rSBA Geometric Mean Titers Research Articles

A phase 2b/3b MenACWY-TT study of long-term antibody persistence after primary vaccination and immunogenicity and safety of a booster dose in individuals aged 11 through 55\u2009years

BackgroundA previous phase 2 study demonstrated the immunogenicity of a single dose of meningococcal A, C, W, Y-tetanus toxoid conjugate (MenACWY-TT) or polysaccharide (MenACWY-PS) vaccine for up to 5 years in individuals aged 11–55 years. This follow-up study evaluated long-term antibody persistence up to 10 years and the immunogenicity and safety of a single MenACWY-TT booster dose given 10 years after primary vaccination.MethodsBlood draws were conducted annually in Years 7–10. At Year 10, all subjects received a MenACWY-TT booster dose. Blood was drawn at 1 month and safety data were collected ≤6 months postbooster. Study endpoints included immunogenicity during the persistence phase (primary), and immunogenicity and safety during the booster phase (secondary). Statistical analyses were descriptive.ResultsA total of 311 subjects were enrolled in the persistence phase (MenACWY-TT, 235; MenACWY-PS, 76); 220 were enrolled in the booster phase (MenACWY-TT, 164; MenACWY-PS, 56). Descriptive analyses indicated that at Years 7–10, the percentages of subjects achieving serum bactericidal antibody assay using baby rabbit complement (rSBA) titers ≥1:8 and ≥1:128 were higher for serogroups A, W, and Y in the MenACWY-TT versus MenACWY-PS group; percentages were similar across groups for serogroup C. rSBA geometric mean titers (GMTs) for serogroups A, W, and Y were higher in the MenACWY-TT group and slightly higher in the MenACWY-PS group for serogroup C. One month postbooster, all primary MenACWY-TT and ≥98.1% of primary MenACWY-PS recipients had rSBA titers ≥1:8. For all serogroups, rSBA GMTs postbooster were higher in the MenACWY-TT versus MenACWY-PS group. Most local and general reactogenicity events were similar between groups and mild to moderate in severity. Adverse events at 1 month postbooster were 9.1% for the MenACWY-TT and 3.6% for the MenACWY-PS groups; all were nonserious.ConclusionsImmune responses to a single MenACWY-TT primary dose administered at age 11–55 years persisted in >70% of individuals evaluated at Years 7–10. A MenACWY-TT booster dose administered at Year 10 was safe and immunogenic with no new safety signals observed. These results provide important insights regarding long-term protection from primary vaccination and the benefits of booster dosing.Trial registrationClinicaltrials.gov, NCT01934140. Registered September 2013.

Long-term antibody persistence after a booster dose of quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in healthy 5-year-old children

BackgroundTo provide continuing protection, available meningococcal vaccines must provide long-term persistence of circulating functional antibodies against prevalent serogroups causing invasive meningococcal disease (IMD). This study assessed antibody persistence and safety of the quadrivalent meningococcal vaccine conjugated to tetanus toxoid (MenACWY-TT) and the meningococcal serogroup C vaccine conjugated to Corynebacterium diphtheriae CRM197 protein (MenC-CRM) for up to 6 years after booster dosing in children. MethodsIn the primary vaccination study, children were vaccinated at age 12 to 23 months. In the first extension study, children who completed the primary study received a booster dose 4 years later with the same primary vaccine. The current study assessed antibody persistence at 2 to 6 years postbooster against each of the 4 meningococcal serogroups using serum bactericidal assays using rabbit (rSBA) or human (hSBA) complement with antibody titer thresholds of ≥1:8 or ≥1:4, respectively, and geometric mean titers (GMTs). Safety evaluations during this period included serious adverse events (SAEs) related to vaccination and any event related to lack of vaccine efficacy. ResultsA total of 184 subjects were enrolled (MenACWY-TT = 159; MenC-CRM = 25). For MenACWY-TT, the percentages of subjects with rSBA titers ≥1:8 ranged from 96.7% to 100% across serogroups at 2 years postbooster and 71.6% to 94.0% at 6 years postbooster; rSBA GMTs decreased from Year 2 to 4 and generally remained stable thereafter. The percentages of subjects in the MenACWY-TT group with hSBA titers ≥1:4 were 70.0% to 100% across serogroups at 2 years postbooster and 58.5% to 98.5% at 6 years postbooster. No lack of efficacy, SAEs, or vaccine-related adverse events were reported. ConclusionsThe persistence of rSBA and hSBA antibodies was shown up to 6 years postbooster (10 years postprimary vaccination) with either MenACWY-TT or MenC-CRM, suggesting that this schedule may provide long-term protection against IMD. Clinicaltrials.gov: NCT01900899.

2722 B. Efficacy and Safety of a Booster Dose of the MenACWY-TT Vaccine Administered 10 Years After Primary Vaccination with MenACWY-TT or MenACWY-PS

BackgroundThe quadrivalent meningococcal ACWY polysaccharide tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix) is licensed in various countries to prevent disease caused by meningococcal serogroups A, C, W, and Y. In a previous study (NCT00464815), subjects aged 11‒17 years received a primary dose of MenACWY-TT or a quadrivalent polysaccharide vaccine (MenACWY-PS). Here, we report the long-term antibody persistence of the primary dose and the immunogenicity and safety of a booster dose given 10 years after primary vaccination of subjects.MethodsParticipants were enrolled from the Philippines and received a booster dose of MenACWY-TT at 10 years postvaccination. Antibody persistence 10 years postprimary vaccination and immunogenicity 1 month after the booster dose were evaluated by serum bactericidal activity assays using rabbit complement (rSBA) to assess the percentages of subjects with titers ≥ 1:8 and ≥ 1:128 and geometric mean titers (GMTs) for each serogroup. Safety was assessed for the booster dose.ResultsOf 229 subjects enrolled in this extension study, 169 and 58 subjects in the MenACWY-TT and MenACWY-PS groups, respectively, completed the booster phase. The percentages of primary MenACWY-TT recipients with prebooster rSBA titers ≥ 1:8 and ≥ 1:128 at year 10 ranged from 71.6%‒90.7% and 64.8%‒85.2% for all serogroups, respectively, compared with 43.1%‒82.4% and 25.5%‒76.5% of primary MenACWY-PS recipients; rSBA GMTs for all serogroups were higher in the MenACWY-TT group than in the MenACWY-PS group at year 10. For the MenACWY-TT and MenACWY-PS groups, respectively, the MenACWY-TT booster dose elicited rSBA titers ≥ 1:8 in 100% and ≥ 98.0% of subjects (figure); 100% and ≥ 96.1% of all subjects had titers ≥ 1:128. For all serogroups, rSBA GMTs at 1 month after the booster dose were higher than before the booster dose. No new safety signals were observed during the booster phase.ConclusionFunctional antibody responses elicited by MenACWY-TT persisted 10 years after primary vaccination; the booster dose was well tolerated and elicited robust immune responses.ClinicalTrials.govNCT03189745, EudraCT # 2013-001512-29. Funded by Pfizer. Disclosures All authors: No reported disclosures.

1478. Efficacy and Safety of a Booster Dose of the MenACWY-TT Vaccine Administered 10 Years After Primary Vaccination with MenACWY-TT or MenACWY-PS

BackgroundThe quadrivalent meningococcal ACWY polysaccharide tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix) is licensed in various countries to prevent disease caused by meningococcal serogroups A, C, W, and Y. In a previous study (NCT00464815), subjects aged 11‒17 years received a primary dose of MenACWY-TT or a quadrivalent polysaccharide vaccine (MenACWY-PS). Here, we report the long-term antibody persistence of the primary dose and the immunogenicity and safety of a booster dose given 10 years after primary vaccination of subjects.MethodsParticipants were enrolled from the Philippines and received a booster dose of MenACWY-TT at 10 years postvaccination. Antibody persistence 10 years postprimary vaccination and immunogenicity 1 month after the booster dose were evaluated by serum bactericidal activity assays using rabbit complement (rSBA) to assess the percentages of subjects with titers ≥1:8 and ≥1:128 and geometric mean titers (GMTs) for each serogroup. Safety was assessed for the booster dose.ResultsOf 229 subjects enrolled in this extension study, 169 and 58 subjects in the MenACWY-TT and MenACWY-PS groups, respectively, completed the booster phase. The percentages of primary MenACWY-TT recipients with prebooster rSBA titers ≥ 1:8 and ≥ 1:128 at year 10 ranged from 71.6%‒90.7% and 64.8%‒85.2% for all serogroups, respectively, compared with 43.1%‒82.4% and 25.5%‒76.5% of primary MenACWY-PS recipients; rSBA GMTs for all serogroups were higher in the MenACWY-TT group than in the MenACWY-PS group at year 10. For the MenACWY-TT and MenACWY-PS groups, respectively, the MenACWY-TT booster dose elicited rSBA titers ≥1:8 in 100% and ≥98.0% of subjects (figure); 100% and ≥96.1% of all subjects had titers ≥1:128. For all serogroups, rSBA GMTs at 1 month after the booster dose were higher than before the booster dose. No new safety signals were observed during the booster phase.ConclusionFunctional antibody responses elicited by MenACWY-TT persisted 10 years after primary vaccination; the booster dose was well tolerated and elicited robust immune responses.ClinicalTrials.gov: NCT03189745, EudraCT # 2013-001512-29. Funded by Pfizer. Disclosures All authors: No reported disclosures.

Immunogenicity and safety of the quadrivalent meningococcal vaccine MenACWY-TT co-administered with a combined diphtheria-tetanus-acellular pertussis vaccine versus their separate administration in adolescents and young adults: A phase III, randomized study

BackgroundThis study evaluated the immunogenicity and safety of quadrivalent meningococcal conjugate vaccine using tetanus (T) toxoid as carrier protein (MenACWY-TT) co-administered with combined diphtheria-tetanus-acellular pertussis vaccine (Tdap) versus their separate administration in adolescents and young adults. MethodsIn this phase III, randomized, partially-blind study (NCT01767376), healthy 11–25-year-olds (N = 660) were randomized (1:1:1) to receive MenACWY-TT and Tdap at Month 0 (Co-ad group), MenACWY-TT at Month 0 and Tdap at Month 1 (ACWY_Tdap group) or Tdap at Month 0 and MenACWY-TT at Month 1 (Tdap_ACWY group). Immune responses to MenACWY-TT were measured by serum bactericidal assay using rabbit complement (rSBA). Anti-diphtheria (D), anti-tetanus (T), anti-pertussis toxin (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN) antibody concentrations were assessed using enzyme-linked immunosorbent assays. Non-inferiority of immunogenicity was assessed using pre-defined clinical criteria. Safety was also evaluated. ResultsNon-inferiority of immunogenicity of MenACWY-TT and Tdap when co-administered versus their separate administration was demonstrated in terms of rSBA geometric mean titers (GMTs) for 4 meningococcal serogroups and of the percentage of participants with antibody concentrations >1 IU/ml for D and T. Among the pertussis antigens, non-inferiority criteria for geometric mean concentrations (GMCs) were reached for PT, but not met for FHA and PRN. Across all groups, ≥93.2% of participants had vaccine responses to each meningococcal serogroup, ≥99.1% were seroprotected against T and D, and ≥85.5% had booster responses to each pertussis antigen. Robust increases in antibody GMTs/GMCs were observed for all antigens between pre-and post-vaccination. Both vaccines had clinically acceptable safety profiles. ConclusionImmune responses to MenACWY-TT and to the T and D antigens from Tdap were not impacted by their co-administration. The lower antibody concentrations observed against the pertussis components may be of limited clinical relevance since robust anti-pertussis booster responses were observed. This study supports concurrent administration of the 2 vaccines in adolescents.

Population-Level Persistence of Immunity 2 Years After the PsA-TT Mass-Vaccination Campaign in Mali.

Background. In 2010, Africa's first preventive meningococcal mass vaccination campaign was launched using a newly developed Neisseria meningitidis group A (NmA) polysaccharide–tetanus toxoid conjugate vaccine, PsA-TT (MenAfriVac), designed specifically for the meningitis belt. Given PsA-TT's recent introduction, the duration of protection against meningococcal group A is unknown.Methods. We conducted a household-based, age-stratified seroprevalence survey in Bamako, Mali, in 2012, 2 years after the vaccination campaign targeted all 1- to 29-year-olds. Randomly selected participants who had been eligible for PsA-TT provided a blood sample and responded to a questionnaire. Sera were analyzed to assess NmA-specific serum bactericidal antibody titers using rabbit complement (rSBA) and NmA-specific immunoglobulin G (IgG) by enzyme-linked immunosorbent assay. The proportion of participants putatively protected and the age group- and sex-specific rSBA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) were determined.Results. Two years postvaccination, nearly all of the 800 participants (99.0%; 95% confidence interval [CI], 98.3%–99.7%) maintained NmA-specific rSBA titers ≥8, the accepted threshold for protection; 98.6% (95% CI, 97.8%–99.4%) had titers ≥128, and 89.5% (95% CI, 87.4%–91.6%) had titers ≥1024. The rSBA GMTs were significantly higher in females than in males aged <18 years at vaccination (P < .0001). NmA-specific IgG levels ≥2 µg/mL were found in 88.5% (95% CI, 86.3%–90.7%) of participants.Conclusions. Two years after PsA-TT introduction, a very high proportion of the population targeted for vaccination maintains high antibody titers against NmA. Assessing the duration of protection provided by PsA-TT is a priority for implementing evidence-based vaccination strategies. Representative, population-based seroprevalence studies complement clinical trials and provide this key evidence.

Long-term immunogenicity and safety after a single dose of the quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine in adolescents and adults: 5-year follow-up of an open, randomized trial

BackgroundLong-term protection against meningococcal disease is associated with persistence of post-vaccination antibodies at protective levels. We evaluated the bactericidal antibody persistence and safety of the quadrivalent meningococcal serogroups A, C, W and Y tetanus-toxoid conjugate vaccine (MenACWY-TT) and the meningococcal polysaccharide serogroups A, C, W, and Y vaccine (MenACWY-PS) up to 5 years post-vaccination.MethodsThis phase IIb, open, randomized, controlled study conducted in the Philippines and Saudi Arabia consisted of a vaccination phase and a long-term persistence phase. Healthy adolescents and adults aged 11–55 years were randomized (3:1) to receive a single dose of MenACWY-TT (ACWY-TT group) or MenACWY-PS (Men-PS group). Primary and persistence results up to 3 years post-vaccination have been previously reported. Antibody responses against meningococcal serogroups A, C, W, and Y were assessed by a serum bactericidal antibody assay using rabbit complement (rSBA, cut-off titers 1:8 and 1:128) at Year 4 and Year 5 post-vaccination. Vaccine-related serious adverse events (SAEs) and cases of meningococcal disease were assessed up to Year 5.ResultsOf the 500 vaccinated participants, 404 returned for the Year 5 study visit (Total Cohort Year 5). For the Total Cohort Year 5, 71.6–90.0 and 64.9–86.3 % of MenACWY-TT recipients had rSBA titers ≥1:8 and ≥1:128, respectively, compared to 24.8–74.3 and 21.0–68.6 % of MenACWY-PS recipients. The rSBA geometric mean titers (GMTs) remained above the pre-vaccination levels in both treatment groups. Exploratory analyses suggested that both rSBA GMTs as well as the percentages of participants with rSBA titers above the cut-offs were higher in the ACWY-TT than in the Men-PS group for serogroups A, W and Y, with no apparent difference for MenC. No SAEs related to vaccination or cases of meningococcal disease were reported up to Year 5.ConclusionThese results suggest that a single dose of MenACWY-TT could protect at least 72 % of vaccinated adolescents and adults against meningococcal disease at least 5 years post-vaccination.Trial registrationClinicalTrials.gov NCT00356369Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-015-1138-y) contains supplementary material, which is available to authorized users.

Persistence of serogroup C antibody responses following quadrivalent meningococcal conjugate vaccination in United States military personnel

Serogroup C meningococcal (MenC) disease accounts for one-third of all meningococcal cases and causes meningococcal outbreaks in the U.S. Quadrivalent meningococcal vaccine conjugated to diphtheria toxoid (MenACYWD) was recommended in 2005 for adolescents and high risk groups such as military recruits. We evaluated anti-MenC antibody persistence in U.S. military personnel vaccinated with either MenACYWD or meningococcal polysaccharide vaccine (MPSV4). Twelve hundred subjects vaccinated with MenACYWD from 2006 to 2008 or MPSV4 from 2002 to 2004 were randomly selected from the Defense Medical Surveillance System. Baseline serologic responses to MenC were assessed in all subjects; 100 subjects per vaccine group were tested during one of the following six post-vaccination time-points: 5–7, 11–13, 17–19, 23–25, 29–31, or 35–37 months. Anti-MenC geometric mean titers (GMT) were measured by rabbit complement serum bactericidal assay (rSBA) and geometric mean concentrations (GMC) by enzyme-linked immunosorbent assay (ELISA). Continuous variables were compared using the Wilcoxon rank sum test and the proportion of subjects with an rSBA titer ≥8 by chi-square. Pre-vaccination rSBA GMT was <8 for the MenACWYD group. rSBA GMT increased to 703 at 5–7 months post-vaccination and decreased by 94% to 43 at 3 years post-vaccination. GMT was significantly lower in the MenACWYD group at 5–7 months post-vaccination compared to the MPSV4 group. The percentage of MenACWYD recipients achieving an rSBA titer of ≥8 decreased from 87% at 5–7 months to 54% at 3 years. There were no significant differences between vaccine groups in the proportion of subjects with a titer of ≥8 at any time-point. GMC for the MenACWYD group was 0.14μg/mL at baseline, 1.07μg/mL at 5–7 months, and 0.66μg/mL at 3 years, and significantly lower than the MPSV4 group at all time-points. Anti-MenC responses wane following vaccination with MenACYWD; a booster dose is needed to maintain protective levels of circulating antibody.

Re-evaluation of the immunogenicity of meningococcal serogroups A and C polysaccharide vaccine among a healthy population aged 5 to 59

Objective To re-evaluate the immunogenicity of meningococcal serogroups A and C polysaccharide vaccine among a healthy population of age 5 to 59.Methods Pre and post-vaccination ser-um samples were collected from the subjects involved in a randomized , controlled clinical trial conducted in 2005 at Hechi, Guangxi, China.Enzyme-linked immunosorbent assay （ELISA） was performed for the quan-titative detection of specific anti-capsule IgG antibody against meningococcal serogroups A and C in serum samples.Serum bactericidal assay （ SBA） was used to measure the bactericidal antibody activity against se-rougroups A and C bacterial strains .Results Geometric mean concentrations （GMCs） of specific anti-cap-sule IgG antibody were 23.66 μg/ml and 78.83 μg/ml for serogroup A （P〈0.05）, and 1.23 μg/ml and 51.25 μg/ml for serogroup C （P〈0.05） in serum samples of pre and post-vaccination, respectively.Be-fore immunization , 99% of serum samples （ 97/98 ） showed serogroup A-specific IgG concentration ≥2μg/ml, which reached up to 100%（98/98） after vaccination （P〉0.05）.The percentage of serum sam-ples with serogroup C-specific IgG concentration ≥2 μg/ml rose from 20%to 99% after vaccination （ P〈0.05）.The ratio of positive serum samples with at least four times of increases in concentration of specific IgG against serogroup A and serogroup C after vaccine immunization were 34% and 100%, respectively . The rSBA geometric mean titers （ GMTs） for serogroups A and C in serum sample of post-vaccination were＆amp;nbsp;respectively elevated from 1164 to 5530 （P〈0.05）, and from 4 to 6225 （P〈0.05）.The percentage of se-rum samples with rSBA GMTs≥128 increased from 91% to 99% for serogroup A （P〉0.05）, and from 14%to 96%for serogroup C （P〈0.05） after vaccination.The rSBA GMTs with at least four times of in-creases after vaccination were detected respectively in 53% and 100% of serogroups A and C vaccinated subjects.Pearson correlation coefficient between IgG concentration and rSBA GMTs was r=0.15 （pre） and r=0.23 （post） for serogroup A, and r=-0.14 （pre） and r=0.58 （post） for serogroup C （P〈0.05）. Conclusion This study has demonstrated an efficient and sustained immunogenicity with meningococcal sero -groups A and C polysaccharide vaccine as evidenced by the data from standardized assays of ELISA and SBA . Key words: Meningococcal serogroups A and C polysaccharide vaccine; Immuogenicity

Meningococcal Polysaccharide A O -Acetylation Levels Do Not Impact the Immunogenicity of the Quadrivalent Meningococcal Tetanus Toxoid Conjugate Vaccine: Results from a Randomized, Controlled Phase III Study of Healthy Adults Aged 18 to 25 Years

In this study, we compared the immunogenicities of two lots of meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT) that differed in serogroup A polysaccharide (PS) O-acetylation levels and evaluated their immunogenicities and safety in comparison to a licensed ACWY polysaccharide vaccine (Men-PS). In this phase III, partially blinded, controlled study, 1,170 healthy subjects aged 18 to 25 years were randomized (1:1:1) to receive one dose of MenACWY-TT lot A (ACWY-A) (68% O-acetylation), MenACWY-TT lot B (ACWY-B) (92% O-acetylation), or Men-PS (82% O-acetylation). Immunogenicity was evaluated in terms of serum bactericidal activity using rabbit complement (i.e., rabbit serum bactericidal activity [rSBA]). Solicited symptoms, unsolicited adverse events (AEs), and serious AEs (SAEs) were recorded. The immunogenicities, in terms of rSBA geometric mean titers, were comparable for both lots of MenACWY-TT. The vaccine response rates across the serogroups were 79.1 to 97.0% in the two ACWY groups and 73.7 to 94.1% in the Men-PS group. All subjects achieved rSBA titers of ≥1:8 for all serogroups. All subjects in the two ACWY groups and 99.5 to 100% in the Men-PS group achieved rSBA titers of ≥1:128. Pain was the most common solicited local symptom and was reported more frequently in the ACWY group (53.9 to 54.7%) than in the Men-PS group (36.8%). The most common solicited general symptoms were fatigue and headache, which were reported by 28.6 to 30.3% and 26.9 to 31.0% of subjects, respectively. Two subjects reported SAEs; one SAE was considered to be related to vaccination (blighted ovum; ACWY-B group). The level of serogroup A PS O-acetylation did not affect vaccine immunogenicity. MenACWY-TT (lot A) was not inferior to Men-PS in terms of vaccine response and was well tolerated.

Immunogenicity and Safety of a Quadrivalent Meningococcal Serogroups A, C, W-135 and Y Tetanus Toxoid Conjugate Vaccine (MenACWY-TT) Administered to Adults Aged 56 Years and Older: Results of an Open-Label, Randomized, Controlled Trial

BackgroundThe burden of invasive meningococcal disease is substantial in older adults in whom the case fatality rate is high. Travelers to regions with high rates of meningococcal disease, such as Hajj pilgrims, are at increased risk of meningococcal infection, and disease transmission from travelers to their close contacts has been documented. In younger individuals, meningococcal conjugate vaccines offer advantages over polysaccharide vaccines in terms of duration of protection and boostability, and induction of herd immune effects through reductions in nasopharyngeal carriage of meningococci. To date, few data are available evaluating meningococcal conjugate vaccine use in adults >55 years of age.ObjectiveTo evaluate the immunogenicity and safety of quadrivalent meningococcal serogroups A, C, W-135 and Y vaccine with all serogroups conjugated to tetanus toxoid (MenACWY-TT, Nimenrix™, GlaxoSmithKline, Belgium) and a licensed quadrivalent polysaccharide vaccine (MenPS, Mencevax™ GlaxoSmithKline, Belgium) in adults >55 years of age.MethodsThis was a phase IIIb, open-label, randomized (3:1), controlled study conducted at one study center in Lebanon. A total of 400 healthy adults between 56 and 103 years of age without previous MenPS or tetanus toxoid vaccination within the previous 5 years or meningococcal conjugate vaccination at any time previously were included. They received a single-dose vaccination with MenACWY-TT or MenPS with blood sampling before and 1 month after vaccination. The main outcome measures were serum bactericidal activity (rabbit complement source: rSBA) vaccine response (VR) rate [rSBA titer of ≥1:32 in initially seronegative subjects (rSBA titer <1:8); ≥4-fold increase in subjects with pre-vaccination rSBA titers between 1:8 and 1:128, and ≥2-fold increase in subjects with pre-vaccination rSBA titers ≥1:128]. The percentages of subjects with rSBA titers ≥1:8 and ≥1:128 and rSBA geometric mean titers (GMTs) were assessed. Solicited adverse events were recorded for 4 days following vaccination, and all other adverse events, including the incidence of new onset chronic diseases, were recorded for 31 days after vaccination.ResultsOne month after a single dose of MenACWY-TT, the rSBA VR rate in the MenACWY-TT group was 76.6 % for serogroup A, 80.3 % for serogroup C, 77.5 % for serogroup W-135 and 81.9 % for serogroup Y. VR rates in the MenPS group were 91.7, 84.8, 87.1 and 89.1 %, respectively. One month after vaccination, ≥93.2 % of subjects in the MenACWY-TT group and ≥93.9 % in the MenPS group had rSBA titers ≥1:128. In each group, GMTs increased by ≥13-fold for each serogroup. rSBA VR and GMTs tended to be lower in subjects who were over 65 years compared to 56–65 years of age. Only 6.3 % of MenACWY-TT recipients had anti-TT ≥0.1 IU/ml prior to vaccination, increasing to 28.1 % post-vaccination. The rSBA GMTs were 1.9- to 4-fold higher in anti-TT responders. Each local and general solicited symptom was reported by no more than 3.0 % of subjects in either group. No serious adverse events were considered vaccine related.ConclusionIn adults 56 years of age and older, MenACWY-TT was immunogenic, with a vaccine response rate ≥76 % and with ≥93 % of subjects achieving rSBA titers ≥1:128 against all four serogroups after a single dose. MenACWY-TT induced low anti-TT concentrations in this population, which deserves further study.Electronic supplementary materialThe online version of this article (doi:10.1007/s40266-013-0065-0) contains supplementary material, which is available to authorized users.

Randomized trial to assess the immunogenicity, safety and antibody persistence up to three years after a single dose of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in toddlers

Effective vaccines offering broad protection to toddlers, who are at high risk for invasive meningococcal disease, are needed. Here, the immunogenicity, safety and antibody persistence of the tetravalent meningococcal ACWY tetanus toxoid conjugate vaccine (MenACWY-TT) were evaluated in toddlers. Healthy participants aged 12 to 23 mo (n = 304) were randomized (3:1) to receive one dose of MenACWY-TT or a monovalent meningococcal serogroup C conjugate vaccine (MenC-CRM197). Serum bactericidal activity was evaluated with assays using rabbit (rSBA) and human (hSBA) complement up to three years post-vaccination. MenACWY-TT was demonstrated to be non-inferior to MenC-CRM197 in terms of immunogenicity to serogroup C, and the pre-specified immunogenicity criteria for serogroups A, W-135 and Y were met. Exploratory analyses suggested that rSBA geometric mean titers (GMTs), hSBA GMTs and proportions of toddlers with rSBA titers ≥ 1:128 and hSBA titers ≥ 1:4 and ≥ 1:8 were higher for all serogroups at one month post-vaccination with MenACWY-TT compared with MenC-CRM197. At three years post-vaccination, at least 90.8% and 73.6% of MenACWY-TT recipients retained rSBA titers ≥ 1:8 for all serogroups and hSBA titers ≥ 1:4 for serogroups C, W-135 and Y, respectively, but the percentages of toddlers with hSBA titers ≥ 1:4 for serogroup A decreased to 21.8%. In both groups, grade 3 adverse events were infrequently reported and no serious adverse events were considered causally related to vaccination. These results suggest that one single dose of MenACWY-TT induces a robust and persistent immune response and has an acceptable safety profile in toddlers. This study has been registered at www.clinicaltrials.gov NCT00427908.

A randomized study to assess the immunogenicity, antibody persistence and safety of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in children aged 2–10 years

Incidence of meningococcal diseases is high in children, and effective vaccines are needed for this age group. In this phase II, open, controlled study, 309 children aged 2–10 y from Finland were randomized (3:1) into two parallel groups to receive one dose of meningococcal ACWY-tetanus toxoid conjugate vaccine (ACWY-TT group; n = 231) or a licensed meningococcal ACWY polysaccharide vaccine (Men-PS group; n = 78). Serum bactericidal activity using rabbit complement (rSBA) was evaluated up to three years post-vaccination. Exploratory comparisons suggested that rSBA vaccine response rates and geometric mean titers (GMTs) for each serogroup at one month post-vaccination and rSBA GMTs for serogroups A, W-135 and Y up to three years post-vaccination were higher in the ACWY-TT compared with Men-PS group, but did not detect any difference between groups in terms of rSBA-MenC GMTs at three years post-vaccination; this is explained by the higher proportion of children from the Men-PS group who were excluded because they were re-vaccinated with a monovalent meningococcal serogroup C vaccine due to loss of protective antibody levels against this serogroup. Although there was a higher incidence of local reactogenicity in the ACWY-TT group, general and unsolicited symptoms reporting rates were comparable in both groups. This study showed that MenACWY-TT was immunogenic with a clinically acceptable safety profile in children aged 2–10 y. MenACWY-TT induced higher functional antibody titers for all serogroups, which persisted longer for serogroups A, W-135 and Y, than the MenACWY polysaccharide vaccine. This study has been registered at www.clinicaltrials.gov NCT00427908.

Safety and Immunogenicity of a Meningococcal Quadrivalent Conjugate Vaccine in Five- to Eight-Year-Old Saudi Arabian Children Previously Vaccinated with Two Doses of a Meningococcal Quadrivalent Polysaccharide Vaccine

Saudi Arabian children respond poorly to 2 doses of meningococcal quadrivalent polysaccharide vaccine (MPSV4) when given before 2 years of age. This study examined whether such children were able to respond to 1 dose of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MCV4) when they were older. Saudi Arabian children 5 to 8 years of age who had previously been vaccinated with 2 doses of MPSV4 when they were under 2 years of age (termed the prior-MPSV4 group) were enrolled in a controlled, open-label, multicenter study. In the prior-MPSV4 group, children (n = 153) received 1 dose of MCV4, as did a group of age-matched meningococcal vaccine-naïve children (n = 85). Blood samples collected prevaccination and 28 days postvaccination were measured for serogroup-specific serum bactericidal antibody (SBA) levels in the presence of baby rabbit complement (rSBA) and for IgG antibody levels. Vaccine tolerability and safety were also evaluated. For all of the measured serogroups (A, C, Y, and W-135), the meningococcal vaccine-naïve participants achieved higher postvaccination rSBA geometric mean titers (GMTs) than did those in the prior-MPSV4 group. This was statistically significant for serogroup C (512 versus 167). Percentages of participants with postvaccination titers of ≥8 and with ≥4-fold increases in prevaccination to postvaccination titers appeared to be quite similar in the 2 groups. No worrisome safety signals were detected. MCV4 induced robust immune responses and was well tolerated in Saudi Arabian children who previously received 2 doses of MPSV4 as well as in those who were previously meningococcal vaccine naïve.

The tetravalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine is immunogenic with a clinically acceptable safety profile in subjects previously vaccinated with a tetravalent polysaccharide vaccine

The immunogenicity and safety of the tetravalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT) were evaluated in subjects previously vaccinated with a tetravalent meningococcal polysaccharide vaccine and in subjects without previous meningococcal vaccination. In this phase II, open, controlled study (NCT00661557), healthy subjects aged 4.5-34 years received one dose of MenACWY-TT at month 0. Subjects in the MPS group (n=192) had received polysaccharide vaccine in a study conducted 30-42 months earlier; age-matched subjects in the noMPS control group (n=79) had received no meningococcal vaccination within the past 10 years. Serum bactericidal activity using rabbit complement (rSBA) was measured at month 0 and month 1. At month 1, ≥97.0% of subjects had rSBA titers ≥1:128. Post-vaccination rSBA geometric mean titers (GMTs) were ≥3.9-fold higher than pre-vaccination in both treatment groups. Exploratory analyses showed no statistically significant differences between groups in percentages of subjects with rSBA titers ≥1:8 and ≥1:128, but significantly lower rSBA GMTs and vaccine response rates for each serogroup in the MPS versus the noMPS group. MenACWY-TT had an acceptable safety profile in both groups. These results suggest that MenACWY-TT could be used in vaccination programs irrespective of the pre-vaccination status with polysaccharide vaccine.

Immunogenicity and Safety of a Meningococcal Quadrivalent Conjugate Vaccine in Saudi Arabian Adolescents Previously Vaccinated with One Dose of Bivalent and Quadrivalent Meningococcal Polysaccharide Vaccines: a Phase III, Controlled, Randomized, and Modified Blind-Observer Study

Reduced immune responses to repeated polysaccharide vaccination have been previously reported, but there are limited immunogenicity data on the use of meningococcal polysaccharide vaccine (PSV) followed by meningococcal conjugate vaccine. Saudi Arabian adolescents (aged 16 to 19 years) who had previously been vaccinated with ≥1 dose of bivalent meningococcal polysaccharide vaccine and 1 dose of quadrivalent meningococcal polysaccharide (MPSV4) were enrolled in a controlled, randomized, and modified observer-blind study (collectively termed the PSV-exposed group). The PSV-exposed group was randomized to receive either quadrivalent meningococcal conjugate vaccine (MCV4) (n = 145 PSV-exposed/MCV4 group) or MPSV4 (n = 142 PSV-exposed/MPSV4 group), and a PSV-naïve group received MCV4 (n = 163). Serum samples collected prevaccination and 28 days postvaccination were measured by baby rabbit serum bactericidal antibody (rSBA) assay, and vaccine tolerability and safety were also evaluated. For each serogroup, the postvaccination geometric mean titers (GMTs) were significantly higher in the PSV-naïve group than in either group comprised of the PSV-exposed participants. The postvaccination serogroup C rSBA GMT was significantly higher in the PSV-MCV4 group than in the PSV-MPSV4 group after adjusting for prevaccination GMTs. Although not statistically significant, similar differences were observed for serogroups A, Y, and W-135. No worrisome safety signals were detected. This study demonstrated MCV4 to be safe and immunogenic in those who had previously received polysaccharide vaccination, and it suggests that conjugate vaccine can partially compensate for the hyporesponsiveness seen with repeated doses of polysaccharide vaccine.