Publications by authors named "Daniela Toneatto"

44 Publications

Does vaccination with 4CMenB convey protection against meningococcal serogroup B strains not predicted to be covered by MATS? A study of the UK clonal complex cc269.

Hum Vaccin Immunother 2020 04 6;16(4):945-948. Epub 2019 Dec 6.

GSK, Siena, Italy.

The Meningococcal Antigen Typing System (MATS) has been developed as an hSBA surrogate to evaluate potential coverage afforded by the 4-component meningococcal serogroup B vaccine (4CMenB: , GSK). We investigated whether the lower value of MATS coverage among invasive Meningococcus serogroup B clonal complex 269 strains from the United Kingdom (53% in 2014-2015 versus 73% in 2007-2008) reflected the lower bactericidal activity of the vaccine against these isolates. A total of 34 MATS-negative strains (31 were cc269 or closely related) were tested against pooled sera from 32 or 72 4CMenB-vaccinated infants in a serum bactericidal antibody assay in presence of human complement (hSBA). All infants had received four 4CMenB doses in the first 2 y of life. Baseline sera comprised 180 pooled samples from healthy-unvaccinated 2-month-old infants. Twenty of the 34 (59%) MATS-negative strains were killed in hSBA with titers ≥4 by pooled sera from vaccinated infants. There were 13/34 strains with hSBA titers ≥4 and at least a 4-fold rise in titer with respect to pooled baseline sera, and 10/34 with hSBA titers ≥8 and at least a 4-fold rise in titer with respect to baseline. These data confirm MATS as a conservative estimate for predicting strain coverage by 4CMenB.
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http://dx.doi.org/10.1080/21645515.2019.1688039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227617PMC
April 2020

Immunogenicity of the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) administered concomitantly with the meningococcal serogroup B (4CMenB) vaccine in infants: A post-hoc analysis in a phase 3b, randomised, controlled trial.

Vaccine 2019 08 18;37(35):4858-4863. Epub 2019 Jul 18.

GSK, Wavre, Belgium. Electronic address:

Background: No data are currently available on immunogenicity of higher-valent pneumococcal conjugate vaccines when co-administered with a 4-component meningococcal serogroup B vaccine (4CMenB).

Methods: Post-hoc analysis of pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) immunogenicity when co-administered with 4CMenB (2 + 1 schedule) and/or a CRM-conjugated meningococcal serogroup C vaccine (MenC-CRM) in a trial assessing 4CMenB reduced schedules and co-administration with MenC-CRM (NCT01339923). Infants were randomized to receive 4CMenB and MenC-CRM (Group 1) or MenC-CRM (Group 2) at 3, 5, and 12 months (M) of age. Both groups received PHiD-CV (3 + 1 schedule) as part of the Brazilian national immunisation programme at 3 M, 5 M, 7 M, and 12 M of age. Antibody responses were assessed pre-vaccination, 1 M post-dose 2, pre-booster, and 1 M post-booster.

Results: Anti-pneumococcal antibody responses were in similar ranges in the two study groups.

Conclusions: 4CMenB co-administration did not seem to impact antibody responses to PHiD-CV in infants.
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http://dx.doi.org/10.1016/j.vaccine.2019.07.021DOI Listing
August 2019

Persistence of the immune response after 4CMenB vaccination, and the response to an additional booster dose in infants, children, adolescents, and young adults.

Hum Vaccin Immunother 2019 9;15(12):2940-2951. Epub 2019 Jul 9.

GSK, Marburg, Germany.

The multicomponent meningococcal serogroup B vaccine, 4CMenB, has demonstrated effectiveness in preventing invasive MenB disease in infants and in controlling MenB outbreaks. The need for/timing of additional booster doses is not yet established. We reviewed eight studies that evaluated antibody persistence and booster following primary 4CMenB vaccination of infants, children, adolescents, and young adults. Putative seroprotective hSBA titers for ≥1 vaccine antigen were maintained by 76-100% of children 24-36 months after priming during infancy and in 84-100% after priming in the second year of life. hSBA levels were higher in vaccinees at 4 and 7.5 years following priming during adolescence than in vaccine-naïve individuals of a similar age. Antibodies persisted at higher levels to NHBA and NadA than to PorA or fHbp. Booster vaccination induced robust anamnestic responses, demonstrating effective priming by 4CMenB across age-groups. These data can inform decision-making to optimize vaccination strategies.
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http://dx.doi.org/10.1080/21645515.2019.1627159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930112PMC
May 2020

Antibody persistence and booster response in adolescents and young adults 4 and 7.5 years after immunization with 4CMenB vaccine.

Vaccine 2019 02 26;37(9):1209-1218. Epub 2019 Jan 26.

Microbiology and Mycology Program, Institute of Biomedical Sciences, and Millennium Institute of Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, Santiago, Chile. Electronic address:

Background: Data on duration of protection against invasive meningococcal disease post-vaccination with the recombinant, 4-component, meningococcal serogroup B vaccine (4CMenB) are limited. We evaluated bactericidal activity persistence in adolescents/young adults up to 7.5 years post-primary vaccination with 4CMenB, and response to a booster dose compared with vaccine-naïve controls.

Methods: This open-label, multicenter study (NCT02446743) enrolled 15-24 year-old-previously vaccinated participants from Canada, Australia (group Primed_4y) 4 years post-priming with 4CMenB (2 doses; 0,1-month schedule), and Chile (Primed_7.5y) 7.5 years after priming with 4CMenB (2 doses; 0,1/0,2/0,6-month schedule) and vaccine-naïve participants of similar age (Naïve_4y and Naïve_7.5y groups). Primed participants received a booster dose; vaccine-naïve participants received 2 catch-up doses of 4CMenB, 1 month apart. We evaluated antibody persistence and immune responses using hSBA in terms of geometric mean titers and percentages of participants with hSBA titers ≥4, the kinetics of bactericidal activity post-booster (previously vaccinated) or post-2 doses (vaccine-naïve), and safety.

Results: Antibody levels declined at 4 (Primed_4y) and 7.5 (Primed_7.5y) years post-primary vaccination, but remained higher than in vaccine-naïve participants at baseline (≤44% vs ≤ 13% [fHbp]; ≤84% vs ≤ 24% [NadA]; ≤29% vs ≤ 14% [PorA]) for all vaccine antigens except NHBA (≤81% vs ≤ 79%). One month post-booster and post-second dose, 93-100% of primed and 79-100% of vaccine-naïve participants had hSBA titers ≥4 for all antigens. Kinetics of the antibody response were similar across groups with an early robust response observed 7 days post-booster/second dose. No vaccine-related serious adverse event was reported.

Conclusion: For all antigens except NHBA, a higher proportion of primed participants had hSBA titers ≥4, at 4 and 7.5 years post-vaccination, compared with vaccine-naïve participants. A more robust immune response after booster compared to a first dose in vaccine-naïve individuals, showed effective priming in an adolescent/young adult population. No safety or new reactogenicity issues were identified.
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http://dx.doi.org/10.1016/j.vaccine.2018.12.059DOI Listing
February 2019

Immunogenicity and safety of the 4CMenB and MenACWY-CRM meningococcal vaccines administered concomitantly in infants: A phase 3b, randomized controlled trial.

Vaccine 2018 Nov 7;36(50):7609-7617. Epub 2018 Nov 7.

GSK, Via Fiorentina, 1, 53100 Siena, Italy. Electronic address:

Background: Invasive meningococcal disease has its highest incidence in infants. Co-administration of serogroup B (4CMenB) and quadrivalent conjugate (MenACWY-CRM) vaccines could protect against 5 clinically-relevant meningococcal serogroups.

Methods: This phase 3b, open, multicenter study (NCT02106390), conducted in Mexico and Argentina, enrolled and randomized (1:1:1) 750 healthy infants to receive either 4CMenB co-administered with MenACWY-CRM (4CMenB/MenACWY group), 4CMenB (4CMenB group), or MenACWY-CRM alone (MenACWY group) at ages 3, 5, 7 and 13 months. Non-inferiority of immune responses of co-administration to single administration of vaccines was assessed at 1 month post-booster dose (primary objective). Immunogenicity was evaluated pre- and 1 month post-primary and booster vaccinations using human serum bactericidal assay (hSBA). Safety was assessed.

Results: At 1 month post-booster vaccination, between-group hSBA geometric mean titer (GMT) ratios ranged from 0.89 to 1.03 for serogroup B strains (group 4CMenB/MenACWY over 4CMenB), and from 1.05 to 2.48 for ACWY serogroups (group 4CMenB/MenACWY over MenACWY). The lower limit of the 2-sided 95% confidence intervals for all GMT ratios was >0.5; the primary objective was demonstrated. Across all groups and serogroup B strains, 68-100% and 87-100% of children had hSBA titers ≥5 at 1 month post-primary and booster vaccination, respectively. For serogroups ACWY, ≥96% (post-primary vaccination) and ≥98% (post-booster vaccination) of children in all groups had hSBA titers ≥4. Post-booster vaccination, GMTs increased ≥5.99-fold from pre-booster values for each strain/serogroup. Solicited adverse events (AEs) were more frequent in groups 4CMenB/MenACWY and 4CMenB than in MenACWY; incidence of all other AEs was similar between groups. Serious AEs were reported for 6, 13, and 11 participants in groups 4CMenB/MenACWY, 4CMenB, and MenACWY, respectively; 1 (group 4CMenB) was considered vaccine-related.

Conclusion: Immune responses elicited by co-administration of 4CMenB and MenACWY-CRM was non-inferior to single immunization. Co-administration of vaccines was immunogenic and well tolerated in infants. ClinicalTrials.gov: NCT02106390.
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http://dx.doi.org/10.1016/j.vaccine.2018.10.096DOI Listing
November 2018

Evaluation of strain coverage of the multicomponent meningococcal serogroup B vaccine (4CMenB) administered in infants according to different immunisation schedules.

Hum Vaccin Immunother 2019 2;15(3):725-731. Epub 2019 Jan 2.

a GSK , Siena , SI , Italy.

The 4-component vaccine 4CMenB, developed against invasive disease caused by meningococcal serogroup B, is approved for use in infants in several countries worldwide. 4CMenB is mostly used as 3 + 1 schedule, except for the UK, where a 2 + 1 schedule is used, and where the vaccine showed an effectiveness of 82.9%. Here we compared the coverage of two 4CMenB vaccination schedules (3 + 1 [2.5, 3.5, 5, 11 months] versus 2 + 1 [3.5, 5, 11 months of age]) against 40 serogroup B strains, representative of epidemiologically-relevant isolates circulating in England and Wales in 2007-2008, using sera from a previous phase 3b clinical trial. The strains were tested using hSBA on pooled sera of infants, collected at one month post-primary and booster vaccination. 4CMenB coverage was defined as the percentage of strains with positive killing (hSBA titres ≥ 4 after immunisation and negative baseline hSBA titres < 2). Coverage of 4CMenB was 40.0% (95% confidence interval [CI]: 24.9-56.7) and 87.5% (95%CI: 73.2-95.8) at one month post-primary and booster vaccination, respectively, regardless of immunisation schedule. Using a more conservative threshold (post-immunisation hSBA titres ≥ 8; baseline ≤ 2), at one month post-booster dose, strain coverages were 80% (3 + 1) and 70% (2 + 1). We used a linear regression model to assess correlation between post-immunisation hSBA data for each strain in the two groups; Pearson's correlation coefficients were 0.93 and 0.99 at one month post-primary and booster vaccination. Overall, there is no evidence for a difference in strain coverage when 4CMenB is administered according to a 3 + 1 or 2 + 1 infant vaccination schedule.
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http://dx.doi.org/10.1080/21645515.2018.1537756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605712PMC
February 2020

Meningococcal B Vaccine Immunogenicity in Children With Defects in Complement and Splenic Function.

Pediatrics 2018 09 1;142(3). Epub 2018 Aug 1.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom;

Background: The capsular group B meningococcal vaccine (4CMenB) is recommended for children with complement deficiencies, asplenia, and splenic dysfunction; however, data on the immunogenicity of 4CMenB in these "at-risk" children are missing.

Methods: Participants aged 2 to 17 years in Italy, Spain, Poland, the United Kingdom, and Russia with complement deficiencies, asplenia, or splenic dysfunction received 2 doses of 4CMenB 2 months apart, as did healthy children in the control group. Exogenous and endogenous human complement serum bactericidal activity (SBA) was determined at baseline and 1 month after the second immunization against 4 test strains: H44/76 (assessing vaccine antigen factor H binding protein), 5/99 (Neisserial adhesion A), NZ98/254 (Porin A), and M10713 (Neisserial heparin binding antigen).

Results: Of 239 participants (mean age 10.3 years, 45% female), 40 children were complement deficient (9 eculizumab therapy, 4 terminal-chain deficiencies, 27 "other"), 112 children had asplenia or splenic dysfunction (8 congenital asplenia, 8 functional asplenia, 96 splenectomy), and 87 children were in the control group. After immunization, the proportions of complement-deficient participants with exogenous complement SBA titers ≥1:5 were 87% (H44/76), 95% (5/99), 68% (NZ98/254), and 73% (M10713), compared with 97%, 100%, 86%, and 94%, respectively, for asplenic children and 98%, 99%, 83%, and 99% for children in the control group. When testing with endogenous complement, strain-specific bactericidal activity was evident in only 1 eculizumab-treated participant and 1 terminal chain complement-deficient participant.

Conclusions: 4CMenB administration is similarly immunogenic in healthy children and those with asplenia or splenic dysfunction. The significance of the trend to lower responses of SBA titers in complement-deficient children (especially those with terminal chain complement deficiency or those on eculizumab therapy) must be determined by ongoing surveillance for vaccine failures.
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http://dx.doi.org/10.1542/peds.2017-4250DOI Listing
September 2018

Breadth of coverage against a panel of 110 invasive disease isolates, immunogenicity and safety for 2 and 3 doses of an investigational MenABCWY vaccine in US adolescents - Results from a randomized, controlled, observer-blind phase II study.

Vaccine 2018 08 27;36(35):5309-5317. Epub 2018 Jul 27.

GSK, Via Fiorentina, 1, 53100 Siena, Italy. Electronic address:

Background: Neisseria meningitidis serogroups A, B, C, W and Y cause most meningococcal disease worldwide. An investigational MenABCWY vaccine combining serogroup B antigens and a meningococcal ACWY CRM-glycoconjugate vaccine (MenACWY-CRM) could provide protection against all 5 serogroups. Complement mediated bactericidal activity induced by MenABCWY was tested against a panel of 110 randomly-selected serogroup B strains causing invasive disease in the US to evaluate the vaccine's breadth of coverage (BoC).

Methods: We conducted this observer-blind study (NCT02140762) and its extension (NCT02285777) in 8 centers in the US. Adolescents aged 10-18 years were randomized (1:1) to receive either 3 MenABCWY doses (MenABCWY group), on a 0, 2, 6-month (M) schedule or a single MenACWY-CRM dose at M2 and placebo at 0,6-M (Control group). MenABCWY BoC was calculated as (1 - relative risk) × 100 (relative risk = ratio between the percentage of samples seronegative at 1:4 dilution against the selected strains in the MenABCWY vs Control group). BoC was determined at 1 M and 4 M after 2 and 3 doses, using an endogenous complement serum bactericidal assay. Immunogenicity and safety were assessed.

Results: 301 and 189 adolescents were vaccinated in the parent and extension study, respectively. At 1 M post-vaccination, the BoC of MenABCWY across the 110 serogroup B strains was 67% (95%CI: 65-69) after 2 doses and 71% (95%CI: 69-73) after 3 doses. BoC decreased to 44% (95%CI: 41-47) and 51% (95%CI: 48-55) at 4 M after 2 and 3 MenABCWY doses, respectively. Robust immune responses to antigen-specific test strains for each serogroup were observed at all timepoints in the MenABCWY group. No reactogenicity or safety concerns arose during the study.

Conclusion: Two or 3 doses of MenABCWY showed similar BoC against the panel of invasive US serogroup B isolates and comparable immunogenicity against the antigen-specific test strains, with no safety concerns identified.
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http://dx.doi.org/10.1016/j.vaccine.2018.07.016DOI Listing
August 2018

Four-year antibody persistence and response to a booster dose of a pentavalent MenABCWY vaccine administered to healthy adolescents and young adults.

Hum Vaccin Immunother 2018 05 9;14(5):1161-1174. Epub 2018 May 9.

e GSK , Siena , Italy.

This open-label, multicenter extension study (NCT02451514) assessed persistence of Neisseria meningitidis serogroups ABCWY antibodies 4 years after primary vaccination. Adolescents and young adults who previously received 2 doses of MenABCWY+OMV (Group III), 1 dose of MenACWY-CRM (Group VI), or newly-recruited vaccine-naïve participants (Group VII) were administered 1 (Group III) or 2 doses (Groups VI and VII) of MenABCWY+OMV, 1 month apart. Immunogenicity was assessed by human serum bactericidal assay (hSBA). Safety and reactogenicity were also evaluated. Percentages of participants with hSBA titers ≥8 (serogroups ACWY), ≥5 (serogroup B) and hSBA geometric mean titers (GMTs) were evaluated in all 129 enrolled participants (Group III: 33; Group VI: 46; Group VII: 50). Anti-ACWY antibody concentrations waned over 4 years post-vaccination, but remained above pre-vaccination concentrations. Similarly, levels of antibodies against serogroup B test strains also waned over 4 years post-vaccination, but remained above pre-vaccination concentrations for some strains. MenABCWY+OMV booster induced a robust anamnestic anti-ACWY response in Group III and VI and a good response against serogroup B test strains (≥82%) in Group III. In serogroup B-naïve participants (Groups VI and VII), anti-B responses to 2 doses of MenABCWY+OMV were less homogenous and lower than in Group III. MenABCWY+OMV was reactogenic, but well-tolerated. No safety concerns were identified. These findings indicate that although antibodies against N. meningitidis serogroups ABCWY waned over 4 years post-vaccination, exposure to a MenABCWY+OMV booster dose elicits an anamnestic response in adolescents previously exposed to the same or another multivalent meningococcal vaccine.
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http://dx.doi.org/10.1080/21645515.2018.1457595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989907PMC
May 2018

Safety and immunogenicity of a meningococcal B recombinant vaccine when administered with routine vaccines to healthy infants in Taiwan: A phase 3, open-label, randomized study.

Hum Vaccin Immunother 2018 05 15;14(5):1075-1083. Epub 2018 Feb 15.

f Research and Development Center, GSK , Siena , Italy.

Neisseria meningitidis is associated with high mortality and morbidity in infants and children worldwide. This phase 3 study (NCT02173704) evaluated safety and immunogenicity of a 4-component serogroup B recombinant meningococcal vaccine (4CMenB) co-administered with routine vaccines in Taiwanese infants. In total, 225 healthy infants were randomized (2 : 1 ) to receive 4CMenB and routine vaccines (4CMenB+Routine) or routine vaccines only (Routine group) at 2, 4, 6 and 12 months of age. Routine vaccines were diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b, 13-valent pneumococcal, hepatitis B, measles-mumps-rubella and varicella vaccines. Immune responses to 4CMenB components (factor H binding protein [fHbp], Neisserial adhesin A [NadA], porin A [PorA] and Neisseria heparin-binding antigen [NHBA]) were evaluated at 1 month post-primary and post-booster vaccination, using human serum bactericidal assay (hSBA). Reactogenicity and safety were also assessed. A sufficient immune response was demonstrated for fHbp, NadA and PorA, at 1 month post-primary and booster vaccination. In the 4CMenB+Routine group, hSBA titers ≥5 were observed in all infants for fHbp and NadA, in 79% and 59% of infants for PorA and NHBA, respectively, at 1 month post-primary vaccination and in 92-99% of infants for all antigens, at 1 month post-booster vaccination. In the 4CMenB+Routine group, hSBA geometric mean titers for all antigens increased post-primary (8.41-963) and post-booster vaccination (17-2315) compared to baseline (1.01-1.36). Immunogenicity of 4CMenB was not impacted by co-administration with routine pediatric vaccines in infants. Reactogenicity was slightly higher in the 4CMenB+Routine group compared with Routine group, but no safety concerns were identified.
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http://dx.doi.org/10.1080/21645515.2018.1425659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989895PMC
May 2018

Immune Responses to Booster Vaccination With Meningococcal ABCWY Vaccine After Primary Vaccination With Either Investigational or Licensed Vaccines: A Phase 2 Randomized Study.

Pediatr Infect Dis J 2018 05;37(5):475-482

GSK Vaccine, Rockville, MD.

Background: Current meningococcal prime-boost vaccination schedules include separate vaccines for serogroups ACWY and B. An investigational combined serogroups ABCWY vaccine (MenABCWY) was developed to protect against clinically important Neisseria meningitidis serogroups.

Methods: In this phase 2, randomized, observer-blind, extension study (NCT01272180), participants 10-25 years of age received 1 booster dose of MenABCWY vaccine at 24 months (M) postprimary series of MenABCWY (2 doses), 4CMenB (2 doses) or MenACWY-CRM vaccine (1 dose). Immune responses to booster dose (1M postbooster) and antibody persistence (24M, 36M postprimary series) were assessed using bactericidal assay with human complement (hSBA). Reactogenicity and safety were evaluated.

Results: One hundred ninety participants were vaccinated. At 1M after the MenABCWY booster dose, seroresponse rates against serogroups ACWY ranged between 85% and 96%, 73% and 100% and 83% and 95% for participants previously receiving MenABCWY, 4CMenB and MenACWY-CRM, respectively. At 12M postbooster dose, ≥67% of participants across all groups had hSBA titers ≥8 for serogroups ACWY, except in 4CMenB-primed individuals for serogroup Y (45%). Across MenABCWY and 4CMenB-primed groups, hSBA titers ≥5 across serogroup B test strains were observed in 82%-100% and 29%-100% of participants at 1M and 12M postbooster, respectively. Geometric mean titers against serogroups ACWY increased from pre- to 1M postboosting with MenABCWY and persisted at 12M. The reactogenicity and safety profile of MenABCWY was similar to that of 4CMenB.

Conclusions: MenABCWY may be suitable for prime-boost schedules against meningococcal disease, including regimens involving a primary series of either 4CMenB or MenACWY-CRM licensed vaccines.
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http://dx.doi.org/10.1097/INF.0000000000001896DOI Listing
May 2018

Antibody persistence and booster responses 24-36 months after different 4CMenB vaccination schedules in infants and children: A randomised trial.

J Infect 2018 03 15;76(3):258-269. Epub 2017 Dec 15.

GSK, Siena, Italy.

Objectives: This phase IIIb, open-label, multicentre, extension study (NCT01894919) evaluated long-term antibody persistence and booster responses in participants who received a reduced 2 + 1 or licensed 3 + 1 meningococcal serogroup B vaccine (4CMenB)-schedule (infants), or 2-dose catch-up schedule (2-10-year-olds) in parent study NCT01339923.

Materials And Methods: Children aged 35 months to 12 years (N = 851) were enrolled. Follow-on participants (N = 646) were randomised 2:1 to vaccination and non-vaccination subsets; vaccination subsets received an additional 4CMenB dose. Newly enrolled vaccine-naïve participants (N = 205) received 2 catch-up doses, 1 month apart (accelerated schedule). Antibody levels were determined using human serum bactericidal assay (hSBA) against MenB indicator strains for fHbp, NadA, PorA and NHBA. Safety was also evaluated.

Results: Antibody levels declined across follow-on groups at 24-36 months versus 1 month post-vaccination. Antibody persistence and booster responses were similar between infants receiving the reduced or licensed 4CMenB-schedule. An additional dose in follow-on participants induced higher hSBA titres than a first dose in vaccine-naïve children. Two catch-up doses in vaccine-naïve participants induced robust antibody responses. No safety concerns were identified.

Conclusion: Antibody persistence, booster responses, and safety profiles were similar with either 2 + 1 or 3 + 1 vaccination schedules. The accelerated schedule in vaccine-naïve children induced robust antibody responses.
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http://dx.doi.org/10.1016/j.jinf.2017.12.005DOI Listing
March 2018

Persistence of immunity after vaccination with a capsular group B meningococcal vaccine in 3 different toddler schedules.

CMAJ 2017 Oct;189(41):E1276-E1285

Oxford Vaccine Group, Department of Paediatrics (Sadarangani, Sell, Iro, Snape, Voysey, Pollard), University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, UK; Vaccine Evaluation Center (Sadarangani), BC Children's Hospital Research Institute, The University of British Columbia, Vancouver, BC; Nuffield Department of Primary Care Health Sciences (Voysey), University of Oxford, Oxford, UK; Bristol Children's Vaccine Centre (Finn), School of Clinical Sciences, University of Bristol, Bristol, UK; St. George's Vaccine Institute (Heath), University of London, London, UK; Azienda Ospedaliero-Universitaria Maggiore della Carità (Bona), Clinica Pediatrica, Novara, Italy; Pediatric Highly Intensive Care Unit (Esposito), Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Vaccine Research Area (Diez-Domingo), Fundación para el Fomento de la Investigación Sanitaria y Biomédica (FISABIO), Valencia, Spain; Charles University Prague, School of Medicine, Department of Social Sciences (Prymula), Hradec Kralove, Czech Republic; Novartis Vaccines and Diagnostics Inc. (Odueyungbo), Cambridge, Mass.; Hoffmann-La Roche Limited (Odueyungbo), Mississauga, Ont.; GSK (Toneatto), Siena, Italy.

Background: One schedule for the capsular group B meningococcal vaccine 4CMenB is 2 doses that are administered 2 months apart for children aged 12-23 months, with a booster dose 12-24 months later. Our objective was to provide data on persistence of human serum bactericidal antibody (hSBA) titres in children up to 4 years of age after initial doses at 12-24 months, and immunogenicity of a booster dose at 48 months of age compared with vaccine-naive children.

Methods: Children previously immunized, as part of a randomized controlled trial, with 2 doses of 4CMenB vaccine at 12-24 months of age received a booster at 4 years of age. Vaccine-naive age-matched toddlers received 2 doses of 4CMenB. Human serum bactericidal antibody titres against reference strains H44/76, 5/99, NZ98/254 and M10713 were evaluated before and after innoculation with 4CMenB vaccine in 4-year-old children.

Results: Of 332 children in the study, 123 had previously received 4CMenB and 209 were vaccine-naive controls. Before the booster, the proportions of participants (previously vaccinated groups compared with controls) with hSBA titres of 1:5 or more were as follows: 9%-11% v. 1% (H44/76), 84%-100% v. 4% (5/99), 0%-18% v. 0% (NZ98/254) and 59%-60% v. 60% (M10713). After 1 dose of 4CMenB in previously immunized children, the proportions of participants achieving hSBA titres of 1:5 or more were 100% (H44/76 and 5/99), 70%-100% (NZ98/254) and 90%-100% (M10713).

Interpretation: We found that waning of hSBA titres by 4 years of age occurred after 2 doses of 4CMenB vaccine administered at 12-24 months, and doses at 12-24 months have a priming effect on the immune system. A booster may be necessary to maintain hSBA titres of 1:5 or more among those children with increased disease risk. : ClinicalTrials.gov, no. NCT01717638.
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http://dx.doi.org/10.1503/cmaj.161288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647166PMC
October 2017

Reduced schedules of 4CMenB vaccine in infants and catch-up series in children: Immunogenicity and safety results from a randomised open-label phase 3b trial.

Vaccine 2017 06 19;35(28):3548-3557. Epub 2017 May 19.

GSK, Via Fiorentina, 1, 53100 Siena, Italy. Electronic address:

Background: This study evaluated the immunogenicity and safety of a licensed meningococcal serogroup B vaccine (4CMenB) administered alone according to reduced schedules in infants or catch-up series in children.

Methods: In this open-label, multicentre, phase 3b study (NCT01339923), infants randomised 1:1:1 received 4CMenB: 2+1 doses at 3½-5-11months or 6-8-11months of age, 3+1 doses at ages 2½-3½-5-11months. Children aged 2-10years received 2 catch-up doses administered 2months apart. Immune responses were measured by hSBA assays against 4 strains specific for vaccine components fHbp, NadA, PorA and NHBA. Sufficiency of immune responses was defined in groups with 2+1 doses schedules as a lower limit ≥70% for the 97.5% confidence interval of the percentage of infants with hSBA titres ≥4, 1month post-dose 2 for fHbp, NadA, PorA. Adverse events were collected for 7days post-vaccination; serious adverse events (SAEs) throughout the study.

Results: 754 infants and 404 children were enrolled. Post-primary vaccination, 98-100% of infants across all groups developed hSBA titres ≥4 for fHbp, NadA, PorA, and 48-77% for NHBA. Sufficiency of immune responses in infants receiving 2+1 schedules was demonstrated for fHbp, NadA, PorA after 2 doses of 4CMenB, as pre-specified criteria were met. Following receipt of 2 catch-up doses, 95-99% of children developed hSBA titres ≥4 for 4CMenB components. Similar safety profiles were observed across groups. A total of 45 SAEs were reported, 3 of which were related to vaccination.

Conclusion: Reduced infant schedules and catch-up series in children were immunogenic and safe, having the potential to widen 4CMenB vaccine coverage.

Funding: GlaxoSmithKline Biologicals SA.
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http://dx.doi.org/10.1016/j.vaccine.2017.05.023DOI Listing
June 2017

Emerging experience with meningococcal serogroup B protein vaccines.

Expert Rev Vaccines 2017 May 10;16(5):433-451. Epub 2017 Apr 10.

d Research & Development, GSK , Siena , Italy.

Introduction: The successful development of two broadly protective vaccines targeting Neisseria meningitidis serogroup B (MenB); 4CMenB and rLP2086, is the most significant recent advance in meningococcal disease prevention. Areas covered: Here we review the principles underlying the development of each vaccine and the novel methods used to estimate vaccine coverage. We update clinical and post-licensure experience with 4CMenB and rLP2086. Expert commentary: The immunogenicity and acceptable safety profile of 4CMenB and rLP2086 has been demonstrated in clinical trials. Continuing uncertainties exist around the appropriate age groups to be immunized, the degree and duration of efficacy, and the impact on nasopharyngeal carriage which has implications for strategies to interrupt transmission and maximize herd protection effects. Universal vaccination programs such as those undertaken in Quebec and the United Kingdom are providing important information on these issues. The potential for MenB vaccines to prevent infection by other serogroups appears promising, and the impact of MenB vaccines on other pathogenic neisserial species with similar surface proteins warrants further investigation.
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http://dx.doi.org/10.1080/14760584.2017.1308828DOI Listing
May 2017

Immunogenicity and safety of concomitant administration of meningococcal serogroup B (4CMenB) and serogroup C (MenC-CRM) vaccines in infants: A phase 3b, randomized controlled trial.

Vaccine 2017 04 18;35(16):2052-2059. Epub 2017 Mar 18.

GSK, Siena, Italy.

Background: After implementation of routine infant MenC vaccination, MenB remains a serious cause of meningococcal disease, yet to be targeted by vaccination programs in several countries. This study (NCT01339923) investigated the immunogenicity and safety of MenC CRM-conjugated vaccine (MenC-CRM) concomitantly administered with MenB vaccine (4CMenB).

Methods: Infants (N=251) were randomised 1:1 to receive 4CMenB and MenC-CRM (Group 1) or MenC-CRM alone (Group 2) at 3 and 5months (M3, M5) and a booster at 12months of age (M12), and pneumococcal vaccine at M3, M5, M7, M12. Antibody responses to meningococcal vaccines were measured at M3, M6, M12, and M13. Non-inferiority of MenC-CRM response in Group 1 vs Group 2 was demonstrated at M6 and M13, if the lower limit of the 95% confidence interval (LL95%CI) of the difference in percentage of infants with hSBA titres ≥1:8 was >-10%. Sufficiency of MenB response was achieved if LL95%CI of the percentage of infants with hSBA titres ≥1:4 against fHbp, NadA and PorA strains was ≥70% at M6 or ≥75% at M13. Adverse events (AEs) were collected for 7days post-vaccination, and serious AEs (SAEs) and medically attended AEs throughout the study.

Results: Non-inferiority of MenC response in Group 1 vs Group 2 (LL95%CI -6.4% [M6]; -5.2% [M13]) and sufficiency of MenB response in Group 1 (LL95%CI 92%, 90%, 89% [M6]; 97%, 92%, 93% [M13] against fHbp, NadA, PorA, respectively) were demonstrated. Higher rates of mild to moderate solicited AEs were reported in Group 1. Unsolicited AEs and SAEs incidences were similar across groups.

Conclusions: Concomitant administration of MenC-CRM and 4CMenB in infants was immunogenic, resulting in non-inferior responses against MenC compared to MenC-CRM alone and demonstration of sufficient immune response to MenB, after primary and booster vaccination. Reactogenicity was higher for concomitant vaccines administration, but no safety concerns were identified.
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http://dx.doi.org/10.1016/j.vaccine.2017.03.002DOI Listing
April 2017

Persistence of bactericidal antibodies following booster vaccination with 4CMenB at 12, 18 or 24months and immunogenicity of a fifth dose administered at 4years of age-a phase 3 extension to a randomised controlled trial.

Vaccine 2017 01 30;35(2):395-402. Epub 2016 Nov 30.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK.

Background: 4CMenB is immunogenic in infants and toddlers. We assessed persistence of human complement serum bactericidal activity (hSBA) following a fourth dose administered at 12, 18 or 24months and characterised the antibody response to a fifth dose administered at 4years of age.

Methods: A phase 3, open label, multi-centre extension to a randomised controlled trial conducted in four countries (number of centres): Czech Republic (nineteen), Italy (four), Spain (four) and the United Kingdom (four). Four-year-old children who were either 4CMenB-naïve or had previously received a variety of 3-dose infant priming schedules and a booster vaccine as toddlers (follow-on group) were recruited. Venous blood samples were obtained to determine hSBA against four reference strains; acting as targets to assess immunity to each of the vaccine antigens, NadA (5/99), fHbp (H44/76), PorA (NZ98/254), and NHBA (M10713) at baseline (prior to vaccination, all participants) and one month following a dose of 4CMenB for all vaccine-naïve and follow-on participants primed with the 2, 3, 4 schedule, and a third of follow-on participants primed with a 2, 4, 6month schedule.

Results: At baseline (prior to vaccination), the proportion of participants (n=468) with hSBA titers⩾5 was similar across all followon groups: 89-100% against 5/99; 12-35% for H44/76; 8-12% for NZ98/254 and 53-80% for M10713 compared with 5%, 0%, 0%; and 60% respectively, for the vaccine-naïve controls (n=206). Following a dose of 4CMenB at 4years of age, this increased to 100% (5/99), 97-100% (H44/76), 80-95 % (NZ98/254) and 84-100% (M10713) (n=210), compared with 89%, 70%, 24%, and 76% respectively for vaccine-naïve controls (n=192).

Conclusion: Waning of protective antibodies occurred 24–36 months after toddler booster regardless of age at boost. This was least marked against target strains 5/99 and M10713. A robust memory response occurred after a booster dose given at 4 years of age.
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http://dx.doi.org/10.1016/j.vaccine.2016.11.009DOI Listing
January 2017

A phase III observer-blind randomized, controlled study to evaluate the immune response and the correlation with nasopharyngeal carriage after immunization of university students with a quadrivalent meningococcal ACWY glycoconjugate or serogroup B meningococcal vaccine.

Vaccine 2017 01 29;35(3):427-434. Epub 2016 Nov 29.

Vaccine Evaluation Unit, Public Health England, Manchester Royal Infirmary, Manchester, UK.

Background: University students have high rates of pharyngeal carriage of Neisseria meningitidis. Interruption of carriage acquisition is an important mechanism of vaccines for inducing herd protection. 4CMenB and MenACWY-CRM vaccines have been shown to be immunogenic against meningococcal serogroups B and ACWY respectively in younger age groups, and also to elicit a modest impact on meningococcal carriage in vaccinated students. However, vaccine responses in university students and the impact of serum bactericidal antibody (SBA) titers on meningococcal carriage are undetermined.

Methods: Immunogenicity of two 4CMenB doses or one MenACWY-CRM dose was measured in university students at Months 2, 4, 6 and 12 post-first vaccination. Immunogenicity of one MenACWY-CRM dose in students with previous meningococcal serogroup C conjugate vaccination was also assessed. Immune responses were measured with an SBA assay using human complement (hSBA) against three reference strains for serogroup B and against one strain for each for serogroups C and Y. Correlations between hSBA titers and meningococcal carriage were analyzed.

Results: All subjects demonstrated robust functional antibody responses to both vaccines at Month 2 and a high proportion maintained protective hSBA titers up to Month 12. At baseline, carriage of disease-associated serogroup B strains and serogroups C and Y were higher in subjects with already-protective hSBA titers. Post-vaccination, while both 4CMenB and MenACWY-CRM elicited robust immunogenicity in students, significant correlations between post-vaccination hSBA titers and carriage of disease-associated serogroups were not observed.

Conclusions: 4CMenB and MenACWY-CRM were both highly immunogenic. There was no correlation between carriage and post-vaccination hSBA titers.
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http://dx.doi.org/10.1016/j.vaccine.2016.11.071DOI Listing
January 2017

Persistence of Bactericidal Antibodies After Infant Serogroup B Meningococcal Immunization and Booster Dose Response at 12, 18 or 24 Months of Age.

Pediatr Infect Dis J 2016 04;35(4):e113-23

From the *Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom; †NIHR Oxford Biomedical Centre, Oxford University Hospital NHS Trust, Oxford, United Kingdom; ‡Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom; §Bristol Children's Vaccine Centre, University of Bristol and University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom; ¶Azienda Ospedaliero-Universitaria, Azienda Ospedaliero-Universitaria Maggiore della Carità-Clinica Pediatrica, Novara, Italy; ‖Pediatric Highly Intensive Care Unit, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; **Vaccine Research Department, FISABIO-Public Health, Valencia, Spain; ††Department of Pediatrics, Cliniques Saint Luc, Université Catholique de Louvain, Bruxelles, Belgium; ‡‡Clinical Trial Centre, Department of Pediatrics, Johannes Gutenberg University Medical School, Mainz, Germany; §§Department of Social Medicine, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic; ¶¶Novartis Vaccines and Diagnostics Inc., Cambridge, MA; ‖‖Novartis Vaccines and Diagnostics S.r.l., Siena, Italy; and ***Novartis Pharma BV, Amsterdam, The Netherlands.

Background: A serogroup B meningococcal vaccine (4CMenB) is licensed for infant use in countries including Canada, Australia and those of the European Union. Data on serum bactericidal antibody (hSBA) waning and the ideal timing of a "toddler" booster dose are essential to optimize vaccine utilization.

Methods: An open-labeled, multicenter phase-2b follow-on European study conducted from 2009 to 2012. Participants previously receiving 4CMenB with routine vaccines at 2, 4 and 6 or 2, 3 and 4 months (246Con and 234Con) or at 2, 4 and 6 months intercalated with routine vaccines (246Int) received a booster dose at 12, 18 or 24 months. 4CMenB-naïve "Control" participants aged 12, 18 or 24 months received 2 doses of 4CMenB 2 months apart.

Results: One thousand five hundred eighty-eight participants were recruited. At 12 months, before any booster doses, the proportions with hSBA titers ≥1:5 for strain 44/76-SL (testing vaccine component fHBP) were 73% (120/165) for the "246Con" group, 85% (125/147) for "246Int," 57% (51/90) for "234Con" and 13% (26/199) for Controls. For strain 5/99 (NadA) proportions were ≥96% (all 4CMenB-recipients) and 1% (Controls). For strain NZ98/254 (PorA), these were 18-35% (4CMenB-recipients) and 1% (Controls). By 24 months, 4CMenB-recipient proportions were 13-22% (44/76-SL), 82-94% (5/99) and 7-13% (NZ98/254) and in controls ≤4%. After a 12-month booster-dose, ≥95% of previously immunized participants had titers ≥1:5 (all strains).

Conclusions: A 4CMenB booster-dose can overcome waning hSBA titers after early-infant immunization. Administration at 12 months could help to maintain immunity during an age of high risk, and the persistence of this response requires further study.
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http://dx.doi.org/10.1097/INF.0000000000001056DOI Listing
April 2016

Immune responses to a recombinant, four-component, meningococcal serogroup B vaccine (4CMenB) in adolescents: a phase III, randomized, multicentre, lot-to-lot consistency study.

Vaccine 2015 Sep 29;33(39):5217-24. Epub 2015 Jul 29.

Vaccine and Immunisation Research Group (VIRGo), Murdoch Childrens Research Institute and Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. Electronic address:

Background: For decades, a broadly effective vaccine against serogroup B Neisseria meningitidis (MenB) has remained elusive. Recently, a four-component recombinant vaccine (4CMenB) has been developed and is now approved in Europe, Canada, Australia and some Latin American countries. This phase III, randomized study evaluated the lot consistency, early immune responses and the safety profile of 4CMenB in 11 to 17-year-old adolescents in Australia and Canada (NCT01423084).

Methods: In total, 344 adolescents received two doses of one of 2 lots of 4CMenB, 1-month apart. Immunogenicity was assessed before, 2-weeks and 1-month following the second vaccination. Serum bactericidal activity using human complement (hSBA) was measured against three reference strains 44/76-SL, 5/99 and NZ98/254, selected to express one of the vaccine antigens; Neisseria adhesin A (NadA), factor H binding protein (fHbp) and porin A (PorA) containing outer membrane vesicle (OMV), respectively. Responses to the Neisseria heparin binding antigen (NHBA) were assessed with enzyme linked immunosorbent assay (ELISA). Local and systemic reactions were recorded for 7 days following each vaccination; unsolicited adverse events were monitored throughout the study.

Results: Immunological equivalence of the two lots of 4CMenB was established at 1-month. At baseline, ≤7% of participants had hSBA titers ≥5 to all three reference strains. Two weeks following the second dose of 4CMenB, all participants had hSBA titers ≥5 against fHbp and NadA compared with 84-96% against the PorA reference strains. At 1-month, corresponding proportions were 99%, 100% and 70-79%, respectively. Both lots were generally well tolerated and had similar adverse event profiles.

Conclusions: Two doses of 4CMenB had an acceptable safety profile and induced a robust immune response in adolescents. Peak antibody responses were observed at 14 days following vaccination. While a substantial non-uniform antigen-dependent early decline in antibody titers was seen thereafter, a significant percentage of participants continued to maintain protective hSBA titers at 1-month.
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http://dx.doi.org/10.1016/j.vaccine.2015.06.103DOI Listing
September 2015

Meningococcal serogroup B vaccine (4CMenB): Booster dose in previously vaccinated infants and primary vaccination in toddlers and two-year-old children.

Vaccine 2015 Jul 30;33(32):3850-8. Epub 2015 Jun 30.

Novartis Vaccines and Diagnostics, Cambridge, MA, United States.

Objective: The multicomponent, recombinant serogroup B vaccine, 4CMenB, is approved in Europe, Canada and Australia from two months of age. We investigated persistence to booster doses at 12 months of age following infant vaccination, and immune response to catch-up vaccination of toddlers and children up to two years of age.

Methods: We assessed persistence of immune responses after one year in participants vaccinated as infants, and responses to two doses at 12-15 or 24-26 months of age in vaccine-naïve children, as serum bactericidal activity with human complement (hSBA) against indicator strains for four vaccine antigens. Adverse events were recorded after each vaccination.

Results: High antibody titers were induced against all four 4CMenB components following booster vaccination in infant-primed toddlers and after two doses in previously unvaccinated toddlers or two-year-olds. Antibodies waned over 12 months, particularly those against NZ OMV. Systemic reactogenicity in toddlers was lower than in infants, and lower again in vaccine-naïve two-year-olds. Local reactogenicity was common in all groups.

Conclusions: Four infant or two toddler 4CMenB vaccinations elicit immune responses believed to be protective for the first two years of life, which can be boosted. Reactogenicity is lower in toddlers than in infants.
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http://dx.doi.org/10.1016/j.vaccine.2015.06.079DOI Listing
July 2015

Persistence of specific bactericidal antibodies at 5 years of age after vaccination against serogroup B meningococcus in infancy and at 40 months.

CMAJ 2015 Apr 23;187(7):E215-E223. Epub 2015 Mar 23.

Oxford Vaccine Group, Department of Paediatrics (McQuaid, Snape, John, Kelly, Robinson, Pollard), and Nuffield Department of Primary Care Health Sciences (Yu), University of Oxford, Oxford, UK; Oxford Biomedical Research Centre (McQuaid, Snape, John, Kelly, Robinson, Pollard), National Institute for Health Research, Oxford, UK; Novartis Vaccines and Diagnostics S.r.l. (Toneatto), Siena, Italy; Novartis Pharma BV (D'Agostino), Amsterdam, Netherlands; Novartis Vaccines and Diagnostics Inc. (Dull), Cambridge, Mass.

Background: The multicomponent serogroup B meningococcal (4CMenB) vaccine induces antibodies against indicator strains of serogroup B meningococcus under various schedules. We investigated the persistence of antibodies in 5-year-old children 18-20 months after their last dose (at about 3.5 years of age).

Methods: We assessed 5-year-old children who received the 4CMenB vaccine or a recombinant protein vaccine in a previous randomized trial. We also recruited 50 vaccine-naive 5-year-olds and administered 2 doses of 4CMenB to each child. We measured serum bactericidal antibody titres against 4 indicator strains of serogroup B meningococcus matched to each individual vaccine component and against 4 mismatched strains.

Results: Of those who received the 4CMenB vaccine at 2, 4, 6, 12 and 40 months (n = 16), the percentage with protective antibody titres (≥ 1:4) at 60 months ranged from 44% to 88% against matched strains and from 13% to 81% against mismatched strains. Loss of protective titres was also observed for those who received the 4CMenB vaccine at 12, 40 and 42 months (n = 5) (80%-100% against matched strains, 60%-100% against mismatched strains) or at 40 and 42 months (n = 29) (31%-100% against matched strains, 41%-81% against mismatched strains). Administering the 4CMenB vaccine to 5-year-old children yielded protective titres against matched strains in 92%-100% and against mismatched strains in 59%-100%. The majority of these children reported injection-site pain (40/50 [80%] after dose 1, 39/46 [85%] after dose 2) and erythema (47/50 [94%] and 40/46 [87%], respectively); rates of fever were low (5/50 [10%] and 2/46 [4%], respectively).

Interpretation: Waning of immunity by 5 years of age occurred after receipt of the 4CMenB vaccine in infancy, even with an additional booster at 40 months. The 4CMenB vaccine is immunogenic and was fairly well tolerated by 5-year-old children, although injection-site pain was noteworthy.

Trial Registration: ClinicalTrials.gov, no. NCT01027351.
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http://dx.doi.org/10.1503/cmaj.141200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401613PMC
April 2015

Neisseria meningitidis factor H-binding protein fHbp: a key virulence factor and vaccine antigen.

Expert Rev Vaccines 2015 Jun 23;14(6):841-59. Epub 2015 Feb 23.

Institute for Glycomics, Griffith University, Southport, Queensland, 4215, Australia.

Neisseria meningitidis is a leading cause of meningitis and sepsis worldwide. The first broad-spectrum multicomponent vaccine against serogroup B meningococcus (MenB), 4CMenB (Bexsero(®)), was approved by the EMA in 2013, for prevention of MenB disease in all age groups, and by the US FDA in January 2015 for use in adolescents. A second protein-based MenB vaccine has also been approved in the USA for adolescents (rLP2086, Trumenba(®)). Both vaccines contain the lipoprotein factor H-binding protein (fHbp). Preclinical studies demonstrated that fHbp elicits a robust bactericidal antibody response that correlates with the amount of fHbp expressed on the bacterial surface. fHbp is able to selectively bind human factor H, the key regulator of the alternative complement pathway, and this has important implications both for meningococcal pathogenesis and for vaccine design. Here, we review the functional and structural properties of fHbp, the strategies that led to the design of the two fHbp-based vaccines and the data generated during clinical studies.
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http://dx.doi.org/10.1586/14760584.2015.1016915DOI Listing
June 2015

Prevention of rare diseases: how revolutionary techniques can help vulnerable individuals-the example of serogroup B meningococcal infection.

Ther Adv Vaccines 2015 Jan;3(1):13-23

Novartis Vaccines, Amsterdam, The Netherlands.

In countries with established programmes for vaccination of infants, toddlers and adolescents with meningococcal conjugate vaccines, serogroup B invasive meningococcal disease remains the major cause of septicaemia and meningitis in the paediatric and adolescent age groups. Novartis has developed a serogroup B meningococcal vaccine, 4CMenB, to meet this need. We reviewed all 4CMenB studies. The studies found 4CMenB to be highly immunogenic when administered in all schedules, with protective antibody levels (serum bactericidal antibody titres ≥4 or ≥5 with human complement, hSBA) against serogroup B strains expressing vaccine antigens in >95% of vaccinated cohorts. When antibody levels waned, all tested groups demonstrated booster responses. Although possibly an underestimation, the Meningococcal Antigen Typing System (MATS) technique predicts that global coverage of 4CMenB against all serogroup B strains is in the range 66% (Canada) to 91% (USA). The vaccine was found to be generally well tolerated, although local and systemic reactions, notably fever in infants, typical of many vaccines, were increased following concomitant administration of 4CMenB with routine vaccines. When tested, prophylactic paracetamol significantly decreased the frequency and severity of reactions in infants, with no clinically significant impact on immunogenicity of 4CMenB or concomitant routine vaccines. The vaccine is approved for use in the following age groups in the European Union (2 months+), Canada (2 months through 17 years), Australia (2 months+) and Chile (2 months+), following clinical evaluation in 4843 infants and toddlers, and 1712 adolescents and adults, in schedules including a three-dose (2, 3, 4 or 2, 4, 6 months) and a two-dose (6-11 months) infant series with a booster in the second year of life, a two-dose series in toddlers (12-23 months) and children (2-10 years) given 2 months apart (with a booster at least in the EU), and a two-dose series in adolescents (11-17 years) given 1-6 months apart. 4CMenB presents a solution to the unmet medical need of offering protection against serogroup B invasive meningococcal disease in all age groups above 2 months.
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http://dx.doi.org/10.1177/2051013614557477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266687PMC
January 2015

A phase 2 randomized controlled trial of a multicomponent meningococcal serogroup B vaccine, 4CMenB, in infants (II).

Hum Vaccin Immunother 2014 ;10(7):2005-14

a Pediatric Highly Intensive Care Unit; Department of Pathophysiology and Transplantation; University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Milan, Italy.

The licensed meningococcal serogroup B vaccine, 4CMenB (Bexsero(®)), contains recombinant membrane proteins (rMenB) and outer membrane vesicles (OMV) of the New Zealand serogroup B strain. We investigated whether reducing the OMV and/or protein content influences 4CMenB immunogenicity and reactogenicity in healthy two month-old infants. Six formulations were studied: 4CMenB, rMenB with 0, ¼ or ½ the OMV dose in 4CMenB, a half-dose of 4CMenB or a prelicensure formulation of 4CMenB, as a 4-dose primary/booster series, concomitantly with routine vaccines (DTaP-HBV-IPV/Hib and 7-valent pneumococcal conjugate) at 2, 3, 4 and 12 months of age. Immunogenicity was assessed as serum bactericidal activity measured with human complement (hSBA) against indicator strains for Men B vaccine antigens before and after the 2,3,4-month series and 12-month dose. Parents recorded solicited reactions for 7 days after each vaccination, and any adverse events throughout the study period. All formulations elicited robust immune response against rMenB components at 5 months, there was some evidence of OMV and protein dose-dependence for Men B indicator strains tested. Titers waned up to the 12-month dose, which elicited further strong responses, which were still OMV and protein dose-dependent. Groups with no, or low-dose OMV displayed slightly lower reactogenicity profiles, but all formulations were generally well-tolerated, high fever was rare and transient, and only three transient SAEs were considered possibly vaccine-related. Decreasing or removing the OMV content reduced reactogenicity of 4CMenB to a certain extent, but had an unacceptable negative impact on the immunogenicity profile. Trial: Clinicaltrials.gov NCT00937521.
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http://dx.doi.org/10.4161/hv.29218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186018PMC
February 2016

A phase 2 randomized controlled trial of a multicomponent meningococcal serogroup B vaccine (I).

Hum Vaccin Immunother 2014 ;10(7):1993-2004

a University Hospital Hradec Kralove; Hradec Kralove, Czech Republic.

The novel meningococcal serogroup B vaccine (4CMenB, Bexsero(®)), recently approved in Europe and Australia, may soon be included in routine infant immunization schedules, subject to guidance from national or regional recommending bodies. In the development of 4CMenB and consistent with other newly introduced vaccines, clinical studies have shown concomitant administration with routine infant vaccines induces an incremental increase in some reactions, including fever. As this may hinder acceptability, we examined the impact of prophylactic paracetamol on the occurrence of fever and other solicited reactions, as well as the immune responses to study vaccines, in a prospectively designed study. 4CMenB was administered as a 4-dose series at 2, 3, 4, and 12 months of age concomitantly with routine infant vaccines: DTaP-HBV-IPV/Hib and PCV7, with or without prophylactic paracetamol; a third group received MenC vaccine. Immune responses to 4CMenB were not decreased by the use of paracetamol prophylaxis and there were no clinically relevant effects on immune responses to routine vaccines. Occurrence of fever was higher in infants co-administered with 4CMenB compared with those given MenC vaccine, but was significantly decreased by prophylactic paracetamol, as were other solicited reactions to vaccination, both local and systemic. Co-administration of 4CMenB had an acceptable tolerability profile, with no withdrawals due to vaccination-related adverse events. Inclusion of 4CMenB in routine infant immunization schedules will be a major advance in the control of meningococcal disease, and our study indicates that by using paracetamol prophylaxis, post-vaccination reactions are reduced without clinically relevant negative consequences on vaccine immunogenicity.
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http://dx.doi.org/10.4161/hv.28666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186040PMC
February 2016

Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial.

Lancet 2014 Dec 18;384(9960):2123-31. Epub 2014 Aug 18.

Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Public Health England, Manchester Royal Infirmary, Manchester, UK.

Background: Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds.

Methods: In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850.

Findings: Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified.

Interpretation: Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented.

Funding: Novartis Vaccines.
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http://dx.doi.org/10.1016/S0140-6736(14)60842-4DOI Listing
December 2014

Persistence of bactericidal antibodies to 5 years of age after immunization with serogroup B meningococcal vaccines at 6, 8, 12 and 40 months of age.

Pediatr Infect Dis J 2014 Jul;33(7):760-6

From the *Oxford Vaccine Group Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre; †Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom; ‡Novartis Vaccines and Diagnostics S.r.l. Siena, Italy; and §Novartis Vaccines and Diagnostics, Inc. Cambridge, MA.

Background: A serogroup B meningococcal vaccine (4CMenB) has been licensed by the European commission for use in various infant schedules. However, data are limited on persistence of serum bactericidal antibodies (SBA), which is necessary to inform cost-effectiveness analysis.

Methods: Sera were obtained from 3 groups of 5-year-old children previously immunized at 6, 8, 12 and 40 months with either 4CMenB or rMenB (which lacks the outer membrane vesicle of 4CMenB) or at 40 and 42 months with 4CMenB only. Forty-nine control children were also recruited and blood obtained before and after 2 doses of 4CMenB at 60 and 62 months of age. Sera were tested for SBA to meningococcal B reference strains.

Results: At 5 years of age, 67% of those receiving 4CMenB in infancy had SBA titers ≥1:4 for strain 44/76, 100% for 5/99, 17% for NZ98/254 and 45% for M10713. Results for rMenB recipients varied from 0 (NZ98/254) to 100% (5/99). Of those immunized with 4CMenB at 40 and 42 months, 38% had SBA titers ≥1:4 at age 5 for 44/76, 100% for 5/99, 0% (NZ98/254) and 83% (M10713). Among controls, SBA titers were ≥1:4 in 4% (H44/76, 5/99), 0% (NZ98/254) and 67% (M10713) at baseline, increasing to 100% (H44/76 and 5/99), 89% (NZ98/254) and 97% (M10713) postimmunization.

Conclusion: The variable rates of waning of antibody to the 4 components of 4CMenB complicates estimates of duration of protection and should be taken into account in cost-effectiveness analyses. A 2-dose schedule of 4CMenB in 5-year-old children was immunogenic.
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http://dx.doi.org/10.1097/INF.0000000000000327DOI Listing
July 2014

A multi-component meningococcal serogroup B vaccine (4CMenB): the clinical development program.

Drugs 2014 Jan;74(1):15-30

Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Avda Independencia 1027, Santiago, Chile,

Recently approved in Europe and Australia, the multi-component meningococcal B vaccine, 4CMenB (Bexsero®, Novartis Vaccines and Diagnostics), contains three surface-exposed recombinant proteins (fHbp, NadA, and NHBA) and New Zealand strain outer membrane vesicles (NZ OMV) with PorA 1.4 antigenicity. This comprehensive review of the 4CMenB clinical development program covers pivotal phase I/IIb/III studies in over 7,000 adults, adolescents, and infants. The immunological correlate for clinical protection used was human complement-mediated serum bactericidal activity titers ≥4 or 5 against indicator strains for individual antigens. Based on achievement of protective titers, a four-dose schedule (three primary doses and one booster dose) for infants and a two-dose schedule for adolescents provided the best results. Observed increases in injection site pain/tenderness and fever in infants, and injection site pain, malaise, and headache in adolescents compared with routine vaccines, were mostly mild to moderate; frequencies of rare events (Kawasaki disease, juvenile arthritis) were not significantly different from non-vaccinated individuals. 4CMenB is conservatively estimated to provide 66-91 % coverage against meningococcal serogroup B strains worldwide.
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http://dx.doi.org/10.1007/s40265-013-0155-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890039PMC
January 2014