Immunogenicity of a single 4CMenB vaccine booster in adolescents 11 years after childhood immunisation.

The clinical development of the meningococcal vaccine, 4CMenB, included 2 doses in vaccine-naïve adolescents, which was considered unlikely to be cost-effective for implementation. Theoretically, priming with 4CMenB in early childhood might drive strong immune responses after only a single booster dose in adolescents and reduce programmatic costs. To address this question, children over 11 years old who took part in previous trials involving the administration of 3-5 doses of 4CMenB at infant/preschool age from 2006 were recruited into a post licensure single-centre trial, and were divided into two groups: those who received their last dose at 12 months old (infant group) and those who received their last dose at 3 years old (infant + preschool group). Naïve age-matched controls were randomised to receive one (adolescent 1 group) or two doses at days 0 and 28 (adolescent 2 group) of 4CMenB. Serum bactericidal antibody (SBA) assays using human complement were performed against three reference strains prior to vaccination, and at 1, 6 and 12 months. Previous vaccination was associated with a higher response to a single booster dose at 11 years of age, one-month post-vaccination, when compared with a single dose in naïve age-matched controls. At day 180, the highest responses were observed in participants in the infant + preschool group against strain 5/99 (GMT 316.1 [CI 158.4 to 630.8]), as compared with naïve adolescents who received two doses (GMTs 84.5 [CI 57.7 to 123.6]). When the last dose was received at 12-months of age, responses to a single adolescent dose were not as robust (GMT 61.1 [CI 14.8 to 252.4] to strain 5/99). This descriptive study indicates that the highest SBA responses after a single dose in adolescence were observed in participants who received a preschool dose, suggesting that B cell memory responses are not sufficiently primed at less than 12 months of age. Trial registration EudraCT 2017-004732-11, ISRCTN16774163.

Genetic characterization of clonal complex sequence type 2057 (cc2057) serogroup B Neisseria meningitidis strains unique to Japan and identification of a capsular-switched serogroup Y isolate cc2057.

Introduction. Only approximately 40 cases of invasive meningococcal diseases are reported annually in Japan, and the dominant strains are serogroup Y meningococci (MenY) followed by serogroup B meningococci (MenB). Within the last 10 years, Neisseria meningitidis strains belonging to clonal complex (cc)2057 have become dominant among Japanese MenB and have not been identified in countries other than Japan.Hypothesis/Gap Statement. The uniqueness of cc2057 N. meningitidis strains was considered to be epidemiologically of importance, and some genetic features could be hidden in the genome of cc2057 meningococci.Method. We investigated 22 cc2057 MenB and one cc2057 MenY using whole genome sequencing (WGS) and also predicted the potential coverage of 4CMenB and bivalent rLP2086 vaccines in silico.Results. cc2057 N. meningitidis strains were phylogenetically assigned to two clades. Three hypothetical genes homologous to those in Neisseria lactamica and sequences related to a new CRISPR Cas9 system were found only in the genome of cc2057 strains. Moreover, one cc2057 MenY strain was presumed to be capsular-switched at the capsule synthesis (cps) locus. The potential coverage of 4CMenB and rLP2086 for cc2057 MenB strains was estimated to be very low.Conclusion. To the best of our knowledge, this is the first study to provide genetic insights from epidemiologically unique N. meningitidis cc2057 strains isolated only in Japan, an island country.

A Mouse Immunogenicity Model for the Evaluation of Meningococcal Conjugate Vaccines.

The identification of an appropriate animal model for use in the development of meningococcal vaccines has been a challenge as humans are the only natural host for Neisseria meningitidis. Small animal models have been developed and are widely used to study the efficacy or immunogenicity of vaccine formulations generated against various diseases. Here, we describe the development and optimization of a mouse model for assessing the immunogenicity of candidate tetravalent meningococcal polysaccharide (MenACYW-TT) protein conjugate vaccines. Three inbred (BALB/c [H-2d], C3H/HeN [H-2k], or C57BL/6 [H-2b]) and one outbred (ICR [H-2g7]) mouse strains were assessed using serial two-fold dose dilutions (from 2 µg to 0.03125 µg per dose of polysaccharide for each serogroup) of candidate meningococcal conjugate vaccines. Groups of 10 mice received two doses of the candidate vaccine 14 days apart with serum samples obtained 14 days after the last dose for the evaluation of serogroup-specific anti-polysaccharide IgG by ELISA and bactericidal antibody by serum bactericidal assay (SBA). C3H/HeN and ICR mice had a more dose-dependent antibody response to all four serogroups than BALB/c and C57Bl/6 mice. In general, ICR mice had the greatest antibody dose-response range (both anti-polysaccharide IgG and bactericidal antibodies) to all four serogroups and were chosen as the model of choice. The 0.25 µg per serogroup dose was chosen as optimal since this was in the dynamic range of the serogroup-specific dose-response curves in most of the mouse strains evaluated. We demonstrate that the optimized mouse immunogenicity model is sufficiently sensitive to differentiate between conjugated polysaccharides, against unconjugated free polysaccharides and, to degradation of the vaccine formulations. Following optimization, this optimized mouse immunogenicity model has been used to assess the impact of different conjugation chemistries on immunogenicity, and to screen and stratify various candidate meningococcal conjugate vaccines to identify those with the most desirable profile to progress to clinical trials.

Immunogenicity and Safety of Investigational MenABCWY Vaccine and of 4CMenB and MenACWY Vaccines Administered Concomitantly or Alone: a Phase 2 Randomized Study of Adolescents and Young Adults.

This phase 2, randomized, open-label study assessed the immunogenicity and safety of an investigational meningococcal ABCWY vaccine (MenABCWY) that contains components of licensed vaccines against meningococcal serogroup B (4CMenB) and serogroups ACWY (MenACWY). A total of 500 healthy 10- to 25-year-old participants were randomly assigned to one of five study groups in a 1:1:1:1:1 ratio. Four groups received two doses 2 months apart of MenABCWY and 4CMenB plus MenACWY administered concomitantly in the same arm (4CMenB+ACWY/S group) or different arms (4CMenB+ACWY/D group) or 4CMenB administered alone. A fifth group received a single MenACWY dose. Immunogenicity was determined by serum bactericidal assay using human complement (hSBA). The study was powered to assess immunological interference against pooled serogroup B test strains. One month after the second vaccine dose, hSBA geometric mean titers (GMTs) (with 80% confidence intervals [CI]) against pooled serogroup B strains were 31.84 (80% CI, 28.18 to 35.98), 38.48 (80% CI, 34.23 to 43.26), 40.08 (80% CI, 35.44 to 45.33), and 42.38 (80% CI, 37.31 to 48.13) in the MenABCWY, 4CMenB+ACWY/S, 4CMenB+ACWY/D, and 4CMenB groups, respectively. Immune responses (GMTs and 80% CIs) were lower for PorA and NHBA serogroup B test strains in the MenABCWY group compared to the 4CMenB+ACWY/D group and 4CMenB group. Evaluation of solicited and unsolicited adverse events (AEs) identified no safety concerns for the MenABCWY vaccine. One serious AE (syncope in the 4CMenB group) was considered related to vaccination. In conclusion, there is no evidence of substantial immunological interference between 4CMenB and MenACWY vaccine components against serogroup B. The safety and tolerability profile of the investigational MenABCWY vaccine was acceptable. (This study has been registered at ClinicalTrials.gov under registration no. NCT03587207.) IMPORTANCE The bacterial species Neisseria meningitidis is a major cause of meningitis, with six meningococcal groups (serogroups) causing most cases. A licensed vaccine, MenACWY (Menveo), targets four of these meningococcal serogroups, and another vaccine, 4CMenB (Bexsero), targets serogroup B. A combined vaccine (MenABCWY) that targets all five serogroups is under development to simplify the vaccination schedule. In a previous study, the immune response to serogroup B was found to be overall higher in individuals who received 4CMenB than in those who received an investigational MenABCWY vaccine. We investigated this further by giving healthy adolescents and young adults the MenABCWY vaccine, 4CMenB plus MenACWY vaccine in the same or different arms, 4CMenB vaccine alone, or MenACWY vaccine alone. Immunogenicity results for serogroup B across study groups suggest no major interference between the MenB and MenACWY vaccine components. This supports further development of the combined MenABCWY vaccine.

Efficacy of a Cell-Culture-Derived Quadrivalent Influenza Vaccine in Children.

BACKGROUND: Cell-culture-derived influenza vaccines may enable a closer antigenic match to circulating strains of influenza virus by avoiding egg-adapted mutations. METHODS: We evaluated the efficacy of a cell-culture-derived quadrivalent inactivated influenza vaccine (IIV4c) using a Madin-Darby canine kidney cell line in children and adolescents 2 to less than 18 years of age. During three influenza seasons, participants from eight countries were enrolled in an observer-blinded, randomized clinical trial comparing IIV4c with a noninfluenza vaccine (meningococcal ACWY). All the participants received a dose of a trial vaccine. Children 2 to less than 9 years of age without previous influenza vaccination who were assigned to the IIV4c group received a second dose on day 29; their counterparts who were assigned to the comparator group received placebo. Participants were followed for at least 180 days for efficacy and safety. The presence of influenza virus in nasopharyngeal swabs from participants with influenza-like illness was confirmed by reverse-transcriptase-polymerase-chain-reaction assay and viral culture. A Cox proportional-hazards model was used to evaluate the efficacy of IIV4c as measured by the first occurrence of laboratory-confirmed type A or B influenza (primary end point). RESULTS: Between 2017 and 2019, a total of 4514 participants were randomly assigned to receive IIV4c or the meningococcal ACWY vaccine. Laboratory-confirmed influenza occurred in 175 of 2257 participants (7.8%) in the IIV4c group and in 364 of 2252 participants (16.2%) in the comparator group, and the efficacy of IIV4c was 54.6% (95% confidence interval [CI], 45.7 to 62.1). Efficacy was 80.7% (95% CI, 69.2 to 87.9) against influenza A/H1N1, 42.1% (95% CI, 20.3 to 57.9) against influenza A/H3N2, and 47.6% (95% CI, 31.4 to 60.0) against influenza B. IIV4c showed consistent vaccine efficacy in subgroups according to age, sex, race, and previous influenza vaccination. The incidences of adverse events were similar in the IIV4c group and the comparator group. CONCLUSIONS: IIV4c provided protection against influenza in healthy children and adolescents across seasons, regardless of previous influenza vaccination. (Funded by Seqirus; EudraCT number, 2016-002883-15; ClinicalTrials.gov number, NCT03165617.).

Intracluster correlation coefficients in a large cluster randomized vaccine trial in schools: Transmission and impact of shared characteristics.

Cluster randomized trials (cRCT) to assess vaccine effectiveness incorporate indirect effects of vaccination, helping to inform vaccination policy. To calculate the sample size for a cRCT, an estimate of the intracluster correlation coefficient (ICC) is required. For infectious diseases, shared characteristics and social mixing behaviours may increase susceptibility and exposure, promote transmission and be a source of clustering. We present ICCs from a school-based cRCT assessing the effectiveness of a meningococcal B vaccine (Bexsero, GlaxoSmithKline) on reducing oropharyngeal carriage of Neisseria meningitidis (Nm) in 34,489 adolescents from 237 schools in South Australia in 2017/2018. We also explore the contribution of shared behaviours and characteristics to these ICCs. The ICC for carriage of disease-causing Nm genogroups (primary outcome) pre-vaccination was 0.004 (95% CI: 0.002, 0.007) and for all Nm was 0.007 (95%CI: 0.004, 0.011). Adjustment for social behaviours and personal characteristics reduced the ICC for carriage of disease-causing and all Nm genogroups by 25% (to 0.003) and 43% (to 0.004), respectively. ICCs are also reported for risk factors here, which may be outcomes in future research. Higher ICCs were observed for susceptibility and/or exposure variables related to Nm carriage (having a cold, spending ≥1 night out socializing or kissing ≥1 person in the previous week). In metropolitan areas, nights out socializing was a highly correlated behaviour. By contrast, smoking was a highly correlated behaviour in rural areas. A practical example to inform future cRCT sample size estimates is provided.

Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals.

Dysregulation of complement activation causes a number of diseases, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. These conditions can be treated with monoclonal antibodies (mAbs) that bind to the complement component C5 and prevent formation of the membrane attack complex (MAC). While MAC is involved in uncontrolled lysis of erythrocytes in these patients, it is also required for serum bactericidal activity (SBA), i.e. clearance of encapsulated bacteria. Therefore, terminal complement blockage in these patients increases the risk of invasive disease by Neisseria meningitidis more than 1000-fold compared to the general population, despite obligatory vaccination. It is assumed that alternative instead of terminal pathway inhibition reduces the risk of meningococcal disease in vaccinated individuals. To address this, we investigated the SBA with alternative pathway inhibitors. Serum was collected from adults before and after vaccination with a meningococcal serogroup A, C, W, Y capsule conjugate vaccine and tested for meningococcal killing in the presence of factor B and D, C3, C5 and MASP-2 inhibitors. B meningococci were not included in this study since the immune response against protein-based vaccines is more complex. Unsurprisingly, inhibition of C5 abrogated killing of meningococci by all sera. In contrast, both factor B and D inhibitors affected meningococcal killing in sera from individuals with low, but not with high bactericidal anti-capsular titers. While the anti-MASP-2 mAb did not impair SBA, inhibition of C3 impeded meningococcal killing in most, but not in all sera. These data provide evidence that vaccination can provide protection against invasive meningococcal disease in patients treated with alternative pathway inhibitors.

Development and Immunogenicity of a Brazilian Glycoconjugate vaccine against Meningococcal W in a Pilot Scale.

Recent changes in the epidemiology of meningococcal have been reported and meningococcal group W (MenW) has become the third most prevalent group isolated in Brazil in the last 10 years. In this study we have developed a conjugate vaccine for MenW using a modified reductive amination conjugation method through a covalent linkage between periodate-oxidized MenW non-O-acetylated polysaccharide and hydrazide-activated monomeric tetanus toxoid. Process control of bulks was done by physicochemical analysis including polysaccharide and protein quantification, high performance liquid chromatography - size exclusion chromatography, capillary electrophoresis, and hydrogen nuclear magnetic resonance. Conjugate bulks were best produced with concentration of polysaccharide twice as high as protein, at room temperature, and pH approximately 6.0. A scaled-up bulk (100 mg scale) was formulated and inoculated intramuscularly in mice in a dose-response study (0.1, 0.5, 1.0 and 10.0 µg of polysaccharide/dose). The immunogenicity of conjugate bulks was determined by serum bactericidal assay and ELISA assays of serum from immunized mice. ELISA and SBA titers revealed high titers of IgG and demonstrated the functionality of the antibodies produced in all doses studied 15 days after the third dose. However, significant differences were observed among them by ELISA. In conclusion, this study established the best conditions to produce MenW conjugate bulks and showed the efficacy of the obtained conjugate bulk in induce a good immune response in mice. Further experiments will need to be done to scale up the conjugation reaction and then allow the use of this conjugate in clinical trials.

Neisseria meningitidis Serogroup Z Meningitis in a Child With Complement C8 Deficiency and Potential Cross Protection of the MenB-4C Vaccine.

Complement deficient patients are susceptible to rare meningococcal serogroups. A 6-year-old girl presented with serogroup Z meningitis. This led to identification of a C8 deficiency. The MenB-4C vaccine induced cross-reactive antibodies to serogroup Z and increased in vitro opsonophagocytic killing and may thus protect complement deficient patients.

Meningococcal Serogroup ACWYX Conjugate Vaccine in Malian Toddlers.

BACKGROUND: Neisseria meningitidis serogroups A, B, C, W, X, and Y cause outbreaks of meningococcal disease. Quadrivalent conjugate vaccines targeting the A, C, W, and Y serogroups are available. A pentavalent vaccine that also includes serogroup X (NmCV-5) is under development. METHODS: We conducted a phase 2, observer-blinded, randomized, controlled trial involving Malian children 12 to 16 months of age. Participants were assigned in a 2:2:1 ratio to receive nonadjuvanted NmCV-5, alum-adjuvanted NmCV-5, or the quadrivalent vaccine MenACWY-D, administered intramuscularly in two doses 12 weeks apart. Participants were followed for safety for 169 days. Immunogenicity was assessed with an assay for serum bactericidal antibody (SBA) with rabbit complement on days 0, 28, 84, and 112. RESULTS: A total of 376 participants underwent randomization, with 150 assigned to each NmCV-5 group and 76 to the MenACWY-D group; 362 participants received both doses of vaccine. A total of 1% of the participants in the nonadjuvanted NmCV-5 group, 1% of those in the adjuvanted NmCV-5 group, and 4% of those in the MenACWY-D group reported local solicited adverse events; 6%, 5%, and 7% of the participants, respectively, reported systemic solicited adverse events. An SBA titer of at least 128 was seen in 91 to 100% (for all five serotypes) of the participants in the NmCV-5 groups and in 36 to 99% (excluding serogroup X) of those in the MenACWY-D group at day 84 (before the second dose); the same threshold was met in 99 to 100% (for all five serotypes) of the participants in the NmCV-5 groups and in 92 to 100% (excluding serogroup X) of those in the MenACWY-D group at day 112. Immune responses to the nonadjuvanted and adjuvanted NmCV-5 formulations were similar. CONCLUSIONS: No safety concerns were identified with two doses of NmCV-5. A single dose of NmCV-5 elicited immune responses that were similar to those observed with two doses of MenACWY-D. Adjuvanted NmCV-5 provided no discernible benefit over nonadjuvanted NmCV-5. (Funded by the U.K. Foreign, Commonwealth, and Development Office; ClinicalTrials.gov number, NCT03295318.).

Two human antibodies to a meningococcal serogroup B vaccine antigen enhance binding of complement Factor H by stabilizing the Factor H binding site.

Microbial pathogens bind host complement regulatory proteins to evade the immune system. The bacterial pathogen Neisseria meningitidis, or meningococcus, binds several complement regulators, including human Factor H (FH). FH binding protein (FHbp) is a component of two licensed meningococcal vaccines and in mice FHbp elicits antibodies that inhibit binding of FH to FHbp, which defeat the bacterial evasion mechanism. However, humans vaccinated with FHbp develop antibodies that enhance binding of FH to the bacteria, which could limit the effectiveness of the vaccines. In the present study, we show that two vaccine-elicited antibody fragments (Fabs) isolated from different human subjects increase binding of complement FH to meningococcal FHbp by ELISA. The two Fabs have different effects on the kinetics of FH binding to immobilized FHbp as measured by surface plasmon resonance. The 1.7- and 2.0-Å resolution X-ray crystal structures of the Fabs in complexes with FHbp illustrate that the two Fabs bind to similar epitopes on the amino-terminal domain of FHbp, adjacent to the FH binding site. Superposition models of ternary complexes of each Fab with FHbp and FH show that there is likely minimal contact between the Fabs and FH. Collectively, the structures reveal that the Fabs enhance binding of FH to FHbp by altering the conformations and mobilities of two loops adjacent to the FH binding site of FHbp. In addition, the 1.5 Å-resolution structure of one of the isolated Fabs defines the structural rearrangements associated with binding to FHbp. The FH-enhancing human Fabs, which are mirrored in the human polyclonal antibody responses, have important implications for tuning the effectiveness of FHbp-based vaccines.

Seroprevalence of meningococcal serogroup C bactericidal antibodies in the Portuguese population, a decade after vaccine introduction in the National Immunisation Programme.

BACKGROUND: The incidence of invasive meningococcal disease due to serogroup C (MenC) decreased in Portugal since the introduction of the conjugate vaccine (MCC) in the free market in 2001 and in the National Immunisation Plan in 2006. Considering the potential waning of the antibody response reported in the literature, the different vaccination schemes that were used in our country over the past decade, and that Neisseria meningitidis serogroup C continues to circulate, the Portuguese population may currently be at increased risk of infection. In the absence of national data, we evaluated the seroprotection level of the Portuguese population against MenC, in order to identify the protected fraction of the population and ponder on the necessity of a booster dose of the MCC vaccine. METHODS: We measured serum bactericidal antibody levels against MenC in a representative sample of the population (n = 1500) aged 2-64 years who participated in the 2015/2016 National Serological Survey. RESULTS: A total of 31.1% (466/1500, 95%CI: 29-33%) of the individuals studied were protected against MenC. The geometric mean titre was 6.5. The proportion of seroprotected was particularly low in children aged 2-4 years (<16%) who received a single dose of the vaccine at 12 months of age (vaccination strategy since 2012). The proportion of seroprotected was higher (44.7% to 53.5%) in adolescent and young adults (15-24 years of age), resulting from vaccination during the catch-up campaign at 5-15 years of age. The highest protection rates were observed when the vaccine was administered during adolescence. CONCLUSION: The small fraction of population seroprotected, combined with the already known waning effect of the antibody response over time, may indicate that the Portuguese population will become progressively more exposed to the risk of infection. Taking in consideration our results, we recommend to change the current vaccination strategy and introduce a booster dose of the MCC vaccine during adolescence.

Carbohydrate based meningococcal vaccines: past and present overview.

Neisseria meningitidis is a major cause of bacterial meningitidis worldwide. Children less than five years and adolescents are particularly affected. Nearly all invasive strains are surrounded by a polysaccharide capsule, based on which, 12 N. meningitidis serogroups are differentiated. Six of them, A, B, C, W, X, and Y, cause the vast majority of infections in humans. Mono- and multi-valent carbohydrate-based vaccines against meningococcal infections have been licensed or are currently in clinical development. In this mini-review, an overview of the past and present approaches for producing meningococcal glycoconjugate vaccines is provided.

Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine administered concomitantly with other paediatric vaccines in toddlers: a phase III randomised study.

Invasive meningococcal disease has high morbidity and mortality, with infants and young children among those at greatest risk. This phase III, open-label, randomised study in toddlers aged 12-23 months evaluated the immunogenicity and safety of meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT), a tetanus toxoid conjugated vaccine against meningococcal serogroups A, C, W and Y, when coadministered with paediatric vaccines (measles, mumps and rubella [MMR]; varicella [V]; 6-in-1 combination vaccine against diphtheria, tetanus, pertussis, polio, hepatitis B and Haemophilus influenzae type b [DTaP-IPV-HepB-Hib] and pneumococcal conjugate vaccine [PCV13])(NCT03205371). Immunogenicity to each meningococcal serogroup was assessed by serum bactericidal antibody assay using human complement (hSBA). Vaccine safety profiles were described up to 30 days post-vaccination. A total of 1183 participants were enrolled. The proportion with seroprotection (hSBA ≥1:8) to each meningococcal serogroup at Day 30 was comparable between the MenACYW-TT and MenACYW-TT + MMR + V groups (≥92 and ≥96%, respectively), between the MenACYW-TT and MenACYW-TT + DTaP-IPV-HepB-Hib groups (≥90% for both) and between the MenACYW-TT and MenACYW-TT + PCV13 groups (≥91 and ≥84%, respectively). The safety profiles of MenACYW-TT, and MMR + V, DTaP-IPV-HepB-Hib, and PCV13, with or without MenACYW-TT, were generally comparable. Coadministration of MenACYW-TT with paediatric vaccines in toddlers had no clinically relevant effect on the immunogenicity and safety of any of the vaccines.

Tralokinumab does not impact vaccine-induced immune responses: Results from a 30-week, randomized, placebo-controlled trial in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease. Interleukin (IL) 13 is a type 2 cytokine that is key to the inflammation underlying AD. Tralokinumab is a first-in-class, fully human, monoclonal antibody that specifically binds with high affinity to IL-13, neutralizing it in AD. Immunomodulatory treatments may impair vaccine-induced immune responses. OBJECTIVE: Assess the immune responses to standard vaccines in adults with moderate-to-severe AD who are undergoing treatment with tralokinumab. METHODS: ECZema TRAlokinumab Trial No. 5 (ECZTRA 5; NCT03562377) was a phase 2, double-blind, randomized, placebo-controlled trial taking place over 30 weeks. Eligible adults were randomized 1:1, with 107 patients receiving tralokinumab 300 mg and 108 patients receiving a placebo every 2 weeks for 16 weeks. All patients received Tdap (tetanus/diphtheria/pertussis) and meningococcal vaccines at week 12. The primary end points were positive antitetanus and antimeningococcal responses between weeks 12 and 16 (noninferiority margin, -25%; responder, >3-fold increase in IgG). RESULTS: The noninferiority of tralokinumab versus placebo for immune response to Tdap (91.9% vs 96.1%) and meningococcal (86.0% vs 84.2%) vaccines was demonstrated at week 16. During treatment, the rates of adverse events were lower for tralokinumab than for the placebo, with most events being mild or moderate. LIMITATIONS: Responses to other vaccines (including influenza) were not examined. CONCLUSIONS: Treatment with tralokinumab 300 mg every 2 weeks did not affect immune responses to Tdap and meningococcal vaccines. Treatment was well tolerated when administered concomitantly with the vaccines and demonstrated a safety profile comparable to phase 3 trials.

Molecular modeling provides insights into the loading of sialic acid-containing antigens onto CRM197: the role of chain flexibility in conjugation efficiency and glycoconjugate architecture.

Vaccination is the most cost-effective way to control disease caused by encapsulated bacteria; the capsular polysaccharide (CPS) is the primary virulence factor and vaccine target. Neisseria meningitidis (Nm) serogroups B, C, Y and W all contain sialic acid, a common surface feature of human pathogens. Two protein-based vaccines against serogroup B infection are available for human use while four tetravalent conjugate vaccines including serogroups C, W and Y have been licensed. The tetravalent Menveo® conjugate vaccine is well-defined: a simple monomeric structure of oligosaccharides terminally conjugated to amino groups of the carrier protein CRM197. However, not only is there a surprisingly low limit for antigen chain attachment to CRM197, but different serogroup saccharides have consistently different CRM197 loading, the reasons for which are unclear. Understanding this phenomenon is important for the long-term goal of controlling conjugation to prepare conjugate vaccines of optimal immunogenicity. Here we use molecular modeling to explore whether antigen flexibility can explain the varying antigen loading of the conjugates. Because flexibility is difficult to separate from other structural factors, we focus on sialic-acid containing CPS present in current glycoconjugate vaccines: serogroups NmC, NmW and NmY. Our simulations reveal a correlation between Nm antigen flexibility (NmW > NmC > NmY) and the number of chains attached to CRM197, suggesting that increased flexibility enables accommodation of additional chains on the protein surface. Further, in silico models of the glycoconjugates confirm the relatively large hydrodynamic size of the saccharide chains and indicate steric constraints to further conjugation.

Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT) vs. a licensed quadrivalent meningococcal tetanus toxoid-conjugate vaccine in meningococcal vaccine-naïve and meningococcal C conjugate vaccine-primed toddlers: a phase III randomised study.

Vaccination remains the best strategy to reduce invasive meningococcal disease. This study evaluated an investigational tetanus toxoid-conjugate quadrivalent meningococcal vaccine (MenACYW-TT) vs. a licensed tetanus toxoid-conjugate quadrivalent meningococcal vaccine (MCV4-TT) (NCT02955797). Healthy toddlers aged 12-23 months were included if they were either meningococcal vaccine-naïve or MenC conjugate (MCC) vaccine-primed (≥1 dose of MCC prior to 12 months of age). Vaccine-naïve participants were randomised 1:1 to either MenACYW-TT (n = 306) or MCV4-TT (n = 306). MCC-primed participants were randomised 2:1 to MenACYW-TT (n = 203) or MCV4-TT (n = 103). Antibody titres against each of the four meningococcal serogroups were measured by serum bactericidal antibody assay using the human complement. The co-primary objectives of this study were to demonstrate the non-inferiority of MenACYW-TT to MCV4-TT in terms of seroprotection (titres ≥1:8) at Day 30 in both vaccine-naïve and all participants (vaccine-naïve and MCC-primed groups pooled). The immune response for all four serogroups to MenACYW-TT was non-inferior to MCV4-TT in vaccine-naïve participants (seroprotection: range 83.6-99.3% and 81.4-91.6%, respectively) and all participants (seroprotection: range 83.6-99.3% and 81.4-98.0%, respectively). The safety profiles of both vaccines were comparable. MenACYW-TT was well-tolerated and demonstrated non-inferior immunogenicity when administered to MCC vaccine-primed and vaccine-naïve toddlers.

Implementation Experience With Meningococcal Serogroup B Vaccines in the United States: Impact of a Nonroutine Recommendation.

BACKGROUND: Meningococcal serogroup B (MenB) is the leading cause of invasive meningococcal disease among US adolescents and young adults, accounting for 62% of cases in 16-23-year-olds in 2018. Since 2015, the Advisory Committee on Immunization Practices (ACIP) has recommended vaccination of healthy adolescents against MenB based on shared clinical decision-making (previously called "Category B" or individual clinical decision-making). However, MenB vaccine coverage and series completion rates remain low. Herein we examine implementation experience of adolescent MenB vaccination in the United States under this nonroutine ACIP recommendation. METHODS: PubMed was searched for English-language articles published after 2015 examining MenB vaccination implementation in the United States. Studies reporting MenB vaccination awareness, coverage, knowledge of recommendations and implementation barriers or access disparities were included. RESULTS: Identified studies provided evidence that ACIP's MenB vaccination recommendation is poorly understood and prone to misinterpretation by US healthcare providers. Parental awareness of MenB vaccines is low, and racial and socioeconomic disparities exist regarding vaccine receipt. Parents rely on providers to learn about MenB disease risk and benefits of vaccination, with provider recommendations carrying substantial weight in vaccination decisions. CONCLUSIONS: Five years of evidence regarding the MenB vaccination implementation experience suggest that the nonstandard recommendation for MenB vaccines is partly responsible for low vaccine coverage. Further, inconsistent implementation of ACIP recommendations could be limiting access to MenB vaccines. Providers need additional support and guidance to implement the shared clinical decision-making recommendation, in turn ensuring equitable access for vaccine-eligible adolescents to enable comprehensive protection against meningococcal disease.