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After administration of injectable vaccines, skin manifestations are common and they usually disappear in a few hours or days. We describe a case series of recurrent injection site reactions in 8 children undergoing vaccines of the regional immunization schedule, which required specialized evaluation and advice for subsequent vaccinations. Two clinical patterns of reactions were observed. Four children manifested recurrent wheal and erythema with pruritus at vaccine injection site for up to 7 months; the remaining children showed an itching plaque or nodule at injection site, that lasted several months after vaccination with exacerbations of pruritus and erythema. Hypersensitivity to aluminium salts was demonstrated in the second group. The flare-up manifestations, related to Meningococcal B vaccine in 5 reactions, were triggered by concurrent viral infections in two patients. Communication of risks and diagnostic testing, when appropriate, resulted important to reassure parents of children and favour adequate completion of vaccination.

Background Serogroup B meningococcal (MenB) vaccination recommendations for adolescents in the United States (US) include routine vaccination for all individuals at increased risk and vaccination for individuals not at increased risk aged 16–23 years (preferred age 16–18 years) based on shared clinical decision-making. The two licensed MenB vaccines require administration of ≥2 doses. Methods This cross-sectional study analyzed 2017–2018 National Immunization Survey-Teen (NIS-Teen) data to evaluate ≥1 dose and ≥2 dose MenB vaccination coverage among adolescents aged 17 years. Multivariable logistic regression was used to further evaluate determinants of MenB vaccination. Results Nationally, MenB vaccination coverage among 17-year-olds increased from 14.5% in 2017 to 17.2% in 2018 for ≥1 dose and from 6.3% to 8.4% for ≥2 doses. MenB vaccination coverage (2017–2018) was the lowest in the South (≥1 dose: 14.6%; ≥2 doses: 6.3%) and highest in the Northeast region (18.3% and 9.3%), with variation observed by census division. Adolescents were more likely to have received ≥1 dose of MenB vaccine if they had any Medicaid insurance (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.32–2.39) or had received human papillomavirus (OR, 1.94; 95% CI, 1.41–2.67) or meningococcal A, C, W, and Y (OR, 4.03; 95% CI, 2.92–5.56) vaccinations. Conclusions MenB first-dose coverage in the US is low, and even lower for a second dose, with regional variation. Being up to date with other routinely administered vaccines increased the likelihood of receiving MenB vaccination.

Invasive meningococcal disease (IMD), an uncommon but severe disease, affects mainly infants, young children and adolescents. Meningococcal B (4CMenB) and ACWY (MenACWY) vaccines targeting IMD-causing serogroups B and A, C, W and Y, respectively are available for these mostly-affected age-groups. The objective was to assess the impact of 4CMenB and/or MenACWY vaccination strategies on IMD in England, considering MenACWY carriage protection and potential cross-protection of 4CMenB against non-B serogroups. A novel dynamic transmission model was developed, accounting for vaccine characteristics, with separate variables for meningococcal carriage and IMD for three groups: B; ACWY; and 'Other' mostly non-pathogenic serogroups. A dynamic force of infection is assumed for each group. The model analysis uses data from England before 2015 (when 4CMenB and MenACWY were introduced), and accounts for existing MenC vaccination impact. Compared with no vaccination, the smallest decrease in IMD cases is observed for MenACWY strategies (toddler and/or adolescent). 4CMenB (infant or infant/adolescent), alone or with MenACWY, always results in the most rapid and steep decline in IMD cases. Combined strategies with adolescent 4CMenB result in the largest decrease in IMD cases, whereas adding MenACWY for toddlers has a minor impact. With potential 4CMenB cross-protection, 4CMenB infant strategy has a notable impact on reduction of MenW and MenY IMD cases in strategies where MenACWY toddler and/or adolescent vaccination is absent. This novel model allows for analysis of combined 4CMenB and MenACWY strategies including potential 4CMenB cross-protection. In settings comparable to England, a comprehensive meningococcal vaccination programme should include infant 4CMenB as essential building block. Decisions to include MenACWY toddler programmes should consider herd effects of MenACWY adolescent programmes and 4CMenB potential cross-protection effects. Extending 4CMenB infant and MenACWY adolescent programmes with a 4CMenB adolescent programme allows for the largest overall reduction in IMD cases.

Background Four-component meningococcal B (4CMenB) vaccine is licensed in many countries but has had limited use in adolescents despite this age group being at increased risk of meningococcal disease. Objectives To assess the safety profile of two doses of 4CMenB in adolescents. Methods Cluster randomised controlled trial of senior school students in South Australia (SA) with participating schools randomised to intervention (4CMenB) or control. Vaccine safety was monitored using the South Australian Vaccine Safety Surveillance System (SAVSS), a spontaneous reporting system for adverse events following immunisation (AEFI) with enhanced follow-up of AEFI. Results 58,637 doses of 4CMenB vaccine were administered to 30,522 students (median age 16 years) during 2017–2018. Of 18,348 and 12,174 students vaccinated in 2017 and 2018, 97.3% and 84.3%, respectively, received both scheduled doses (N = 28,115). 193 AEFI in 187 students were reported with a reporting rate of 0.32% (95%CI: 0.28–0.39%). Seventy individuals sought medical review, including nine serious adverse events. 98% (166/169) of those who were contactable for AEFI follow-up (87.6% 169/193) reported resolution of the event. Most common AEFI were injection site reaction (126/193), headache (99/193) and nausea (61/193). AEFI were more frequently reported in females (aOR = 1.409 (95%CI: 1.002, 1.980)), schools with high level of educational advantage (adjusted Odds Ratio (aOR) = 1.515 (95%CI: 1.005, 2.284)), following first dose (aOR = 1.619 (95%CI: 1.168, 2.244)), and in 2017 (aOR = 1.437 (95%CI: 1.001, 2.064)). Reported AEFI declined with increasing age (aOR = 0.771 (95%CI: 0.673, 0.883)). Conclusion In this largest post-licensure use of 4CMenB in adolescents, the low AEFI reporting rate provides real-world evidence of 4CMenB safety in this age group. (ClinicalTrials.gov number: NCT03089086).

A possible increased risk of nephrotic syndrome (NS) following a meningococal group B vaccination campaign was identified during active safety surveillance in a province in Quebec, Canada where 4 cases were reported from an exposed population of ~490,000, a higher rate than in provinces not using the vaccine. Meningococcal B vaccine has been given routinely at 2, 4 and 12 months of age in the United Kingdom since September 2015. To investigate the Canadian signal we used English hospital admissions data from 2005 to 2019 in 2–23 month old children to determine whether the rate of NS changed following the introduction of the vaccine. The analysis was stratified by age 2–5 months, 6–11 months, 12–17 months and 18–23 months. The results showed no evidence of an increased risk with incidence rate ratios between 0.81 (95% confidence interval 0.56–1.19) for age 6–11 months and 1.18 (0.84–1.66) for age 12–17 months.

Kawasaki disease (KD) is an uncommon condition occasionally reported after childhood vaccination. Admissions with a KD-compatible diagnosis identified from a national database in England were linked to immunisation records to investigate the risk after pneumococcal conjugate (PCV) or meningococcal B (MenB) vaccines. Both are given at 2/4/12 months of age but were introduced sequentially, allowing their effects to be separately assessed. A total of 553 linked admissions in 512 individuals were validated as KD. The relative incidence (RI) within 28 days of PCV doses 1 or 2 measured by the self-controlled case-series method was 0.62 (95% confidence interval (CI) 0.38–1.00) with a significantly decreased risk after dose 3 (RI 0.30 (95% CI 0.11–0.77)). For MenB vaccine, the RI after doses 1 or 2 was 1.03 (95% CI 0.51–2.05) and 0.64 (95% CI 0.08–5.26) after dose 3. This study shows no evidence of an increased risk of KD after either vaccine.

Background In the US, Meningococcal B (MenB) vaccines were first licensed in 2014. In 2015, the Advisory Committee on Immunization Practices recommended that parents of teens talk to their provider about receiving MenB vaccine, rather than issuing a routine recommendation. We assessed parental awareness of MenB vaccines and willingness to vaccinate their teens with MenB vaccines compared to MenACWY vaccines, which have been routinely recommended for many years. Methods We surveyed parents of teens attending high school in 2017–18 during the Minnesota State Fair. Parents reported via iPad their knowledge of and concern about meningococcal disease and their awareness of and willingness to vaccinate with MenB and MenACWY vaccines. We assessed the relationship between meningococcal disease knowledge and concern, MenB and MenACWY vaccine awareness, and willingness to vaccinate with MenB and MenACWY using adjusted logistic regression. Results Among 445 parents, the majority had not heard of the newly introduced MenB vaccines Bexsero® (80.0%; 95% CI: 76.0–83.6) or Trumenba® (82.0%; 95% CI: 78.1–85.5) or the MenACWY vaccines Menactra® or Menveo® (68.8%; 95% CI: 64.2–73.0). The majority were at least somewhat willing to vaccinate their teen with MenB vaccine (89.6%; 95% CI: 86.5, 92.3) and MenACWY vaccine (91.2%; 95% CI: 88.2, 93.7). Awareness of MenB vaccines (OR: 3.8; 95% CI: 1.2–12.2) and concern about meningococcal disease (OR: 3.1; 95% CI: 1.5–6.3) were significantly associated with willingness to vaccinate with MenB vaccine. Conclusions Awareness of MenB vaccine is lacking among parents of teens but is an important predictor of willingness to vaccinate with the newly licensed MenB vaccines.

Background Invasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB) remains a health risk in Canada and globally. Two MenB vaccines are now approved for use. An understanding of the genotype of Canadian strains and the potential strain coverage conferred by the MenB-FHbp vaccine is needed to inform immunization policies. Methods Serogroup B Neisseria meningitidis strains responsible for meningococcal disease in Canada from 2006 to 2012 were collected as part of the Canadian Immunization Monitoring Program Active surveillance network. Genotypic analysis was done on MenB isolates from 2006 to 2012 with determination of fHbp surface expression for a subset of isolates: those occurring from 2010 to 2012. Results Two clonal complexes (cc269 and cc41/44) were observed in 68.8% of the 276 isolates. A total of 50 different fHbp peptides were identified among isolates from 2006 to 2012. Surface expression of fHbp was detected on 95% of MenB isolates from 2010 to 2012 and 91% of isolates expressed fHbp at levels that are predicted to be susceptible to the bactericidal immune response elicited by the MenB-FHbp vaccine. Some regional differences were observed, particularly in isolates from British Columbia and Quebec. Conclusion The majority of MenB isolates responsible for meningococcal disease in Canada expressed fHbp at levels predicted to be sufficient for complement mediated bactericidal activity in the presence of MenB-FHbp induced serum antibodies.

It is imperative to ensure biological products are free of contaminating pyrogenic material prior to administration to patients. Historically the rabbit pyrogen test (RPT) was used to screen for such contamination in medicines for intravenous delivery. This test was adapted for use to screen vaccines. However, some, including meningococcal vaccines containing outer membrane vesicles, are intrinsically pyrogenic. Indeed, this is the case for Bexsero which contains relatively high levels of endotoxin and other potential pyrogens such as lipoproteins and porins. The RPT proved a difficult method for measuring the pyrogenic content of Bexsero and differences between laboratories in different countries made repeat testing at the control laboratories problematic resulting in batches being wrongly identified as unsafe. At NIBSC a monocyte activation test (MAT) was adapted and validated as an alternative. This required setting of a specification in-house and deciding on a decisional procedure using multiple donors, allowing batches equally pyrogenic or less, than those batches shown to be safe in a clinical trial, to be certified as safe. The resulting format was a reference comparison method with an upper limit of 1.8 relative pyrogen units (RPU). The batch passed if an initial four donors had a response equal to or less than 1.8 RPU, if one donor is above this limit the batch was tested in a further four donors and seven of the eight must be equal to or below 1.8 RPU. If two donors have a response greater than 1.8 the batch failed.

The aim of this collaborative study was to evaluate the robustness of the monocyte activation test (MAT) for quantifying the pyrogenic content in the outer membrane vesicle (OMV)-containing vaccine Bexsero: the first meningococcal B vaccine to be licenced. We analysed datasets from 9 laboratories covering 15 test systems for 3 batches of Bexsero with higher, equivalent and lower activity relative to a reference lot in the MAT. Activity was measured in terms of relative pyrogen units (RPU) based on European Pharmacopoeia (Ph. Eur.) MAT Chapter 2.6.30 Method C: Reference Lot Comparison Test. We report that all 15 test systems were consistent in that they showed sample A to be the most active in the MAT; that 13 of 15 test systems had an accuracy of more than 80% and an overall geometric mean RPU of 1.03 with lower and upper 95% confidence limits of 0.97 and 1.09 respectively for a sample with an expected value of 1.00 RPU. We also report larger variability in the results for test systems involving cells from individual blood donations for sample A suggesting that there could be donor to donor differences in sensitivity to the vaccine constituents responsible for the higher activity of this batch. Overall, the consistency and accuracy of the MAT was remarkable given the range of test systems used by participants, all of which are permitted by the Ph. Eur. General MAT Chapter. This is important given the limitations of the rabbit pyrogen test for the control of pyrogenicity in general and particularly with products with intrinsic pyrogenicity such as Bexsero.

Recently an investigational meningococcal B vaccine has been used in two college outbreaks in the US. This is the first time that a meningococcal B vaccine has been used for outbreak control in the US. However, strain specific vaccines for meningococcal B outbreaks have been developed in Norway, Cuba and to control a large prolonged outbreak in New Zealand. Although meningococcal disease is mostly endemic and baseline rates in the US have fallen over the past decade, outbreaks are not uncommon in the US and globally. In an outbreak, disease risk can rise 1000 fold or more and such outbreaks can last a decade or longer causing significant morbidity and mortality. Here we review the evolution of several serogroup B outbreaks, and, when applicable, the development and impact of meningococcal B vaccines to control these outbreaks. Prior to the availability of “broad spectrum” meningococcal B vaccines, vaccines developed to control meningococcal B outbreaks were strain specific. With the development of two newly licensed meningococcal B vaccines – a four component meningococcal B vaccine (Bexsero®, Novartis) and the two component fHBP vaccine (Trumenba®, Pfizer) that target a broad array of meningococcal B strains, there is now the potential to prevent outbreaks and as well as to shorten the delay between identification of an outbreak and availability of a vaccine.

Recently approved in the EU, US, Australia, and Canada, 4CMenB (Bexsero®, GSK Vaccines) is a multi-component meningococcal B (MenB) vaccine containing 3 surface exposed recombinant proteins (fHbp, NadA, and NHBA) and New Zealand strain outer membrane vesicles (NZ OMV) containing PorA 1.4. The accepted correlate of protection to assess response to MenB vaccines, the serum bactericidal assay with human complement, is impractical for large panels of strains with diverse antigenic profile and expression. Therefore, the Meningococcal Antigen Typing System (MATS) was developed to identify MenB strains with a high likelihood of being covered by 4CMenB. MATS is used to assess MenB strain coverage without requiring sera, an advantage for testing large panels of bacterial isolates. MATS provides an accurate, conservative estimate of 4CMenB coverage. In a public–private partnership, 10 reference laboratories around the world were established and standardized to facilitate the timely collection and analysis of regional data. MATS has global public health implications for informing local policy makers of the predicted effect of the implementation of the 4CMenB vaccine. Coverage estimates are similar to or better than other recently approved vaccines, ranging from 66% to 91%. The use of MATS in post-vaccine implementation surveillance could provide data regarding vaccine effectiveness in the field and duration of protection on a global scale that will aid in the development of vaccine booster schedules, if necessary. This MATS approach could potentially be applied rapidly to assess epidemiology of other bacterial pathogens and coverage by other protein-based vaccines.

Incidence of invasive meningococcal disease is low in Germany at 0.5 cases/100,000 inhabitants. Serogroup B (MenB) is most common, causing 70% of cases, with highest incidence in infants (5.9/100,000). In 2013, a MenB vaccine was licensed in Europe. To assess pediatricians’ attitudes towards MenB vaccination and its potential use in Germany we conducted a nationwide cross-sectional survey among 5677 pediatricians. Of 3107 participants (response: 55%), 79.1% would recommend a MenB vaccination to parents, with 66.7% favoring a schedule at 6, 8 and 12 months over 2, 3, 4 and 12 months (13.4%). Administration separately from other vaccines was preferred (63.2%); 38.5% feared that a recommendation would lead to refusal of other recommended vaccinations. In conclusion, pediatricians showed distinct preferences regarding possible integration of MenB vaccination into the existent immunization schedule. As physicians play a crucial role in the implementation, findings will be useful in decision-making regarding potential introduction.

Although significant advances have been made toward the control of bacterial meningitis in children with the development of capsular polysaccharide protein conjugate vaccines, this approach has proven problematic for the serogroup B meningococcus. Non-capsular vaccines based upon outer membrane vesicles of Neisseria meningitidis have been useful in control of clonal serogroup B outbreaks, although due to variability of PorA, these vaccines may be less useful in control of endemic disease. Genome-based vaccine discovery was evaluated in an attempt to produce a candidate capable of conferring a broadly protective vaccine against a diversity of meningococcal B strains.

This paper briefly reviews work on vaccine development since the early 1950s with special emphasis on identification of immunogens and their presentation to the host so as to elicit an immune response. This is illustrated primarily by a discussion of the development of a candidate meningococcal B vaccine based on a capsular carbohydrate outer membrane protein complex. Work on malaria and living Salmonella typhi vaccine is also discussed.