血清杀菌试验和酶联免疫吸附试验测定C群脑膜炎奈瑟菌血清抗体滴度比较

目的 比较血清杀菌试验(SBA)和酶联免疫吸附试验(ELISA)测定两种C群脑膜炎奈瑟菌(Nm)疫苗免疫后血清抗体滴度的差异.方法 采用SBA测定75名未免疫健康成年人(40～70岁)血清、143名3～8月龄婴儿及194名3～5岁儿童NmA和C群结合疫苗或A+C群多糖疫苗免疫前后血清中Nm杀菌抗体水平,然后用ELISA测定相应血清的Nm特异性IgG含量,并利用线性相关与回归分析两种测定结果的相关性.结果 未免疫健康成年人血清中Nm杀菌抗体水平和特异性IgG含量之间的相关性较高(r=0.814 33,P＜0.001);3～8月龄婴儿和3～5岁儿童接种结合/多糖疫苗前,Nm杀菌抗体水平和特异性IgG含量之间相关性较差(3～8月龄:r=0.140 64,P＞0.l00/r=0.2899,P＜0.05;3 ～5岁:r=0.540 40,P＜0.05/r=0194 36,P＜0.05),接种1剂结合疫苗后,杀菌抗体水平和特异性IgG含量之间的相关性较好(r=0.809 38,P＜0.001和r=0.837 23,P＜0.001);接种多糖疫苗后,杀菌抗体水平和特异性IgG含量之间的相关性较差(r＜0.500 00).结论 健康成年人血清和结合疫苗免疫后的婴幼儿血清中特异性C群Nm IgG含量可以间接反映血清杀菌抗体水平,ELISA方法可以替代SBA.但ELISA检测方法不适用于3～8月龄婴儿多糖疫苗免疫后的效果评价.     

Association of serum bactericidal antibody and opsonic antibody levels after Neisseria meningitidis serogroup C conjugate vaccine in Brazilian children and adolescents infected or not infected with HIV

Neisseria meningitidis serogroup C (MenC) is the main causative agent of meningitis in Brazil. HIV infection affects the quality of the immune system. HIV⁺ children have an increased risk of infection to encapsulated bacteria such as N. meningitidis. We evaluated the opsonic antibody (OPA) levels and its correlation with serum bactericidal antibody (SBA) levels induced by one and two doses of a MenC conjugate vaccine in children and adolescents HIV⁺ and HIV-exposed but uninfected children (HEU) group. Overall the data show the importance of two doses of vaccine for HIV⁺ individuals. About 79% and 58% of HIV⁺ patients showed SBA and OPA positive response after two doses of vaccine, respectively. For HEU group, 62% and 41% of patients showed SBA and OPA positive response after one dose of vaccine, respectively. A positive and significant association between SBA and OPA levels was seen after two doses of vaccine in HIV⁺ patients.     

A putative amino acid ABC transporter substrate-binding protein,NMB1612, from Neisseria meningitidis,induces murine bactericidal antibodies against meningococci expressing heterologous NMB1612 proteins

The nmb1612 (NEIS1533) gene encoding the ∼27-kDa putative amino acid ATP-binding cassette (ABC) transporter, periplasmic substrate-binding protein from Neisseria meningitidis serogroup B (MenB) strain MC58 was cloned and expressed in Escherichia coli, and the purified recombinant (r)NMB1612 was used for animal immunization studies. Immunization of mice with rNMB1612 adsorbed to Al(OH)₃ and in liposomes with and without MPLA, induced antiserum with bactericidal activity in an assay using baby rabbit complement, against the homologous strain MC58 (encoding protein representative of Allele 62) and killed heterologous strains encoding proteins of three other alleles (representative of Alleles 1, 64 and 68), with similar SBA titres. However, strain MC58 was not killed (titre <4) in a human serum bactericidal assay (hSBA) using anti-rNMB1612 sera, although another strain (MC168) expressing the same protein was killed (median titres of 16–64 in the hSBA). Analysis of the NMB1612 amino acid sequences from 4351 meningococcal strains in the pubmlst.org/Neisseria database and a collection of 13 isolates from colonized individuals and from patients, showed that antibodies raised against rNMB1612 could potentially kill at least 72% of the MenB strains in the complete sequence database. For MenB disease occurring specifically in the UK from 2013 to 2015, >91% of the isolates causing disease in this recent period expressed NMB1612 protein encoded by Allele 1 and could be potentially killed by sera raised to the recombinant antigen in the current study. The NMB1612 protein was surface-accessible and expressed by different meningococcal strains. In summary, the properties of (i) NMB1612 protein conservation and expression, (ii) limited amino acid sequence variation between proteins encoded by different alleles, and (iii) the ability of a recombinant protein to induce cross-strain bactericidal antibodies, would all suggest a promising antigen for consideration for inclusion in new meningococcal vaccines.     

Tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine is well tolerated and immunogenic when co-administered with measles-mumps-rubella-varicella vaccine during the second year of life: An open, randomized controlled trial

Co-administration of meningococcal ACWY-tetanus toxoid conjugate vaccine (ACWY-TT) with MMRV vaccine was investigated in 1000 12-23-month old children randomized (3:3:1:1) to receive co-administered ACWY-TT + MMRV, or a single dose of ACWY-TT, MMRV or MenC-CRM₁₉₇. Non-inferiority of ACWY-TT to MenC-CRM₁₉₇ and non-inferiority of ACWY-TT + MMRV to ACWY-TT and MMRV alone, and the immunogenicity of serogroups AWY were demonstrated according to pre-defined criteria. Fever reactions in ACWY + MMRV and MMRV groups were comparable. ACWY-TT can be co-administered with MMRV without affecting immunogenicity or safety profiles of either vaccine.This study has been registered at www.clinicaltrials.gov NCT00474266.     

A dose-range study assessing immunogenicity and safety of one dose of a new candidate meningococcal serogroups A,C, W-135, Y tetanus toxoid conjugate (MenACWY-TT) vaccine administered in the second year of life and in young children

Meningococcal disease incidence is highest in young children, yet a tetravalent conjugate vaccine is currently not available for this age group. This study evaluated a single dose of four different ACWY-TT conjugate vaccine formulations in 240 toddlers (12–14 months) and 268 children (3–5 years) compared to licensed age-appropriate control vaccines. In toddlers, rSBA-MenC GMTs for the selected formulation were statistically higher than after monovalent-MenC-conjugate vaccine. In children, rSBA-GMTs against each serogroup were statistically higher than after tetravalent polysaccharide vaccine. The safety profile was comparable to licensed controls. The new ACWY-TT conjugate vaccine promises high seroprotection levels against meningococcal disease from 1 year of age.     

Cost-effectiveness of meningococcal polysaccharide serogroups A,C, W-135 and Y conjugate vaccine in Australian adolescents

ObjectivesThe incidence of invasive meningitis disease (IMD) is increasing in Australia. A conjugate vaccine of meningococcal polysaccharide serogroups A, C, W and Y (MenACWY) is currently indicated for infants aged 12 months on the Australian National Immunisation Program. This study sought to determine the cost-effectiveness of a broader MenACWY vaccination program for Australians aged 15 to 19 years.MethodsA Markov model was constructed to simulate the incidence and consequences of IMD in Australians aged 0–84 years, with follow up until age 85 years. The model comprised four health states: ‘Alive with no previous IMD’, ‘Alive, post IMD without long-term complications’, ‘Alive, post IMD with long-term complications’ and ‘Dead’. Decision analysis compared the clinical consequences and costs of a vaccination program versus no vaccination from the perspective of the Australian health care system. Age-specific incidence of IMD and fatality rates were derived from Australian surveillance data. Vaccine coverage, vaccine efficacy and herd immunity were based on published data. The total cost for MenACWY vaccination was AU$56 per dose. Costs and health outcomes were discounted by 5% per annum (in the base-case analysis).ResultsCompared to no vaccination, a MenACWY vaccination program targeted at Australians aged 15–19 years was expected to prevent 1664 IMD cases in the Australian population aged 0–84 years followed up until age 85 years. The program would lead to 1131 life years (LYs) and 2058 quality adjusted life years (QALYs) gained at a total cost of AU$115 million (all discounted values). These equated to incremental cost-effectiveness ratios of AU$101,649 per LY gained and AU$55,857 per QALY gained. A probabilistic sensitivity analysis demonstrated a likelihood of cost-effectiveness of 34.6%, assuming a willingness to pay threshold of AU$50,000 per QALY gained.ConclusionThe likelihood of this program being cost-effective under a willingness to pay threshold AU$50,000 per QALY gained is 35%.     

C群脑膜炎奈瑟菌血清杀菌力试验的优化及其应用

目的 优化血清杀菌力试验方法,检测和分析A+C群脑膜炎球菌多糖疫苗接种前后人群血清对C群脑膜炎奈瑟菌(Nm)的杀菌抗体水平.方法 以C群Nm疫苗株(C11)和中国目前C群Nm流行株(053442)作为靶菌,国家Nm标准品测试血清为参考血清,选用Pel-Freez幼兔补体,确定靶菌最适工作浓度.122人接种A+C群脑膜炎球菌多糖疫苗前后分别采集血清标本,共244份,进行C群Nm杀菌抗体水平的检测.结果 菌株C11和053442均可作为靶菌用于血清杀菌力试验;靶菌的工作浓度为A 0.35(600 nm)的菌液稀释4×104倍;A+C群脑膜炎球菌多糖疫苗接种前,122份血清对C11和053442的杀菌抗体几何平均滴度(GMT)分别为1:1.75和1:2.63,人群抗体保护率分别为9.8%和17.2%,A+C群脑膜炎球菌多糖疫苗接种后,122份血清的杀菌抗体GMT和人群保护率均显著升高(P<0.01),对疫苗株和流行株的杀菌抗体GMT分别为1:483.73和1:412.57,保护率分别为100%和95.9%.结论 接种A+C群脑膜炎球菌多糖疫苗,能够显著提高人群对不同亚型的C群Nm的抵抗力,但仍需要针对不同的靶菌进行疫苗免疫效果的监测.     

血清杀菌试验和酶联免疫吸附试验测定C群脑膜炎奈瑟菌血清抗体滴度比较

目的比较血清杀菌试验(SBA)和酶联免疫吸附试验(ELISA)测定两种C群脑膜炎奈瑟菌(Nm)疫苗免疫后血清抗体滴度的差异。方法采用SBA钡fJ定75名未免疫健康成年人(40～70岁)血清、143名3—8月龄婴儿及194名3—5岁儿童NmA和C群结合疫苗或A+C群多糖疫苗免疫前后血清中Nm杀菌抗体水平,然后用ELISA测定相应血清的Nm特异性lgG含量,并利用线性相关与回归分析两种测定结果的相关性。结果未免疫健康成年人血清中Nm杀菌抗体水平和特异性lgG含量之问的相关性较高(r-O．814 33,P<0．001);3～8月龄婴儿和3—5岁儿童接种结合／多糖疫苗前,Nm杀菌抗体水平和特异性IgG含量之间相关性较差(3．8月龄：r=O．140 64,P>0．100／r=O．2899,P<0．05;3—5岁：r=0．54040．P<0．0S／r=0．94 36,P<0．05),接种l剂结合疫苗后,杀菌抗体水平和特异性lgG含量之问的相关性较好(r=O．80938,P结论健康成年人血清和结合疫苗免疫后的婴幼儿血清中特异性C群NmlgG含量可以间接反映血清杀菌抗体水平,ELISA方法可以替代SBA。但ELISA检测方法不适用于3—8月龄婴儿多糖疫苗免疫后的效果评价。     

Immune responses following meningococcal serogroups A,C, Y and W polysaccharide vaccination in C2-deficient persons: Evidence for increased levels of serum bactericidal antibodies

Complement C2 deficiency (C2D) is associated with immunological diseases and increased susceptibility to invasive infections caused by encapsulated bacteria such as Neisseria menigitidis. In this study we evaluate the immunogenicity of vaccination against N. menigitidis in C2D.C2D patients (n = 22) and controls (n = 52) were given a tetravalent meningococcal polysaccharide vaccine. Serum bactericidal antibody (SBA) titres (serogroups A, C, Y and W) were analysed using a rabbit complement source. Levels of IgG, IgM, and IgA, factor B, and factor H, polymorphisms of MBL and Fc-gamma receptors were determined.The C2D patients responded with an increased SBA titre to all four serogroups (p < 0.001). The response rates define as SBA titres ≥8 were found to be between 85.7% and 92.5%. The post-vaccination titres for serogroups C, Y and W were equal to healthy controls. C2D patients with a history of invasive infection had a lower post-vaccination SBA titres both compared to healthy C2D persons (p = 0.03) and compared to controls (p < 0.0001). We found that the G2M*n/G2M*n genotype were associated with a higher SBA titres after immunization (p = 0.03). None of the other investigated immunological factors appear to be important in influencing the vaccine responses. Autoimmune diseases in C2D did not affect the vaccine response.In general, vaccination against meningococci gave rise to antibody responses in the C2D patients that equal healthy controls. The response rate was lower to serogroup A and among C2D patients with history of invasive infections. The presence of G2M*n/G2M*n genotype was associated with higher SBA titres after immunization.     

江苏省14岁以下健康儿童脑膜炎奈瑟菌A、C、W135、Y群抗体水平保护性分析

目的 通过检测江苏省健康儿童脑膜炎奈瑟菌A、C、W₁₃₅、Y群抗体水平,了解人群免疫状况,评价疫苗接种效果。 方法 分层随机抽样的方式抽取淮安、盐城两市14岁以下健康儿童517名,采用间接ELISA测定脑膜炎奈瑟菌A、C、W₁₃₅、Y群多糖抗体IgG。用SPSS 20.0进行统计分析。 结果 脑膜炎奈瑟菌(Neisseria meningitides,Nm)A、C、W₁₃₅、Y群抗体达到2 μg/ml保护性水平的健康儿童比例分别为:76.02%、65.38% 、29.21%、45.26%;抗体几何平均浓度(geometric mean concentration,GMC)分别为4.59、2.90、1.06、1.55 μg/ml。不同年龄组之间Nm A、C群抗体浓度差异有统计学意义(F=14.118、32.008,P＜0.05);抗体浓度≥2 μg/ml的受试者所占比例差异有统计学意义(χ²=31.745、41.354,P＜0.05);抗体 GMC和达保护性抗体水平比例最高的皆为6~岁年龄组。各年龄组NmW₁₃₅、Y抗体浓度差异以及抗体浓度≥2 μg/ml儿童的百分比差异则均无统计学意义(F=2.558, F=0.611; χ²=0.800, χ²=1.896;P>0.05)。不同免疫史组别,Nm A、C抗体浓度差异有统计学意义(F=11.021、22.421,P＜0.05),抗体浓度≥2 μg/ml的儿童百分率差异有统计学意义(χ²=41.578、46.300,P＜0.05);均随着免疫次数递增而增加。 结论 现行我国脑膜炎球菌疫苗的预防接种可获得一定的针对A、C群脑膜炎奈瑟菌的免疫保护,但免疫应答强度及免疫持久性仍存在不足。建议继续提高脑膜炎球菌疫苗免疫效力及扩大型别覆盖范围,同时进一步调整免疫策略,阻止脑膜炎奈瑟菌的传播流行。