Safety data from the MenB-FHbp clinical development program in healthy individuals aged 10 years and older

BackgroundThe MenB-FHbp vaccine (Trumenba®) is licensed in various countries for the prevention of meningococcal serogroup B disease in individuals ≥ 10 years of age. The clinical development program included 11 completed trials where, in each trial, MenB-FHbp had an acceptable safety profile after a primary vaccination series was administered to individuals 10–65 years of age. However, the detection of potential rare events was limited because of individual clinical trial size. The current safety analysis evaluates pooled reactogenicity and other adverse events (AEs) reported in these trials to identify new safety signals not detectable in individual trials.MethodsEleven trials contributed safety data, of which 10 recorded local and systemic reactogenicity events; 8 of the trials were controlled, and reactogenicity data were pooled for 7 of these 8 trials. Additional AE evaluations included immediate AEs (IAEs), medically attended AEs (MAEs), serious AEs (SAEs), newly diagnosed chronic medical conditions (NDCMCs), and autoimmune or neuroinflammatory conditions.ResultsLocal and systemic reactions were more frequent in the MenB-FHbp group (n = 15,294) compared with controls (n = 5509), although most reactions were transient and mild to moderate in severity. Frequencies of IAEs, SAEs, MAEs, NDCMCs, and autoimmune or neuroinflammatory conditions were similar between the MenB-FHbp and control groups.ConclusionsMenB-FHbp demonstrated a favorable safety and tolerability profile in the clinical development program of > 15,000 vaccine recipients ≥ 10 years of age. No new safety signals were identified in the pooled analysis compared with data from the individual trials. Continued postmarketing safety surveillance is important for the identification of rare events.Clinicaltrials.gov: NCT01299480; NCT000808028; NCT00879814; NCT00780806; NCT01352845; NCT01352793; NCT01461993; NCT01323270; NCT01830855; NCT01461980; NCT01768117.     

An observational study of antibody responses to a primary or subsequent pertussis booster vaccination in Australian healthcare workers

Adult pertussis vaccination is increasingly recommended to control pertussis in the community. However, there is little data on the duration and kinetics of immunity to pertussis boosters in adults. We compared IgG responses to vaccination with a tetanus, low-dose diphtheria, low-dose acellular pertussis (Tdap) booster at 1 week, 1 month and 1 year post-vaccination in whole-cell (wP)-primed Australian paediatric healthcare workers who had received an adult Tdap booster 5–12 years previously, to those who received their first Tdap booster.Tdap vaccination was well tolerated in both groups. Previously boosted adults had significantly higher pre-vaccination IgG concentrations for all vaccine-antigens, and more were seropositive for pertussis toxin (PT)-specific IgG (≥ 5 IU/mL) (69.5%; 95% confidence interval (CI) 59.5–79.5) than adults in the naïve group (45.2%; 95% CI 32.8-57.5). Tdap vaccination significantly increased IgG responses 1 month post-vaccination in both groups. This increase was more rapid in previously boosted than in naïve adults, with geometric mean fold-increases in PT-IgG at 1 week post vaccination of 3.6 (95% CI 2.9–4.3) and 2.6 (95% CI 2.2–3.2), respectively. Antibody waning between 1 month and 1 year post-vaccination was similar between groups for IgG specific to PT and filamentous haemagglutinin (FHA), but was faster for IgG against pertactin (PRN) in the naïve group (GMC ratio 0.36; 95% CI 0.31–0.42) than the previously boosted group (GMC ratio 0.45; 95% CI 0.39–0.50). At baseline, all but one adult had protective IgG titres against tetanus toxin (TT) (≥ 0.1 IU/mL), and 75.6% in the previously boosted and 61.3% in the naïve group had protective IgG titres against diphtheria toxoid (DT) of ≥ 0.1 IU/mL.This study shows that pertussis immune memory is maintained up to 12 years after Tdap vaccination in wP-primed Australian adults. There was no evidence that pertussis immune responses waned faster after a booster dose. These findings support current recommendations of repeating Tdap booster vaccination in paediatric healthcare workers at least every 10 years. Clinical trials registry: ACTRN12615001262594.     

非新生儿破伤风诊疗规范

破伤风分为新生儿破伤风和非新生儿破伤风。我国已于2012年消除了新生儿破伤风,但非新生儿破伤风仍是一个严重的公共卫生问题。非新生儿破伤风重症患者在无医疗干预的情况下,病死率接近100%,即使经过积极的综合治疗,全球范围病死率仍为30%~50%,是一种极为严重的潜在致命性疾病。为规范我国非新生儿破伤风诊疗行为,提高医疗质量,保障医疗安全,特制定本规范。本规范包括了非新生儿破伤风的病原学、流行病学、发病机制、临床表现及实验室检查、诊断、鉴别诊断、分级、治疗等方面内容。     

Muscle–Tendon Model with Length History-Dependent Activation–Velocity Coupling

We developed muscle–tendon models incorporating Hill-type structure and length-dependent coupling between activation and velocity. The models were evaluated in electrically stimulated cat soleus muscles. Dynamic model parameters were estimated by a nonlinear parameter estimation algorithm from input–output data obtained during simultaneous random stimulation and length changes. Static parameters were estimated from the length–tension curve. A model with length history-dependent activation–velocity coupling predicted the behavior of the muscle under a wide variety of conditions, including during random perturbations and during isovelocity movements, where it captured short range stiffness and length history-dependent postyielding behavior. Furthermore, the model predicted twitch responses. The generality of this fixed parameter model makes it especially suitable for simulation and feedforward control, where muscle responses are not available for on-line parameter adaptation.     

14型肺炎球菌荚膜多糖-破伤风类毒素结合疫苗研究

目的：探讨制备肺炎球菌荚膜多糖（PNCPS）－蛋白结合疫苗适宜条件。方法：采用碳二亚胺法将14型PNCPS与破伤风类毒素（TT）结合，将结合物免疫NIH小鼠，用ELISA法检测小鼠血清中抗14例PNCPS的IgG抗体滴度。结果：结合反应产率和结合物中多糖，蛋白含量的测定显示试验成功合成了14型PNCPS－TT结合物，该结合物具有14型PNCPS的血清学特异性，将之免疫小鼠诱生的抗14型PNCPS特异性IgG抗水平显著高于单纯14型PNCPS。结论：试验成功地合成了14型PNCPS－TT结合物，本试验采用的结合方法可行。     

Effect of Encephalitogenic Protein, PPD, and Tetanus Toxoid on Leukocyte Migration in Agarose

The reactivity to three antigens: bovine encephalitogenic protein (EP), PPD, and tetanus toxoid, was studied with blood leukocytes from healthy humans using Clausen's (5) leukocyte migration in agarose technique. There is an obvious correlation between the reactivity to EP (all concentrations studied) and to low concentrations of PPD; and between the reactivity to low concentrations of EP and low concentrations of tetanus toxoid. After vaccination with tetanus vaccine, a marked increase in reactivity to the toxoid sometimes occurred: at the same time, a marked reactivity to EP appeared. Various explanations are discussed: a true immunological cross-reactivity, that the correlations are due to a variability in individual response with respect to lymphokine production, and that BCG and tetanus vaccinations produce an adjuvant effect increasing a pre-existing low reactivity to EP.     

Active Immunization Against Gonadotropin-Releasing Hormone Combined With Androgen Supplementation Is a Promising Antifertility Vaccine for Males

ABSTRACT: Male rats and rabbits were immunized against gonadotropin-releasing hormone (GnRH) conjugated to tetanus toxoid (GnRH-TT) using only materials approved for humans. Testosterone (T)-releasing implants or the long-lasting T ester testosterone-17-trans-4-n-butyl-cyclohexane carboxylate (TE) was used as supplemental androgen for maintaining libido. Immunization against GnRH-TT effectively suppressed fertility (spermatogenesis) in rats and rabbits. Neither T nor TE administration restored fertility. Both androgens were effective in maintaining normal libido in rats. TE, which is not hydrolyzed in rabbits, was less effective in maintaining normal ejaculatory behavior in this species. Active immunization against GnRH could be a convenient and cost-effective method of fertility control in males.     

用破伤风毒素免疫荧光法显示体外培养的神经细胞

用破伤风毒素和异硫氰酸荧光素标记马抗破伤风血清可以特异地显示体外培养的神经细胞。市售马抗破伤风血清经标记后效果满意。培养神经细胞先固定,后做免疫荧光染色,形态保存较好,荧光反应仍很满意。     

育龄期妇女接种破伤风类毒素血清学效果初步研究

为了评价育龄期妇女破伤风类毒素 (TT)突击接种的效果 ,并采用血清学回顾性研究探讨TT免疫应答 ,从而为开展育龄期妇女TT常规接种及制定育龄期妇女TT免疫策略提供科学依据。采用间接血凝方法 ,按容量比例概率抽样 ,随机抽取 36 7名 15～ 35岁育龄期妇女测定血清破伤风抗毒素 (TAT)水平。结果显示 ,5 6 %的育龄期妇女具有保护水平TAT(>0 0 1IU/ml) ,TAT几何平均滴度 (GMT)为 0 0 73IU/ml。接种 1针TT后育龄期妇女TAT >0 0 1IU/ml的占 5 0 % ,GMT为 0 0 39IU/ml;接种 2针TT后育龄期妇女TAT >0 0 1IU/ml的占 6 8% ,GMT为 0 14 5IU/ml,37个月后可检测到TAT ;接种 3针TT后育龄期妇女TAT>0 0 1IU/ml的占 90 % ,GMT为 0 5 76IU/ml,37个月后仍可检测到TAT ;育龄期妇女接种TT各剂次的TAT水平差异有显著的统计学意义。不同接种剂次免疫接种间隔、免疫年龄的TAT水平差异无显著统计学意义。建议 :提高重点地区和育龄期妇女中重点人群TT接种率 ;尽快开展TT常规接种 ;确定重点免疫人群策略     

rCTB和TT为蛋白载体的A群流脑多糖黏膜免疫初步研究

目的 对重组霍乱毒素B亚单位(rCTB)作为多糖蛋白结合疫苗候选载体的可行性进行分析,并对以破伤风类毒素(TT)与rCTB为蛋白载体的黏膜投递型疫茸的免疫效果进行初步探讨.方法 首先通过基因工程手段获得具有五聚体结构的rCTB.再将rCTB五聚体蛋白利用化学方法(ADH方法)与A群脑膜炎球菌多糖(GAMP)耦联,获得多糖蛋白结合物GAMP-rCTB,并将其与TT为蛋白载体的A群流脑多糖蛋白结合物(GAMP-TT)以滴鼻和注射途径免疫BALB/c小鼠,并对其进行免疫学评价.结果 以rCTB和TT为载体的A群流脑多糖蛋白结合物,通过黏膜投递途径均可在血清中产生相对较高的多糖特异性IgG抗体,在肺部盥洗液和小肠黏膜也产生了相应的特异性IgA抗体.结论 rCTB和TT均可作为黏膜投递型多糖结合疫苗的候选蛋白载体.以rCTB为载体的多糖蛋白结合物,黏膜途径可能在免疫功能方面优于注射途径.