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1.  A phase II randomized controlled trial of a multicomponent meningococcal serogroup B vaccine, 4CMenB, in infants (II) 
Human Vaccines & Immunotherapeutics  2014;10(7):2005-2014.
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
doi:10.4161/hv.29218
PMCID: PMC4186018  PMID: 25424810
infants; meningococcal; serogroup B; vaccination; outer membrane vesicles
2.  A phase 2 randomized controlled trial of a multicomponent meningococcal serogroup B vaccine (I) 
Human Vaccines & Immunotherapeutics  2014;10(7):1993-2004.
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.
doi:10.4161/hv.28666
PMCID: PMC4186040  PMID: 25424809
infants; meningococcal; serogroup B; vaccination; antipyretics
3.  Persistence of specific bactericidal antibodies at 5 years of age after vaccination against serogroup B meningococcus in infancy and at 40 months 
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
doi:10.1503/cmaj.141200
PMCID: PMC4401613  PMID: 25802309
4.  Immunogenicity and safety of a CRM-conjugated meningococcal ACWY vaccine administered concomitantly with routine vaccines starting at 2 months of age 
Background: Infants are at the highest risk for meningococcal disease and a broadly protective and safe vaccine is an unmet need in this youngest population. We evaluated the immunogenicity and safety of a 4-dose infant/toddler regimen of MenACWY-CRM given at 2, 4, 6, and 12 months of age concomitantly with pentavalent diphtheria-tetanus-acellular pertussis-Hemophilus influenzae type b-inactivated poliovirus-combination vaccine (DTaP-IPV/Hib), hepatitis B vaccine (HBV), 7- or 13-valent conjugate pneumococcal vaccine (PCV), and measles, mumps, and rubella vaccine (MMR).
Results: Four doses of MenACWY-CRM induced hSBA titers ≥8 in 89%, 95%, 97%, and 96% of participants against serogroups A, C, W-135, and Y, respectively. hSBA titers ≥8 were present in 76–98% of participants after the first 3 doses. A categorical linear analysis incorporating vaccine group and study center showed responses to routine vaccines administered with MenACWY-CRM were non-inferior to routine vaccines alone, except for seroresponse to the pertussis antigen fimbriae. The reactogenicity profile was not affected when MenACWY-CRM was administered concomitantly with routine vaccines.
Conclusion: MenACWY-CRM administered with routine concomitant vaccinations in young infants was well tolerated and induced highly immunogenic responses against each of the serogroups without significant interference with the immune responses to routine infant vaccinations.
Methods: Healthy 2 month old infants were randomized to receive MenACWY-CRM with routine vaccines (n = 258) or routine vaccines alone (n = 271). Immunogenicity was assessed by serum bactericidal assay using human complement (hSBA). Medically attended adverse events (AEs), serious AEs (SAEs) and AEs leading to study withdrawal were collected throughout the study period.
doi:10.4161/hv.27051
PMCID: PMC4185919  PMID: 24220326
meningococcal disease; conjugate vaccine; immunogenicity; safety; infants
5.  Persistence of bactericidal antibodies following early infant vaccination with a serogroup B meningococcal vaccine and immunogenicity of a preschool booster dose 
Background:
The multicomponent serogroup B meningococcal (4CMenB) vaccine was recently licensed for use in Europe. There are currently no data on the persistence of bactericidal antibodies induced by use of this vaccine in infants. Our objective was to evaluate serogroup B–specific bactericidal antibodies in children aged 40–44 months previously vaccinated at 2, 4, 6 and 12 months of age.
Methods:
Participants given 4 doses of 4CMenB as infants received a fifth dose of the vaccine at 40–44 months of age. Age-matched participants who were MenB vaccine–naive received 4CMenB and formed the control group. We evaluated human complement serum bactericidal activity (hSBA) titres at baseline and 1 month after each dose of 4CMenB.
Results:
Before a booster dose at enrolment, 41%–76% of 17 participants previously vaccinated with 4CMenB in infancy had hSBA titres of 4 or greater against 4 reference strains. Before vaccination in the control group (n = 40) these proportions were similar for strains 44/76-SL (63%) and M10713 (68%) but low for strains NZ98/254 (0%) and 5/99 (3%). A booster dose in the 4CMenB-primed participants generated greater increases in hSBA titres than in controls.
Interpretation:
As has been observed with other meningococcal vaccines, bactericidal antibodies waned after vaccination with 4CMenB administered according to an approved infant vaccination schedule of 2, 4, 6 and 12 months of age, but there was an anamnestic response to a booster dose at 40–44 months of age. If 4CMenB were introduced into routine vaccination schedules, assessment of the need for a booster dose would require data on the impact of these declining titres on vaccine effectiveness. ClinicalTrials.gov, no. NCT01027351
doi:10.1503/cmaj.130257
PMCID: PMC3796620  PMID: 24062178
6.  Randomized Trial on the Safety, Tolerability, and Immunogenicity of MenACWY-CRM, an Investigational Quadrivalent Meningococcal Glycoconjugate Vaccine, Administered Concomitantly with a Combined Tetanus, Reduced Diphtheria, and Acellular Pertussis Vaccine in Adolescents and Young Adults▿ †  
This study evaluated the safety, tolerability, and immunogenicity of an investigational quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, when administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis (Tdap) vaccine, in subjects aged 11 to 25 years. Subjects received either MenACWY-CRM and Tdap, MenACWY-CRM and saline placebo, or Tdap and saline placebo. No significant increase in reactogenicity and no clinically significant vaccine-related adverse events (AEs) occurred when MenACWY-CRM and Tdap were administered concomitantly. Similar immunogenic responses to diphtheria, tetanus, and meningococcal (serogroups A, C, W-135, and Y) antigens were observed, regardless of concomitant vaccine administration. Antipertussis antibody responses were comparable between vaccine groups for filamentous hemagglutinin and were slightly lower, although not clinically significantly, for pertussis toxoid and pertactin when the two vaccines were administered concomitantly. These results indicate that the investigational MenACWY-CRM vaccine is well tolerated and immunogenic and that it can be coadministered with Tdap to adolescents and young adults.
doi:10.1128/CVI.00436-09
PMCID: PMC2849330  PMID: 20164251
7.  Quadrivalent Meningococcal Vaccination of Adults: Phase III Comparison of an Investigational Conjugate Vaccine, MenACWY-CRM, with the Licensed Vaccine, Menactra▿  
Clinical and Vaccine Immunology : CVI  2009;16(12):1810-1815.
Neisseria meningitidis is a leading cause of bacterial meningitis in the United States, with the highest case fatality rates reported for individuals ≥15 years of age. This study compares the safety and immunogenicity of the Novartis Vaccines investigational quadrivalent meningococcal CRM197 conjugate vaccine, MenACWY-CRM, to those of the licensed meningococcal conjugate vaccine, Menactra, when administered to healthy adults. In this phase III multicenter study, 1,359 adults 19 to 55 years of age were randomly assigned to one of four groups (1:1:1:1 ratio) to receive a single dose of one of three lots of MenACWY-CRM or a single dose of Menactra. Serum samples obtained at baseline and 1 month postvaccination were tested for serogroup-specific serum bactericidal activity using human complement (hSBA). The hSBA titers following vaccination with MenACWY-CRM and Menactra were compared in noninferiority and prespecified superiority analyses. Reactogenicity was similar in the MenACWY-CRM and Menactra groups, and neither vaccine was associated with a serious adverse event. When compared with Menactra, MenACWY-CRM met the superiority criteria for the proportions of recipients achieving a seroresponse against serogroups C, W-135, and Y and the proportion of subjects achieving postvaccination titers of ≥1:8 for serogroups C and Y. MenACWY-CRM's immunogenicity was statistically noninferior (the lower limit of the two-sided 95% confidence interval was more than −10%) to that of Menactra for all four serogroups, with the postvaccination hSBA geometric mean titers being consistently higher for MenACWY-CRM than for Menactra. MenACWY-CRM is well tolerated in adults 19 to 55 years of age, with immune responses to each of the serogroups noninferior and, in some cases, statistically superior to those to Menactra.
doi:10.1128/CVI.00207-09
PMCID: PMC2786376  PMID: 19812260

Results 1-7 (7)