Postpandemic Sentinel Surveillance of Respiratory Diseases in the Context of the World Health Organization Mosaic Framework: Protocol for a Development and Evaluation Study Involving the English Primary Care Network 2023-2024.

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.

Prevention and treatment of infection in patients with an absent or hypofunctional spleen: A British Society for Haematology guideline.

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.

Use of a meningococcal group B vaccine (4CMenB) in populations at high risk of gonorrhoea in the UK.

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.

Neisseria gonorrhoeae lipooligosaccharide glycan epitopes recognized by bactericidal IgG antibodies elicited by the meningococcal group B-directed vaccine, MenB-4C.

Introduction: Outer membrane vesicles (OMVs) of Neisseria meningitidis in the group B-directed vaccine MenB-4C (BexseroR) 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 rfaK mutant without α-, ß-, 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.

The important lessons lurking in the history of meningococcal epidemiology.

INTRODUCTION: The epidemiology of invasive meningococcal disease (IMD), a rare but potentially fatal illness, is typically described as unpredictable and subject to sporadic outbreaks. AREAS COVERED: Meningococcal epidemiology and vaccine use during the last ~ 200 years are examined within the context of meningococcal characterization and classification to guide future IMD prevention efforts. EXPERT OPINION: Historical and contemporary data highlight the dynamic nature of meningococcal epidemiology, with continued emergence of hyperinvasive clones and affected regions. Recent shifts include global increases in serogroup W disease, meningococcal antimicrobial resistance (AMR), and meningococcal urethritis; additionally, unvaccinated populations have experienced disease resurgences following lifting of COVID-19 restrictions. Despite these changes, a close analysis of meningococcal epidemiology indicates consistent dominance of serogroups A, B, C, W, and Y and elevated IMD rates among infants and young children, adolescents/young adults, and older adults. Demonstrably effective vaccines against all 5 major disease-causing serogroups are available, and their prophylactic use represents a powerful weapon against IMD, including AMR. The World Health Organization's goal of defeating meningitis by the year 2030 demands broad protection against IMD, which in turn indicates an urgent need to expand meningococcal vaccination programs across major disease-causing serogroups and age-related risk groups.

Meningococcal disease in the Middle East: A report from the Global Meningococcal Initiative.

This review details recent findings from the Global Meningococcal Initiative's (GMI) recent meeting on the surveillance and control strategies for invasive meningococcal disease in the Middle East. The nature of case reporting and notification varies across the region, with many countries using bacterial meningitis as an IMD case definition in lieu of meningitis and septicaemia. This may overlook a significant burden associated with IMD leading to underreporting or misreporting of the disease. Based on these current definitions, IMD reported incidence remains low across the region, with historical outbreaks mainly occurring due to the Hajj and Umrah mass gatherings. The use of case confirmation techniques also varies in Middle Eastern countries. While typical microbiological techniques, such as culture and Gram staining, are widely used for characterisation, polymerase chain reaction (PCR) testing is utilised in a small number of countries. PCR testing may be inaccessible for several reasons including sample transportation, cost, or a lack of laboratory expertise. These barriers, not exclusive to PCR use, may impact surveillance systems more broadly. Another concern throughout the region is potentially widespread ciprofloxacin resistance since its use for chemoprophylaxis remains high in many countries.

Propositive follow-up: Long-term immune responses to the 4CMenB and MenACWY vaccines in people living with HIV.

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.

Serum HCoV-spike specific antibodies do not protect against subsequent SARS-CoV-2 infection in children and adolescents.

SARS-CoV-2 infections in children are generally asymptomatic or mild and rarely progress to severe disease and hospitalization. Why this is so remains unclear. Here we explore the potential for protection due to pre-existing cross-reactive seasonal coronavirus antibodies and compare the rate of antibody decline for nucleocapsid and spike protein in serum and oral fluid against SARS-CoV-2 within the pediatric population. No differences in seasonal coronaviruses antibody concentrations were found at baseline between cases and controls, suggesting no protective effect from pre-existing immunity against seasonal coronaviruses. Antibodies against seasonal betacoronaviruses were boosted in response to SARS-CoV-2 infection. In serum, anti-nucleocapsid antibodies fell below the threshold of positivity more quickly than anti-spike protein antibodies. These findings add to our understanding of protection against infection with SARS-CoV-2 within the pediatric population, which is important when considering pediatric SARS-CoV-2 immunization policies.

Beyond the usual suspects: Reviewing infections caused by typically-commensal Neisseria species.

OBJECTIVE: Few data outside of individual case reports are available on non-meningococcal, non-gonococcal species of Neisseria as causative agents of invasive disease. This review collates disease, organism and patient information from case reports on the topic. METHODS: A literature search was performed examining articles describing diseases caused by non-meningococcal and non-gonococcal Neisseria. FINDINGS: Neisseria present as opportunistic pathogens causing a wide variety of diseases including serious presentations, endocarditis being the most common condition described and N. mucosa the most commonly presenting pathogen overall. Disease may occur in otherwise healthy patients, although risk factors for infection include recent surgery, an immunocompromised state, poor oral health, and intravenous drug use. CONCLUSIONS: Commensal Neisseria infections are rare but can present serious invasive diseases. Further research is required to determine why some species cause disease more than others or why some are inclined towards particular manifestations.

Reassurance of population immunity to diphtheria in England: Results from a 2021 national serosurvey.

BACKGROUND: Diphtheria is rare in England because of an effective national immunisation schedule that includes 5 doses of a diphtheria-containing vaccine at 2, 3, 4 months, preschool and adolescent boosters. However, in recent years there has been a notable increase in cases due to Corynebacterium ulcerans among older adults and evidence of endemic transmission of C. diphtheriae (normally associated with travel to endemic countries). We aimed to update 2009 estimates of diphtheria immunity considering the evolving epidemiology. METHODS: Residual sera collected from diagnostic laboratories and general practitioners in England in 2021 were randomly selected and tested for diphtheria antibody, to estimate proportions protected per age group. Diphtheria antibody levels were defined as susceptible (<0.01 IU/mL), basic protection (0.01-0.099 IU/mL) and full protection (≥0.1 IU/mL). Immunity estimates were standardised to the England population and compared to 2009. RESULTS: Based on 3,745 residual sera tested, 89% (95%CI: 87%-90%) of the 2021 England population had at least basic diphtheria protection (vs. 90% [88%-92%] in 2009) and 50% (48%-52%) full protection (vs. 41% [38%-44%]). Higher antibody levels were observed in those aged 1 and under, 10-11, 12-15, 25-34 and 35-44 years compared to 2009. The largest proportion susceptible were observed in those aged 70+, 26% (21%-31%) vs 12% (7%-18%) in 2009. CONCLUSIONS: Basic diphtheria protection is comparable between 2021 and 2009. The increase in immunity in working age adults is likely due to the school leaver booster introduced in 1994. The current vaccination schedule is maintaining sufficient population immunity. However, we recommend clinicians remain vigilant to severe diphtheria outcomes in older adults, because of their observed susceptibility.

Epidemiological and strain characteristics of invasive meningococcal disease prior to, during and after COVID-19 pandemic restrictions in England.

OBJECTIVES: In 2020, COVID-19 pandemic restrictions led to a major suppression of meningococcal disease in England. Here we describe the epidemiology of invasive meningococcal disease in the three years prior to the COVID-19 pandemic, and the three years immediately after the introduction of restrictions. METHODS: The UK Health Security Agency conducts national meningococcal disease surveillance in England consisting of laboratory-based case confirmation with strain characterisation by culture and/or molecular detection, as well as clinical follow-up of all cases. RESULTS: In the pre-pandemic period, 554-742 IMD cases were laboratory-confirmed per year. MenB caused 57.2% of cases, followed by MenW (22.7%), MenY (10.6%) and MenC (7.7%). The introduction of restrictions in late March 2020 led to a 73% reduction in IMD. After the removal of restrictions in 2021, a resurgence in MenB was observed, primarily in teenagers and young adults. During the following winter period (2022/23), MenB disease increased to the highest level since 2012 with cases rising across multiple age groups, however, cases in young children eligible for MenB vaccination remained lower than prior to the pandemic. MenACWY cases remained very low throughout the pandemic period. CONCLUSIONS: Once pandemic restrictions in England were removed, MenB quickly rebounded- initially driven by a resurgence in teenagers/young adults, but later among other age groups. MenACWY cases remain very low due to the protection afforded by the adolescent MenACWY conjugate vaccine programme.

Paediatric acute hepatitis of unknown aetiology: a national investigation and adenoviraemia case-control study in the UK.

BACKGROUND: An increase in acute severe hepatitis of unknown aetiology in previously healthy children in the UK in March, 2022, triggered global case-finding. We aimed to describe UK epidemiological investigations of cases and their possible causes. METHODS: We actively surveilled unexplained paediatric acute hepatitis (transaminase >500 international units per litre) in children younger than 16 years presenting since Jan 1, 2022, through notifications from paediatricians, microbiologists, and paediatric liver units; we collected demographic, clinical, and exposure information. Then, we did a case-control study to investigate the association between adenoviraemia and other viruses and case-status using multivariable Firth penalised logistic regression. Cases aged 1-10 years and tested for adenovirus were included and compared with controls (ie, children admitted to hospital with an acute non-hepatitis illness who had residual blood samples collected between Jan 1 and May 28, 2022, and without known laboratory-confirmed diagnosis or previous adenovirus testing). Controls were frequency-matched on sex, age band, sample months, and nation or supra-region with randomised selection. We explored temporal associations between frequency of circulating viruses identified through routine laboratory pathogen surveillance and occurrence of cases by linear regression. SARS-CoV-2 seropositivity of cases was examined against residual serum from age-matched clinical comparison groups. FINDINGS: Between Jan 1 and July 4, 2022, 274 cases were identified (median age 3 years [IQR 2-5]). 131 (48%) participants were male, 142 (52%) were female, and one (<1%) participant had sex data unknown. Jaundice (195 [83%] of 235) and gastrointestinal symptoms (202 [91%] of 222) were common. 15 (5%) children required liver transplantation and none died. Adenovirus was detected in 172 (68%) of 252 participants tested, regardless of sample type; 137 (63%) of 218 samples were positive for adenovirus in the blood. For cases that were successfully genotyped, 58 (81%) of 72 had Ad41F, and 57 were identified as positive via blood samples (six of these were among participants who had undergone a transplant). In the case-control analysis, adenoviraemia was associated with hepatitis case-status (adjusted OR 37·4 [95% CI 15·5-90·3]). Increases in the detection of adenovirus from faecal samples, but not other infectious agents, in routine laboratory pathogen surveillance correlated with hepatitis cases 4 weeks later, which independently suggested an association (ß 0·06 [95% CI 0·02-0·11]). No association was identified for SARS-CoV-2 antibody seropositivity. INTERPRETATION: We observed an association between adenovirus 41F viraemia and paediatric acute hepatitis. These results can inform diagnostic testing recommendations, clinical management, and exploratory in vitro or clinical studies of paediatric acute hepatitis of unknown aetiology. The role of potential co-factors, including other viruses and host susceptibility, requires further investigation. FUNDING: None.

Use of expanded Neisseria meningitidis serogroup B panels with the serum bactericidal antibody assay for the evaluation of meningococcal B vaccine effectiveness.

INTRODUCTION: Neisseria meningitidis serogroup B (NmB) antigens are inherently diverse with variable expression among strains. Prediction of meningococcal B (MenB) vaccine effectiveness therefore requires an assay suitable for use against large panels of epidemiologically representative disease-causing NmB strains. Traditional serum bactericidal antibody assay using exogenous human complement (hSBA) is limited to the quantification of MenB vaccine immunogenicity on a small number of indicator strains. AREAS COVERED: Additional and complementary methods for assessing strain coverage developed previously include the Meningococcal Antigen Typing System (MATS), Meningococcal Antigen Surface Expression (MEASURE) assay, and genotyping approaches, but these do not estimate vaccine effectiveness. We provide a narrative review of these methods, highlighting a more recent approach involving the hSBA assay in conjunction with expanded NmB strain panels: hSBA assay using endogenous complement in each vaccinated person's serum (enc-hSBA) against a 110-strain NmB panel and the traditional hSBA assay against 14 (4 + 10) NmB strains. EXPERT OPINION: The enc-hSBA is a highly standardized, robust method that can be used in clinical trials to measure the immunological effectiveness of MenB vaccines under conditions that mimic real-world settings as closely as possible, through the use of endogenous complement and a diverse, epidemiologically representative panel of NmB strains.

Meningococcal disease refers to illnesses caused by the bacterium Neisseria meningitidis (meningococcus), including infections of the brain lining and spinal cord (meningitis) and bloodstream (septicemia). It is rare but often severe and can be deadly. Invasive meningococcal disease can be prevented through vaccination. Nearly all cases are caused by six serogroups (types) of meningococci, including meningococcal serogroup B. Vaccines are available against meningococcal serogroup B but, because of the uncommonness of the disease, standard clinical trials could not be performed to prove these vaccines are effective. Instead, an indirect measure, called the 'hSBA assay' (serum bactericidal antibody assay using human complement), is used to measure the ability of vaccines to provide protection against specific N. meningitidis strains that have antigens (substances that cause the immune system to react) sharing characteristics with components of the vaccines. However, meningococcal serogroup B strains are diverse in the genetic composition and expression of vaccine antigens. Hence, a large number of N. meningitidis serogroup B strains would have to be tested to make sure that the vaccine is effective against these strains. This is not feasible using the traditional hSBA assay, which requires a human complement (a protein system, which is part of the immune system) that has not come from the vaccinated person and is difficult and time-consuming to source. Recently, an alternative hSBA assay was developed that uses the complement present in each vaccinated person's blood (endogenous complement) and which overcomes these challenges. By allowing testing against a broad panel of N. meningitidis serogroup B strains, this new assay may enable a more accurate estimation of the effectiveness of vaccines against serogroup B meningococci.

Safety and immunogenicity of quadrivalent meningococcal polysaccharide vaccine (MPV ACYW135) compared with quadrivalent meningococcal conjugate vaccine (Menactra®) in Malian children.

Affordable, polyvalent meningococcal vaccines are needed for use in emergency reactive immunization campaigns. A phase IV randomized, observer-blind, controlled study compared the safety and immunogenicity of a quadrivalent meningococcal polysaccharide vaccine (MPV-4, MPV ACYW135) and quadrivalent meningococcal ACWY conjugate vaccine (MCV-4, Menactra®). Healthy, 2- to 10-year-old children in Bamako, Mali, were randomized 1:1 to receive one dose of MPV-4 or MCV-4. Safety outcomes were evaluated for 6 months post-immunization. Immunogenicity for all serogroups was assessed for non-inferiority between MPV-4 and MCV-4 30 days post immunization by serum bactericidal antibody assay using baby rabbit complement (rSBA). From December 2020 to July 2021, 260 healthy subjects were consented and randomized. At Day 30 post-immunization, the proportions of subjects with rSBA titers ≥ 128 for all serogroups in the MPV-4 group were non-inferior to those in MCV-4 group. The proportions of subjects with rSBA ≥ 4-fold increase and rSBA titers ≥ 8 for all serogroups were similar among vaccine groups (P > .05). Geometric Mean Titers and Geometric Mean Fold Increases for all serogroups in both vaccine groups were similar (P > .05). Few local and systemic post-immunization reactions of similar severity and duration were observed within 7 days and were similar in both groups (P > .05). All resolved without sequelae. Unsolicited adverse events were similar in both groups regarding relationship to study vaccine, severity and duration. No serious adverse events were reported during the study period. MPV ACYW135 showed a non-inferior immunogenicity profile and a comparable reactogenicity profile to MCV-4 in Malian children aged 2-10 years.Clinical Trial Registration: NCT04450498.

Carriage of Neisseria meningitidis among travelers attending the Hajj pilgrimage, circulating serogroups, sequence types and antimicrobial susceptibility: A multinational longitudinal cohort study.

BACKGROUND: Travel to international mass gatherings such as the Hajj pilgrimage increases the risk of Neisseria meningitidis transmission and meningococcal disease. We investigated carriage and acquisition of N. meningitidis among travelers to Hajj and determined circulating serogroups, sequence types and antibiotic susceptibility among isolates. METHOD: We conducted a multinational longitudinal cohort study among 3921 traveling pilgrims in two phases: Pre-Hajj and Post-Hajj. For each participant, a questionnaire was administered and an oropharyngeal swab was obtained. N. meningitidis was isolated, serogrouped, and subjected to whole genome sequence analysis and antibiotic susceptibility testing. RESULTS: Overall carriage and acquisition rates of N. meningitidis were 0.74% (95%CI: 0.55-0.93) and 1.10% (95%CI: 0.77-1.42) respectively. Carriage was significantly higher Post-Hajj (0.38% vs 1.10%, p = 0.0004). All isolates were nongroupable, and most belonged to the ST-175 complex and were resistant to ciprofloxacin with reduced susceptibility to penicillins. Three potentially invasive isolates (all genogroup B) were identified in the Pre-Hajj samples. No factors were associated with Pre-Hajj carriage. Suffering influenza like illness symptoms and sharing a room with >15 people were associated with lower carriage Post-Hajj (adjOR = 0.23; p = 0.008 and adjOR = 0.27; p = 0.003, respectively). CONCLUSION: Carriage of N. meningitidis among traveler attending Hajj was low. However, most isolates were resistant to ciprofloxacin used for chemoprophylaxis. A review of the current meningococcal disease preventive measures for Hajj is warranted.

The propositive study: Immunogenicity and safety of a four-component recombinant protein-based vaccine against MenB and a quadrivalent conjugate MenACWY vaccine in people living with HIV.

BACKGROUND: People living with HIV have been shown to have an increased risk of invasive meningococcal disease. In some countries, meningococcal vaccines are now routinely recommended to all people living with HIV, but no study has yet assessed the immunogenicity and safety of a meningococcal serogroup B vaccine or the co-administration of a MenB and MenACWY vaccine in people living with HIV. METHODS: This phase IV open-label clinical trial investigated the immunogenicity and safety 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 a population of people living with HIV. Immunogenicity analysis was performed before vaccination and 1 month after the second doses of 4CMenB and MenACWY. Primary outcome measures were serum bactericidal assay geometric mean titres against three MenB reference strains at baseline and 1 month post vaccination, the proportion of participants achieving a putative protective titre of ≥4, and the proportion of participants with a ≥4-fold rise in titre from baseline. Secondary outcome measures were serum bactericidal assay geometric mean titres against MenA, C, W, and Y reference strains at baseline and 1 month post vaccination, the proportion achieving a putative protective titre of ≥8, and the proportion with a ≥4-fold rise in titre from baseline. Safety outcomes were solicited and unsolicited adverse events in the 7 days following vaccination. The trial was registered with clinicaltrials.gov (NCT03682939). FINDINGS: In total, 55 participants aged 20-45 years were enrolled. All participants (100%; 95% confidence interval [CI] 93-100) achieved putative protective titres for two of the three MenB strains and for MenA, W, and Y. A total of 98% (95% CI 89-100) achieved a protective titre for the third MenB strain and 94% (95% CI 83-99) for MenC. No serious adverse events were reported. INTERPRETATION: 4CMenB and MenACWY were immunogenic and well-tolerated in a population of people living with HIV 1 month after two doses.

Antibody Persistence After Primary SARS-CoV-2 Infection and Protection Against Future Variants Including Omicron in Adolescents: National, Prospective Cohort Study.

BACKGROUND: Antibodies are a measure of immunity after primary infection, which may help protect against further SARS-CoV-2 infections. They may also provide some cross-protection against SARS-CoV-2 variants. There are limited data on antibody persistence and, especially, cross-reactivity against different SARS-CoV-2 variants after primary infection in children. METHODS: We initiated enhanced surveillance in 18 secondary schools to monitor SARS-CoV-2 infection and transmission in September 2020. Students and Staff provided longitudinal blood samples to test for variant-specific SARS-CoV-2 antibodies using in-house receptor binding domain assays. We recruited 1189 students and 1020 staff; 160 (97 students, 63 staff) were SARS-CoV-2 nucleocapsid-antibody positive at baseline and had sufficient serum for further analysis. RESULTS: Most participants developed sustained antibodies against their infecting [wild-type (WT)] strain as well as cross-reactive antibodies against the Alpha, Beta and Delta variants but at lower titers than WT. Staff had significantly lower antibodies titers against WT as cross-reactive antibodies against the Alpha, Beta and Delta variants than students (all P < 0.01). In participants with sufficient sera, only 2.3% (1/43) students and 17.2% (5/29) staff had cross-reactive antibodies against the Omicron variant; they also had higher antibody titers against WT (3042.5; 95% confidence interval: 769.0-12,036.2) than those who did not have cross-reactive antibodies against the Omicron variant (680.7; 534.2-867.4). CONCLUSIONS: We found very high rates of antibody persistence after primary infection with WT in students and staff. Infection with WT induced cross-reactive antibodies against Alpha, Beta and Delta variants, but not Omicron. Primary infection with WT may not be cross-protective against the Omicron variant.

Outcomes of meningococcal serogroup B disease in children after implementation of routine infant 4CMenB vaccination in England: an active, prospective, national surveillance study.

BACKGROUND: In 2015, the UK included 4CMenB, a multi-component, recombinant protein-based vaccine against meningococcal serogroup B (MenB) disease, in the national infant immunisation programme. We aimed to assess the effect of 4CMenB vaccination on the severity of MenB disease presentation and outcomes. METHODS: In this active, prospective, national surveillance study, we used data from the UK Health Security Agency national surveillance of meningococcal disease. We included data from follow-up of children younger than 5 years with laboratory-confirmed MenB disease who were eligible for 4CMenB vaccination with general practice 3-6 months after disease onset. All invasive MenB isolates were tested using the Meningococcal Antigen Typing System to determine whether the isolate was potentially preventable by 4CMenB. Admission to intensive care, death, and, when possible, reported sequelae in survivors were reviewed alongside vaccine status. For the epidemiological analysis, we compared laboratory-confirmed MenB disease cases before 4CMenB implementation (Sept 1, 2010, to March 31, 2015) with those after implementation (Sept 1, 2015, to March 31, 2020). For clinical follow-up and outcomes, we included all children younger than 5 years with laboratory-confirmed MenB disease between Sept 1, 2015, and March 31, 2021. FINDINGS: Between Sept 1, 2015, and March 31, 2021, there were 371 cases of MenB disease in children younger than 5 years, including 256 (69%) in those younger than 1 year and 128 (35%) in those younger than 3 months. After the introduction of 4CMenB, the peak age of patients with MenB disease shifted from 5-6 months to 1-3 months. Overall, 108 (29%) of 371 children were too young for vaccination, unvaccinated, or developed MenB disease within 14 days of the first dose. Of 110 meningococcal strains characterised, 11 (92%) of 12 were potentially preventable by 4CMenB in unvaccinated children compared with 53 (66%) of 80 in partly vaccinated and 11 (69%) of 16 in fully vaccinated children. 78 (21%) of 371 children required intensive care, and the case fatality ratio was 5% (17 of 371), with 11 of 17 deaths occurring before 1 year of age, including seven in infants who were too young (<8 weeks) for vaccination. Of 354 survivors, 57 (16%) had 74 sequelae reported; 45 (61%) of 74 were neurological, 17 (23%) were physical, two (3%) were behavioural or psychological, and ten (14%) were other complications. Prevalence of sequelae was similar in unvaccinated (15 [15%] of 98) and vaccinated (42 [16%] 256) children, as were composite outcomes of death or sequelae, and intensive care or death or sequelae. INTERPRETATION: Cases of MenB disease in vaccine-eligible children declined after 4CMenB implementation, but morbidity in vaccinated and unvaccinated children remained unchanged, highlighting the importance of vaccination to prevent MenB disease. The lower peak age of infants with MenB disease after 4CMenB implementation, with a higher case fatality ratio in young infants, highlights the importance of timely vaccination. FUNDING: UK Health Security Agency.

Immunogenicity and safety of seasonal influenza vaccines in children under 3 years of age.

INTRODUCTION: Despite children aged 6-35 months developing more severe influenza infections, not all countries include influenza vaccines in their national immunization programs. AREAS COVERED: This literature review examines the efficacy, immunogenicity, and safety of seasonal trivalent influenza vaccines (TIVs) and quadrivalent influenzae vaccines (QIVs) in children 6-35 months old to determine if greater valency promotes greater protection while maintaining a similar safety profile. EXPERT OPINION: TIVs and QIVs are safe for children under 3 years old. TIVs and QIVs provided good seroprotection, and immunogenicity (GMT, SCR, and SPR) meeting recommended levels set by CHMP (European) and CBER (USA). However, as QIVs carry two influenza B strains and TIVs only one, QIVs has an overall higher seroprotection against particularly influenza B. Vaccines containing adjuncts had better immunogenicity, particularly after the first dose. Seroprotection of all vaccines lasted 12 months. Increasing the dosage from 0.25 mL to 0.5 mL did not cause more systemic or local side-effects. Further comparisons of efficacy, and wider promotion of influenza vaccines in general are required in preschool children.

A review of the DTaP-IPV-HB-PRP-T Hexavalent vaccine in pediatric patients.

INTRODUCTION: Hexaxim is a hexavalent vaccine approved as primary and booster vaccination in infants 6 weeks and older, protecting against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B and Haemophilus influenzae type b. AREAS COVERED: To evaluate the immunogenicity and reactogenicity (safety) of Hexaxim (Hexyon, Hexacima) in primary and booster vaccine schedules; long-term antibody persistence; concomitant use with other childhood vaccines and use in immunocompromised infants. Hexaxim was found to be noninferior to other licensed hexavalent vaccines, being highly immunogenic for all toxoids/antigens and with an acceptable safety profile. It can be administered concomitantly with other childhood vaccines. Hexaxim can be given as a booster for infants primed with Infanrix Hexa and given in a pentavalent-hexavalent-pentavalent series. Hexaxim elicits a similar immune response and safety profile in human immunodeficiency virus (HIV) positive infants. It has the benefit of being a ready-to-use liquid formulation, minimizing dosage errors and preparation time. EXPERT OPINION: Hexaxim has an acceptable safety profile and provides immunity against all six targeted diseases. It is an acceptable alternative to other hexavalent vaccines on the market. Further studies are required on the use of immunocompromised patients as well as the antibody persistence of each of the vaccine components.