Impact of an adolescent meningococcal ACWY immunisation programme to control a national outbreak of group W meningococcal disease in England: a national surveillance and modelling study.

BACKGROUND: In August, 2015, the UK implemented an emergency adolescent immunisation programme with the meningococcal ACWY conjugate vaccine to combat a national outbreak of meningococcal group W (MenW) disease due to a hypervirulent ST-11 complex strain, which is currently causing regional and national outbreaks worldwide. This immunisation programme specifically targeted adolescents aged 13-18 years, an age group with low disease incidence but high nasopharyngeal carriage, with the aim of interrupting transmission and providing indirect (herd) protection across the population. Here, we report the impact of the first 4 years of the programme in England. METHODS: Public Health England conducts meningococcal disease surveillance in England. Laboratory-confirmed cases of invasive meningococcal disease during the academic years 2010-11 to 2014-15 (Sept 1 to Aug 31) were used to predict post-vaccination trends, based on the assumption that cases would plateau 1 year after vaccine implementation (conservative scenario) or that cases would continue to rise for 4 years after vaccine implementation (extreme scenario). Vaccine uptake evaluated in August, 2019, was 37-41% in adolescents aged 18 years immunised in primary care and 71-86% in younger teenagers routinely vaccinated in school. Vaccine effectiveness was estimated with the indirect screening method. FINDINGS: MenW and MenY cases plateaued within 12 months and then declined, while MenC cases remained low throughout. Significant reductions were observed among adolescents aged 14-18 years for MenW (incidence rate ratio [IRR] 0·35 [95% CI 0·17-0·76]) and MenY (0·21 [0·07-0·59]) cases, with a non-significant reduction in MenC cases (0·11 [0·01-1·01]). Based on conservative and extreme scenarios, 205-1193 MenW cases were prevented through the indirect effects of the programme and 25 through direct protection. For MenY, an estimated 60-106 cases were prevented through the indirect effects of the programme and 19 through direct protection. Ignoring any residual effect from an earlier MenC-containing vaccine, the overall vaccine effectiveness against MenCWY disease combined was 94% (95% CI 80-99). INTERPRETATION: A meningococcal immunisation programme specifically targeting adolescent carriers succeeded in rapidly controlling a national MenW outbreak, even with moderate initial vaccine uptake. FUNDING: Public Health England.

An Update on Meningococcal Vaccination.

Neisseria meningitidis bacterial infection can cause severe life-threatening meningitis. Individuals who survive may be left with profound sequelae. In epidemic regions such as the meningitis belt of Africa, the case rate is drastically higher than in nonepidemic regions and is due to distinct outbreak serogroups. Two highly effective conjugate meningococcal vaccine against serogroups A, C, W and Y are licensed and indicated for prevention in childhood vaccination schedules and for travelers to outbreak regions. In the US, meningococcus serogroup B is the main cause of outbreaks, in areas with crowding such as college dorms. It has taken over 40 years to develop a meningitis type B vaccine and now there are 2 brands available for children and teens. All college-bound individuals should complete schedules of both conjugate ACWY serotypes and meningitis B vaccine series. This paper reviews details on who to vaccinate and how to use the currently available meningococcal meningitis vaccines.

Effect on meningococcal serogroup W immunogenicity when Tdap was administered prior, concurrent or subsequent to the quadrivalent (ACWY) meningococcal CRM197-conjugate vaccine in adult Hajj pilgrims: A randomised controlled trial.

Immune responses to the capsular polysaccharide administered in the polysaccharide-protein conjugate vaccines can be either improved or suppressed by the pre-existence of immunity to the carrier protein. Receiving multiple vaccinations is essential for travellers such as Hajj pilgrims, and the use of conjugated vaccines is recommended. We studied the immune response to meningococcal serogroup W upon prior, concurrent and sequential administration of a quadrivalent meningococcal conjugate vaccine (MCV4) conjugated to CRM197 (coadministered with 13 valent pneumococcal vaccine conjugate CRM197 [PCV13]), and tetanus-diphtheria-acellular pertussis (Tdap) vaccine in Australian adults before attending the Hajj pilgrimage in 2014. Participants were randomly assigned, by computer-generated numbers, to three study arms by 1:1:1 ratio. Group A received Tdap followed by MCV4-CRM197 (+PCV13) 3-4 weeks later. Group B received all three vaccines in a single visit. Group C received MCV4-CRM197 (+PCV13) followed by Tdap 3-4 weeks later. Blood samples obtained prior to and 3-4 weeks after immunisation with MCV4-CRM197 were tested for meningococcal serogroup W-specific serum bactericidal antibody responses using baby rabbit complement (rSBA). One hundred and seven participants aged between 18 and 64 (median 40) years completed the study. No significant difference in meningococcal serogroup W rSBA geometric mean titre (GMT) was observed between the study arms post vaccination with MCV-CRM197 but Group A tended to have a slightly lower GMT (A = 404, B = 984 and C = 1235, p = 0.15). No statistical difference was noticed between the groups in proportions of subjects achieving a ≥4-fold rise in rSBA titres or achieving rSBA titre ≥8 post vaccination. In conclusion, receipt of MCV4-CRM197 vaccine prior, concurrent or subsequent to Tdap has similar immunologic response, and hence concurrent administration is both immunogenic and practical. However, further investigation into whether carrier induced suppression is a public health issue is suggested. Clinical trial registration: ANZCTR no. ACTRN12613000536763.

Characterization of strains of Neisseria meningitidis causing meningococcal meningitis in Mozambique, 2014: Implications for vaccination against meningococcal meningitis.

INTRODUCTION: In sub Saharan Africa, the epidemiology, including the distribution of serogroups of strains of N. meningitidis is poorly investigated in countries outside "the meningitis belt". This study was conducted with the aim to determine the distribution of serogroups of strains of N. meningitidis causing meningococcal meningitis in children and adults in Mozambique. METHODS: A total of 106 PCR confirmed Neisseria meningitidis Cerebrospinal Fluid (CSF) samples or isolates were obtained from the biobank of acute bacterial meningitis (ABM) surveillance being implemented by the National Institute of Health, at three central hospitals in Mozambique, from January to December 2014. Serogroups of N. meningitidis were determined using conventional PCR, targeting siaD gene for Neisseria meningitidis. Outer Membrane Proteins (OMP) Genotyping was performed by amplifying porA gene in nine samples. RESULTS: Of the 106 PCR confirmed Neisseria meningitidis samples, the most frequent serotype was A (50.0%, 53/106), followed by W/Y (18.9%, 20/106), C (8.5%, 9/106), X (7.5%, 8/106) and B (0.9%, 1/106). We found non-groupable strains in a total of 15 (14.2%) samples. PorA genotypes from nine strains showed expected patterns with the exception of two serogroup C strains with P1.19,15,36 and P1.19-36,15 and one serogroup X with P1.19,15,36, variants frequently associated to serogroup B. CONCLUSION: Our data shows that the number of cases of meningococcal meningitis routinely reported in central hospitals in Mozambique is significant and the most dominant serogroup is A. In conclusion, although serogroup A has almost been eliminated from the "meningitis belt", this serogroup remains a major concern in countries outside the belt such as Mozambique.

Implementation of MenACWY vaccination because of ongoing increase in serogroup W invasive meningococcal disease, the Netherlands, 2018.

The annual incidence rate of serogroup W invasive meningococcal disease in the Netherlands increased from < 0.05/100,000 (n < 10) before 2015 to 0.5/100,000 (n = 80) in 2017. Most isolates (94%) belong to clonal complex 11. The incidence rate is highest among < 5 year-olds and 15-24 year-olds. The case fatality rate was 12% (17/138) in 2015-2017. From May 2018, MenACWY vaccination replaces MenC vaccination at age 14 months and from October 2018, 13-14 year-olds are offered MenACWY vaccination.

Investigation of correlates of protection against pharyngeal carriage of Neisseria meningitidis genogroups W and Y in the African meningitis belt.

BACKGROUND: Serum bactericidal antibody titres that correlate with protection against invasive meningococcal disease have been characterised. However, titres that are associated with protection against acquisition of pharyngeal carriage of Neisseria meningitidis are not known. METHODS: Sera were obtained from the members of a household in seven countries of the African meningitis belt in which a pharyngeal carrier of N. meningitidis had been identified during a cross-sectional survey. Serum bactericidal antibody titres at baseline were compared between individuals in the household of the carrier who became a carrier of a meningococcus of the same genogroup during six months of subsequent follow-up and household members who did not become a carrier of a meningococcus of this genogroup during this period. RESULTS: Serum bacterial antibody titres were significantly higher in carriers of a serogroup W or Y meningococcus at the time of recruitment than in those who were not a carrier of N. meningitidis of the same genogroup. Serum bactericidal antibody titres to a strain of N. meningitis of the same genogroup as the index cases were no different in individuals who acquired carriage with a meningococcus of the same genogroup as the index case than in those who did not become a carrier during six months of follow-up. CONCLUSION: Serum bacterial antibody titres to N. meningitidis of genogroup W or Y in the range of those acquired by natural exposure to meningococci of these genogroups, or with cross-reactive bacteria, are not associated with protection against acquisition of carriage with meningococci of either of these genogroups.

Immunogenicity of a Booster Dose of Quadrivalent Meningococcal Conjugate Vaccine in Previously Immunized HIV-Infected Children and Youth.

BACKGROUND: The US Advisory Committee on Immunization Practices recommends a booster dose of quadrivalent meningococcal conjugate vaccine (MCV4) after initial immunization for patients at high risk for meningococcal infection. METHODS: The International Maternal Pediatric Adolescents AIDS Clinical Trials (IMPAACT) P1065 trial evaluated the use of MCV4 in human immunodeficiency virus (HIV)-infected children and youth. The final step of this trial was an open-label study of an MCV4 booster dose 3.5 years after primary MCV4 immunization. Antibody titers were evaluated at the time of the booster vaccine and 1, 4, and 24 weeks after the booster. Immunogenicity was measured by rabbit serum bactericidal antibody (rSBA) against each meningococcal serogroup. Immunologic memory was defined as either seroprotection (rSBA titer ≥1:128) or a ≥4-fold increase 1 week after the booster dose. Primary response was defined as either a ≥4-fold response or seropositivity 4 weeks after the booster in the absence of immunologic memory. Adverse events were assessed for 4 weeks after the booster dose. RESULTS: Of 174 participants with serology results at entry and 1 and 4 weeks later, the percentage with protective antibody levels at entry varied according to serogroup, ranging from a low of 26% for serogroup C to a high of 68% for serogroup A. A memory response to at least 1 serogroup occurred in 98% of the participants: 93% each for serogroups A and Y, 88% for serogroup C, and 94% for serogroup W-135; 83% had a memory response to all 4 serogroups. Overall, rates of any memory or primary response were ≥90% for all serogroups. No serious adverse events were encountered. CONCLUSIONS: A booster dose of MCV4 elicited a memory response in 88% to 94% of previously immunized HIV-infected participants depending on serogroup, including those who lacked a protective titer level for that serogroup before booster vaccination.

Immune responses of a meningococcal A + W outer membrane vesicle (OMV) vaccine with and without aluminium hydroxide adjuvant in two different mouse strains.

Meningococci (Neisseria meningiditis) of serogroups A and W have caused large epidemics of meningitis in sub-Saharan Africa for decades, and affordable and multivalent vaccines, effective in all age groups, are needed. A bivalent serogroup A and W (A + W) meningococcal vaccine candidate consisting of deoxycholate-extracted outer membrane vesicles (OMV) from representative African disease isolates was previously found to be highly immunogenic in outbred mice when formulated with the adjuvant aluminium hydroxide (AH). OMV has been shown to have inherent adjuvant properties. In order to study the importance of AH and genetical differences between mice strains on immune responses, we compared the immunogenicity of the A + W OMV vaccine when formulated with or without AH in inbred C57BL/6J and BALB/cJ mice (Th1 and Th2 dominant strains, respectively). The immunogenicity of the vaccine was found to be comparable in the two mice strains despite their different immune profiles. Adsorption to AH increased anti-OMV IgG levels and serum bactericidal activity (SBA). The immune responses were increased by each dose for the adsorbed vaccine, but the third dose did not significantly improve the immunogenicity further. Thus, a vaccine formulation with the A and W OMV will likely benefit from including AH as adjuvant.

Low immunogenicity of quadrivalent meningococcal vaccines in solid organ transplant recipients.

Immunization against meningococcal disease is recommended for solid organ transplant (SOT) recipients at high risk for meningococcal disease or travelling to an endemic country. However, the immunogenicity of meningococcal vaccines has not been studied in this population. We analyzed the immune response of quadrivalent (against Neisseria meningitidis serogroups A, C, Y, and W) polysaccharidic non-conjugate and conjugate meningococcal vaccines in kidney- and liver-transplant patients using bactericidal assays against the targeted serogroups. Upon vaccination with a non-conjugate (n = 5) or a conjugate vaccine (n = 10), respectively, 40% and 50% of patients were able to mount an immune response, achieving at least the threshold correlated with protection defined as human serum bactericidal antibody titers of ≥4. Responders showed only partial and low responses (titers ≤64), thus predicting a rapid decline in bactericidal response. Only 1 patient developed a booster response to preexisting immunity. Our data argue for the need of additional measures for SOT recipients, when they are at risk of meningococcal disease.

Safety and immunogenicity of meningococcal ACWY CRM197-conjugate vaccine in children, adolescents and adults in Russia.

Neisseria meningitidis is the leading cause of bacterial invasive infections in people aged <15 years in the Russian Federation. The aim of this phase III, multicenter, open-label study was to assess the immunogenicity and safety of the quadrivalent meningococcal CRM197-conjugate vaccine MenACWY when administered to healthy Russian subjects aged 2 years and above. A total of 197 subjects were immunized with a single dose of the vaccine, and serogroup-specific serum bactericidal activity was measured pre and 1-month post-vaccination with human complement (hSBA) serum titers. Regardless of baseline serostatus, 1 month after a single dose of MenACWY-CRM197 85% (95%CI, 79-90%) of subjects showed serologic response against serogroup A, 74% (67-80%) against serogroup C, 60% (53-67%) against serogroup W, and 83% (77-88%) against serogroup Y. The percentage of subjects with hSBA titers ≥ 1:8 1 month after vaccination was 89% (83-93%) against serogroup A, 84% (78-89%) against serogroup C, 97% (93-99%) against serogroup W, and 88% (82-92%) against serogroup Y. Comparable results were obtained across all subjects: children (2 to 10 years), adolescents (11 to 17 years), and adults (≥18 years). The MenACWY-CRM197 vaccine showed an acceptable safety profile and was well tolerated across all age groups, with no serious adverse events or deaths reported during the study. In conclusion, a single dose of meningococcal MenACWY-CRM197 vaccine is immunogenic and has an acceptable safety profile, provides a broad protection against the most frequent epidemic serogroups, and is a suitable alternative to currently available unconjugated monovalent or bivalent polysaccharide vaccines in Russia.

Meningococcal serogroup A, C, W, and Y serum bactericidal antibody profiles in Hajj pilgrims.

BACKGROUND: The religious seasons of Hajj and Umra in the Kingdom of Saudi Arabia (KSA) have historically been associated with epidemics of meningococcal disease. Due to the effective preventive measures taken in recent years, including vaccination, no meningococcal outbreaks have been reported during Hajj or were Hajj-associated. However, little is known about the immunological profile of pilgrims. The aim of this study was to assess the immunological profile of pilgrims on arrival in KSA against the four meningococcal serogroups, A, C, W, and Y, contained within the quadrivalent vaccine. METHODS: Following consent, socio-demographic factors and health-related information was collected from pilgrims arriving at King Abdul Aziz International Airport and a blood sample taken. Antibodies were quantified by serum bactericidal antibody assay using baby rabbit complement (rSBA) against the four meningococcal serogroups, A, C, W, and Y. RESULTS: Serum samples were collected from 796 pilgrims; rSBA results were obtained for all four serogroups for 741 of these samples. A total of 48 (6.5%) Hajjis had previously attended Hajj, ranging from 1 to 14 times (median 2 times); 98.2% had received meningococcal quadrivalent vaccine in the last 3 years. Of the 13 who had not, all originated from Bangladesh, with four reporting no previous meningococcal vaccination and nine reporting having received the vaccination more than 3 years ago. For serogroup A, only one pilgrim from Indonesia had an rSBA titre <8. For serogroups C, W, and Y, the percentages of pilgrims with rSBA titres <8 were 9.9%, 17.4%, and 9.4%, respectively. Of note was the high prevalence of non-complement-mediated lysis in pilgrims originating from Nigeria (28/47; 59.6%) and Afghanistan (21/47; 44.7%), but not the other countries. This may be a reflection of the type and pattern of antibiotic usage among these communities. CONCLUSION: The vast majority of pilgrims are vaccinated and protected against meningococcal serogroups A, C, W, and Y.

Serogroup W meningococcal disease: global spread and current affect on the Southern Cone in Latin America.

Meningococcal serogroup W strains have been emerging throughout the current century with most of the isolates belonging to the sequence type (ST11)/electrophoretic type (ET37) clonal complex (ST11/E37 CC), particularly since the international outbreak following Hajj 2000. That outbreak appears to have triggered off that trend, contributing to the spread of W ST11/ET37 CC strains globally; however, local strains could be also responsible for increases in the percentage and/or incidence rates of this serogroup in some countries. More recently, unexpected increases in the percentage and incidence rate of W has been noticed in different countries located in the South Cone in Latin America, and W ST11/ET37 CC strains now appear as endemic in the region and an extensive immunization programme with tetravalent conjugate vaccine (covering serogroups A, C, Y and W) has been recently implemented in Chile. It is difficult to ascertain whether we are observing the emergence of W ST11 CC strains in different geographical areas or whether the Hajj 2000 strain is still spreading globally. Several aspects of the evolution of that situation are analysed in this paper, reviewing also the implications in immunization programmes. Closely related with the analysis of this potential evolution, it will be very interesting to monitor the evolution of serogroup W in the African meningitis belt after implementation of the extensive immunization programme with serogroup A conjugate vaccine that is currently underway. More data about carriers, transmission, clonal lineages, etc. are needed for taking decisions (target groups, outbreak control, defining the extent, etc.) to adapt the response strategy with potential interventions with broad coverage vaccines against the emergent serogroup W.

Combined meningococcal serogroup A and W135 outer-membrane vesicles activate cell-mediated immunity and long-term memory responses against non-covalent capsular polysaccharide A.

Outer-membrane vesicles (OMVs) have inherent adjuvant properties, and many vaccines use OMV as vaccine components. Utilizing the adjuvant properties of OMV could lead to the formulation of vaccines that are less expensive and potentially more immunogenic than covalently conjugated polysaccharide vaccines. We evaluated the adjuvant effect in Balb/c mice of combinations of OMV from Neisseria meningitidis serogroup A and W135 as compared to that of the non-covalently conjugated capsular polysaccharide A. Both antigens were adsorbed onto aluminum hydroxide. The mice were given a booster dose of plain polysaccharide A to stimulate an immunologic memory response. Subclasses determination and cytokine assays demonstrated the capacity of OMV to induce a IgG2a/IgG2b isotype profile and IFN-γ production, suggesting the induction of a Th1 pattern immune response. Lymphoproliferative responses to OMVs were high, with affinity maturation of antibodies observed. Bactericidal titers after the booster dose were also observed. Memory B cells and long-term memory T cells were also detected. The results of this study indicate that combined meningococcal serogroup A and W135 OMV can activate cell-mediated immunity and induce a long-term memory response.

Preclinical immunogenicity and functional activity studies of an A+W meningococcal outer membrane vesicle (OMV) vaccine and comparisons with existing meningococcal conjugate- and polysaccharide vaccines.

Meningococci of serogroups A and W (MenA and MenW) are the main causes of epidemic bacterial meningitis outbreaks in sub-Saharan Africa. In this study we prepared a detergent extracted outer membrane vesicle (dOMV) vaccine from representative African MenA and MenW strains, and compared the immunogenicity of this vaccine with existing meningococcal conjugate and polysaccharide (PS) vaccines in mice. NMRI mice were immunized with preclinical batches of the A+W dOMV vaccine, or with commercially available vaccines; a MenA conjugate vaccine (MenAfriVac(®), Serum Institute of India), ACYW conjugate vaccine (Menveo(®), Novartis) or ACYW PS vaccine (Mencevax(®), GlaxoSmithKline). The mice received 2 doses of 1/10 or 1/50 of a human dose with a three week interval. Immune responses were tested in ELISA, serum bactericidal activity (SBA) and opsonophagocytic activity (OPA) assays. High levels of IgG antibodies against both A and W dOMV were detected in mice receiving the A+W dOMV vaccine. High SBA titers against both MenA and MenW vaccine strains were detected after only one dose of the A+W dOMV vaccine, and the titers were further increased after the second dose. The SBA and OPA titers in mice immunized with dOMV vaccine were significantly higher than in mice immunized with the ACYW-conjugate vaccine or the PS vaccine. Furthermore, the A+W dOMV vaccine was shown to induce SBA and OPA titers against MenA of the same magnitude as the titers induced by the A-conjugate vaccine. In conclusion, the A+W dOMV vaccine induced high levels of functional antibodies to both MenA and MenW strains, levels that were shown to be higher or equal to the levels induced by licensed meningococcal vaccines. Thus, an A+W dOMV vaccine could potentially serve as an alternative or a supplement to existing conjugate and PS vaccines in the African meningitis belt.