Efficacy,immunogenicity, and safety of available vaccines in children on biologics: A systematic review and meta-analysis

Vaccinations are essential for preventing infectious diseases in children with chronic diseases as they have increased risk of infection from frequent use of biologics. Response to immunizations in this group is not well known.ObjectiveA systematic review was performed to evaluate three primary outcomes: efficacy; immunogenicity; and safety of vaccines in children with chronic conditions treated with biologics.MethodsThe protocol for our systematic review and meta-analysis was registered and published with PROSPERO. We searched electronic bibliographic databases for studies published from 2009 to 2019, focusing on vaccinations in children with chronic conditions treated with biologics.ResultsWe retrieved 532 records. Thirty-one full-text articles were selected, and 14 were included in the meta-analysis. No significant publication bias was found. Efficacy: limited data are available regarding the efficacy of vaccination, as most studies have focused on immunogenicity as surrogate outcome for efficacy. Immunogenicity: patients receiving anti-TNF-alpha therapy had a statistically significant risk of poor seroconversion (p = 0.028) and seroprotection by the serotype B influenza vaccine [inflammatory bowel disease (IBD) p = 0.013; juvenile idiopathic arthritis (JIA) p = 0.004]. We found adequate responses with H1N1 and H3N2 serotypes. Few studies existed for pneumococcal, hepatitis A virus, hepatitis B virus, varicella-zoster virus, Measles Mumps Rubella virus, and multiple vaccine administration. Safety: vaccine administration was not associated with serious side effects, but JIA patients on anti-TNF alpha therapy had a statistically significant risk of presenting with myalgia or arthralgia postinfluenza vaccine (p = 0.014).ConclusionsMore evidence concerning efficacy, immunogenicity, and safety of vaccinations is needed to guide physicians in the vaccine decision process for this pediatric population.     

放疗干预对宫颈癌荷瘤小鼠的抑瘤作用及对Th1/Th2免疫细胞比例的影响

目的探讨放疗干预对宫颈癌荷瘤小鼠的抑瘤作用及其对辅助性T细胞1(Th1)/Th2细胞比例的影响。方法建立宫颈癌荷瘤小鼠模型,随机分为荷瘤组和放疗组,每组各10只,另设对照组10只。放疗组进行放疗干预14天,荷瘤组和对照组不治疗。放疗后4、6、8、10、12、14天测量肿瘤体积;末次治疗后,ELISA法测定血清干扰素-γ(IFN-γ)、白介素-2(IL-2)、IL-4、IL-10含量;计算抑瘤率、胸腺指数和脾脏指数;HE染色观察肿瘤组织学变化;TUNEL染色观察肿瘤组织细胞凋亡情况;流式细胞术检测脾脏Th1/Th2细胞比例;RT-qPCR和Western blot检测脾脏T盒子转录因子(T-bet)、GATA结合蛋白3(GABA-3)mRNA和蛋白表达。结果与荷瘤组比较,放疗组小鼠4、6、8、10、12、14天肿瘤体积及瘤质量减小,血清IL-2、IFN-γ升高,IL-4、IL-10降低,胸腺指数、脾脏指数升高,Th1细胞比例、Th1/Th2增加,Th2细胞比例减少,T-bet mRNA和蛋白及T-bet/GATA-3表达升高,GATA-3 mRNA和蛋白表达降低(P<0.05)。HE染色显示,荷瘤组肿瘤细胞数量较多,核大深染,无明显坏死;放疗组肿瘤细胞数量减少,出现大量坏死组织。TUNEL染色显示,荷瘤组TUNEL阳性细胞较少,放疗组TUNEL阳性细胞明显增多。结论放疗对宫颈癌荷瘤小鼠具有明显抑瘤作用,可能是通过调节T-bet/GATA-3表达,促进Th1/Th2分化平衡,增强机体免疫功能发挥作用。     

Diagnostic significance of the histopathology of bone marrow macrophages in forensic autopsies

Forensic pathologists often encounter autopsies that require an assessment of antemortem general conditions (e.g., infection, metabolic disorders). To establish evaluation clues for such cases, we quantitatively examined macrophages and the general pathology of bone marrow in samples from 180 forensic autopsy cases of decedents with various conditions. Hematoxylin-eosin staining, Berlin blue staining, and immunostainings for CD163, CD138, and CD61 were performed. We determined the numbers per field (density) of total macrophages, swollen macrophages, macrophages with hemophagocytosis, and hemosiderin-laden macrophages. Each density was standardized by identifying its ratio to the total number of macrophages. The decedents' background data (cause of death, other pathological findings, postmortem interval, antemortem symptoms, and presence of resuscitation) were extracted. No correlations were found between the postmortem interval and the other decedent data, indicating that these data are not affected by postmortem changes. In the group in which inflammatory disease was the cause of death, there were significant elevations in the ratio of the swollen macrophage density to total macrophages. Significantly higher ratios of the density of swollen and hemophagocytic macrophages were observed in the group in which conditions with a prolonged agonal period were the cause of death. The group with a return of spontaneous circulation to resuscitation showed a significantly higher ratio of macrophage density with hemophagocytosis. This study provides the first statistical analysis focused on bone marrow histopathology in forensic autopsies. The results will be useful for elucidating causes of death and agonal-period conditions.     

ArgD of Mycobacterium tuberculosis is a functional N-acetylornithine aminotransferase with moonlighting function as an effective immune modulator

Mycobacterium tuberculosis (M. tuberculosis) encodes an essential enzyme acetyl ornithine aminotransferase ArgD (Rv1655) of arginine biosynthetic pathway which plays crucial role in M. tuberculosis growth and survival. ArgD catalyzes the reversible conversion of N-acetylornithine and 2 oxoglutarate into glutamate-5-semialdehyde and L-glutamate. It also possesses succinyl diaminopimelate aminotransferase activity and can thus carry out the corresponding step in lysine biosynthesis. These essential roles played by ArgD in amino acid biosynthetic pathways highlight it as an important metabolic chokepoint thus an important drug target. We showed that M. tuberculosis ArgD rescues the growth of ΔargD E. coli grown in minimal media validating its functional importance. Phylogenetic analysis of M. tuberculosis ArgD showed homology with proteins in gram positive bacteria, pathogenic and non-pathogenic mycobacteria suggesting the essentiality of this protein. ArgD is a secretory protein that could be utilized by M. tuberculosis to modulate host innate immunity as its moonlighting function. In-silico analysis predicted it to be a highly antigenic protein. The recombinant ArgD protein when exposed to macrophage cells induced enhanced production of pro-inflammatory cytokines TNF, IL6 and IL12 in a dose dependent manner. ArgD also induced the increased production of innate immune effector molecule NOS2 and NO in macrophages. We also demonstrated ArgD mediated activation of the canonical NFkB pathway. Notably, we also show that ArgD is a specific TLR4 agonist involved in the activation of pro-inflammatory signaling for sustained production of effector cytokines. Intriguingly, ArgD protein treatment activated macrophages to acquire the M1 phenotype through the increased surface expression of MHCII and costimulatory molecules CD80 and CD86. ArgD induced robust B-cell response in immunized mice, validating its antigenicity potential as predicted by the in-silico analysis. These properties of M. tuberculosis ArgD signify its functional plasticity that could be exploited as a possible drug target to combat tuberculosis.     

国产隐球菌荚膜多糖胶体金法检测试剂盒性能评价

目的评价由丹娜(天津)生物科技股份有限公司生产的隐球菌荚膜多糖检测试剂盒(胶体金法,考核试剂)的检测性能。方法选取隐球菌和隐球菌近缘菌及肺部感染常见菌种共28属100株菌作为研究对象,配制0.5麦氏浊度单位(0.5 M)菌液检测试剂的特异性,0.5 M阳性的菌株以10倍倍比稀释液作为灵敏度检测菌液,以2 M和4 M浓度菌液作为钩状效应检测菌液,并以美国Immuno Mycologics公司生产的隐球菌抗原检测(胶体金免疫层析法)试剂盒作为对比试剂,比较两家试剂的一致性。结果31株隐球菌属菌株中,考核试剂检测出阳性25株(新型隐球菌和格特隐球菌均为阳性),阴性6株(维多利亚隐球菌、C.dimennae和大隐球菌);16株毛孢子菌属菌株中,检测出阳性12株,阴性4株;1株Cutaneotrichosporon curvatum检测结果为阳性;52株其他菌株的检测结果均为阴性;灵敏度实验结果显示考核试剂隐球菌最低检出限为1.0×10² CFU/mL;2 M和4 M浓度菌液均未出现钩状效应。结论考核试剂隐球菌荚膜多糖检测试剂盒(胶体金法)检测隐球菌属的灵敏度高于比对试剂;特异性方面存在一定的属内和属外交叉反应,但与对比试剂的检测结果高度一致;考核试剂与比对试剂均无钩状效应产生。     

芫根调节免疫功能的小肠转录组学研究

利用生物信息学技术初步探索芫根调控肠道免疫功能的分子生物学机制。方法 选择雄性SPF级BALB/c小鼠18只，随机分为3组，每组6只。SC1组小鼠每只每次灌胃芫根提取液150 μL，SC2组小鼠每只每次灌胃绞碎芫根原浆悬液150 μL，NC组小鼠每只每次灌胃生理盐水150 μL，连续7 d每日灌胃一次。分别取每组小鼠小肠组织样品提取RNA，总RNA的质检合格后，进行转录组测序。按GO功能和KEGG信号通路对差异表达基因聚类分析揭示差异表达高度富集的免疫相关通路。从免疫角度分析芫根灌胃小鼠小肠组织的基因表达变化情况。结果 转录组测序共检测到27733条 mRNA的表达，SC1组与NC组比较，显著差异表达基因1635个，其中上调差异表达基因1236个，下调差异表达基因399个；SC2组与NC组比较，显著差异表达基因2872个，其中上调差异表达基因2233个，下调差异表达基因639个（P＜0.05）。按GO功能和KEGG信号通路聚类分析显示差异表达基因在白介素分泌、干扰素反应、T细胞受体信号通路及维生素和脂肪消化吸收等途径的富集度在两个芫根组中均居于前20位（P＜0.01），肠黏膜趋化因子CCL20和巨噬细胞极化标志物CD274等免疫蛋白编码基因差异表达显著且同属于上述多个免疫通路。结论 芫根灌胃小鼠小肠的差异表达基因在白介素分泌、干扰素反应、T细胞受体信号通路、营养物质消化吸收等途径高度富集，提示芫根对肠道免疫系统及肠黏膜功能的调节，其中CD274的表达上调和CCL20的表达下调提示诱导M1型巨噬细胞极化和T细胞活化可能是芫根调控免疫和维护肠道正常结构功能的重要途径。     

Compliance to Advisory Committee on Immunization Practices recommendations for pneumococcal vaccination

We evaluated compliance to the ACIP pneumococcal vaccination recommendations issued in 2014 for adults aged ≥ 65 years and in 2012 for adults with high-risk (HR) conditions. The MarketScan® Commercial and Medicare Supplemental databases (January 2007-June 2019) were used to identify the cohorts of interest. Analyses for adults aged ≥ 65 years were adjusted to account for missing vaccination history. Two HR cohorts were identified. The HR1 cohort included patients with immunocompromising conditions, functional or anatomic asplenia, cerebrospinal fluid leak, or cochlear implant. The HR2 cohort included patients with chronic heart, lung, or liver disease; diabetes mellitus; alcoholism; cirrhosis; or cigarette smoking. Full compliance for those aged ≥ 65 years or in the HR1 cohort was defined as receipt of PCV13 and PPSV23, and partial compliance was defined as receipt of PCV13 or PPSV23. For those in the HR2 cohort, full compliance was defined as receipt of PPSV23. Annual compliance rates were estimated using the Kaplan–Meier method.Among those aged ≥ 65 years, partial compliance at 4 years post index was 53% and full compliance was 17% in adjusted analyses. In subjects ≥ 65 years receiving the first vaccination, 42% received the second vaccination by year 4. For the HR1 cohort, partial compliance was 19% and full compliance was 5% at 6 years post index date. For the HR2 cohort, full compliance was 20% at 6 years, with the highest rate in patients with diabetes (27%) and the lowest rate in patients with alcoholism (8%).Additional efforts are needed to maximize compliance to the ACIP pneumococcal vaccine recommendations among adults ≥ 65 years of age and adults with HR conditions including streamlined recommendations and single-dose vaccines. These efforts may subsequently reduce the incidence and burden of pneumococcal disease.     

刮痧力度及时间间隔对刮痧效果的影响

目的:观察不同力度对刮痧效果的影响,初步探讨刮痧的作用机制以及效应周期,进一步探究刮痧治疗的最佳间隔时间。方法:用自制的特殊刮痧板控制使刮痧频次等参数保持一致,分别以1N、3N和9N的力进行刮痧,通过ELISA方法检测刮痧后IL-1α、IL-6的变化,结合皮肤HE染色法探究不同力度刮痧对机体的影响,选择适合的刮痧力度,通过血常规和流式细胞术检测刮痧后不同时间点的白细胞总数、淋巴细胞总数及T细胞亚群等的变化,初步探讨刮痧的作用机制和效应周期。结果:1N的力度刮痧未引起明显的变化,9N的力度刮痧造成了较严重的皮肤损伤和大量炎性反应因子释放,3N的力度刮痧较为适中,引起了机体适度的应激反应。以3N的力度刮痧后,血液中白细胞总数和淋巴细胞总数及IL-1α、IL-6缓慢升高,在1 h到24 h之间达到峰值,之后缓慢下降,在72 h左右恢复正常水平。结论:3N的力比较适合于刮痧实验,在刮痧之后1 h到24 h,刮痧对免疫系统的增强作用达到峰值,在72 h左右回归正常值,初步提示可以开始下一次刮痧治疗。     

TcVac1 vaccine delivery by intradermal electroporation enhances vaccine induced immune protection against Trypanosoma cruzi infection in mice

The efforts for the development and testing of vaccines against Trypanosoma cruzi infection have increased during the past years. We have designed a TcVac series of vaccines composed of T. cruzi derived, GPI-anchored membrane antigens. The TcVac vaccines have been shown to elicit humoral and cellular mediated immune responses and provide significant (but not complete) control of experimental infection in mice and dogs. Herein, we aimed to test two immunization protocols for the delivery of DNA-prime/DNA-boost vaccine (TcVac1) composed of TcG2 and TcG4 antigens in a BALB/c mouse model. Mice were immunized with TcVac1 through intradermal/electroporation (IDE) or intramuscular (IM) routes, challenged with T. cruzi, and evaluated during acute phase of infection. The humoral immune response was evaluated through the assessment of anti-TcG2 and anti-TcG4 IgG subtypes by using an ELISA. Cellular immune response was assessed through a lymphocyte proliferation assay. Finally, clinical and morphopathological aspects were evaluated for all experimental animals. Our results demonstrated that when comparing TcVac1 IDE delivery vs IM delivery, the former induced significantly higher level of antigen-specific antibody response (IgG2a?+?IgG2b?>?IgG1) and lymphocyte proliferation, which expanded in response to challenge infection. Histological evaluation after challenge infection showed infiltration of inflammatory cells (macrophages and lymphocytes) in the heart and skeletal tissue of all infected mice. However, the largest increase in inflammatory infiltrate was observed in TcVac1_IDE/Tc mice when compared with TcVac1_IM/Tc or non-vaccinated/infected mice. The extent of tissue inflammatory infiltrate was directly associated with the control of tissue amastigote nests in vaccinated/infected (vs. non-vaccinated/infected) mice. Our results suggest that IDE delivery improves the protective efficacy of TcVac1 vaccine against T. cruzi infection in mice when compared with IM delivery of the vaccine.     

Interleukin-34 drives macrophage polarization to the M2 phenotype in autoimmune hepatitis

BackgroundAutoimmune hepatitis is a chronic inflammatory disease, the abnormal immunological function is the main pathogenesis. Interleukin-34 is a newly identified cytokine that shares the same receptor as colony stimulating factor-1.MethodsWe used interleukin-34 knockout and wild-type mice in a Con A-induced hepatitis model and cocultured RAW264.7 macrophage cells with interleukin-34. We then detected associated inflammatory cytokine and chemokine levels to elucidate the role of interleukin-34.ResultsIn this study, we found that the loss of interleukin-34 resulted in higher sensitivity to Con A-induced hepatitis. RAW264.7 macrophage cells were able to differentiate to the M2 phenotype upon interleukin-34 stimulation.ConclusionsWe conclude that interleukin-34 may protect the liver from Con A-mediated hepatitis by driving M2 macrophage polarization and suppressing inflammation.