Immunogenicity and safety of one or two doses of the quadrivalent meningococcal vaccine MenACWY-TT given alone or with the 13-valent pneumococcal conjugate vaccine in toddlers: A phase III,open-label,randomised study

BackgroundWe evaluated the immunogenicity and safety of 1 and 2 doses of quadrivalent meningococcal serogroup A, C, W and Y tetanus toxoid-conjugate vaccine (MenACWY-TT) given alone or co-administered with 13-valent pneumococcal conjugate vaccine (PCV13) in toddlers.MethodsIn this phase III, open-label, controlled, multicentre study (NCT01939158), healthy toddlers aged 12–14 months were randomised into 4 groups to receive 1 dose of MenACWY-TT at month (M) 0 (ACWY_1), 2 doses of MenACWY-TT at M0 and M2 (ACWY_2), MenACWY-TT and PCV13 at M0 (Co-ad), or PCV13 at M0 and MenACWY-TT at M2 (PCV13/ACWY). Immune responses were assessed 1 month post-each vaccination. Solicited and unsolicited symptoms were recorded for 4 and 31 days post-each vaccination, respectively; serious adverse events (SAEs) and new onset of chronic illnesses (NOCIs) up to M9 from first vaccination.Results802 toddlers were vaccinated. Post-dose 1 of MenACWY-TT, ≥92.8% of toddlers had rSBA titres ≥1:8, and ≥62.5% had hSBA titres ≥1:4 for each meningococcal serogroup. Post-dose 2 of MenACWY-TT, rSBA titres ≥1:8 were observed in ≥98.0% and hSBA titres ≥1:4 in ≥95.3% of toddlers. Percentages of toddlers with hSBA titres ≥1:4 were higher after 2 doses versus 1 dose of MenACWY-TT for MenW (97.1% versus 62.5–68.9%) and MenY (95.3% versus 64.3–67.6%). Non-inferiority of immune responses to co-administered MenACWY-TT and PCV13 over their separate administration was demonstrated. AEs incidence was comparable among groups. SAEs were reported for 4.9%, 5.1%, 5.5% and 7.5%, and NOCIs for 2.0%, 3.0%, 0.5% and 3.5% of toddlers in the ACWY_1, ACWY_2, Co-ad and PCV13/ACWY groups, respectively; 4 SAEs reported in 3 toddlers were vaccine-related. Two fatal vaccine-unrelated SAEs were reported.ConclusionMenACWY-TT was immunogenic when administered as a single dose at 12–14 months of age. A second dose in toddlers increased hSBA responses against MenW and MenY. MenACWY-TT and PCV13 can be co-administered without impairing the immunogenicity or safety profile of either vaccine.     

加速度肌松仪的预刺激方式对维库溴铵药效测定的影响

目的：观察加速度肌松监测仪的预刺激方法对维库溴铵药效测定的影响。方法30名女性患者分为三组,各10例。在同一患者的两手均放置肌松监测,随机选其中一手作为对照手,先给5 s,50 Hz强直刺激,然后行AUTO I校准,再给20 min TOF监测。每分钟记录一次T1值,第20分钟T1值分别与前各次用配对t检验比较。患者另一手为试验手,分为3组,在AUTO I校准后分别给予20 min（组一）、1 min（组二）和6 min（组三）TOF刺激。组一每分钟记录一次T1值,第20分钟T1值分别与前各次用配对t检验比较。然后用累积剂量法测定同一患者两手的维库溴铵ED50、ED90、ED95和斜率（Probit/LOG）。用配对t检验行自身比较。结果在20 min TOF预刺激期间,对照手T1稳定,但试验手最初T1逐渐增加,第6分钟后稳定。维库溴铵的ED50、ED90、ED95和斜率在组一和组三两手间差异无统计学意义（P〉0.05）,组二则对照手数值明显小于试验手（P〈0.05）。结论5 s、50 Hz强直刺激可迅速使T1值稳定,否则需6 min才能使T1值稳定,当T1值稳定后,维库溴铵药效测定不受预刺激方法影响。     

Does prior immunization with measles,mumps, and rubella vaccines contribute to the antibody response to COVID-19 antigens?

Background: Incidence and severity of SARS-CoV2 infection are significantly lower in children and teenagers proposing that certain vaccines, routinely administered to neonates and children may provide cross-protection against this emerging infection. Objective: To assess the cross-protection induced by prior measles, mumps and rubella (MMR) vaccinations against COVID-19. Methods: The antibody responses to MMR and tetanus vaccines were determined in 53 patients affected with SARS-CoV2 infection and 52 age-matched healthy subjects. Serum levels of antibodies specific for NP and RBD of SARS-CoV2 were also determined in both groups of subjects with ELISA. Results: Our results revealed significant differences in anti-NP (p <0.0001) and anti-RBD (p <0.0001) IgG levels between patients and healthy controls. While the levels of rubella- and mumps specific IgG were not different in the two groups of subjects, measles-specific IgG was significantly higher in patients (p <0.01). The serum titer of anti-tetanus antibody, however, was significantly lower in patients compared to healthy individuals (p <0.01). Conclusion: Our findings suggest that measles vaccination triggers those B cells cross-reactive with SARS-CoV2 antigens leading to the production of increased levels of measles-specific antibody.     

Safety and immunogenicity of a fully liquid vaccine containing five-component pertussis-diphtheria-tetanus-inactivated poliomyelitis-Haemophilus influenzae type b conjugate vaccines administered at two, four, six and 18 months of age

OBJECTIVE: The safety, immunogenicity and lot consistency of a fully liquid, five-component acellular pertussis combination vaccine, comprised of diphteria, tetanus and acellular pertussis, inactivated polio vaccine, Haemophilus influenzae type b (DTaP-IPV-Hib [Pediacel, sanofi pasteur, Canada]) were assessed and compared with that of Hib vaccine reconstituted with the five-component acellular pertussis combination vaccine (DTaP-IPV//Hib, Pentacel [sanofi pasteur, Canada]). METHODS: Infants were recruited at vaccine study centres in Montreal, Quebec; Simon Fraser Health Region, British Columbia, and southern Alberta after the protocol had been approved by the relevant institutional ethics committees. Written informed consent was obtained from the parents or guardians of all subjects. At two months of age, the infants were randomly assigned to receive one of three consecutive production lots of DTaP-IPV-Hib by intramuscular injection. Reactions to vaccinations were assessed by parental observation and through telephone interviews conducted by study nurses. Blood samples were obtained at two, six, seven, 18 and 19 months of age for measurement of antibodies to vaccine antigens. RESULTS: Most injection site and systemic reactions were mild or moderate, and of brief duration. All infants were protected against tetanus, diphtheria and all three polio serotypes after both primary and booster vaccinations. Antibody responses to pertussis antigens were similar to those observed in Swedish infants, in whom the five-component vaccine was shown to be 85% effective. Proportions of infants with antipolyribosylribitol phosphate antibody of 0.15 mug/mL or greater and 1.0 mug/mL or greater, were 97.9% and 88.9%, respectively, following primary immunization, and 100% and 99% following booster vaccination. Safety and immunogenicity results with both reconstituted and fully liquid combination vaccines were comparable. CONCLUSIONS: The fully liquid combination vaccine was comparable in terms of safety and immunogenicity with the reconstituted combination vaccine.     

Heat shock increases antigenic peptide generation but decreases antigen presentation

The heat shock response is a universal and highly conserved cellular response to stress. We describe here the effect of elevated temperature on the capacity of B cells to present antigen. Heat shock markedly affects the ability of these cells to process and present tetanus toxin to class II-restricted T cell clones. Inhibition of antigen presentation is due neither to a modification of antigen capture nor to a variation of major histocompatibility complex (MHC) class II molecule synthesis and cell surface expression. Stressed and nonstressed B cells are able to present peptides loaded at the cell surface with the same efficiency. Nevertheless, heat shock leads to an increase of antigen peptide generation in subcellular compartments; an enhancement of cathepsin B activity is also observed. These data suggest that such a stress induces a failure in the intracellular peptide loading onto MHC class II molecules.     

静脉吸毒致破伤风临床特点分析

目的比较分析静脉吸毒所致破伤风与常见的外伤引起的破伤风在临床表现、诊断、治疗上的不同点.方法 15例静脉吸毒所致破伤风与24例外伤引起的破伤风的临床特点和治疗方案进行比较分析.结果静脉吸毒所致破伤风与常见的外伤引起的破伤风相比,没有明确的外伤史,临床症状复杂,常合并其他血源性传染病.结论静脉吸毒所致破伤风有特殊的症状,在诊断和治疗上应分别对待.     

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.     

Comparison of CRM197, diphtheria toxoid and tetanus toxoid as protein carriers for meningococcal glycoconjugate vaccines

Glycoconjugate vaccines are among the most effective and safest vaccines ever developed. Diphtheria toxoid (DT), tetanus toxoid (TT) and CRM₁₉₇ have been mostly used as protein carriers in licensed vaccines. We evaluated the immunogenicity of serogroup A, C, W-135 and Y meningococcal oligosaccharides conjugated to CRM₁₉₇, DT and TT in naïve mice. The three carriers were equally efficient in inducing an immune response against the carbohydrate moiety in immunologically naïve mice. The effect of previous exposure to different dosages of the carrier protein on the anti-carbohydrate response was studied using serogroup A meningococcal (MenA) saccharide conjugates as a model. CRM₁₉₇ showed a strong propensity to positively prime the anti-carbohydrate response elicited by its conjugates or those with the antigenically related carrier DT. Conversely in any of the tested conditions TT priming did not result in enhancement of the anti-carbohydrate response elicited by the corresponding conjugates. Repeated exposure of mice to TT or to CRM₁₉₇ before immunization with the respective MenA conjugates resulted in a drastic suppression of the anti-carbohydrate response in the case of TT conjugate and only in a slight reduction in the case of CRM₁₉₇. The effect of carrier priming on the anti-MenA response of DT-based conjugates varied depending on their carbohydrate to protein ratio. These data may have implications for human vaccination since conjugate vaccines are widely used in individuals previously immunized with DT and TT carrier proteins.     

Challenges and opportunities for the implementation of the Three Rs in Canadian vaccine quality control

A case-study approach was used to identify opportunities and challenges to the implementation of the Three Rs in vaccine testing in Canada. Data was obtained through interviews with 16 Canadian stakeholders involved in the production, testing and evaluation of vaccines. Participants identified inconsistent regulatory testing requirements, the lack of biological functionality of some in vitro methods, the benchmarking of in vitro against in vivo assays, and high caution towards method changes as major challenges to implementation. Opportunities to implementation were identified as the desire for and steps taken towards harmonization of test methods between countries, collaborations on new method development, the poor performance of traditional animal methods, the domino effect of one regulatory authority accepting a method after another, and stakeholder concerns for the ethical care and use of animals used in vaccine testing. These results suggest that industry and the Canadian government are open to implementing the Three Rs in vaccine quality control, but methods adopted must be reliable and biologically relevant. Improving the harmonization of regulatory requirements will assist in furthering the implementation of alternative methods.     

Attendance and vaccination at immunization clinics in rural Gambia before and during the COVID-19 pandemic

IntroductionThe COVID-19 pandemic has affected the delivery of essential health services, such as routine immunization. We assessed the impact of the pandemic on the uptake of routine immunization in rural Gambia.MethodsWe collected real-time vaccine administration data in the Basse and Fuladu West Health & Demographic Surveillance Systems from September 01, 2019, to December 31, 2020. We assessed the monthly number of Expanded Program on Immunization (EPI) clinic attendances and vaccines administered, comparing data during the baseline period (September 01, 2019–March 31, 2020), COVID-19 interruption period (April 01–June 30, 2020), initial recovery period (Jul 01–September 30, 2020) and the late recovery period (October 01–December 31, 2020).ResultsCompared to the baseline period, there was an overall average monthly decline of 13.4% in EPI attendance and 38.3% reduction in average monthly immunizations during the interruption period. This decrease was particularly noticeable for Bacille Calmette-Guérin (BCG) (47.2%), birth dose hepatitis B (Hep B) (46.9%), 1st dose pentavalent (Penta1) (43.1%), 1st dose pneumococcal conjugate vaccine (PCV1) (42.4%), and measles vaccines (15.5%). Comparing the late recovery to baseline period, average monthly EPI attendance was 5.3% higher, with 1.9% increase in average monthly immunizations. Monthly immunizations for BCG were 3.0% greater, 2.5% greater for Hep B, 22.7% greater for oral polio vaccine (OPV1), 2.0% less for Penta1, 19.2% less for Penta2, and 2.6% less for PCV1.ConclusionThe reduced EPI attendance during the pandemic interruption period lasted only 3 months. Significant recovery in EPI attendance occurred during the late recovery period, while rates of monthly immunization returned to pre-pandemic levels for most antigens. EPI programmes should implement strategies to deliver missed antigens when infants do present to EPI clinics, aware that missed doses may be age dependent.