Primary vaccination in adult patients after allogeneic hematopoietic stem cell transplantation – A single center retrospective efficacy analysis

Allogeneic hematopoietic stem cell transplantation (alloHSCT) results in a loss of humoral immunity and subsequent risk for severe infections. Thus, re-vaccination is required but may fail due to incomplete immune reconstitution. We retrospectively analyzed predictors of immune response to primary vaccination applied according to the EBMT (European Blood and Marrow Transplantation Group) recommendations. Serologic response to vaccination against diphtheria (D), tetanus (T), Bordetella pertussis (aP) and Haemophilus influenzae (Hib) (administrated as combined DTaP-Hib-IPV vaccination) was studied in 84 alloHSCT patients transplanted between 2008 and 2015 (age at alloHSCT: 18.6–70.6 years). All patients with a relapse-free survival of ≥9 months, at least 3 consecutive vaccinations and absence of intravenous immunoglobulin administration within 3 months before and after vaccination met the primary inclusion criteria. Additionally, immunological response to a pneumococcal conjugate vaccine was analyzed in a subgroup of 67 patients. Patients’ characteristics at the time of first vaccination were recorded. Responses were measured as vaccine-specific antibody titers. Regarding DTaP-Hib-IPV vaccination, 89.3% (n = 75) of all patients achieved protective titers to at least 3 of the 4 vaccine components and were thus considered responders. 10.7% (n = 9) of the patients were classified as non-responders with positive immune response to less than 3 components. Highest response was observed for Hib (97.4%), tetanus (95.2%) and pneumococcal vaccination (83.6%) while only 68.3% responded to vaccination against Bordetella pertussis. Significant risk factors for failure of vaccination response included low B cell counts (p < 0.001; cut-off: 0.05 B cells/nl) and low IgG levels (p = 0.026; mean IgG of responders 816 mg/dl vs. 475 mg/dl of non-responders). Further, a trend was observed that prior cGvHD impairs vaccination response as 88.9% of the non-responders but only 54.7% of the responders had prior cGvHD (p = 0.073). The results demonstrate, that the currently proposed vaccination strategy leads to seroprotection in the majority of alloHSCT patients.     

Non-typeable Haemophilus influenzae protein vaccine in adults with COPD: A phase 2 clinical trial

Loss of airway microbial diversity is associated with non-typeable Haemophilus influenzae (NTHi) infection and increased risk of exacerbation in chronic obstructive pulmonary disease (COPD). We assessed the safety and immunogenicity of an investigational vaccine containing NTHi antigens, recombinant protein D (PD) and combined protein E and Pilin A (PE-PilA), and AS01 adjuvant in adults with moderate/severe COPD and prior exacerbations.In this phase 2, observer-blind, controlled trial (NCT02075541), 145 COPD patients aged 40–80 years randomly (1:1) received two doses of NTHi vaccine or placebo 60 days apart, on top of standard care.Reactogenicity in the 7-day post-vaccination period was higher following NTHi vaccine than placebo. Most solicited adverse events (AEs) were mild/moderate. At least one unsolicited AE was reported during the 30-day post-vaccination period by 54.8% of NTHi vaccine and 51.4% of placebo recipients. One serious AE (placebo group) was assessed by the investigator as vaccine-related. Anti-PD, anti-PE and anti-PilA geometric mean antibody concentrations increased up to 30 days after each NTHi vaccine dose, waned thereafter, but remained higher than baseline (non-overlapping confidence intervals) up to 13 months post-dose 2. The frequency of specific CD4⁺ T cells increased following two doses of NTHi vaccine and remained higher than baseline. Exploratory analysis showed a statistically non-significant lower yearly rate of moderate/severe exacerbations in the NTHi vaccine group than following placebo (1.49 versus 1.73) in the one-year period post-dose 2, with estimated vaccine efficacy of 13.3% (95% confidence interval −24.2 to 39.5; p = 0.44).The NTHi vaccine had an acceptable safety and reactogenicity profile and good immunogenicity in adults with COPD.     

Vaccine timeliness and prevalence of undervaccination patterns in children ages 0–19 months,U.S., National Immunization Survey-Child 2017

ObjectivesTypically, early childhood vaccination coverage in the U.S. is measured as the proportion of children by age 24 months who completed recommended vaccine series. However, these measures do not reflect whether vaccine doses were received at the ages recommended by the U.S. Advisory Committee on Immunization Practices, or whether children received vaccines concomitantly, per the ACIP recommended schedule. This study’s objective was to quantify vaccine timeliness and prevalence of specific patterns of undervaccination in U.S. children ages 0–19 months.MethodsUsing 2017 National Immunization Survey-Child data, we calculated days undervaccinated for the combined 7-vaccine series and distinguished undervaccination patterns indicative of parental vaccine hesitancy, such as spreading out vaccines across visits (“shot-limiting”) or starting some but not all recommended vaccine series (“selective vaccination”), from other non-hesitancy patterns, such as missing final vaccine doses or receiving all doses, with some or all late. We measured associations between demographic, socioeconomic and other characteristics with undervaccination patterns using multivariable log-linked binomial regression. Analyses accounted for the complex survey design.ResultsAmong n = 15,333 U.S. children, only 41.2% received all recommended vaccine doses on-time by age 19 months. Approximately 20.9% of children had an undervaccination pattern suggestive of parental vaccine hesitancy, and 36.2% had other undervaccination non-hesitancy patterns. Uninsured children and those with lower levels of maternal education were more likely to exhibit undervaccination patterns suggestive of parental hesitancy. Lower levels of maternal education were also associated with other non-hesitancy undervaccination patterns.ConclusionsMore than half of children in the U.S. are undervaccinated at some point by 19 months of age. Ongoing assessment of vaccine timeliness and immunization schedule adherence could facilitate timely and targeted public health interventions in populations with high levels of undervaccination.     

Effect of HIV-exposure and timing of antiretroviral treatment initiation in children living with HIV on antibody persistence and memory responses to Haemophilus influenzae type b and pneumococcal polysaccharide-protein conjugate vaccines

BackgroundWe investigated the effect of in utero HIV-exposure, timing of antiretroviral treatment (ART) initiation, and ART interruption on memory responses and persistence of immunity induced by pneumococcal (PCV) and Haemophilus influenzae type b (HibCV) polysaccharide-protein conjugate vaccines.MethodsChildren were enrolled (6–12 weeks of age), and vaccinated with a three-dose primary series of 7-valent PCV (PCV7) and HibCV at 6, 10 and 14 weeks of age. Study groups included infants infected with HIV perinatally with CD4+ ≥ 25% initiating ART following immunological or clinical deterioration (ART-Def), or immediately upon enrolment followed by interruption at 40 (ART-Immed/40w) or 96 weeks (ART-Immed/96w); and HIV-uninfected infants with (HEU), and without HIV (HIV-unexpsoed) exposure in utero. Within each group, children were randomized to receive either a booster dose of PCV7 or HibCV at 15 months of age. PCV serotype-specific and polyribosyl ribitol phosphate (PRP) IgG were measured pre-boost, two-weeks post-boost and at two-years of age. Opsonophagocytic activity (OPA) to serotypes 9V, 19F and 23F was measured post-booster dose.ResultsPersistence of IgG to PCV vaccine–serotypes and anti-PRP was similar in all groups of children living with HIV (CLWH) compared to HIV-unexposed children. Anamnestic responses to PCV and HibCV were also similar in all three groups of CLWH compared to HIV-unexposed children. CLWH, however, tended to have lower functional antibody (OPA) titers than HIV-unexposed children after the PCV booster dose for some serotypes. Immunity to PCV and HibCV was similar between the ART-Immed/40w and ART-Immed-96w groups. There were no differences in IgG kinetics between HEU and HIV-unexposed children.ConclusionsA three dose primary series, with or without PCV or HibCV booster doses in CLWH initiated on ART during infancy, would likely be similarly effective in preventing invasive bacterial disease as in HIV-unexposed children.     

Improving knowledge and trust in vaccines: A survey-based assessment of the potential of the European Union Clinical Trial Regulation No 536/2014 plain language summary to increase health literacy

The European Clinical Trial Regulation No 536/2014 is the first mandate for a non-technical, publicly disclosed, plain language summary (PLS) of clinical trial results. This easy-to-understand summary has the potential to inform the public about clinical trial results and thereby improve health literacy in vaccines.To investigate the utility of the PLS, we undertook 2 online surveys (July/October 2020) in the United Kingdom, the United States and India. Participants were selected by quota sampling to ensure representation of gender, age and parental status. Those lacking interest in vaccine clinical research were excluded. In survey 1, participants were questioned about their interest in and expectations of vaccine trial results. In survey 2, the perceptions of participants to a range of written communication styles used in publicly available PLSs were evaluated.A total of 66 (13%) and 122 (29%) individuals were excluded solely due to lack of interest in vaccine clinical research in surveys 1 and 2, respectively; 450 respondents (150/country) completed survey 1 and 300 (100/country) completed survey 2. In survey 1, there was a correlation (p < 0.01) between claimed knowledge of and trust in vaccines. Healthcare professionals were the most trusted source for vaccine information, while vaccine companies were ranked relatively low. In survey 2, infographic PLS formats were considered easiest to understand, most engaging and the strongest communicators. Emphasizing the main points of the infographics in the text did not improve comprehension or recall. Most respondents (86%) indicated that they would like to see this type of communication in the future.Overall, this research suggests that the PLS, by optimizing content and format, has a potential to increase health literacy, and thereby, as part of a wider integrated communication strategy, build vaccine knowledge and confidence.     

Vaccines do not cause atopic dermatitis: A systematic review and meta-analysis

BackgroundPrevious studies found conflicting results about the association of vaccinations and likelihood of atopic dermatitis (AD).ObjectivesTo determine whether vaccinations increase the likelihood of AD.MethodsA systematic review was performed of all published studies in MEDLINE, EMBASE, LILACS, Scopus, and Web of Science databases. At least 2 reviewers conducted title/abstract, full-text review, and data extraction. Quality of evidence was assessed using the Newcastle-Ottawa Scale (NOS).ResultsForty-four studies met inclusion criteria; 37 had sufficient data for meta-analysis. There were no associations any vaccine regimen (random-effects logistic regression: odds ratio [95% confidence interval]: 0.961 [0.822–1.124]; n = 21 studies) BCG (0.927 [0.701–1.226]; n = 8), pertussis (0.790 [0.416–1.499]; n = 4), single (1.031 [0.920–1.155]; n = 17) or multiple vaccines (0.902 [0.608–1.338]; n = 7) with likelihood of AD. This remained true in studies with high-quality (NOS ≥ 7) (OR [95% CI]: 0.941 [0.793–1.117]; n = 13 studies) or low-quality (NOS < 7) (OR [95% CI]: 1.058 [0.669–1.674]; n = 8 studies).LimitationsNo randomized controlled trials.ConclusionsNo vaccine regimen was consistently associated with developing AD.     

Prevalence of β-lactamase-nonproducing ampicillin-resistant <Emphasis Type="Italic">Haemophilus influenzae</Emphasis> and <Emphasis Type="Italic">Haemophilus influenzae</Emphasis> type b strains obtained from children with lower respiratory tract infections

The prevalence of strains with ampicillin (ABPC) resistance among Haemophilus influenzae strains isolated from the nasopharynx of children with lower respiratory tract infections has increased significantly during the 6 years from 2000, when it was 41.9%, to 2005, when it reached 60.1%. From 2002, the prevalence exceeded 50%, and the prevalence of β-lactamase-nonproducing ABPC-resistant (BLNAR) strains with a minimum inhibitory concentration (MIC) of ABPC of over 4 μg/ml doubled, from 28.2% in 2002 to 54.7% in 2005. In H. influenzae strains obtained from the nasopharynx of children with lower respiratory tract infections between April 2004 and March 2006, identification of serotype b was defined, using the slide agglutination method. The frequency of isolation of H. influenzae type b (Hib) strains was then measured and the ABPC resistance conditions of the Hib strains were also evaluated. The frequency of the Hib strains was found to be 30 out of 479 strains, 6.3%. Of these 30 strains, BLNAR accounted for 53.3% (16 strains), approximately the same frequency of isolation as that of the BLNAR isolated from all H. influenzae strains during the same period. In Japan, the prevalence of BLNAR strains among clinically isolated H. influenzae strains has continued to increase, and the frequency of isolation of BLNAR strains among Hib strains has also continued to rise. As a countermeasure, attempts at improving resistance have been made through judicious antibiotic use, but concern that the choice of antibiotics for Hib meningitis may become complicated has sparked a keen interest in the introduction of Hib conjugate vaccine. Part of this report was presented at the fifty-fourth general meeting of the Japanese Society of Chemotherapy (Kyoto, May 2006).     

肺炎支原体肺炎患儿口咽部常见细菌及临床意义北大核心CSCD

目的:了解肺炎支原体肺炎(MPP)患儿口咽部常见细菌及临床意义。方法:回顾性分析。选取中国医科大学附属盛京医院小儿呼吸内科2016年12月至2017年6月住院治疗的134例MPP患儿为研究对象,选取同期同医院42例健康儿童为健康对照组。采用荧光定量聚合酶链反应Taqman探针法检测入组儿童口咽部常见细菌[肺炎链球菌(SP)、卡他莫拉杆菌(CTA)、流感嗜血杆菌(HI)]。首先比较MPP患儿及健康儿童口咽部细菌检出情况,再将134例MPP患儿根据年龄(<1岁、1~<3岁、3~<6岁及6~14岁)、有无细菌检出[肺炎支原体(MP)、MP+细菌]及检出菌种不同(MP+SP、MP+CTA及MP+HI)进行分组比较。采用秩和检验及 χ^(2)检验对相关临床资料进行分析。 结果:134例MPP患儿检出细菌79例(58.96%),42例健康儿童检出细菌17例(40.48%),差异有统计学意义( χ^(2)=4.404, P<0.05)。与MP组相比,MP+细菌组外周血中白细胞(WBC)水平[8.5(6.7,12.0)×10^(9)/L比7.8(5.8,9.3)×10^(9)/L, Z=-2.232]、C反应蛋白(CRP)水平[19.2(7.2,35.0) mg/L比8.4(3.4,24.6) mg/L, Z=-2.810]、乳酸脱氢酶(LDH)水平[286(244,365) U/L比250(210,302) U/L, Z=-2.474]及大叶性肺炎比例[40.51%(32/79例)比18.18%(10/55例), χ^(2)=7.510]、胸腔积液比例[13.92%(11/79例)比3.64%(2/55例), χ^(2)=3.917]、难治性肺炎支原体肺炎(RMPP)比例[34.18%(27/79例)比18.18%(10/55例), χ^(2)=4.151]均较高;总热程[10(7,12) d比8(6,10) d, Z=-2.706]及抗生素使用时间[16(13,19) d比12(9,16) d, Z=-3.747]均较长,差异均有统计学意义(均 P<0.05)。MP+SP组外周血中WBC高于MP+HI组[12.20(7.80,17.30)×10^(9)/L比6.75(5.37,9.44)×10^(9)/L],差异有统计学意义( Z=11.574, P<0.05);MP+SP组[56.67%(17/30例)]大叶性肺炎发生率高于MP+CTA组[0(0/3例)]和MP+HI组[18.75%(3/16例)],差异有统计学意义( χ^(2)=9.770, P<0.05)。 结论:MPP患儿口咽部更易发生细菌定植或感染,当WBC、CRP及LDH均明显升高,影像表现为大片实变影或有胸腔积液时,提示可能混合细菌感染,热程更长,难治性MPP比例增高,且常见的混合细菌为SP。     

桉柠蒎对慢性阻塞性肺疾病大鼠肺功能和气道细菌负荷的影响

目的：探讨桉柠蒎与慢性组塞性肺疾病（ COPD）大鼠肺功能及气道细菌负荷的影响。方法：将雄性Wistar大鼠120只分为对照组（正常喂养12周）、模型组、预防组和治疗组,后3组给予熏烟12周,预防组大鼠在熏烟前30 min给予桉柠蒎灌胃,治疗组大鼠熏烟第9周后给予桉柠蒎灌胃,烟熏12周后,通过小动物肺功能议检测第0.3秒用力呼气容积与用力肺活量的百分比（ FEV0.3/FVC）、功能残气量（ FRC）等肺功能指标;将4组大鼠统一气管滴入流感嗜血杆菌混悬液,并于接种后3h、6h、12h和24h时取其左肺胞灌洗液和右肺组织匀浆接种于巧克力培养基培养,计数细菌菌落。结果：预防组和治疗组FRC明显低于模型组,预防组改善更为显著（P＜0.01）;模型组的支气管肺泡灌洗液（ BALF）和肺组织匀浆的菌落计数在各时间点均明显高于对照组（ P＜0.01）;预防组和治疗组的 BALF和肺组织匀浆的菌落计数较模型组明显降低,且预防组下降更为显著（P ＜0.01）;各组菌落计数均于种菌后6 h时达到高峰,种菌后3 h、12 h、24 h时的肺匀浆菌落计数与FRC呈正相关（P＜0.01）,FEV0.3/FVC与6 h的肺匀浆菌落计数呈负相关（P＜0.05）。结论：桉柠蒎能改善肺泡过度充气,但短期内应用不能延缓肺功能的下降趋势或改善肺功能,桉柠蒎可以降低COPD大鼠气道的细菌负荷,预防给药效果更优;气道细菌负荷受肺功能的影响,肺功能越差,细菌负荷越重。     

Treatment strategies for central nervous system infections: an update

Introduction: Central nervous system infection continues to be an important cause of mortality and morbidity worldwide. Our incomplete knowledge on the pathogenesis of how meningitis-causing pathogens cause CNS infection and emergence of antimicrobial resistance has contributed to the mortality and morbidity. An early empiric antibiotic treatment is critical for the management of patients with bacterial meningitis, but early recognition of bacterial meningitis continues to be a challenge.

Areas covered: This review gives an overview on current therapeutic strategies for CNS infection with a focus on recent literature since 2010 on bacterial meningitis. Bacterial meningitis is a medical emergency, requiring early recognition and treatment. The selection of appropriate empiric antimicrobial regimen, after incorporating the epidemiology of bacterial meningitis, impact of vaccination, emergence of antimicrobial-resistant bacteria, role of adjunctive therapy and the current knowledge on the pathogenesis of meningitis and associated neuronal injury are covered.

Expert opinion: Prompt treatment of bacterial meningitis with an appropriate antibiotic is essential. Optimal antimicrobial treatment of bacterial meningitis requires bactericidal agents able to penetrate the blood–brain barrier, with efficacy in cerebrospinal fluid. Emergence of CNS-infecting pathogens with resistance to conventional antibiotics has been increasingly recognized, but development of new antibiotics has been limited. More complete understanding of the microbial and host factors that are involved in the pathogenesis of bacterial meningitis and associated neurologic sequelae is likely to help in developing new strategies for the prevention and therapy of bacterial meningitis.