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To test for immunologic memory after a single dose of meningococcal C conjugate (MCC) vaccine in toddlers, 226 children 12-18 months old were randomized to receive 1 of 3 MCC vaccines, with a C polysaccharide booster 6 months later. The protein conjugate was diphtheria mutant toxoid in 2 vaccines (MCC-CRM(197)) and was tetanus toxoid in the third (MCC-TT). One month after the MCC vaccines, 91%-100% of children had serum bactericidal antibody (SBA) titers > or =8, and 89%-100% had a > or =4-fold increase. Geometric mean titer (GMT) increased from <4 to 215 (95% confidence interval [CI], 166-279). MCC-TT induced higher SBA GMTs (P<.001) and higher proportions with SBA > or =8 (P=.02) than did the MCC-CRM(197) vaccines. By 6 months, GMTs had decreased to 55.1 (95% CI, 40-76), but IgG antibody avidity increased (P<.001). Induction of immunologic memory was confirmed by a GMT of 1977 (range, 1535-2547) after the polysaccharide booster and a further increase in avidity. This evidence justified the use of a single dose in a catch-up immunization program for children 1-18 years old. [ABSTRACT FROM AUTHOR]

Abstract Background Meningococcal meningitis is a major cause of disease worldwide, with frequent epidemics particularly affecting an area of sub-Saharan Africa known as the “meningitis belt”. Neisseria meningitidis group A (MenA) is responsible for major epidemics in Africa. Recently W-135 has emerged as an important pathogen. Currently, the strategy for control of such outbreaks is emergency use of meningococcal (MC) polysaccharide vaccines, but these have a limited ability to induce herd immunity and elicit an adequate immune response in infant and young children. In recent times initiatives have been taken to introduce meningococcal conjugate vaccine in these African countries. Currently there are two different types of MC conjugate vaccines at late stages of development covering serogroup A and W-135: a multivalent MC conjugate vaccine against serogroup A,C,Y and W-135; and a monovalent conjugate vaccine against serogroup A. We aimed to perform a structured assessment of these emerging meningococcal vaccines as a means of reducing global meningococal disease burden among children under 5 years of age. Methods We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In the first stage we systematically reviewed the literature related to emerging MC vaccines relevant to 12 criteria of interest. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). They answered questions from CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%. Results For MenA conjugate vaccine the experts showed very high level of optimism (~ 90% or more) for 7 out of the 12 criteria. The experts felt that the likelihood of efficacy on meningitis was very high (~ 90%). Deliverability, acceptability to health workers, end users and the effect on equity were all seen as highly likely (~ 90%). In terms of the maximum potential impact on meningitis disease burden, the median potential effectiveness of the vaccines in reduction of overall meningitis mortality was estimated to be 20%; (interquartile range 20-40% and min. 8%, max 50 %). For the multivalent meningococcal vaccines the experts had similar optimism for most of the 12 CHNRI criteria with slightly lower optimism in answerability and low development cost criteria. The main concern was expressed over the cost of product, its affordability and cost of implementation. Conclusions With increasing recognition of the burden of meningococcal meningitis, especially during epidemics in Africa, it is vitally important that strategies are taken to reduce the morbidity and mortality attributable to this disease. Improved MC vaccines are a promising investment that could substantially contribute to reduction of child meningitis mortality world-wide.

A correction to the article "Prevalence of human papillomavirus antibodies in young female subjects in England," that was published in the previous issue is presented.

Studies the relation of certain forms of genes, interleukin-I genes, to meningococcal disease. Symptoms and problems caused by the disease; Methodology employed to study the patients and blood donors; Association of survival of meningococcal infections and the interleukin-I gene; Limitations of the study.

Invasive meningococcal disease (IMD) is associated with high case fatality rates and long-term sequelae among survivors. Meningococci belonging to six serogroups (A, B, C, W, X, and Y) cause nearly all IMD worldwide, with serogroup B meningococci (MenB) the predominant cause in many European countries, including Greece (~80% of all IMD). In the absence of protein-conjugate polysaccharide MenB vaccines, two protein-based vaccines are available to prevent MenB IMD in Greece: 4CMenB (Bexsero™, GlaxoSmithKline), available since 2014; and MenB-FHbp, (Trumenba™, Pfizer), since 2018. This study investigated the potential coverage of MenB vaccines in Greece using 107 MenB specimens, collected from 2010 to 2017 (66 IMD isolates and 41 clinical samples identified solely by non-culture PCR), alongside 6 MenB isolates from a carriage study conducted during 2017–2018. All isolates were characterized by multilocus sequence typing (MLST), PorA, and FetA antigen typing. Whole Genome Sequencing (WGS) was performed on 66 isolates to define the sequences of vaccine components factor H-binding protein (fHbp), Neisserial Heparin Binding Antigen (NHBA), and Neisseria adhesin A (NadA). The expression of fHbp was investigated with flow cytometric meningococcal antigen surface expression (MEASURE) assay. The fHbp gene was present in-frame in all isolates tested by WGS and in 41 MenB clinical samples. All three variant families of fHbp peptides were present, with subfamily B peptides (variant 1) occurring in 69.2% and subfamily A in 30.8% of the samples respectively. Sixty three of 66 (95.5%) MenB isolates expressed sufficient fHbp to be susceptible to bactericidal killing by MenB-fHbp induced antibodies, highlighting its potential to protect against most IMD in Greece. [ABSTRACT FROM AUTHOR]

Highlights • Immunisation with MCV during pregnancy resulted in an antibody response. • Maternal immunization with MCV conveyed protective levels of MenA IgG at birth. • Infant antibody levels declined over the first 3 months of life. Abstract A prospective, randomised, controlled observer-blind trial measuring the efficacy and immunogenicity of trivalent influenza vaccine (TIV) and the immunogenicity of quadrivalent meningococcal conjugate vaccine (MCV) in pregnant women and their infants up to 6 months of age was conducted in Mali. Here we reported the immunogenicity of MCV, which was used as a comparator vaccine to TIV, in this population. Third-trimester pregnant Malian women were randomized to receive TIV or MCV. Blood samples were collected from women prior to vaccination, 28 days post-vaccination, at delivery and 3 and 6 months post-delivery and from infants at birth and 3 and 6 months of age. Meningococcal-specific serogroup (Men) A, C, Y and W-specific antibodies were measured by enzyme linked immunosorbent assay in a randomly selected subset of 50 mother-infant pairs where the mother had received MCV. At birth, 94.0% (47/50) of infants had MenA specific IgG levels ≥ 2 µg/mL decreasing to 72.9% and 30.4% at 3 and 6 months of age. For MenC, 81.3% (39/48) of infants had MenC specific IgG levels ≥ 2 µg/mL at birth decreasing to 29.4% and 17.8% at 3 and 6 months of age. For MenY, 89.6% (43/48) of infants had MenY specific IgG levels ≥ 2 µg/mL at birth decreasing to 64.6% and 62.5% at 3 and 6 months of age. For MenW, 89.6% (43/48) of infants had MenW specific IgG levels ≥ 2 μg/ml at birth decreasing to 62.5% and 41.7% at 3 and 6 months of age. Maternal immunization with MCV conveyed protective levels of IgG at birth through to 3 months of age in the majority of infants. [ABSTRACT FROM AUTHOR]

Hajj pilgrims are susceptible to several serious infections and are required to receive multiple vaccinations. Polysaccharide-protein conjugate vaccines contain carrier proteins such as tetanus toxoid (TT), diphtheria toxoid or a mutant of diphtheria toxoid (CRM197). These carrier proteins may interact with other conjugate or combination vaccines containing tetanus or diphtheria on concurrent or sequential administration. We examined the immune interaction of separate and concomitant administration of a tetanus/diphtheria/acellular pertussis (Tdap) vaccine with a TT-conjugated quadrivalent meningococcal vaccine (MCV4) (coadministered with 13-valent pneumococcal CRM197-conjugate vaccine [PCV13]) in adult Australian pilgrims before attending Hajj in 2015. We randomly assigned each participant to one of three vaccination schedules. Group 1 received Tdap 3–4 weeks before receiving MCV4 coadministered with PCV13. Group 2 received all three vaccines concomitantly. Group 3 received MCV4 and PCV13 3–4 weeks before Tdap. Blood samples were collected at baseline, at each vaccination visit and 3–4 weeks after vaccination and tested for response to meningococcal serogroups C, W and Y using a serum bactericidal antibody (rSBA) assay with baby rabbit complement, and to diphtheria and tetanus toxoid, measuring IgG antibodies by ELISA. Participants completed symptom diaries after each vaccination. A total of 166 participants aged 18–64 (median 42) years were recruited, of whom 160 completed the study. Compared to the other groups, Group 1 (given Tdap first) had significantly lower proportion of subjects achieving a ≥4-fold rise in rSBA for serogroup W. No difference was detected across the three groups in achieving protection threshold (rSBA ≥8 post vaccination) or SBA geometric mean titre (GMT) post vaccination. Group 3, which was given MCV4/PCV13 first, had high levels of antibody against diphtheria and tetanus than the other groups, when tested prior to receipt of Tdap; Only the anti-tetanus responses remained significantly higher after Tdap administration. No serious adverse events were reported. In conclusion, when multiple vaccination is required for Hajj pilgrims, administering Tdap concurrently with MCV4/PCV13 produces adequate immune responses, and avoids meningococcal immune interference, in the convenience of a single consultation. However, giving Tdap 3–4 weeks after MCV4/PCV13 has the advantage of an enhanced tetanus toxoid response. The trial is Trials Registry (ANZCTR): ACTRN12613000536763. [ABSTRACT FROM AUTHOR]

A cluster of four confirmed cases of meningococcal disease was seen in the same nuclear family across a 15-week period. The cases were three siblings and a parent and all recovered well. The first case was confirmed by meningococcal PCR only but the subsequent three cases were due to indistinguishable strains of serogroup B (B:NT:P1.19-1,15-11). Contact tracing was initially undertaken and reviewed in detail after each subsequent case. Antibiotic prophylaxis was administered to close family contacts on three separate occasions, including switching of antibiotic agents, with good compliance. Subsequent investigation of the family has not revealed any obvious immunological problem and no further significant infections have been recognised. A cluster of meningococcal disease of this nature and timescale is highly unusual. Details of the cluster, investigation and implications for health protection practice are discussed. [ABSTRACT FROM AUTHOR]

Complement is an essential component of the immune system and human pathogenic organisms have developed various mechanisms for evading complement mediated serum killing. The “gold standard” for measuring the ability of vaccine-induced antibody to kill Neisseria meningitidis is the serum bactericidal antibody (SBA) assay which measures complement mediated killing via antibody. This assay requires active complement, either intrinsic from the serum being tested or the addition of exogenous complement, either from a human or from another species such as rabbit. For serogroup C, an SBA titre of ≥4 was established as the correlate of protection when using human complement and ≥8 as the threshold when using rabbit complement, based on comparative assay results. Licensure of meningococcal vaccines, including polysaccharide protein conjugate vaccines and serogroup B vaccines has been based on the immune responses measured with the SBA assay, thus on a surrogate of vaccine efficacy. This review examines the use of complement and the SBA assay to assess immunity to meningococcal infection, and provides examples of vaccine trials in different age groups where various assays have been used. [ABSTRACT FROM AUTHOR]

Mannose binding lectin ( MBL2) is a soluble pattern recognition receptor that is key to generating innate immune responses to invasive infection, including against the cardinal Gram-negative bacterium Neisseria meningitidis. Individuals homozygous or heterozygous for any of three variant alleles of MBL2 (O/O or A/O genotypes) have deficient concentrations of MBL2 in circulating blood, but previous studies linking MBL deficiency to susceptibility to meningococcal disease have not revealed a consistent association. We genotyped 741 patients with microbiologically - proven meningococcal disease and correlated MBL2 genotype with plasma bacterial load of N. meningitidis with blood samples taken during hospital admission. We show that individuals with genotypes compatible with MBL2 deficiency have higher measurable levels of bacterial plasma genomic load with the greatest effect seen in children <2 years of age. However, the overall impact of this is minor, because there was no evidence that such genotypes are more common in children with meningococcal disease compared with uninfected cohorts. The findings suggest that MBL2 supports innate immune defence against meningococcal disease in the early months of life, before acquired immunity is sufficiently robust for effective natural protection. [ABSTRACT FROM AUTHOR]

Highlights: [•] 29 Patients were studied: AQP4 Ab positive NMO (n =19) and MS (n =10). [•] Higher IL17a (p =0.0005), G-CSF (p =0.051) and CCL4 (p =0.086) in NMO. [•] IL17a (p =0.008), G-CSF (p <0.01), MPO (p <0.01), CCL4 (p <0.01) identified NMO. [•] 17 Correctly identified NMO, 9 as MS (OR 54, p <0.001); overall 26 (89.7%) correct. [•] Importance of mediators with predominant function with neutrophils and eosinophils. [Copyright &y& Elsevier]

Invasive infection caused by Neisseria meningitidis is a worldwide public health problem. Previous reports have indicated that carriage of common 'defective' structural polymorphisms of the host mannose-binding lectin gene ( MBL2) greatly increases an individual's risk of developing the disease. We report the largest case-control study so far to investigate the effect of these polymorphisms in meningococcal disease (296 PCR-positive cases and 5196 population controls, all of European ancestry) and demonstrate that no change in risk is associated with the polymorphisms overall or in any age-defined subgroup. This finding contrasts with two smaller studies that reported an increase in risk. A systematic review of all studies of MBL2 polymorphisms in people of European ancestry published since 1999, including 24 693 individuals, revealed a population frequency of the combined 'defective' MBL2 allele of 0.230 (95% confidence limits: 0.226-0.234). The past reported associations of increased risk of meningococcal disease were because of low 'defective' allele frequencies in their study control populations (0.13 and 0.04) that indicate systematic problems with the studies. The data from our study and all other available evidence indicate that MBL2 structural polymorphisms do not predispose children or adults to invasive meningococcal disease. [ABSTRACT FROM AUTHOR]

Background. After immunization with serogroup C meningococcal (MenC) conjugate vaccine, antibody responses and vaccine effectiveness are sustained in adolescents, in contrast to rapid waning in young children. We investigated the persistence of serum bactericidal antibody (SBA) titers in children 6 years after immunization with MenC vaccine (primed between 2 months and 6 years of age). The response to a Haemophilus influenzae type b-MenC conjugate (Hib-MenC) booster was also measured. Methods. A phase 4 clinical trial was conducted among 250 healthy 6-12-year-old children. SBA titers were measured before, 1 month after, and 1 year after Hib-MenC administration. The correlate of protection was an SBA titer of ⩾8. Results. An SBA titer of ⩾8 was observed in 61 (25% [95% confidence interval (CI), 20%-30%]) of 244 participants (mean age, 9.1 years; mean interval since MenC immunization, 6.75 years). The proportion with an SBA titer of ⩾8 and the SBA geometric mean titer increased with age, from 12% (95% CI, 4%-23%) to 48% (95% CI, 29%-67%) and from 2.90 (95% CI, 2.11-3.99) to 17.20 (95% CI, 6.80-43.5), respectively, from a mean age of 7.0 to 12.1 years. One month after the Hib-MenC booster, all participants had an SBA titer of ⩾8, which was sustained in 99.6% at 1 year. Conclusions. As a result of waning antibody, the majority of 6-12-year-old children in the United Kingdom have inadequate serological protection against MenC. The persistence of MenC immunity and the response to a Hib-MenC booster is dependent on age at priming. A booster was highly effective in this cohort and could sustain population immunity against MenC disease. [ABSTRACT FROM AUTHOR]

Although pituitary hormones are known to affect immune function, treated hypopituitarism is not a recognized cause of immune deficiency in humans. We set out to assess integrity of baseline and stimulated immune function in severely hypopituitary adults. Twenty-one panhypopituitary adults (group 1), on stable pituitary replacement including growth hormone, and 12 healthy volunteers (group 2) were studied. Lymphocyte subsets, pneumococcal antibody levels pre- and 1 month after polysaccharide vaccination, T cell numbers and in-vitro interferon (IFN)-γ response were studied. There were no significant differences in T cell numbers or IFN-γ secretion. B cell numbers were lower in group 1, especially those with low prolactin levels. Independent of this finding, nine of 21 patients in this group had low antibody response to polysaccharide antigen. This was most striking in those with low insulin-like growth factor 1 levels and appeared to be independent of the use of anti-convulsants or corticosteroid replacement. Significant humoral immune deficiency is seen in panhypopituitarism and may contribute to morbidity. [ABSTRACT FROM AUTHOR]

This article presents a study that examined the persistence of bacterial antibody titres in the aftermath of immunization with serogroup C meningococal glycoconjugate vaccine between the ages of 6-15 years old. The researchers were interested in examining the changes that occur in the persistence of antibodies with age. Their findings indicate that patients that received the vaccination after the age of 10 had higher concentrations of bactericidal antibodies. They suggest that this could be the result of immunization maturation.

The article discusses a study on the impact of splenectomy on vaccine immunogenicity. Serum bacterial activity and antibodies against serogroups A and C were tested among children with hereditary spherocytosis who had complete and near-total splenectomy and received monovalent meningococcal C conjugate vaccine and meningococcal polysaccharide vaccine. The authors conclude the favorable immunological effects of near-total splenectomy and the immunogenicity of sequential meningococcal vaccination.

Aims: To describe the immune response of preterm infants to combined diphtheria/tetanus/5 component acellulor pertussis-Haemophilus influenzae type b inactivated polio vaccine (DT5aP-Hib-IPV) and meningococcal serogroup C conjugate vaccine (MCC) under accelerated schedule. To compare results with term infants immunised with DT5aP-Hib-IPV and with historical data from preterm infants immunised with a DT3 component aP-Hib vaccine. Methods: Prospective observational study in preterm infants born at <32 weeks gestation with comparison to contemporary cohort of term infants. DT5aP-Hib-IPV and MCC vaccines were given at 2, 3, and 4 months. Results: Fifty preterm infants (mean gestational age 28.5 weeks) completed the study. After three doses of vaccines Hib polysaccharide IgG geometric mean concentration (GMC) was 1.21 μg/ml with 80% &ges;0.15 μg/ml; MCC serum bactericidal assay geometric mean titre (GMT) was 1245 with 100% &ges;8. All infants achieved protective titres to diphtheria, tetanus, and the three poliovirus types with &ges;80% achieving protective rises in IgG ago inst the five pertussis antigens. Conclusion: Preterm infants immunised with DT5aP-Hib-IPV and MCC vaccines show IgG responses to Hib and MCC greater than seen historically in both term and preterm infants with a DT3aP-Hib vaccine, and for pertussis antigens and poliovirus type 1 responses similar to that seen in term infants immunised with DTSaP-Hib-IPV. Responses to poliovirus types 2 and 3 are reduced, but all infants achieved protective titres. [ABSTRACT FROM AUTHOR]

SUMMARY The detection of pneumococcal IgG antibodies is helpful for the evaluation of response to pneumococcal vaccination and need for revaccination. Results generated by the clinical assay which is currently used, in which the 23 valent polysaccharide vaccine is the antigen, were compared to those obtained by a capsular polysaccharide serotype-specific assay that measures IgG antibodies to 9 common serotypes causing invasive disease. Discrepancies in 21/47 (45%) of the results were observed in a direct comparison between the two assays. In each case a positive titre was obtained on the clinical assay but IgG levels on the serotype-specific assay were below the putative protective level of 0·2 µ g/ml for at least one of the 9 serotypes assayed. The generation of false positives by the current clinical assay is due to its lack of specificity. Antibodies to C-polysaccharide and all of the 23 serotypes included in the pneumococcal polysaccharide vaccine are incorporated into the final titre whereas the serotype-specific assay adsorbs out noncapsular polysaccharide antibodies. The discrepancies between the two assays highlight the importance of standardized assays that measure putative correlates of protection and demonstrate the need to re-evaluate the current clinical assay. A tool that allows the interpretation of the results of the serotype-specific assay is provided and its potential for assessing individual susceptibility levels to vaccine preventable pneumococcal infection is discussed. [ABSTRACT FROM AUTHOR]

Objective: To describe cases of invasive meningococcal disease (IMD) in women of childbearing age and to estimate the disease incidence and relative risk of IMD in pregnant compared with non-pregnant women.Design: Prospective enhanced national surveillance for IMD.Setting: England.Population: Women of reproductive age (15-44 years) with laboratory-confirmed IMD.Methods: Public Health England conducts enhanced national surveillance for IMD in England. Laboratory-confirmed cases are followed up with postal questionnaires to general practitioners. All cases confirmed in women of reproductive age from 1 January 2011 to 31 December 2014 were included.Main Outcome Measures: Annual IMD incidence and relative risk of IMD in pregnant compared with non-pregnant women of reproductive age.Results: During the 4-year surveillance period, there were 1502 cases of IMD in females across England; of these, 310 (20.6%) cases were in women of reproductive age, including four women who were pregnant at the time of IMD confirmation (1.3%). Serogroup distribution of IMD cases in women of childbearing age was similar to the overall distribution. The four cases in otherwise healthy pregnant women were confirmed across all trimesters and all survived; one case in the first trimester had a septic miscarriage. The incidence of IMD was lower in pregnant than in non-pregnant women (0.16 compared with 0.76 per 100 000 pregnant and non-pregnant years, respectively), giving a lower risk of IMD in pregnant women (incidence rate ratio, IRR, 0.21; 95% confidence interval, 0.06-0.54).Conclusions: Pregnant women are nearly five times less likely to develop IMD compared with non-pregnant women, but the infection can be severe.Tweetable Abstract: The risk of meningococcal disease is lower in pregnant women compared with non-pregnant women; the infection can occur across all trimesters and can be severe. [ABSTRACT FROM AUTHOR]

Introduction: Following the CHAMPION-NMOSD trial, the FDA recently granted approval for ravulizumab, a humanized monoclonal antibody against complement C5 protein in AQP-4 seropositive neuromyelitis optica spectrum disorder (NMOSD). Similar to eculizumab, ravulizumab offers near-complete prevention of NMOSD relapses, but has a longer half-life, providing decreased infusion frequency and increased convenience for patients. While targeting the complement pathway has clear advantages, patients are at risk for infection with encapsulated organisms, in particular Neisseria meningitidis ., Areas Covered: In this paper, we discuss the details of the CHAMPION-NMOSD trial and discuss challenges in meningitis prevention and strategies for switching therapies., Expert Opinion: Ravulizumab improves on eculizumab's success as a highly effective NMOSD therapy by decreasing infusion frequency, thereby increasing patient convenience. We predict that ravulizumab will eventually replace eculizumab but may not have a similar impact on inebelizumab or satralizumab. Patients taking C5 complement inhibitors have an increased risk of serious meningococcal infections, such as invasive meningococcal disease (IMD), and have incomplete protection against IMD despite immunization. Thus, we recommend that in addition to standard pre-immunizations against Neisseria meningitidis , patients should also be assessed for starting on appropriate antibiotic prophylaxis against IMD, based on local resistance patterns.

In Western Europe, many countries have robust and well-established surveillance systems and case reporting mechanisms. IMD incidence across Western Europe is low with a predominance of meningococcal serogroup B (MenB). Case confirmation and antimicrobial susceptibility testing is often standardised in this region, with many countries also having robust vaccination programmes in place. Both MenB and MenACWY vaccines form part of National Immunisation Programmes (NIPs) in most European countries, with Sweden only offering vaccination in special circumstances. Despite these established programmes, there remains a critical need for advocacy efforts in affecting change in diagnosis, testing, and treatment. Recent campaigns, such as the World Meningitis Day digital toolkit, have helped raise awareness and draw attention to meningococcal disease. Awareness around antibiotic resistance has also led to the identification of antibiotic-resistant meningococcal strains, with an increase, albeit small, in these strains noted across the region. Countries such as Spain, Portugal, Germany, Switzerland, and France have either reported strains resistant to penicillin, ciprofloxacin and/or isolates with a reduced susceptibility to third-generation cephalosporins., Competing Interests: Declaration of Competing Interest Ray Borrow performs contract research on behalf of UKHSA for GSK, PATH, Pfizer and Sanofi. Heike Claus has received personal fee for scientific presentation for Sanofi. Ener Cagri Dinleyici performs contract work for the Eskisehir Osmangazi University funded by GSK, Sanofi Pasteur and Pfizer. Lee Harrison has served on advisory boards and/or made scientific presentations for GSK, Pfizer, Sanofi, and Merck, for which he does not receive any personal fees. William P. Hausdorff has served on advisory boards for Sanofi, Merck, and Vaxcyte, for which he does not receive any personal fees or reimbursement. Corinne Levy reports personal fees for advisory board and scientific presentations for MSD and Pfizer. Wesley Mattheus reports research grants funded by GSK and Pfizer. Marco A. P. Sáfadi reports research grants and personal fees for advisory boards from GSK, Pfizer, and Sanofi. Vinny Smith works for Meningitis Research Foundation that receives income from grants, sponsorship and consultancy income from GSK, MSD, Pfizer, Sanofi and Serum Institute of India. M.K. Taha performs contract work for the Institut Pasteur funded by GSK, Pfizer and Sanofi. M.K. Taha and A-E Deghmane have a patent NZ630133A Patent with GSK “Vaccines for serogroup X meningococcus” issued. Georgina Tzanakaki reports contract work on behalf of the University of West Attica as participation on advisory boards and scientific presentations for Pfizer, Sanofi and Merck. J.A. Vázquez performs contract work for the Institute of Health Carlos III funded by GSK and Pfizer and he has received personal fees from Pfizer and Sanofi. Nina van Sorge receives fee for service and presentations (directly paid to the institution) from MSD and GSK. Finnish Institute for Health and Welfare has received research funding from Pfizer and GSK for projects in which Maija Toropainen has acted as a researcher without personal remuneration., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Genome-wide association studies (GWAS) with binary or single phenotype data have successfully identified disease-associated genotypes and determinants of antimicrobial resistance. We describe a novel phenotype-to-genotype approach for a major bacterial pathogen that involves simultaneously testing for associations among multiple disease-related phenotypes and linkages between phenotypic variation and genetic determinants. High-throughput assays quantified variation among 163 Neisseria meningitidis serogroup W ST-11 clonal complex isolates for 11 phenotypic traits. A comparison of carriage and two disease subgroups detected significant differences between groups for eight phenotypic traits. Candidate genotypic testing indicated that indels in csw , a capsular biosynthesis gene, were associated with reduced survival in antibody-depleted heat-inactivated serum. GWAS testing detected 341 significant genetic variants (3 single-nucleotide polymorphisms and 338 unitigs) across all traits except serum bactericidal antibody-depleted assays. Growth traits were associated with variants of capsular biosynthesis genes, carbonic anhydrase, and an iron-uptake system while adhesion-linked variation was in pilC2 , marR, and mutS . Multiple phase variation states or combinatorial phasotypes were associated with significant differences in multiple phenotypes. Controlling for group effects through regression and recursive random forest approaches detected group-independent effects for nalP with biofilm formation and fetA with a growth trait. Through random forest testing, nine phenotypes were weakly predictive of MenW:cc11 sub-lineage, original or 2013, for disease isolates while three characteristics separated carriage and disease isolates with >80% accuracy. This study demonstrates the power of combining high-throughput phenotypic testing of pathogenically relevant isolate collections with genomics for identifying genetic determinants of specific disease-relevant phenotypes and the pathobiology of microbial pathogens.IMPORTANCENext-generation sequencing technologies have led to the creation of extensive microbial genome sequence databases for several bacterial pathogens. Mining of these databases is now imperative for unlocking the maximum benefits of these resources. We describe a high-throughput methodology for detecting associations between phenotypic variation in multiple disease-relevant traits and a range of genetic determinants for Neisseria meningitidis , a major causative agent of meningitis and septicemia. Phenotypic variation in 11 disease-related traits was determined for 163 isolates of the hypervirulent ST-11 lineage and linked to specific single-nucleotide polymorphisms, short sequence variants, and phase variation states. Application of machine learning algorithms to our data outputs identified combinatorial phenotypic traits and genetic variants predictive of a disease association. This approach overcomes the limitations of generic meta-data, such as disease versus carriage, and provides an avenue to explore the multi-faceted nature of bacterial disease, carriage, and transmissibility traits.

Objective: To compare immunological responses of preterm infants to a four-component meningococcal B vaccine (4CMenB; Bexsero) following a 2+1 vs a 3+1 schedule, and to describe reactogenicity of routine vaccines., Design: An open-label, phase IV randomised study conducted across six UK sites., Setting: Neonatal units, postnatal wards, community recruitment following discharge., Participants: 129 preterm infants born at a gestation of <35 weeks (64 in group 1 (2+1), 65 in group 2 (3+1)) were included in the analysis. Analysis was completed for postprimary samples from 125 participants (59 in group 1, 66 in group 2) and for postbooster samples from 118 participants (59 in both groups)., Interventions: Infants randomised to 4CMenB according to a 2+1 or a 3+1 schedule, alongside routine vaccines., Main Outcome Measures: Serum bactericidal antibody (SBA) assays performed at 5, 12 and 13 months of age: geometric mean titres (GMTs) and proportions of infants achieving titres ≥4 compared between groups., Results: There were no significant differences in SBA GMTs between infants receiving a 2+1 compared with a 3+1 schedule following primary or booster vaccination, but a significantly higher proportion of infants had an SBA titre ≥4 against strain NZ98/254 (porin A) at 1 month after primary vaccination using a 3+1 compared with a 2+1 schedule (3+1: 87% (95% CI 76 to 94%), 2+1: 70% (95% CI 56 to 81%), p=0.03).At 12 weeks of age those in the 3+1 group, who received a dose of 4CMenB, had significantly more episodes of fever >38.0°C than those in the 2+1 group who did not (group 2+1: 2% (n=1); 3+1: 14% (n=9); p=0.02)., Conclusions: Both schedules were immunogenic in preterm infants, although a lower response against strain NZ98/254 was seen in the 2+1 schedule; ongoing disease surveillance is important in understanding the clinical significance of this difference., Trial Registration Number: NCT03125616., Competing Interests: Competing interests: JL and RB perform contract research on behalf of UKHSA for GlaxoSmithKline (GSK), Pfizer and Sanofi. JC works for an institution which conducts meningococcal vaccine research on behalf of GSK; he receives no personal payment or inducement of any kind. MS was an employee of the University of Oxford and Oxford University Hospitals Foundation NHS trust up until September 2022, and in this role acted as an investigator for clinical research studies funded or otherwise supported by the vaccine manufacturers GSK, Janssen, AstraZeneca, Pfizer, Novavax and MCM vaccines. He received no personal financial benefit for this work. As of September 2022, MS has been an employee of Moderna UK and holds equity in this company; however, all study activities and data analysis were completed before this date., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The meningococcal group B vaccine, 4CMenB, is a broad-spectrum, recombinant protein vaccine that is licensed for protection against meningococcal group B disease in children and adults. Over the past decade, several observational studies supported by laboratory studies have reported protection by 4CMenB against gonorrhoea, a sexually transmitted infection caused by Neisseria gonorrhoeae. Gonorrhoea is a major global public health problem, with rising numbers of diagnoses and increasing resistance to multiple antibiotics. In England, more than 82 000 cases of gonorrhoea were diagnosed in 2022, with nearly half of the cases diagnosed among gay, bisexual, and other men who have sex with men. There are currently no licensed vaccines against gonorrhoea but 4CMenB is estimated to provide 33-47% protection against gonorrhoea. On Nov 10, 2023, the UK Joint Scientific Committee on Vaccination and Immunisation agreed that a targeted programme should be initiated using 4CMenB to prevent gonorrhoea among individuals at higher risk of infection attending sexual health services in the UK. This decision was made after reviewing evidence from retrospective and prospective observational studies, laboratory and clinical data, national surveillance reports, and health economic analyses. In this Review, we summarise the epidemiology of invasive meningococcal disease and gonorrhoea in England, the evidence supporting the use of 4CMenB for protection against gonorrhoea, and the data needed to inform long-term programme planning and extension to the wider population., Competing Interests: Declaration of interests PJW has received payment from Pfizer for teaching of mathematical modelling of infectious disease transmission and vaccination. RB performs contract serology on behalf of UKHSA for GlaxoSmithKline, Pfizer, and Sanofi but receives no personal remuneration. SNL performs contract research for St George's University of London for vaccine manufacturers but receives no personal remuneration. All other authors declare no competing interests., (Crown Copyright © 2024 Published by Elsevier Ltd. All rights reserved.)

The 4-component meningococcal serogroup B (MenB) vaccine, 4CMenB, the first broadly protective, protein-based MenB vaccine to be licensed, is now registered in more than 50 countries worldwide. Real-world evidence (RWE) from the last decade confirms its effectiveness and impact, with infant immunization programs showing vaccine effectiveness of 71-95% against invasive MenB disease and cross-protection against non-B serogroups, including a 69% decrease in serogroup W cases in 4CMenB-eligible cohorts in England. RWE from different countries also demonstrates the potential for additional moderate protection against gonorrhea in adolescents. The real-world safety profile of 4CMenB is consistent with prelicensure reports. Use of the endogenous complement human serum bactericidal antibody (enc-hSBA) assay against 110 MenB strains may enable assessment of the immunological effectiveness of multicomponent MenB vaccines in clinical trial settings. Equitable access to 4CMenB vaccination is required to better protect all age groups, including older adults, and vulnerable groups through comprehensive immunization policies.

Invasive meningococcal disease (IMD), caused by infection with the bacterium Neisseria meningitidis, usually manifests as meningitis or septicemia and can be severe and life-threatening (1). Six serogroups (A, B, C, W, X, and Y) account for most cases (2). N. meningitidis is transmitted person-to-person via respiratory droplets and oropharyngeal secretions. Asymptomatic persons can carry N. meningitidis and transmit the bacteria to others, potentially causing illness among susceptible persons. Outbreaks can occur in conjunction with large gatherings (3,4). Vaccines are available to prevent meningococcal disease. Antibiotic prophylaxis for close contacts of infected persons is critical to preventing secondary cases (2)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Jay Lucidarme, Stephen A. Clark, and Ray Borrow report performing contract research on behalf of the UK Health Security Agency (UKHSA) for GSK, Pfizer, and Sanofi. Muhamed-Kheir Taha reports performing contract research on behalf of the Institut Pasteur for GSK, Pfizer, and Sanofi. Shamez N. Ladhani reports performing contract research on behalf of the UKHSA and St. George’s University of London for GSK, Pfizer, Merck Sharp & Dohme, and Sanofi. Helen Campbell and Mary Ramsay report receipt of a recovery charge by the Immunisation and Vaccine Preventable Diseases Division at UKHSA for provision to vaccine manufacturers (GSK, Pfizer, and Sanofi) of postmarketing surveillance reports on meningococcal, Haemophilus influenzae, and pneumococcal infections, which are required by the U.K. Licensing Authority in compliance with their risk management strategy. Jennifer Zipprich reports that her spouse is employed by Pfizer. No other potential conflicts of interest were disclosed.

Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen were published by the British Committee for Standards in Haematology in 1996 and updated in 2002 and 2011. With advances in vaccinations and changes in patterns of infection, the guidelines required updating. Key aspects included in this guideline are the identification of patients at risk of infection, patient education and information and immunisation schedules. This guideline does not address the non-infective complications of splenectomy or functional hyposplenism (FH). This replaces previous guidelines and significantly revises the recommendations related to immunisation. Patients at risk include those who have undergone surgical removal of the spleen, including partial splenectomy and splenic embolisation, and those with medical conditions that predispose to FH. Immunisations should include those against Streptococcus pneumoniae (pneumococcus), Neisseria meningitidis (meningococcus) and influenza. Haemophilus influenzae type b (Hib) is part of the infant immunisation schedule and is no longer required for older hyposplenic patients. Treatment of suspected or proven infections should be based on local protocols and consider relevant anti-microbial resistance patterns. The education of patients and their medical practitioners is essential, particularly in relation to the risk of serious infection and its prevention. Further research is required to establish the effectiveness of vaccinations in hyposplenic patients; infective episodes should be regularly audited. There is no single group ideally placed to conduct audits into complications arising from hyposplenism, highlighting a need for a national registry, as has proved very successful in Australia or alternatively, the establishment of appropriate multidisciplinary networks., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Prepandemic sentinel surveillance focused on improved management of winter pressures, with influenza-like illness (ILI) being the key clinical indicator. The World Health Organization (WHO) global standards for influenza surveillance include monitoring acute respiratory infection (ARI) and ILI. The WHO's mosaic framework recommends that the surveillance strategies of countries include the virological monitoring of respiratory viruses with pandemic potential such as influenza. The Oxford-Royal College of General Practitioner Research and Surveillance Centre (RSC) in collaboration with the UK Health Security Agency (UKHSA) has provided sentinel surveillance since 1967, including virology since 1993., Objective: We aim to describe the RSC's plans for sentinel surveillance in the 2023-2024 season and evaluate these plans against the WHO mosaic framework., Methods: Our approach, which includes patient and public involvement, contributes to surveillance objectives across all 3 domains of the mosaic framework. We will generate an ARI phenotype to enable reporting of this indicator in addition to ILI. These data will support UKHSA's sentinel surveillance, including vaccine effectiveness and burden of disease studies. The panel of virology tests analyzed in UKHSA's reference laboratory will remain unchanged, with additional plans for point-of-care testing, pneumococcus testing, and asymptomatic screening. Our sampling framework for serological surveillance will provide greater representativeness and more samples from younger people. We will create a biomedical resource that enables linkage between clinical data held in the RSC and virology data, including sequencing data, held by the UKHSA. We describe the governance framework for the RSC., Results: We are co-designing our communication about data sharing and sampling, contextualized by the mosaic framework, with national and general practice patient and public involvement groups. We present our ARI digital phenotype and the key data RSC network members are requested to include in computerized medical records. We will share data with the UKHSA to report vaccine effectiveness for COVID-19 and influenza, assess the disease burden of respiratory syncytial virus, and perform syndromic surveillance. Virological surveillance will include COVID-19, influenza, respiratory syncytial virus, and other common respiratory viruses. We plan to pilot point-of-care testing for group A streptococcus, urine tests for pneumococcus, and asymptomatic testing. We will integrate test requests and results with the laboratory-computerized medical record system. A biomedical resource will enable research linking clinical data to virology data. The legal basis for the RSC's pseudonymized data extract is The Health Service (Control of Patient Information) Regulations 2002, and all nonsurveillance uses require research ethics approval., Conclusions: The RSC extended its surveillance activities to meet more but not all of the mosaic framework's objectives. We have introduced an ARI indicator. We seek to expand our surveillance scope and could do more around transmissibility and the benefits and risks of nonvaccine therapies., (©Xinchun Gu, Conall Watson, Utkarsh Agrawal, Heather Whitaker, William H. Elson, Sneha Anand, Ray Borrow, Anna Buckingham, Elizabeth Button, Lottie Curtis, Dominic Dunn, Alex J. Elliot, Filipa Ferreira, Rosalind Goudie, Uy Hoang, Katja Hoschler, Gavin Jamie, Debasish Kar, Beatrix Kele, Meredith Leston, Ezra Linley, Jack Macartney, Gemma L Marsden, Cecilia Okusi, Omid Parvizi, Catherine Quinot, Praveen Sebastianpillai, Vanashree Sexton, Gillian Smith, Timea Suli, Nicholas P B Thomas, Catherine Thompson, Daniel Todkill, Rashmi Wimalaratna, Matthew Inada-Kim, Nick Andrews, Victoria Tzortziou-Brown, Rachel Byford, Maria Zambon, Jamie Lopez-Bernal, Simon de Lusignan. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 03.04.2024.)

Background: People living with HIV have an increased risk of meningococcal disease. The Propositive trial evaluated co-administration of two doses of a four-component recombinant protein-based MenB vaccine (4CMenB) and a quadrivalent conjugate polysaccharide MenACWY vaccine (MenACWY-CRM197) given 1 month apart in people with HIV. The follow-up trial assessed the immunogenicity of these vaccines at 1.5 and 2.5 years after primary vaccination., Methods: Participants who completed the parent Propositive trial were invited to the follow-up study. Immunogenicity analysis was performed at 18 and 30 months after primary vaccination. Primary outcome measures were serum bactericidal antibody (SBA) geometric mean titres (GMTs) against three MenB reference strains and the proportion of participants maintaining a protective SBA titre of ≥4 at 18 and 30 months. Secondary outcome measures were SBA GMTs against MenA, C, W, and Y serogroups and the proportion of participants maintaining a protective SBA titre of ≥8 at 18 and 30 months. The trial is registered with Clinicaltrials.gov (NCT042394300)., Results: A total of 40 participants aged 22-47 years were enrolled. Geometric mean titres waned by 18 and 30 months but remained higher than pre-vaccination for all MenB strains and MenA, C, W, and Y. In total, 75%-85% of participants retained protective SBA titres by 30 months against individual MenB strains, whereas 68.8% of patients retained protective antibody titres against all three MenB strains. Antibodies against MenC waned more rapidly than did those against MenA, W, and Y. The proportion of participants with protective titres against MenC at 30 months was also lower (46.9%) than that with protective titres against MenA (87.5%), W (78.1%), and Y (87.5%)., Conclusions: Immune responses against MenB in our cohort of people living with HIV at 2.5 years of follow-up were reassuring, with 68.8% of participants retaining protection against all three reference strains. However, responses against MenC were lower than those against MenA, W, and Y serogroups., (© 2023 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Introduction: Outer membrane vesicles (OMVs) of Neisseria meningitidis in the group B-directed vaccine MenB-4C (Bexsero R ) protect against infections with Neisseria gonorrhoeae . The immunological basis for protection remains unclear. N. meningitidis OMV vaccines generate human antibodies to N. meningitidis and N. gonorrhoeae lipooligosaccharide (LOS/endotoxin), but the structural specificity of these LOS antibodies is not defined., Methods: Ten paired human sera obtained pre- and post-MenB-4C immunization were used in Western blots to probe N. meningitidis and N. gonorrhoeae LOS. Post-MenB-4C sera (7v5, 19v5, and 17v5), representing individual human variability in LOS recognition, were then used to interrogate structurally defined LOSs of N. meningitidis and N. gonorrhoeae strains and mutants and studied in bactericidal assays., Results and Discussion: Post-MenB-4C sera recognized both N. meningitidis and N. gonorrhoeae LOS species, ~10% of total IgG to gonococcal OMV antigens. N. meningitidis and N. gonorrhoeae LOSs were broadly recognized by post-IgG antibodies, but with individual variability for LOS structures. Deep truncation of LOS, specifically a rfa K mutant without α -, β -, or γ -chain glycosylation, eliminated LOS recognition by all post-vaccine sera. Serum 7v5 IgG antibodies recognized the unsialyated L1 α -chain, and a 3-PEA-HepII or 6-PEA-HepII was part of the conformational epitope. Replacing the 3-PEA on HepII with a 3-Glc blocked 7v5 IgG antibody recognition of N. meningitidis and N. gonorrhoeae LOSs. Serum 19v5 recognized lactoneotetrose (LNT) or L1 LOS-expressing N. meningitidis or N. gonorrhoeae with a minimal α -chain structure of Gal-Glc-HepI (L8), a 3-PEA-HepII or 6-PEA-HepII was again part of the conformational epitope and a 3-Glc-HepII blocked 19v5 antibody binding. Serum 17v5 LOS antibodies recognized LNT or L1 α -chains with a minimal HepI structure of three sugars and no requirement for HepII modifications. These LOS antibodies contributed to the serum bactericidal activity against N. gonorrhoeae . The MenB-4C vaccination elicits bactericidal IgG antibodies to N. gonorrhoeae conformational epitopes involving HepI and HepII glycosylated LOS structures shared between N. meningitidis and N. gonorrhoeae. LOS structures should be considered in next-generation gonococcal vaccine design., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tzeng, Sannigrahi, Borrow and Stephens.)