 95% CI: -0.53 to -0.34, P < 0.001), 68.3% of meningococcal ABM involved MenB. No change in pneumococcal ABM incidence was observed after the PCV7 recommendation. By contrast, this incidence significantly decreased after the switch to PCV13 (-0.9%/month, 95% CI: -1.6 to -0.2%, P = 0.01). After May 2014, a rebound occurred (0.5%/month, 95% CI: 0.3-0.8%, P < 0.001), with 89.5% of non-PCV13 vaccine serotypes. Hib ABM incidence increased after June 2017. PCV7 and MenC vaccine introduction in France, with slow vaccine uptake and low coverage, had no to little impact as compared to the switch from PCV7 to PCV13, which occurred when coverage was optimal. Our data suggest that MenB and next-generation PCVs could prevent a large part of the ABM incidence in France.

Safety and Immunogenicity of Meningococcal Groups A and C Polysaccharide Vaccine in Adults 18–60 years of age

Relevance. In the Russian Federation, despite the low incidence rate in 2020–2021, there are subjects where the incidence rate of meningococcal infection (MI) exceeds the national average by 2–9 times. MI often becomes fulminant with an extremely rapid development of symptoms up to infectious and toxic shock, which limits the possibility of providing specialized care. Less than 24 hours may pass between the appearance of the first symptoms (nonspecific, similar to ARVI) and the development of shock with a fatal outcome. To date, the most reliable way to protect against meningococcal infection is vaccination. However, the healthcare system until 2022 could use only one domestic vaccine with one serogroup A. Aims. To study the safety, reactogenicity and immunological efficacy of Meningococcal A+C polysaccharide vaccine, manufactured by Microgen, Russia, when used in persons aged 18 to 60 years. Materials and methods. The study included 100 people aged 18–60 years who met the inclusion criteria, the average age of the participants was 31.09 ±1.13 years. All study participants were evenly divided into two groups. The Meningo A+C® vaccine, Sanofi Pasteur, France (hereinafter referred to as MPV2 AC) was used as a comparison. PHA study was carried out using the test system «A set of diagnostic reagents for erythrocyte meningococcal polysaccharide groups A, B, C liquid according to TS 9388-004-68925985-10» manufactured by Bio-Diagnostics LLC, Russia (registration certificate No. FSR 2011/11185 dated 17.10.2011). Results and discussion. The results of the study assessing the reactogenicity and safety of the vaccine: in the first 7 days after vaccination, reactions were registered in 12.0% (95% CI: 5.62–23.80%) vaccinated with Meningococcal A+C polysaccharide vaccine, and in 10.0% (95% CI: 4.35–21.36%) in the comparison group, vaccinated with MPV2 AS. There was no statistically significant difference between the groups (p ≥ 0.05). Results of the study assessing the immunogenicity: on the 28th day after single-dose immunization of the participants of the clinical trial, both in the group vaccinated with Meningococcal A+C polysaccharide vaccine, and in the control group (vaccinated with MPV2 AC), a statistically significant increase in antibody titer was noted, p ≤ 0.001: 76.0% (95% CI: 62.59–85.70%) versus 74.0% (95% CI: 60.45–84.13%) in the control group, χ2 =0.0533 and p=0.818.. Conclusions. Meningococcal A+C polysaccharide vaccine is characterized by safety, low reactogenicity and high immunogenicity comparable to the MPV2 AC vaccine.

Vaccination of Patients with Comorbid Conditions against Meningococcal and Pneumococcal Disease and Influenza during the COVID-19 Pandemic – New Aspects

The review discusses and confirms the important role of vaccination of patients with comorbid conditions against pneumococcus, influenza and meningococcus in the context of the COVID-19 pandemic. There are two main mechanisms of influence of preventive immunization on the course of the fight against the pandemic; by reducing the incidence of preventable infections and reducing the burden on healthcare, and by directly influencing the vaccines used on the infection processes with the SARS-Cov-2 virus and the pathogenetic mechanisms of COVID-19. Information is also provided on the vaccines used and their use, in particular in the context of the COVID-19 pandemic.

Vaccination of Persons Subject to Call-up for Military Service

Relevance. In recent years, there has been an increase in the incidence of a number of vaccine-preventable diseases. The health of military personnel directly affects the combat effectiveness of the army. Aim. Preserving the health of the military and ensuring the sanitary and epidemiological well-being of the troops is one of the most important tasks. Result. Approaches to vaccination of persons subject to conscription for military service and a list of infections against which they should be vaccinated (influenza, meningococcal and pneumococcal infections, chickenpox, COVID-19) are presented. Vaccines, schedule and features of vaccine administration are described. A list of the main regulatory documents for vaccination is provided. Conclusion. Vaccine prevention of persons subject to conscription for military service is an important strategic task, the implementation of which depends on coordinated work between military and civilian healthcare. Vaccination coverage of persons subject to conscription for military service must reach 100%.

Informing the use of a supplementary immunisation programme for the management of a community cluster of invasive meningococcal disease, Yorkshire, 2022

ObjectivesTo outline the management of a community cluster of serogroup B invasive meningococcal disease (IMD) cases, including key factors for decision making and the choice and implementation of control measures. Study designDescriptive report of cluster management. MethodsSubtyping of IMD cases identified a number of potentially linked cases in a defined geographical area. An Incident Management Team (IMT) was convened to coordinate the public health response. A case definition was developed in order to identify further cases within the cluster. ResultsFour cases of IMD met the case definition and were initially considered as part of this cluster. Three resided in the same small town, which was the focus for public health management. The IMT agreed that it would be proportionate to instigate additional control measures. The population at higher risk of infection were identified, and a supplementary vaccination programme was rolled out in the community. Over five clinics, 45.6% (639/1401) of the target cohort received at least one dose of the vaccine, with 34.7% (486/1401) receiving both doses. Inequalities in uptake were observed by sex, age and deprivation. ConclusionsDecision making for public health responses to IMD clusters is complex. Informed by epidemiological evidence, numerous partners engaged in collaborative decision making, which was critical for the effective implementation of the community response. Links between the local authority public health team and the community enabled the use of existing structures and relationships to maximise the number of vaccinations delivered. No further cases of IMD linked to this cluster were identified.

An Overview of Meningococcal Disease's Recent Diagnostic and Treatment Model

An Overview of Meningococcal Disease's Recent Diagnostic and Treatment Model

Diagnosis of Acute Bacterial Meningitis by PCR and the Problem of Isolating the Causative Bacterial Agents by Culture in Burkina Faso

In Burkina Faso, meningitis is epidemic, pneumococcus, meningococcus and Haemophilus influenzae are the most implicated. The aim of this study was to assess the prevalence of ABM characterized by PCR and culture in order to highlight the low yield of the culture. This is a prospective study on 26 health districts of surveillance between 2016 and 2019. The CSF sent were cultured, treated by direct PCR, i.e. from CSF without DNA extraction at the National Meningitis Reference Laboratory of Burkina Faso and at the CDC Atlanta. Several series of direct PCR were carried out for species diagnosis (lytA, sodC and hpd), serotyping of meningococcus and serotyping of pneumococcus (capsular genes) and Haemophilus influenzae (capsular genes). Two thousand eight hundred and forty-five (2,845) CSF were treated with 701 positives and a positivity rate of 24.75%. Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae represent respectively 39.2%, 51.9% and 8.9%. The strains of Neisseria meningitidis and Streptococcus pneumoniae were sensitive to antibiotics except 3 strains of Neisseria meningitidis, resistant to oxacillin. There is a drop in the positivity rate compared to previous years. Pneumococcus remains in the lead with serotype 1 (more than 50%) despite the introduction of PCV13.

Danicopan As Add-on Therapy to Ravulizumab or Eculizumab Versus Placebo in Patients with Paroxysmal Nocturnal Hemoglobinuria and Clinically Significant Extravascular Hemolysis: Phase 3 Long-Term Data

Background C5 inhibitors eculizumab (Ecu) and ravulizumab (Rav) have transformed the natural history of paroxysmal nocturnal hemoglobinuria (PNH). Ecu resulted in patient (pt) survival comparable to that of the general population over 20 y of follow-up under real-world conditions. Overall survival rate at 6 years for pts treated with Rav was 98.4%. Where available, Rav is the standard of care for PNH, inhibiting terminal complement activation to prevent intravascular hemolysis (IVH) and thrombosis. Of pts with PNH treated with Rav/Ecu, 10-20% experience clinically significant extravascular hemolysis (cs-EVH). Efficacy and safety of the first-in-class oral factor D inhibitor danicopan (Dan; ALXN2040) as add-on treatment to Rav or Ecu for pts with PNH and cs-EVH were assessed in a phase 3, randomized, double-blind, placebo (Pbo)-controlled superiority clinical trial (ALPHA, NCT04469465). 12-wk data (double-blind treatment period [TP] 1) showing superiority of Dan vs Pbo on primary and key secondary endpoints were previously reported and represent the final analysis set for the trial. Open-label 24-wk (TP2) and ongoing long-term extension (LTE) data are presented. Methods Pts (≥18 y) with PNH and cs-EVH (hemoglobin [Hgb] ≤9.5 g/dL; absolute reticulocyte count [ARC] ≥120×10 9/L) on Rav/Ecu &amp;gt;6 mos were randomized double-blind 2:1 to Dan or Pbo add-on therapy for 12 wks (TP1). At wk 12, Pbo arm pts switched to Dan (Pbo-Dan) and Dan arm pts continued Dan (Dan-Dan) for another 12 wks (TP2), followed by a 1-y LTE in which all pts received Dan add-on therapy. The initial Dan dose of 150 mg 3 times daily (TID) could be escalated to 200 mg TID based on clinical response at investigator discretion. Primary endpoint was change from baseline (CFB) at wk 12 in Hgb. Other secondary endpoints: proportions of pts with Hgb increase ≥2 g/dL in absence of transfusion and with transfusion avoidance through wk 24; CFB in Hgb at wk 24; and CFB in ARC, lactate dehydrogenase (LDH), and C3 fragment deposition on PNH red blood cells at wks 12 and 24. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory abnormalities throughout the study. Results As of 20 September 2022, 86 pts were randomized; 60 completed TP2 (Dan n=40; Pbo n=20). Baseline characteristics were similar between arms ( Table). At wk 24 ( Fig), mean Hgb level was maintained in the Dan-Dan arm and increased from wk 12 in Pbo-Dan arm. ARC ( Fig) and other secondary endpoints were maintained in the Dan-Dan arm and improved in Pbo-Dan arm ( Table) at wk 24. The proportion of pts with Hgb increase of ≥2 g/dL in the absence of transfusion was maintained in the Dan-Dan arm and improved in the Pbo-Dan arm from wk 12 (Dan, 59.5%; Pbo, 0%) to wk 24 (Dan-Dan 46.3%; Pbo-Dan, 35.0%). Transfusion avoidance was maintained in the Dan-Dan arm and increased in Dan-Pbo arm from wk 12 (Dan, 83.3%; Pbo, 38.1%) to wk 24 (Dan-Dan 78.0%; Pbo-Dan, 90.0%). Mean LDH levels were maintained from wk 12 to 24 ( Table) and were near normal (&amp;lt;1.5×ULN) in both arms. Transfusions decreased in the Pbo-Dan arm from wk 12 (Pbo; mean [SD], 2.2 [2.3]) through 24 wks (Pbo-Dan; mean [SD], 0.1 [0.5]). The safety analysis included the n=80 pts exposed to Dan during the trial. At wk 24, study drug compliance was 98.8% (10.35) in the Dan-Dan arm and 98.3% (3.95) in Pbo-Dan arm. Escalation to 200 mg TID occurred for 41/57 (71.9%) pts in the Dan-Dan arm and 14/23 (60.9%) in Pbo-Dan arm. There were no deaths, meningococcal infections, or discontinuations due to hemolysis. Through data cut-off, 90% (72/80; 464 events) of pts had ≥1 TEAE after exposure to Dan. Serious AEs related to Dan were reported by 2 pts (gastrointestinal disorders/increased blood bilirubin; headache). 6 events in 4 pts led to withdrawal of study drug. 4 events were reported as breakthrough hemolysis (BTH) based on investigator discretion. Only 1 AE was associated with LDH &amp;gt;2×ULN (actual value 2.2×ULN) and potentially met the BTH definition used in other clinical studies. This AE was related to a complement-amplifying condition, COVID-19. This pt continued the study and BTH was resolved. Conclusions Danicopan as add-on to Rav or Ecu significantly improves Hgb and ARC levels and reduces the need for transfusion by addressing cs-EVH while maintaining control of IVH through 48 wks of treatment. Danicopan demonstrated a favorable benefit-risk profile with no deaths, meningococcal infections, or discontinuations due to hemolysis.

Patient-Reported Outcomes: Danicopan As Add-on Therapy to Ravulizumab or Eculizumab Versus Placebo in Patients with Paroxysmal Nocturnal Hemoglobinuria and Clinically Significant Extravascular Hemolysis

Background Treatment with complement C5 inhibitors eculizumab (Ecu) and ravulizumab (Rav) inhibits terminal complement activity, improving hemoglobin (Hgb) levels and clinical outcomes for patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH), including reduced morbidity and mortality by preventing intravascular hemolysis (IVH), thrombotic events, hospitalizations, and death. In an analysis using data from the International PNH Registry (NCT01374360), Ecu improved pt survival through 20 y of real-world follow-up. Rav demonstrated a 98.4% survival rate up to 6 y in an open-label study (NCT03056040). Approximately 10-20% of pts experienced ongoing anemia caused by clinically significant extravascular hemolysis (cs-EVH). The phase 3, international, randomized, double-blind, placebo (Pbo)-controlled ALPHA (NCT04469465) superiority clinical trial assessed the effectiveness and safety of danicopan (Dan) add-on therapy to Rav or Ecu in pts with PNH and cs-EVH. This current analysis examined patient-reported outcomes (PROs) through wk 24. Methods Pts (≥18 y) with PNH and cs-EVH (Hgb ≤9.5 g/dL; absolute reticulocyte count ≥120×10 9/L) on Rav/Ecu &amp;gt;6 mo were randomized 2:1 to Dan or Pbo add-on therapy to Rav/Ecu for 12 wks (treatment period [TP] 1). At wk 12, Pbo arm pts switched to Dan (Pbo-Dan) and Dan arm pts continued treatment (Dan-Dan) for another 12 wks (TP2). The initial Dan dose of 150 mg TID could be escalated to 200 mg TID based on clinical response at investigator's discretion. Endpoints included change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score to wks 12 and 24 (key secondary) and changes in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale (EORTC-QLQ-C30) global health status/QoL and physical functioning subscales and fatigue, nausea/vomiting, appetite loss, constipation, and diarrhea symptom subscales, and EuroQoL-5-Dimensions, 3-level version (EQ-5D-3L) to wk 24 (exploratory). Results As of 20 September 2022, 86 pts were randomized; 60 had completed (n=60) TP2 (Dan n=40; Pbo n=20). Baseline characteristics were similar between arms. The study met its primary endpoint of significant improvement in Hgb and all key secondary endpoints, including FACIT-Fatigue at wk 12 (data previously presented). Clinically meaningful (&amp;gt;5 point) and statistically significant increases from baseline in FACIT-Fatigue score were observed for Dan vs Pbo at wk 12 (least square mean difference [SEM] 7.97 [1.13] vs 1.85 [1.58]; P=0.0021). At wk 24 ( Fig 1), outcomes were maintained in the Dan-Dan arm (40.32) and improved in Pbo-Dan arm (40.55) to levels similar to the general public score of 43.6. Significant improvements from baseline with Dan vs Pbo were demonstrated for EORTC-QLQ-C30 scores (physical function and social function within functional subscales, and fatigue within symptom subscales) at wk 12, maintained at wk 24 for the Dan-Dan arm, and demonstrated at wk 24 in Pbo-Dan arm ( Fig 2). Trends in changes from baseline in other EORTC-QLQ-C30 function subscale scores paralleled that of the physical function subscale. EQ-5D-3L scores (US Health State Index) were similar between arms at baseline (Dan, 0.83; Pbo, 0.80), wk 12 (Dan, 0.90; Pbo, 0.86), and wk 24 (Dan-Dan, 0.90; Pbo-Dan, 0.87); scores at all timepoints are comparable to the general public (0.855-0.958). Dan demonstrated favorable benefit-risk profile with no deaths, meningococcal infections, or discontinuations due to hemolysis; additional safety analyses including adverse events were previously presented. No new safety signals were demonstrated. Conclusions These data suggest that Dan plus Rav or Ecu improves QoL compared to Rav or Ecu alone for pts with PNH and cs-EVH. In this phase 3, randomized, controlled superiority trial, improvements in clinically relevant PROs were observed in the Dan vs Pbo arm in the first double-blind 12 wks of treatment, and FACIT-Fatigue and EORTC-QLQ-C30 scores were maintained during the open-label period to wk 24 in the Dan-Dan arm and improved at wk 24 in Pbo-Dan arm to levels similar to those of the general public. Comparable EQ-5D-3L scores were maintained between arms across the study.

Safety of Crovalimab Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): Pooled Results from the Phase III COMMODORE 1, COMMODORE 2, and COMMODORE 3 Studies

Introduction Crovalimab (crova) is a novel anti-C5 recycling antibody that allows for low-volume, subcutaneous (SC) self-administration every 4 weeks (q4w). The single arm COMMODORE 3 study (NCT04654468) in C5 inhibitor (C5i)-naive patients (pts) with PNH in China was the first Phase III study to show that crova is efficacious and well tolerated (primary analysis; Liu Am J Hematol 2023), and confirmed these findings after 6 additional months of crova exposure (Liu EHA 2023; #P785). COMMODORE 1 (NCT04432584) and COMMODORE 2 (NCT04434092) are global, randomized, open-label, multicenter, Phase III trials that evaluated crova versus eculizumab (ecu) in C5i-experienced and -naive pts with PNH, respectively. COMMODORE 2 demonstrated non-inferior efficacy for crova versus ecu, with a safety profile consistent between crova and ecu (Röth EHA 2023; #S181). COMMODORE 1 supported the favorable benefit-risk profile of crova (Scheinberg EHA 2023; #S183). Here, we report pooled safety data for crova and ecu from COMMODORE 1, 2, and 3. Methods In COMMODORE 1, C5i-experienced pts who were receiving ecu were randomized 1:1 to receive crova or ecu. Pts with the C5 polymorphism or receiving ravulizumab or high-dose ecu, and pediatric pts receiving ecu were enrolled in a descriptive arm to receive crova. In COMMODORE 2, C5i-naive pts were randomized 2:1 to receive crova or ecu. Pediatric pts were enrolled in a descriptive arm to receive crova. In COMMODORE 3, C5i-naive pts received crova. In all 3 studies, crova was administered per a weight-based tiered dosing approach that included loading doses followed by SC q4w maintenance. Ecu was given intravenously every 2 weeks. The primary treatment period was 24 weeks for all 3 studies; all pts continuing after Week 25 received crova. Safety data from the 3 studies were pooled and assessed by C5i-naive versus -switched status and in total. Results Safety data from 488 pts (crova, n=377 [naive, n=192; switched, n=185]; ecu, n=111) were analyzed. Baseline characteristics for the pooled population were generally balanced between the crova and ecu arms, and between the C5i-naive and -switched groups for crova. Median age at baseline was 38 y (range, 13−85) in the crova population and 44 y (17−85) in the ecu population, with 11 (3%) pts and 2 (2%) pts aged &amp;lt;18 y at enrollment, respectively. The median time from PNH diagnosis to enrollment was 4.8 y (range, 0.0-50.3) in crova pts and 5.7 y (range, 0.0-31.0) in ecu pts. At baseline, 38% of crova pts and 37% of ecu pts had a history of aplastic anemia; 3% and 5% of pts had myelodysplastic syndrome, respectively. At the respective clinical cutoff dates, the median treatment duration was 44.4 weeks for crova pts and 22.1 weeks for ecu pts (Table 1). There were 522 adverse events (AEs) per 100 pt years (PY) in crova pts and 583 in ecu pts. There were 7.4 serious infections per 100 PY in crova pts (6.1 naive; 9.3 switched) and 14.1 in ecu pts, with no meningococcal infections. The proportion of pts with common AEs and serious AEs is shown in Table 2. A higher percentage of C5i-naive pts appeared to experience AEs than C5i-switched pts or ecu pts, due to the inclusion of pts with a longer treatment duration from the single-arm COMMODORE 3 study in the C5i-naive group. Fatal AEs occurred in 4 (1%) crova pts (3 naive; 1 switched) and 1 (1%) ecu pt, all unrelated to treatment (Table 1). AEs leading to treatment discontinuation occurred in 1% of crova pts (1% naive; 2% switched) and 1% of ecu pts. 4% of crova pts (4% naive; 4% switched) and 3% of ecu pts had ≥1 AE leading to dose modification or interruption. In crova switched pts only, complexes formed with other C5i could lead to one-time Type III hypersensitivity (T3H) reactions, which occurred in 18% of switched pts. The median time to onset of the T3H reaction was 1.6 weeks (range, 0.7-4.4) and the median duration of T3H reactions was 1.9 weeks (0.4-34.1). The most frequently reported (≥5%) manifestations of T3H reactions were arthralgia (9%) and rash (6%); no pt had renal manifestations. Most T3H reactions were Grade 1-2; Grade 3 events occurred in 7% of switched pts. One pt discontinued crova due to a Grade 3 T3H. The safety profile was consistent between pediatric and adult pts. Conclusions Overall, pooled safety data from COMMODORE 1, 2, and 3 showed that the safety profile of crova was consistent with that of ecu in pts with PNH, and comparable between pts who were C5i-naive and switched from C5i to crova.

Classical Complement Inhibition By SAR445088 (BIVV020) in Adults with Cold Agglutinin Disease: Safety, Tolerability and Activity Results from the Open-Label, Non-Randomized, Single-Dose Phase 1b Study

Background:Cold agglutinin disease (CAD) is a rare, chronic autoimmune hemolytic anemia characterized by complement-mediated hemolysis. The classical complement inhibitor sutimlimab, is the first approved pharmacotherapy for treating patients with CAD. The second-generation complement inhibitor SAR445088 (BIVV020) is a humanized monoclonal antibody that selectively inhibits the activated form of C1s (sutimlimab inhibits total C1s). Furthermore, SAR445088 contains mutations that increase FcRn binding, preventing its degradation and allowing it to be recycled back into the system, resulting in reduced drug clearance and a prolonged half-life, which may allow a longer dosing interval than that of sutimlimab. Aims:This Phase 1b open-label study evaluated the safety, tolerability, effect on hemolysis, and pharmacodynamics (PD)/pharmacokinetics (PK) of a single intravenous (IV) dose of SAR445088. The study aimed to assess the impact of SAR445088 on complement-mediated hemolysis to support proof of concept for SAR445088 as a treatment for patients with CAD. Methods:The study design included up to three single-dose cohorts with a maximum of six patients per cohort. SAR445088 was administered on Day 1 with follow-up visits from Day 2 to Day 71; end of study (EOS) visit was on Day 106. The first cohort received a dose of 30 mg/kg IV with decisions about the selection of the dose for the next cohort being based on safety, biomarker activity, and PD. In the second cohort, patients received a lower dose of 15 mg/kg IV; a third, higher-dose cohort was not enrolled. To be enrolled in the study, participants needed to be aged ≥18 years with a confirmed diagnosis of CAD and a hemoglobin level ≤11.0 g/dL at time of screening. The primary endpoint was assessment of safety, with secondary endpoints of hematologic biomarkers and PD/PK. Results:Twelve patients received a single IV dose of SAR445088 (n=6, 30 mg/kg; n=6, 15 mg/kg). Patients enrolled in the study were mainly female (91.7%, n=11) with a median age (range) of 69 (54-80) years, and median (range) hemoglobin at baseline was 9.60 (4.8-10.9) g/dL. There were no treatment-emergent serious adverse events (AEs), discontinuations or deaths reported in the study. Fifty-eight treatment-emergent AEs (TEAEs) were reported in 11 patients (91.7%). There was one reported pre-treatment severe AE (Grade 3) of hemolytic anemia in a patient in the 15 mg/kg IV cohort which began prior to treatment and continued during the treatment period; the remainder of TEAEs were mild or moderate in severity (Grade 1 or 2). The most frequently reported AE was hematuria. No serious infections, meningococcal infections, hypersensitivity, or thromboembolic events were reported. Nine patients (n=4, 30 mg/kg IV cohort; n=5, 15 mg/kg IV cohort) reached an increase of hemoglobin ≥1.5 g/dL from baseline to Day 106 (EOS visit); eight patients (n=4 for both cohorts) reached an increase in hemoglobin &amp;gt;1.0 g/dL from baseline to Day 15 (Figure A). Total mean bilirubin decreased by Day 1 and this was sustained to Day 106 (EOS visit; Figure B).The decrease was more pronounced in the 30 mg/kg IV cohort. Improvements in clinical markers correlated with sustained reductions in CH50 in both treatment cohorts. Reductions in mean percent classical complement pathway (CP) activity were noted 1 hour after a single dose of 30 or 15 mg/kg IV, followed by gradual rebound of CP activity over the 15-week study period. Conclusion:SAR445088 was generally well tolerated; no safety concerns were identified in patients with CAD. A single IV dose of SAR445088 led to classical complement inhibition, control of hemolysis, and improvement in anemia, which was sustained for 15 weeks.

Detection of Novel US Neisseria meningitidis Urethritis Clade Subtypes in Japan.

Neisseria meningitidis causes invasive meningococcal diseases and has also been identified as a causative agent of sexually transmitted infections, including urethritis. Unencapsulated sequence type 11 meningococci containing the gonococcal aniA-norB locus and belonging to the United States N. meningitidis urethritis clade (US_NmUC) are causative agents of urethral infections in the United States, predominantly among men who have sex with men. We identified 2 subtypes of unencapsulated sequence type 11 meningococci in Japan that were phylogenetically close to US_NmUC, designated as the Japan N. meningitidis urethritis clade (J_NmUC). The subtypes were characterized by PCR, serologic testing, and whole-genome sequencing. Our study suggests that an ancestor of US_NmUC and J_NmUS urethritis-associated meningococci is disseminated worldwide. Global monitoring of urethritis-associated N. meningitidis isolates should be performed to further characterize microbiologic and epidemiologic characteristics of urethritis clade meningococci.

From respiratory diseases to nervous system disorders: Unraveling the certified causes of influenza-associated deaths in Poland from 2000 to 2019.

This study aims to accurately estimate influenza-associated deaths in Poland and their certified cause of death, due to significant discrepancies between official numbers and expected impact. Excess influenza-associated mortality in Poland from 2000 to 2019 was calculated using Seasonal-Trend Decomposition Procedure based on LOESS (STL), which can detect non-linear trends and non-sinusoidal cycles. Excess mortality was then used as an explanatory variable in a model predicting monthly fluctuations of officially recorded causes of death from 2010 to 2019. A total of 142,000 conservative estimates of influenza-associated deaths were identified, representing 1.86% of overall mortality. Only 0.61% of influenza-associated deaths were officially recorded as influenza. Nearly half of certified influenza deaths were attributed to the seasonal baseline mortality, potentially doubling estimated impact based solely on influenza peaks. Influenza-associated deaths were frequently recorded as respiratory diseases (24.36%), with majority attributed to underlying conditions such as cardiovascular diseases (45.31%), cancer (9.06%), or diabetes (2.66%). Influenza-associated deaths were more commonly certified as nervous system diseases (1.84%) or mental disorders (1.04%), rather than influenza itself. There was a noticeable impact of influenza on secondary infections, such as meningococcal and gastrointestinal infections. These findings highlight the importance of improved estimation for informing public health policy decisions.

ВЕСТИБУЛЯРНЫЙ НЕЙРОНИТ: КЛИНИЧЕСКИЙ ПРИМЕР ТЕЧЕНИЯ ЗАБОЛЕВАНИЯ С ИСПОЛЬЗОВАНИЕМ БИОЛОГИЧЕСКИ ОБРАТНОЙ СВЯЗИ (БОС)

The examination was conducted with the consent of patient P., born in 1961, who was undergoing treatment in the neurological department of the Federal State Budgetary Health Care Institution "Clinical Hospital No. 8 of the Federal Medical and Biological Agency" (FGBUZ KB No. 8 FMBA of Russia). The patient was examined for viral and bacterial infections: Herpes simplex virus 1,2 IgM, herpes simplex virus 1,2 IgG, cytomegalovirus IgM, Epstein-Barr virus IgM to AG capsid, SARS-CoV-2 coronavirus, IgM antibodies, meningococcus, haemophilus bacillus, streptococcus (Neisseria meningitidis, heamophilus influenzae, streptococcus pneumoniae, PCR), influenza type B virus. It should be noted that all analyses were performed with quantitative evaluation in order to observe the course of the disease in dynamics. This list of analyses was determined not only to monitor the dynamics of the disease, but also to perform differential diagnosis (e.g. with labyrinthitis, as this disease has a similar clinical picture). In the course of the study, as a result of a rational evaluation, it was identified and decided to focus the study on herpes simplex virus 1, 2 IgG analyses in the dynamics - accordingly, the analyses were taken on day 5 of the disease, on day 14, and then on day 21. The patient underwent instrumental diagnostics: audiometry, SCT study, MRI study to exclude other similar pathological phenomena. In addition to laboratory tests, the patient underwent diagnostic and rehabilitation tests on a stabilisation platform with biofeedback based on StabMed 2-"Stabilan-01-2" software, both at the beginning of treatment and at the end (the main diagnostic test performed was a stabilography test. Various variants of the Romberg test are a standard tool in the arsenal of a modern doctor, for example, clinical recommendations on differential diagnosis of peripheral vertigo include it in the list of mandatory procedures during physical examination of a patient with complaints of dysfunction of the vestibular apparatus ).

General principles of vaccination of patients with neuromuscular diseases

Vaccination is recognized as the most effective, safe, and cost-effective way to prevent infectious diseases and their complications. For patients with chronic diseases, and for patients with neuromuscular diseases in particular, vaccination is the highest priority for the prevention of infectious diseases. In the current literature, there is a lack of information describing the principles of vaccination of patients with spinal muscular atrophy and Duchenne muscular dystrophy. In patients with neuromuscular diseases, full immunization has to be done in accordance with the National calendar and recommendations with the introduction of an additional vaccine against such diseases as: rotavirus infection, pneumococcal infection (using an additional dose of 23-valent vaccine), meningococcal infection, virus human papilloma, respiratory viral infection. syncytial virus and influenza. In this regard, of particular importance is the development of recommendations describing the schemes for the use of vaccines in children suffering from spinal muscular atrophy and Duchenne muscular dystrophy.

Inference of transmission dynamics and retrospective forecast of invasive meningococcal disease.

The pathogenic bacteria Neisseria meningitidis, which causes invasive meningococcal disease (IMD), predominantly colonizes humans asymptomatically; however, invasive disease occurs in a small proportion of the population. Here, we explore the seasonality of IMD and develop and validate a suite of models for simulating and forecasting disease outcomes in the United States. We combine the models into multi-model ensembles (MME) based on the past performance of the individual models, as well as a naive equally weighted aggregation, and compare the retrospective forecast performance over a six-month forecast horizon. Deployment of the complete vaccination regimen, introduced in 2011, coincided with a change in the periodicity of IMD, suggesting altered transmission dynamics. We found that a model forced with the period obtained by local power wavelet decomposition best fit and forecast observations. In addition, the MME performed the best across the entire study period. Finally, our study included US-level data until 2022, allowing study of a possible IMD rebound after relaxation of non-pharmaceutical interventions imposed in response to the COVID-19 pandemic; however, no evidence of a rebound was found. Our findings demonstrate the ability of process-based models to retrospectively forecast IMD and provide a first analysis of the seasonality of IMD before and after the complete vaccination regimen.

Phylogenomic analysis of the understudied Neisseriaceae species reveals a poly- and paraphyletic Kingella genus.

Taxonomic classification and phylogenetic analysis of the Neisseriaceae family have focused on the pathogens Neisseria meningitidis and Neisseria gonorrhoeae. Less is known about the relationships of commensal Neisseria species and other Neisseriaceae genera, raising the possibility that the phylogeny of this family may not agree with current taxonomy. In this study, we used available nucleotide sequences and a phylogenetic approach to assess the Kingella genus and its relatives. We found that this genus is both paraphyletic and polyphyletic. Kingella potus is more closely related to Neisseria bacilliformis than to other Kingella species. The Alysiella and Simonsiella genera form a distinct clade within the Kingella genus that is closely related to the pathogens K. kingae and K. negevensis. We find a phylogenetic relationship between Conchiformibius, Alysiella, Simonsiella, and Kingella, which we name the CASK clade. Finally, we define the gene sets that differentiate each genus of the CASK clade from one another and from the rest of the Neisseriaceae family. IMPORTANCE Understanding the evolutionary relationships between the species in the Neisseriaceae family has been a persistent challenge in bacterial systematics due to high recombination rates in these species. Previous studies of this family have focused on Neisseria meningitidis and N. gonorrhoeae. However, previously understudied Neisseriaceae species are gaining new attention, with Kingella kingae now recognized as a common human pathogen and with Alysiella and Simonsiella being unique in the bacterial world as multicellular organisms. A better understanding of the genomic evolution of the Neisseriaceae can lead to the identification of specific genes and traits that underlie the remarkable diversity of this family.

Increased rates of invasive bacterial disease in late 2022.

Invasive bacterial disease is associated with significant morbidity and mortality. In winter 2022, there was an apparent increased rate of invasive bacterial disease compared to preceding years.Cross-site retrospective analysis of the three Children's Health Ireland (CHI) hospitals looking at children admitted between 1st October 2022-31st December 2022 (Q4) with community-acquired invasive bacterial disease, defined as an abscess in a normally sterile site in the head, neck and chest or isolation or PCR detection of Streptococcus pneumoniae, Neisseria meningitidis, Streptococcus pyogenes (Group A streptococcus) or Haemophilus influenzae from a normally sterile site. Case numbers were compared to Q4 in each of 2018-2021.Eighty-two children met the case definition in Q4 2022 vs 97 (Q4 2018-2021). In 2022, 42/82 (51%) were female, median age 3.75years (1.5-8.25years). Only 2 (2%) were immunosuppressed and 2 others (2%) had underlying neurodisability. Fifty (61%) were admitted on second or subsequent presentation to a healthcare setting. Fifty-six (68%) had an abscess in a sterile site. Bloodstream infection (positive blood culture or PCR: 24 (29%)) was the most common site of infection, followed by neck 22 (27%) and intracranial 12 (15%). Group A streptococcus (GAS) 27 (33%) was the most common organism isolated. Seven cases (9%) died in 2022 compared to 2 patients (2%) from 2018 to 2021 (p < 0.05). More children had Paediatric Overall Performance Category (POPC) scores > 1 in 2022 than 2018-2021 (p = 0.003). Conclusion: Invasive bacterial diseases increased in Q4 2022 with higher morbidity and mortality than in the preceding 4years. Group A streptococcal infection was the most significant organism in 2022. What is known: • Invasive bacterial disease is the leading cause of childhood mortality globally. • There was an increase in cases of invasive Group A streptococcus infections reported in many countries (including Ireland) during the winter of 2022/23. What is new: • Head, neck and chest abscesses increased in Q4 of 2022 compared to the previous 4years combined. • Invasive bacterial infections in Q4 of 2022 were associated with higher rates of mortality (9%), paediatric intensive care unit (PICU) admission (24%) and requirement for surgical drainage or intervention (67%) than in the preceding years.

Role of the National Immunisation Technical Advisory Groups in 13 European countries in the decision-making process on vaccine recommendations.

In Europe, National Immunisation Technical Advisory Groups (NITAGs) were established in most countries to promote evidence-informed decision-making in introducing new or improved vaccines or changing recommendations for existing ones. Still, the role, activities and outcomes of NITAGs have not been optimally implemented across Europe. Within the European Joint Action on Vaccination (EU-JAV), we conducted a survey to collect information on decision-making process including the main criteria for the introduction of new vaccines or changes to recommendations on their use. Between December 2021 and January 2022, 13 of the 28 European countries invited participated in an online survey. The criteria ranked as most relevant were disease burden and availability of financial resources. Only one country specified that the NITAG recommendations were binding for the government or the health authority. Vaccinations more often reported for introduction or recommendation changes were those against herpes zoster, influenza, human papillomavirus infection, pneumococcal and meningococcal disease. The planned changes will mainly address children and adolescents (2-18 years) and adults (≥ 45-65 years). Our findings show potential overlaps in the activities of NITAGs between countries; and therefore, collaboration between NITAGs may lead to optimisation of the workload and better use of resources.

Multivariate control charts for monitoring a bivariate correlated count process with application to meningococcal disease.

In recent years, with the increasing number and complexity of infectious diseases, the idea of using control charts to monitor public health and disease has been proposed. In this paper, we study multivariate control charts for monitoring a bivariate integer-valued autocorrelation process with bivariate Poisson distribution and select the optimal control scheme by comparing the performance of control charts. Furthermore, the meningococcal patient event in two states in Australia serves as an example to illustrate the application of these methods. The results show that the D exponentially weighted moving average control scheme can detect the changes in the mean value faster, which is a significant advantage.