Quadrivalent meningococcal (MenACWY-TT) conjugate vaccine or a fourth dose of H. influenzae–N. meningitidis C/Y conjugate vaccine (HibMenCY-TT) is immunogenic in toddlers who previously received three doses of HibMenCY-TT in infancy

BackgroundImmunogenicity and safety of a single dose of MenACWY-TT or a fourth dose of HibMenCY-TT were evaluated in the second year of life in HibMenCY-TT-primed toddlers.MethodsHealthy infants were randomized (5:1) and primed at 2, 4 and 6 months of age with HibMenCY-TT and diphtheria–tetanus–acellular pertussis–hepatitis B-inactivated poliovirus (DTaP–HBV–IPV) vaccine; or Hib-TT and DTaP–HBV–IPV (control). Recipients of HibMenCY-TT + DTaP–HBV–IPV were re-randomized (2:2:1) to receive MenACWY-TT at 12–15 months and DTaP at 15–18 months; MenACWY-TT co-administered with DTaP at 15–18 months; or HibMenCY-TT at 12–15 months and DTaP at 15–18 months. Controls received DTaP only at 15–18 months due to Hib conjugate vaccine shortage. Serum bactericidal activity using human complement (hSBA) and safety were assessed one month after meningococcal vaccination.ResultsAfter vaccination with MenACWY-TT at 12–15 months or MenACWY-TT + DTaP at 15–18 months, all subjects previously primed for serogroups C/Y had hSBA ≥1:8 for these serogroups. At least 96.1% also had hSBA ≥1:8 for serogroups A/W. All subjects in the HibMenCY-TT group had hSBA ≥1:8 for serogroups C/Y. All pre-defined statistical criteria for meningococcal immunogenicity were satisfied. All vaccination regimens had acceptable safety profiles.ConclusionChildren primed with three doses of HibMenCY-TT who then received a single dose of MenACWY-TT or a fourth dose of HibMenCY-TT had robust increases in hSBA titers for serogroups C/Y. These data provide support that MenACWY-TT, given with or without the fourth scheduled dose of DTaP could be administered as an alternative to a fourth dose of HibMenCY-TT in the second year of life.This study (110870/110871) is registered at www.clinicaltrials.gov NCT00614614.     

Immunogenicity and reactogenicity of Infanrix™ when co-administered with meningococcal MenACWY-TT conjugate vaccine in toddlers primed with MenHibrix™ and Pediarix™

BackgroundCo-administration of an investigational quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) with the fourth dose of diphtheria–tetanus–acellular pertussis vaccine (DTaP) at age 15–18 months was investigated in 3-dose Haemophilus influenzae type b-meningococcal serogroups C/Y conjugate vaccine (HibMenCY-TT)-primed toddlers.MethodsInfants were randomized (5:1) and primed at 2, 4 and 6 months of age with HibMenCY-TT and DTaP-hepatitis B-inactivated poliovirus (DTaP-HBV-IPV) vaccine, or Hib-TT and DTaP-HBV-IPV (Control). HibMenCY-TT+ DTaP-HBV-IPV vaccinees were re-randomized (2:2:1) to receive MenACWY-TT at 12–15 months and DTaP at 15–18 months (MenACWY-TT group); MenACWY-TT co-administered with DTaP at 15–18 months (Coad group); or HibMenCY-TT at 12–15 months and DTaP at 15–18 months (HibMenCY-TT group). Controls received DTaP at 15–18 months. Only children in the HibMenCY-TT group received a fourth dose of Hib conjugate vaccine due to Hib conjugate vaccine shortage at the time of the study. DTaP immunogenicity and reactogenicity were assessed one month post-vaccination.ResultsPre-defined statistical non-inferiority criteria between Coad and Control groups were met for diphtheria, tetanus and filamentous haemagglutinin but not pertussis toxoid and pertactin. Following vaccination ≥99% of children had anti-diphtheria/anti-tetanus concentrations ≥1.0 IU/ml. Pertussis GMCs were lower in all investigational groups versus Control. In post hoc analyses, pertussis antibody concentrations were above those in infants following 3-dose DTaP primary vaccination in whom efficacy against pertussis was demonstrated (Schmitt, von König, et al., 1996; Schmitt, Schuind, et al., 1996). The reactogenicity profile of the Coad group was similar to DTaP administered alone.ConclusionRoutine booster DTaP was immunogenic with an acceptable safety profile when co-administered with MenACWY-TT vaccine in HibMenCY-TT-primed toddlers. These data support the administration of a fourth DTaP dose following a 4-dose HibMenCY-TT vaccination series, or co-administered with MenACWY-TT in HibMenCY-TT-primed children.     

Safety and immunogenicity of fractional dose intradermal injection of two quadrivalent conjugated meningococcal vaccines

BackgroundVaccination with conjugated meningococcal vaccines is the best way to prevent invasive meningococcal disease. Changes in serogroup epidemiology have led to the inclusion of quadrivalent vaccines in the national immunization programs of several countries, but vaccines are frequently in short supply. Intradermal administration has the potential to increase vaccine availability through dose reduction, without sacrificing efficacy. It has never before been investigated for glycoconjugate meningococcal vaccines.MethodsDifferent fractional doses of two quadrivalent meningococcal conjugate vaccines (MenACWY-CRM₁₉₇ (Menveo®) and MenACWY-TT (Nimenrix®)) were administered intradermally to sequential groups of 4 participants, according to an adaptive dose escalation design, starting at 1/10th of the original dose. Booster doses were given after 4–6 months based on interim serology results using a multiplex bead-based assay (MIA). Final analyses were based on serum bactericidal antibody titers (rSBA).ResultsA total of 12 subjects were enrolled (average 25 years old, range 19–48). MenACWY-CRM₁₉₇ became unavailable during the course of the study and was only evaluated for a 1/10th dose. This dose resulted in less than complete seroprotection for serogroup A but complete protection against the other serogroups. MenACWY-TT was evaluated for a 1/10th and 1/5th dose level. Both fractional doses of MenACWY-TT resulted in complete seroprotection against all vaccine serogroups. Geometric mean titers 1 month after vaccination were lower and decayed faster in the MenACWY-CRM₁₉₇ group. Adverse events were mild and there were no serious adverse events.ConclusionFractional intradermal vaccination against meningococcal disease with quadrivalent conjugate vaccine appears to be safe and effective in our small dose finding study. Tetanus toxoid conjugated vaccine (Nimenrix®) shows a trend towards higher antibody levels compared to CRM₁₉₇-conjugated vaccine (Menveo®). The 1/5th fractional dose of MenACWY-TT appears to result in higher antibody levels than does the 1/10th dose. These results can be used for a larger non-inferiority study.This trial was registered in clinicaltrials.gov under NCT01782066.     

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.     

ACYW135群脑膜炎球菌多糖结合破伤风毒素疫苗免疫学效果的Meta分析

目的 评价ACYW135群脑膜炎球菌多糖结合破伤风毒素疫苗(MPCV-ACYW135-TT)的免疫学效果.方法 检索National Center for Biotechnology Information (NCBI)、Cochrane协作网图书馆、中国生物医学文献数据库、中国期刊全文数据库和万方全文数据库,将有关评价MPCV-ACYW135免疫学效果的随机对照试验(RCT)的研究纳入分析.以接种疫苗1个月后产生的血清杀菌活性(SBA)抗体阳转率(PRR)和几何平均滴度(GMT)作为结局指标,合并不同研究中试验组与对照组间的PRR和GMT的率差(RD)或标准化均数差(SMD).使用RevMan5.1软件进行Meta分析.结果 共纳入13篇文献:有9篇比较了MPCV-ACYW135-TT和ACYW135群脑膜炎球菌多糖疫苗(MPV-ACYW135)之间免疫学效果差异,4篇比较了MPCV-ACYW135-TT和C群脑膜炎球菌多糖结合白喉毒素变异体197疫苗(MPCV-C-CMR197)之间免疫学效果差异.相比于MPV-A-CYW135;受试者在接种MPCV-ACYW135-TT后产生的针对A、C、Y和W135这4个血清型抗体PRR的RD在0.03～0.15之间;产生的针对A、Y和W135这3个血清型抗体GMT的SMD在0.33～1.22之间.1～2岁组幼儿在接种MPCV-ACYW135-TT后产生的针对C群抗体GMT与接种MPCV-C-CMR197差异无统计学意义(H＞0.05).结论 MPCV-ACYW135-TT与其他已上市应用的脑膜炎球菌疫苗有相似的免疫效果.     

Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT) in ≥56-year-olds: A Phase III randomized study

BackgroundInvasive meningococcal disease has a high mortality rate in individuals aged ≥56 years, but no vaccine is currently licensed in the USA for this age group. This study assessed the safety and immunogenicity of an investigational quadrivalent meningococcal tetanus toxoid conjugate vaccine (MenACYW-TT) compared with a meningococcal quadrivalent polysaccharide vaccine (MPSV4) in this age group.MethodsThis was a Phase III, modified double-blind, randomized, non-inferiority study (NCT02842866) across 35 clinical sites in the USA and Puerto Rico in individuals aged ≥56 years. A single dose of the MenACYW-TT (n = 451) or MPSV4 vaccine (n = 455) was administered on Day 0. A serum bactericidal assay with human (hSBA) and baby rabbit (rSBA) complement was used to measure antibodies against serogroups A, C, W, and Y test strains at baseline and Day 30. Safety data were collected up to six months post-vaccination.ResultsThe seroresponse to MenACYW-TT was non-inferior to MPSV4 for each of the serogroups (A: 58.2% vs. 42.5%; C: 77.1% vs. 49.7%; W: 62.6% vs. 44.8%, Y: 74.4% vs. 43.4%, respectively). At Day 30, participants achieving hSBA titers ≥1:8 were higher for all serogroups after MenACYW-TT vs. MPSV4 (77.4–91.7 vs. 63.1–84.2%, respectively). No safety concerns were identified for either vaccine.ConclusionMenACYW-TT was well-tolerated and immunogenic in ≥56-year-olds, offering the potential to replace MPSV4 in this age group.     

A phase 3, randomized,controlled, open-label study to evaluate the persistence up to 5 years of 1 or 2 doses of meningococcal conjugate vaccine MenACWY-TT given with or without 13-valent pneumococcal conjugate vaccine in 12–14-month-old children

BackgroundImmunogenicity and safety up to 5 years after administration of 1 or 2 doses of quadrivalent meningococcal serogroup A, C, W, and Y tetanus toxoid conjugate vaccine (MenACWY-TT) given alone or with 13-valent pneumococcal conjugate vaccine (PCV13) in children was investigated.MethodsThis phase 3 study randomized healthy 12–24-month-olds to MenACWY-TT at Month 0 (ACWY1d), MenACWY-TT at Months 0 and 2 (ACWY2d), MenACWY-TT and PCV13 at Month 0 (Co-Ad), or PCV13 at Month 0 and MenACWY-TT at Month 2 (PCV13/ACWY). Immune responses 1, 3, and 5 years after primary vaccination were evaluated with serum bactericidal activity using rabbit complement (rSBA) titers ≥ 1:8 and geometric mean titers (GMTs). Evaluation of serious adverse events up to 5 years after primary vaccination are reported.ResultsOf the 802 children randomized in the study, 619 completed the study through Year 5. Immune responses after vaccination declined over time but were higher 5 years after vaccination compared with levels before vaccination. At Year 5, the percentages of children with rSBA titers ≥ 1:8 across all serogroups were 20.5 %?58.6 %, 28.4 %?65.8 %, 23.9 %?52.8 %, and 19.4 %?55.8 % in the ACWY1d, ACWY2d, Co-Ad, and PCV13/ACWY groups, respectively. Comparable antibody persistence at Year 5 was observed for participants receiving 1 or 2 doses of MenACWY-TT, although GMTs were elevated in those who received 2 versus 1 dose. The percentage of children with protective antibody titers at Year 5 was similar in participants who received PCV13 and MenACWY-TT compared with that observed for participants who only received 1 or 2 MenACWY-TT doses. No new safety concerns were identified during the study period.ConclusionAntibody responses persisted in the majority of children up to 5 years after primary vaccination with MenACWY-TT administered in a 1- or 2-dose regimen with or without PCV13, with no new safety concerns identified.ClinicalTrials.gov Identifier NCT01939158; EudraCT number 2013–001083-28.     

Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story

The introduction of meningococcal C conjugate (MCC) vaccine in the UK in November 1999 as a routine 3 dose infant immunisation course, with a single catch-up dose for all children aged between 12 months and 17 years, was the result of an intensive 5 year collaborative research programme funded by the Department of Health for England and involving public bodies, academia and vaccine manufacturers. The research programme established the safety and immunogenicity of MCC vaccines in infants, toddlers, pre-school and school-aged children. The nature and frequency of common adverse events in school-aged children was similar to that after a booster dose of diphtheria and tetanus vaccine given to the same age groups. The recommendation that a single dose was adequate for children aged 12 months and above was based on antibody levels measured by serum bactericidal assay and evidence of induction of immunological memory as shown by maturation of antibody avidity. Licensure by the Medicines Control Agency was based on serological criteria alone without direct evidence of efficacy and has set a precedent for other meningococcal conjugate polysaccharide vaccines. Vaccine coverage of around 85% was achieved in the targeted age groups and has resulted in a drop in the incidence of serogroup C disease in these groups of over 80% within 18 months of the start of the vaccination programme. Early post-licensure efficacy estimates for toddlers and teenagers (88 and 96%, respectively, in the first 16 months after vaccination) validate the serological criteria used for licensure. Surveillance of the prevalent serogroups and serosubtypes among invasive case isolates has shown no evidence of any capsular switching to serogroup B during the first 18 months of the MCC vaccination programme.     

Safety and immunogenicity of an investigational quadrivalent meningococcal tetanus toxoid conjugate vaccine (MenACYW-TT) co-administered with routine pediatric vaccines in infants and toddlers: A Phase II study

BackgroundThe MenACYW-TT conjugate vaccine is approved for prevention of invasive meningococcal disease (IMD) as a single dose in individuals ≥2 years of age in the United States and ≥12 months in EU and some other countries. This Phase II study evaluated the safety and immunogenicity of this vaccine and of concomitant pediatric vaccines in infants/toddlers (6 weeks–15 months of age).MethodsFive schedules of the MenACYW-TT conjugate vaccine were evaluated in the United States: 2, 4, 6, and 12 months; 2, 4, 6, and 15 months; 2, 4, and 12 months; 6 and 12 months; and 12 months alone. Routine pediatric vaccines (DTaP-IPV/Hib, PCV7/PCV13, MMR, and varicella) were administered per approved schedules. Proportions of participants with serum bactericidal antibodyassay with human complement (hSBA) titers ≥1:4 and ≥1:8, SBA with baby rabbit complement (rSBA) titers ≥1:8 and ≥1:128, and immune responses against concomitant vaccines were determined.ResultsTenderness and irritability were the most frequent solicited injection site and systemic reactions. Similar proportions of participants achieved an hSBA titer ≥1:8 for all four serogroups regardless of whether 2 or 3 doses were administered in the first year of life. Following a second-year dose, 91–100% of participants achieved the threshold for all 4 serogroups in all schedules regardless of the number of doses in the first year of life. Similar responses were seen with rSBA. Immunogenicity and safety profile of concomitant vaccines was similar whether the MenACYW-TT conjugate vaccine was administered or not.ConclusionMenACYW-TT conjugate vaccine administered with pediatric vaccines is safe and immunogenic regardless of the schedule and does not affect the immunogenicity or safety of the concomitant vaccines.Clinical trial registryNCT01049035.     

Safety and immunogenicity of a booster dose of meningococcal (groups A,C, W,and Y) polysaccharide diphtheria toxoid conjugate vaccine

BackgroundQuadrivalent meningococcal conjugate vaccines (MenACWY) were developed to offer long-term protection against invasive disease caused by serogroups A, C, W, and Y. Reduced MenACWY effectiveness within 5 years after primary vaccination (likely due to declining bactericidal antibody titers) has been described, particularly with respect to C and Y disease in the United States. We evaluated the safety and immunogenicity of a single booster dose of quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-D) in adolescents and adults who received a previous dose 4–6 years earlier.MethodsThis phase 2, open-label, multicenter study of 834 persons was conducted in the United States. Participants received a single 0.5-mL booster dose of MenACWY-D. Serogroup-specific bactericidal antibody geometric mean titers (GMTs) were measured with a serum bactericidal antibody assay using human complement (hSBA). Proportions of participants achieving antibody titers of ⩾1:8 for each vaccine serogroup on Days 6 and 28 were determined. Rates of adverse events (AEs), including serious adverse events (SAEs), were also assessed.ResultsBefore booster vaccination, 38.7–68.5% of participants had an hSBA titer ⩾1:8, depending on vaccine serogroup. By Day 6 post-vaccination, 98.2–99.1% of participants had hSBA titers ⩾1:8. By Day 28, >99% of participants achieved this threshold and the primary hypothesis (lower limit of the one-sided 95% confidence limit ⩾85% for each serogroup) was met. The GMT ratios (post-vaccination divided by pre-vaccination) at Day 28 ranged from 47.2 (serogroup A) to 209.1 (serogroup Y). Rates of AEs, including SAEs, were similar to those observed among adolescents and adults who received a primary dose of MenACWY-D in previous studies. There were no study discontinuations due to an AE and no deaths.ConclusionsBooster vaccination with MenACWY-D was safe and induced robust bactericidal antibody responses, consistent with immune memory, among adolescents and adults 4–6 years after primary vaccination.ClinicalTrials.gov registration: NCT01442675.     

A Phase II,randomized, immunogenicity and safety study of a quadrivalent meningococcal conjugate vaccine,MenACYW-TT,in healthy adolescents in the United States

BackgroundMenACYW-TT is an investigational quadrivalent meningococcal conjugate vaccine intended for use in individuals ≥6 weeks of age. We evaluated the safety and immunogenicity of MenACYW-TT when compared to a licensed quadrivalent conjugate meningococcal vaccine (Menveo®; MCV4-CRM; GlaxoSmithKline, Italy), and when co-administered with tetanus, diphtheria, acellular pertussis (Tdap) and human papilloma virus (HPV4) vaccines in healthy meningococcal vaccine-naïve adolescents (10–17 years old) in the United States of America.MethodsIn this pivotal Phase II, open-label, multicenter study, 1715 participants were randomized to receive MenACYW-TT, MCV4-CRM, MenACYW-TT co-administered with Tdap and HPV4, or Tdap and HPV4 vaccines alone (NCT02199691).The primary objective was to evaluate whether antibody responses to MenACYW-TT antigens were non-inferior to antibody responses after MCV4-CRM administration. Meningococcal antibody titers were determined using human complement serum bactericidal assay (hSBA) with titers measured at baseline, and 30 days post vaccination (D30). A vaccine seroresponse was defined as baseline titers <1:8 with post-vaccination titers ≥1:8 or baseline titers ≥1:8 with a ≥4-fold increase at post-vaccination. Safety data were collected up to six months post-vaccination.ResultsNon-inferiority was demonstrated for MenACYW-TT vs MCV4-CRM (primary endpoint), and for MenACYW-TT co-administered with Tdap and HPV4 vs MenACYW-TT alone (secondary endpoint). The vaccine seroresponse rate was higher with MenACYW-TT than with MCV4-CRM, for each serogroup: A: 75.6% vs 66.4%; C: 97.2% vs 72.6%; W: 86.2% vs 66.6%; Y: 97.0% vs 80.8%. The safety profiles of MenACYW-TT, MCV4-CRM, and Tdap and HPV4 vaccines, administered with or without MenACYW-TT, were comparable. There were no vaccine-related serious adverse events.ConclusionsThe MenACYW-TT vaccine was well tolerated and generated an immune response that was non-inferior to the licensed MCV4-CRM vaccine. Immunogenicity and safety profiles were comparable when MenACYW-TT was administered with or without Tdap and HPV4 vaccines in meningococcal vaccine-naïve adolescents.     

Immunogenicity and safety of 7-valent pneumococcal conjugate vaccine (PCV7) in children aged 2–5 years in China

BackgroundThe widespread use of pneumococcal conjugate vaccines (PCVs) has significantly decreased pneumococcal disease worldwide. However, China has not adopted PCVs in their national immunization schedules and had only approved these vaccines for children aged 2–15 months by 2020.MethodsIn an open-label trial, enrolled healthy children aged 2–5 years old were randomized 1:1 and divided into a 7-valent pneumococcal conjugate vaccine (PCV7) group and a Haemophilus influenzae type b conjugate vaccine (Hib) group. Children in the PCV7 group received a single dose of PCV7, and the Hib group received a single dose of Hib vaccine. Blood samples were collected before and 6 months after vaccination. Immunogenicity and safety of PCV7 were assessed at prespecified time points.ResultsSix months after a single dose of PCV7, children in the PCV7 group for all 7 serotypes, IgG mean concentrations (GMCs) and opsonophagocytic geometric mean titres (GMTs) were significantly higher (P < .001) than at baseline, and the proportion of IgG ≥ 0.35 µg/mL ranged from 90.0% to 100%. Although the antibody level increased with age, preexisting antibodies did not induce hyporesponsiveness to PCV7. In the Hib group, the antibody levels were not significantly different or had changed slightly at 6 months. PCV7 was well tolerated in all age groups, and no serious adverse events (AEs) emerged during this study.ConclusionsA single dose of PCV7 was immunogenic and safe for Chinese children aged 2–5 years, and the preexisting antibodies against the PCV7 serotypes did not change the response to vaccination. The findings supported the effectiveness of PCV7 in this age group. PCVs with broader serotype coverage are expected to expand pneumococcal disease protection.     

Antibody responses to meningococcal (groups A, C, Y and W135) polysaccharide diphtheria toxoid conjugate vaccine in children who previously received meningococcal C conjugate vaccine

A randomised, modified, double-blind trial was conducted in children 2 to < 5 years of age to evaluate immunogenicity and reactogenicity of a meningococcal (serogroups A, C, Y, W135) diphtheria toxoid conjugate vaccine (MCV-4) in healthy children previously vaccinated with a monovalent meningococcal C conjugate vaccine. Participants received one dose of either MCV-4 or Haemophilus influenzae type b vaccine (Hib vaccine, control group). Serum bactericidal antibodies (SBA) were determined in sera obtained before and approximately 28 days following vaccination. MCV-4 was highly immunogenic for serogroups A, C, Y and W135, the response to serogroup C being consistent with a booster response in participants primed with monovalent C conjugate vaccine. No major between-group differences in solicited local and systemic reactions or adverse events (AEs).     

Surveillance for meningococcal disease and strategies for use of conjugate meningococcal vaccines in the United States

BACKGROUND: Neisseria meningitidis is a leading cause of bacterial meningitis in US; new capsular type-specific conjugate vaccines offer an opportunity for improved control of meningococcal disease. We evaluated the relative burdens of invasive meningococcal disease in US and examined the projected impact of various meningococcal conjugate vaccination strategies on rates of meningococcal disease. METHODS: Meningococcal disease incidence rates were determined from active, population-based surveillance in selected US areas. Models were created to determine impact of vaccination of infants, toddlers, adolescents or college students with meningococcal conjugate vaccines, with assumptions for vaccine coverage, efficacy and duration of protection. Although we examined possible conjugate vaccine formulations including serogroups A, C, Y and W-135, the final vaccine impact analysis excluded serogroups A and W-135. Outcome measures were cumulative meningococcal disease incidence, and incidence 10 years after initiating vaccination among 0-22-year-olds. RESULTS: In models of serogroup C+Y meningococcal conjugate vaccination of infants, toddlers and adolescents, the cumulative incidence of meningococcal disease was reduced by 54, 48 and 25%, respectively; the toddler strategy had the greatest impact per dose. After 10 years of routine meningococcal conjugate vaccination, meningococcal disease could be reduced by 50% and deaths by 64%. CONCLUSIONS: Use of meningococcal conjugate vaccine could markedly reduce meningococcal disease incidence. Our data, along with vaccine formulation and vaccination program considerations, will be important in determining the optimal choice of vaccination strategy.     

Serogroup A,C, W,and Y meningococcal disease in persons previously vaccinated with a serogroup ACWY meningococcal vaccine – United States, 2014–2018

BackgroundThe Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination with a quadrivalent meningococcal conjugate serogroup A,C,W,Y (MenACWY) vaccine at 11–12 years of age, with a booster dose at 16 years. ACIP also recommends meningococcal vaccination for persons at increased risk of meningococcal disease, including a 2-dose primary series and regular booster doses for persons at increased risk because of underlying medical conditions. U.S. cases of serogroup A, C, W, and Y meningococcal disease in persons previously vaccinated with MenACWY vaccine have not been systematically described since 2008. Characterization of these cases is important to understand potential factors leading to breakthrough disease.MethodsWe analyzed cases of serogroup A,C,W, and Y meningococcal disease reported through the National Notifiable Diseases Surveillance System (NNDSS) from 2014 through 2018. State health departments submitted additional information on risk factors and clinical course.ResultsDuring 2014–2018, 822 cases of serogroup A, C, W, and Y meningococcal disease were reported through NNDSS; 34 (4%) were in patients who previously received ≥ 1 dose of MenACWY vaccine. Twenty-three vaccinated patients were up-to-date on MenACWY vaccine per recommendations, and seven were not up-to-date; four were missing information on the number of doses received. Seventeen cases (50%) occurred > 3 years after the most recent dose. A significantly higher proportion of vaccinated patients were people living with HIV (PLWH) compared to unvaccinated patients. Eight of the 34 vaccinated patients were immunosuppressed, including five PLWH, one taking eculizumab, and two taking other immunosuppressive medications. The case fatality ratio did not differ between vaccinated and unvaccinated patients.ConclusionsImmunosuppression, incomplete vaccination, and waning immunity likely contributed to breakthrough cases of meningococcal disease among people who received MenACWY vaccine. Continued monitoring of serogroup A, C, W, and Y meningococcal disease in previously vaccinated persons will help inform meningococcal disease prevention efforts.     

Antibody persistence and booster response following MenACWY-CRM vaccination in children as assessed by two different assay methods

BackgroundThe quadrivalent meningococcal conjugate vaccine MenACWY-CRM has been shown to be immunogenic and well-tolerated in infants and toddlers. We evaluated antibody persistence for up to 4 years after vaccination with MenACWY-CRM in the first years of life and response to a booster dose administered at 60 months of age.MethodsThis was phase 3b, open-label, multicenter extension trial (NCT01148017). We assessed by hSBA and rSBA the persistence of antibody responses to serogroups ACWY in 203 healthy 60-month-olds receiving 4 doses of MenACWY-CRM during infancy (ACWY-4 group), or 2 doses at 12/13 and 15 months or 1 dose at 18 months of age (ACWY-2 group). We administered a MenACWY-CRM dose to 224 primed and 45 naïve 60-month-olds and evaluated safety and antibody response 1 month later.ResultsAntibody persistence measured by both assays was higher in primed than naïve 60-month-olds. The percentages of primed children with hSBA titers ≥8 was low for serogroup A (6–25%) and moderate for serogroups C (27–43%), Y (69–74%) and W (56–69%). For all serogroups, hSBA antibody geometric mean titers (GMTs) tended to be higher in the ACWY-2 than the ACWY-4 group. Post-booster/single dose, ≥96% of primed and ≥73% of naïve children had hSBA titers ≥8 against each serogroup, and hSBA GMTs were higher in primed children. The booster dose was well-tolerated and no safety concern was identified. We further assessed persistence using rSBA across different age groups and detected no overall correlation between rSBA and hSBA titers.ConclusionsPrimary vaccination of infants/toddlers with MenACWY-CRM resulted in moderate antibody persistence against serogroups C, W and Y for up to 4 years after the last priming dose. Regardless of priming schedule, a MenACWY-CRM booster dose at 60 months of age induced a robust immune response against all serogroups and was well-tolerated in all children.     

Seroprevalence of antibodies against serogroup C meningococci in the region of Valencia,Spain: Impact of meningococcal C conjugate vaccination

Background and aimsMeningococcal C conjugate (MCC) vaccination programs provide direct and indirect protection against meningococcal disease. However, a decrease in the antibodies could affect herd immunity. We conducted a seroprevalence study to assess the immunity in subjects 8–12 years after different MCCV vaccination programs were launched and evaluated the impact of vaccination on seroprotection.MethodsSeroepidemiological study conducted from October 2010 to April 2012 in the region of Valencia, Spain. Sample size was not proportional to the population but to the expected seroprotection by age group. Sera from subjects that were ≥ 3 years old were tested using a standardized complement-mediated serum bactericidal antibodies (SBA) assay. Age-stratified proportions of subjects with SBA titers ≥ 8 were considered seroprotected and evaluated. A multivariate logistic regression model was performed to evaluate the impact of vaccination on the seroprotection.ResultsSerum samples from 1880 subjects were collected. In total, 523 (27.8%) of the 1880 subjects and 446 (31.2%) of the 1430 subjects < 30 years (targeted to any vaccination campaign) showed protective SBA titers. The highest percentage of seroprotected subjects (67.8%, 95%CI 56.9–77.4) was observed in those that were vaccinated in a catch-up campaign at 10–13 years of age (20–21 years old at the time of blood sampling). Those scheduled for immunization in infancy at 2, 4 and 6 months of age (7–8 years at blood sample) represented the lowest (7.1%, 95% CI 3.3–13.1) number of seroprotected subjects. Having received one vaccine dose after 12 months of age was associated with increased seroprotection. The present study revealed a positive correlation between the increasing age at vaccination and longer duration of seroprotection.ConclusionOnly one in three subjects who were vaccinated with MCC vaccine was seroprotected after 8–12 years. These findings emphasize that seroprevalence studies are essential to identify susceptible cohorts and to inform vaccine policy.     

Immunogenicity,safety and inter-lot consistency of a meningococcal conjugate vaccine (MenACYW-TT) in adolescents and adults: A Phase III randomized study

BackgroundMenACYW-TT is an investigational quadrivalent (serogroups A, C, W and Y) meningococcal conjugate vaccine that is being developed for protection against invasive meningococcal disease.MethodsIn this Phase 3, blinded, randomized study, 3344 meningococcal vaccine-naïve 10–55-year-olds were randomized (3:3:3:2) to receive one of three lots of MenACYW-TT or licensed quadrivalent meningococcal conjugate vaccine, MCV4-DT (NCT02842853). Antibody titers were assessed by human and rabbit complement serum bactericidal antibody assays. The co-primary objectives were to demonstrate lot-to-lot consistency of MenACYW-TT by the between-lot geometric mean titer ratios (GMTR) at Day 30, and non-inferiority of Day 30 vaccine seroresponses (titers ≥ 1:16 if pre-vaccination titers < 1:8, or ≥ 4-fold increase if pre-vaccination titers ≥ 1:8) with MenACYW-TT vs MCV4-DT. Further objectives included safety and immunogenicity.ResultsLot consistency was demonstrated for all three lots, with GMTRs ranging from 0.87 to 1.1. The proportion of participants achieving seroresponse in the MenACYW-TT group (data pooled from the 3 lots) was non-inferior to MCV4-DT (A: 74% vs 55%; C: 89% vs 48%; W: 80% vs 61%; Y: 91% vs 73%, respectively). MenACYW-TT and MCV4-DT had similar safety profiles; no safety concerns were identified.ConclusionsThe study met both co-primary endpoints, demonstrating lot-to-lot consistency and non-inferiority of MenACYW-TT vs MCV4-DT in adolescents and adults.     

A comparative evaluation of two investigational meningococcal ABCWY vaccine formulations: Results of a phase 2 randomized,controlled trial

BackgroundA meningococcal vaccine protective against all major disease-associated serogroups (A, B, C, W and Y) is an unmet public health need. In this phase 2 observer-blinded, randomized, controlled study, two investigational meningococcal ABCWY vaccine formulations were evaluated to assess their immunological noninferiority to a licensed quadrivalent meningococcal ACWY glycoconjugate vaccine (MenACWY-CRM) for serogroups ACWY and immunogenicity against serogroup B test strains, as well as for formulation selection based on a desirability index (DI). Each investigational MenABCWY formulation contained recombinant protein and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine (4CMenB) combined with components of MenACWY-CRM.MethodsA total of 484 healthy 10–25 year-old participants were randomized to receive two doses, two months apart, of an investigational MenABCWY formulation that contained either a full or one-quarter dose of OMV, 4CMenB alone, or a Placebo followed by MenACWY-CRM. Immunogenicity against each of serogroups ACWY and four serogroup B test strains was assessed by serum bactericidal assay with human complement (hSBA). MenABCWY formulations were compared by a DI based on key immunogenicity and reactogenicity parameters.ResultsSeroresponse rates for serogroups ACWY were significantly higher after two doses of either MenABCWY formulation than after one dose of MenACWY-CRM: respectively, A: 90–92% vs. 73%; C: 93–95% vs. 63%; W: 80–84% vs. 65%; and Y: 90–92% vs. 75%. Prespecified noninferiority criteria were met. Both MenABCWY formulations induced substantial immune responses against serogroup B test strains, although 4CMenB responses were higher. Overall DIs for both MenABCWY formulations were similar. Reactogenicity profiles of the MenABCWY formulations were similar to each other and to that of 4CMenB. No vaccine-related serious adverse events were reported.ConclusionsBoth investigational MenABCWY formulations elicited robust immune responses against serogroups ACWY and serogroup B test strains, and had acceptable reactogenicity profiles, with no safety concerns identified.