Methodological advances in the design of peptide-based vaccines

The tremendous advances in genomics, recombinant DNA technology, bioengineering and nanotechnology, in conjunction with the development of high-end computations, have been instrumental in the process of rational design of peptide-based vaccines. The use of peptide vaccines was limited owing to their inherent instability when systemically administered; however, advanced formulation techniques have been developed for their systemic delivery, thereby overcoming their degradation, clearance, cellular uptake and off-target effects. With the rise of sophisticated immunological predictors and experimental techniques, several methodological advances have occurred in this field. This review examines contemporary methods to identify and optimize epitopes, engineer their immunogenic properties and develop their safe and efficient delivery into the host.     

HLA-B evolutionary divergence is associated with outcomes after SARS-CoV-2 infection

We examined the correlation between class I HLA evolutionary divergence (HED), a surrogate for the capacity to present different peptides, and the outcomes of 234 adult inpatients with confirmed SARS-CoV-2 infection. Genomic DNA was extracted from peripheral blood and genotyped by next-generation sequencing (NGS). HED scores for HLA class I (HLA-A, -B, and -C) genotypes were calculated using Grantham’s distance. Higher HED scores for HLA-B, but not HLA-A or -C, are significantly associated with a decreased probability of poor outcomes including ICU admission, mechanical ventilation, and death (OR = 0.93; P = 0.04) in the univariate analysis. In the multivariate analysis, increased HLA-B HED score, younger age, and no comorbidity were independently associated with favorable outcomes (P = 0.02, P = 0.01, and P = 0.05, respectively). This finding is consistent with the notion that broader peptide repertoires presented by class I HLA may be beneficial in infection control.     

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.     

麻黄附子细辛汤联合常规疗法治疗感染后咳嗽的临床研究

目的探讨麻黄附子细辛汤治疗感染后咳嗽的临床效果。方法选取漯河市郾城区惠生堂门诊部和河南省漯河市第三人民医院呼吸内科于2017年5月—2018年10月诊治的感染后咳嗽患者240例,采用随机数字表法分为两组,对照组患者120例实施常规治疗(退热、吸氧、补液等),观察组患者120例联用麻黄附子细辛汤(紫苏子9 g,射干9 g,地龙9 g,炙麻黄6 g,细辛6 g)治疗,于治疗前后行生化指标(C反应蛋白、白细胞计数、白细胞介素-4)检测和症状(咳嗽、喘息、咳痰、哮鸣音)评分,比较两组患者的症状(咳嗽、喘息、咳痰、哮鸣音)改善时间、临床效果(显效、有效、无效、总有效)、不良反应情况(恶心呕吐、头晕头痛、胃肠道反应)。结果两组治疗后C反应蛋白、白细胞计数、白细胞介素-4、症状评分(咳嗽、喘息、咳痰、哮鸣音)较治疗前显著降低(P<0.05)。观察组治疗后C反应蛋白、白细胞计数、白细胞介素-4、症状评分(咳嗽、喘息、咳痰、哮鸣音)低于对照组(P<0.05)。观察组症状改善时间(咳嗽、喘息、咳痰、哮鸣音)早于对照组(P<0.05)。观察组总有效率(99.2%,119/120)高于对照组(90.0%,108/120)(P<0.05)。结论麻黄附子细辛汤治疗感染后咳嗽的效果显著,可缩短治疗时间并改善病症,值得临床推广使用。     

New immunosuppressive agents in transplantation

Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival.Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection.The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials.Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.     

聚乙二醇干扰素α联合利巴韦林治疗难治性慢性丙型肝炎过程中血常规变化与疗效的相关性

目的观察难治性慢性丙型肝炎标准治疗过程中血常规的变化与抗病毒疗效的关系。方法收集2011年9月-2012年12月于首都医科大学附属北京佑安医院就诊的难治性慢性丙型肝炎初治患者63例,给予聚乙二醇干扰素α-2a(180μg/周)联合利巴韦林治疗48周,分别在基线、治疗4、12、24、48周和随访24周时进行HCV RNA及血常规的检测,分析血常规与疗效的相关性。根据是否获得持续病毒学应答(SVR),分为SVR组和n SVR组。计量资料组间比较采用t检验,计数资料组间比较采用χ2检验;采用简单线性相关分析法进行相关性分析。结果 63例患者有3例失访,余下60例均完成抗病毒治疗和24周随访,其中46例获得SVR,SVR率为76.7%;SVR组患者治疗4、12、24周时的淋巴细胞计数(LYPH)、白细胞计数(WBC)及中性粒细胞计数(NUET)均低于n SVR组,并且在12周时差异均有统计学意义(t值分别为3.398、2.766、2.037,P值均0.05),在24周时两组WBC及NUET差异亦均有统计学意义(t值分别为2.559、2.151,P值均0.05);此外SVR组患者在治疗4周时上述3项指标较基线的下降幅度均大于n SVR组,其中LYPH下降幅度在两组间差异有统计学意义(t=2.26,P=0.03)。LYPH、WBC、NUET在治疗4、12周时与HCV RNA的下降幅度呈正相关(r值分别为0.36、0.45、0.37、0.47、0.61、0.33,P值均0.05)。结论血常规中LYPH、WBC及NEUT的变化及下降幅度在一定程度上可作为难治性慢性丙型肝炎抗病毒疗效的预测指标。     

Innovative immunosuppression in kidney transplantation: A challenge for unmet needs

Due to the optimal results obtained in kidney transplantation and to the lack of interest of the industries, new innovative drugs in kidney transplantation are difficult to be encountered. The best strategy to find the new drugs recently developed or under development is to search in the sections of kidney transplantation still not completely covered by the drugs on the market. These unmet needs are the prevention of delayed graft function (DGF), the protection of the graft over the long time and the desensitization of preformed anti human leukocyte antigen antibodies and the treatment of the acute antibody-mediated rejection. These needs are particularly relevant due to the expansion of some kind of kidney transplantation as transplantation from non-heart beating donor and in the case of antibody-incompatible grafts. The first are particularly exposed to DGF, the latter need a safe desensitization and a safe treatments of the antibody mediated rejections that often occur. Particular caution is needed in treating these drugs. First, they are described in very recent studies and the follow-up of their effect is of course rather short. Second, some of these drugs are still in an early phase of study, even if in well-conducted randomized controlled trials. Particular caution and a careful check need to be used in trials launched 2 or 3 years ago. Indeed, is always necessary to verify whether the study is still going on or whether and why the study itself was abandoned.