Cell-surface bound pertussis toxin induces polyclonal T cell responses with high levels of interferon-gamma in the absence of interleukin-12

Pertussis toxin (PTx), an exotoxin produced by Bordetella pertussis, has long been used as a mucosal adjuvant. We examined the T cell stimulatory properties of PTx in order to dissect its mechanisms of adjuvanticity. PTx or the B-oligomer of PTx (PTxB) failed to activate purified murine CD4+ or CD8+ T cells, as measured by a lack of proliferation or expression of early T cell activation markers. However, these T cells proliferated extensively in response to the toxin in the presence of syngeneic DC, and proliferation was accompanied by a high level of IFN-gamma production in the absence of IL-12. Interestingly, such responses were independent of signals mediated by MHC-TCR interaction. Both PTx and PTxB were found to bind stably to the surface of DC, and increased the adherence of DC to surrounding cells. These data suggest that polyclonal T cell responses mediated by the toxin are likely to be caused by the toxin bound on the surface of APC, either cross-linking cell surface molecules on T cells, or directly stimulating T cells together with the co-stimulatory molecules expressed on APC. B. pertussis may use this toxin as a mechanism to evade a specific immune response.     

天津市百日咳监测体系介绍及其运行效果的评估

天津市从2009年开始建立百日咳监测体系,10年来不断完善。该监测体系明确了百日咳监测病例的定义及病例分类,建立了统一的、临床上简单可行的采样方法和实验室检测手段,规范了百日咳病例的报告管理及疫情处置措施。该监测体系实施以后,百日咳报告病例数显著上升,由2009年的26例增加到2017年的802例;诊断病例数由2009年的19例增加到2017年的662例;报告百日咳发病率由2009年的0.16/10万增加到2017年的4.28/10万;报告百日咳病例的医疗机构数由2009年的2家增加到2017年的53家;所报告病例的标本采集率达到93.66%。上述监测结果证明该监测体系明显提高了天津市百日咳监测的灵敏度,更加真实准确地反映了天津市百日咳的流行病学特征,为免疫策略的调整提供了参考依据。     

Probiotics and the immunological response to infant vaccinations; a double-blind randomized controlled trial

Objectives

To examine the effect of a combination of probiotics on the antibody response to pneumococcal and pertussis vaccination in healthy Danish children, aged 8–14 months, at the time of starting day care. Moreover, the cytokine response to lipopolysaccharide of whole blood was assessed.

Economic impact of implementing decennial tetanus toxoid,reduced diphtheria toxoid and acellular pertussis (Tdap) vaccination in adults in the United States

BackgroundIn the United States, persons ≥11 years are recommended to receive one dose of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine, followed by decennial tetanus- and diphtheria-toxoid (Td) boosters. Many providers use Tdap instead of Td. We evaluated epidemiologic and economic impacts of replacing Td boosters with Tdap.MethodsWe used a static cohort model to examine replacing Td with Tdap over the lifetime of 4,386,854 adults ≥21 years. Because pertussis is underdiagnosed and true incidence is unknown, we varied incidence from 2.5 cases/100,000 person-years to 500 cases/100,000 person-years. We calculated vaccine and medical costs from claims data. We estimated cost per case prevented and per quality-adjusted life year (QALY) saved; sensitivity analyses were conducted on vaccine effectiveness (VE), protection duration, vaccine cost, disease duration, hospitalization rates, productivity loss and missed work. We did not include programmatic advantages resulting from use of a single tetanus-toxoid containing vaccine.ResultsAt lowest incidence estimates, administering Tdap resulted in high costs per averted case ($111,540) and QALY saved ($8,972,848). As incidence increased, cases averted increased and cost per QALY saved decreased rapidly. With incidence estimates of 250 cases/100,000 person-years, cost per averted case and QALY saved were $984 and $81,678 respectively; at 500 cases/100,000 person-years, these values were $427 and $35,474. In multivariate sensitivity analyses, assuming 250 cases/100,000 person-years, estimated cost per QALY saved ranged from $971 (most favorable) to $217,370 (least favorable).ConclusionsOur findings suggest that replacing Td with Tdap for the decennial booster would result in high cost per QALY saved based on reported cases. However, programmatic considerations were not accounted for, and if pertussis incidence, which is incompletely measured, is assumed to be higher than reported through national surveillance, substituting Tdap for Td may lead to moderate decreases in pertussis cases and cost per QALY.     

Timeliness and equity of infant pertussis vaccination in wales: Analysis of the three dose primary course

Infants aged under one year are at the highest risk of severe complications or death from pertussis infection. Prompt vaccination with a three dose course at two, three and four months of age decreases the amount of time they are vulnerable following waning of maternal antibodies. In Wales, uptake of all three doses of the primary course of pertussis containing vaccine is high. However, timeliness and equity at a population level have not been previously reported.This analysis included 163,733 children born from 1st January 2013 to 31st December 2017. In this cohort 87.9% received the first dose of a pertussis containing vaccine by 12 weeks of age, 87.1% had received all three doses by 24 weeks of age, and 96.3% received three doses by 52 weeks of age.Differences in uptake between those living in the most deprived and least deprived quintiles of Lower Super Output Area (LSOA) were smaller than differences in timeliness, but statistically significant. In 2017 the difference in timely uptake between those living in the most and least deprived quintiles was 4%, 5% and 7% for doses one, two and three respectively. There was a difference of 10% in the proportion of infants receiving all three primary vaccinations on time between the most and least deprived quintile of LSOAs.Consideration is needed on interventions that will help improve timeliness such as enhanced follow up of defaulters, electronic communication between primary care data systems, enhanced health visitor intervention and opportunistic vaccination in those who fail to attend scheduled vaccination appointments. There is also the need for routine monitoring of timeliness and further research into what influences delayed vaccination.     

Incidence and mortality of pertussis disease in infants <12 months of age following introduction of pertussis maternal universal mass vaccination in Bogotá, Colombia

BackgroundMaternal immunization with tetanus, diphtheria, and acellular pertussis (Tdap) vaccine confers protection to young infants. We aimed to describe trends in pertussis incidence and associated mortality in children aged <12 months before and after introduction of maternal Tdap immunization in Bogotá, Colombia.MethodsData on pertussis-related cases/deaths in infants aged <12 months were collected from SIVIGILA for the period 2005–2016, and compared incidence for the pre-vaccine introduction (2005–2012) and post-maternal Tdap vaccination (2014–2016) periods in infants aged <12 months and in three distinct age-strata; ≤6 weeks, 7–<28 weeks, and 28–52 weeks. Mortality comparisons were performed in all infants <12 months.ResultsFrom 2005 to 2016, 2315 laboratory or clinically-confirmed pertussis cases were reported in infants <12 months of age (278 cases in young infants aged ≤6 weeks); 55 pertussis deaths were reported in children aged <12 months. No pertussis deaths were reported in the 2014–2016 period. Since maternal Tdap introduction in 2013, a consistent decline in pertussis incidence and mortality was observed. In the time-series analysis, incidence declined from 209.4/100,000 persons (2005–2012) to 49.1/100,000 persons (2014–2016) in all children <12 months; a 87.5% (95%CI: 77.2-93.2%) reduction. For these same period’s incidence in young infants ≤6 weeks declined from 196.7 to 89.6/100,000 person-years (an 54.4% [95% CI: 35.4–67.9%] reduction). Greater incidence reductions were observed in older infants; 73.4% (95% CI: 68.4–77.6%) in those aged 7–<28 weeks, and 100% in those aged 28–52 weeks. A 100% reduction in Pertussis mortality in infants <12 months was observed. Since Tdap introduction, maternal vaccine coverage rose from <60% in 2013–2015 to 80% in 2016.ConclusionsImplementation of maternal immunization in Bogotá may have contributed to the reduction in pertussis incidence and mortality among infants <12 months of age (ClinicalTrials.gov: NCT02569879).An Audio Summary linked to this article that can be found on Figshare https://doi.org/10.6084/m9.figshare.12943316     

Missed opportunities for simultaneous administration of the fourth dose of DTaP among children in the United States

BackgroundSimultaneous administration of all age-appropriate doses of vaccines is an effective strategy for raising vaccination coverage. Vaccination coverage for ≥4 dose of DTaP (diphtheria, tetanus toxoids, and acellular pertussis vaccine) among children 19–35 months in the United States has not reached the Healthy People 2020 target of 90%. Risk factors for missed opportunities for simultaneous administration of the fourth dose of DTaP have not been investigated.MethodsA missed opportunity for simultaneous administration of the fourth dose of DTaP is defined as the failure to administer an age-eligible fourth dose of DTaP, and during the same age-eligible period for the fourth dose of DTaP other recommended and age-appropriate doses of vaccines are given to children. This study used 2001–2014 National Immunization Survey data to describe the trend in missed opportunities for simultaneous administration of the fourth dose of DTaP from 2001 through 2014, assess the prevalence of children who missed opportunities for simultaneous administration of the fourth dose of DTaP by selected factors, and recognize significant risk factors for missed opportunities for simultaneous administration of the fourth dose of DTaP.ResultsFrom 2001 to 2014, the prevalence of missed opportunities for simultaneous administration of the fourth dose of DTaP among children 19–35 months in the United States ranged from 5.7% to 9.0%; across 13 factors considered, the prevalence of missed opportunities varied from 3.3% to 22.9%. Children who were late in receiving the first to third dose of DTaP had significantly higher prevalence of missed opportunities for simultaneous administration of the fourth dose of DTaP than children who received these doses on-time, with adjusted prevalence ratios for late vs. on-time of 1.7, 1.6, and 3.2, and all P-value < 0.01.ConclusionsImproving on-time vaccination of the third dose of DTaP could substantially reduce missed opportunities for simultaneous administration of the fourth dose of DTaP.     

Evaluation of the effectiveness of maternal immunization against pertussis in Alberta using agent-based modeling: A Canadian immunization research network study

IntroductionThe re-emergence of pertussis has occurred in the past two decades in developed countries. The highest morbidity and mortality is seen among infants. Vaccination in pregnancy is recommended to reduce the pertussis burden in infants.MethodsWe developed and validated an agent-based model to characterize pertussis epidemiology in Alberta. We computed programmatic effectiveness of pertussis vaccination during pregnancy (PVE) in relation to maternal vaccine coverage and pertussis disease reporting thresholds. We estimated the population preventable fraction (PFP) of different levels of maternal vaccine coverage against counterfactual ”no-vaccination” scenario. We modeled the effect of immunological blunting and measured protection through interruption of exposure pathways.ResultsPVE was inversely related to duration of passive immunity from maternal immunization across most simulations. In the scenario of 50% maternal vaccine coverage, PVE was 87% (95% quantiles 82–91%), with PFP of 44% (95% quantiles 41–45%). For monthly age intervals of 0–2, 2–4, 4–6 and 6–12, PVE ranged between 82 and 99%, and PFP ranged between 41 and 49%. At 75% maternal vaccine coverage, PVE and PFP were 90% (95% quantiles 86–92%) and 68% (95% quantiles 65–69%), respectively. At 50% maternal vaccine coverage and 10% blunting, PVE and PFP were 86% (95% quantiles 77–87%) and 43% (95% quantiles 39–44%), respectively, while at 50% blunting, the corresponding values of PVE and PFP were 76% (95% quantiles 70–81%) and 38% (95% quantiles 35–40%). PVE attributable to interruption of exposure pathways was 54–57%.ConclusionsOur model predicts significant reduction in future pertussis cases in infants due to maternal vaccination, with immunological blunting slightly moderating its effectiveness. The model is most sensitive to maternal vaccination coverage. The interruption of exposure pathways plays a role in the reduction of pertussis burden in infants due to maternal immunization. The effect of maternal immunization on population other than infants remains to be elucidated.     

Protective effectiveness of an endotoxin-depleted pertussis vaccine

Pertussis vaccine depleted of endotoxin by the polymyxin-Sepharose affinity chromatography method was tested for toxic activity and protective effectiveness in mice. Preparations containing 1000-fold and 1 000 O00-fold less endotoxin fulfilled the established experimental criteria for freedom from toxicity. A fourfold concentrate of the former demonstrated a protection rate only 10% less than that of standard, untreated pertussis vaccine.