Adjuvanted leptospiral vaccines: Challenges and future development of new leptospirosis vaccines

Leptospirosis is a neglected infectious disease of global importance. Vaccination is the most viable strategy for the control of leptospirosis, but in spite of efforts for the development of an effective vaccine against the disease, few advances have been made, and to date, bacterin is the only option for prevention of leptospirosis. Bacterins are formulations based on inactivated leptospires that present a series of drawbacks, such as serovar-dependence and short-term immunity. Therefore, bacterins are not widely used in humans, and only Cuba, France and China have these vaccines licensed for at-risk populations. The development of recombinant DNA technology emerges as an alternative to solve the problem. Recombinant protein-based vaccines or DNA vaccines seem to be an attractive strategy, but the use of adjuvants is critical for achievement of a protective immune response. Adjuvants are capable of enhancing and/or modulating immune responses by exposing antigens to antigen-presenting cells. In the last years, several components have been tested as adjuvants, such as aluminum salts, oil based-emulsion adjuvants, bacteria-derived components and liposomes. This review highlights the use of adjuvants in the multiple vaccine approaches that have been used for leptospirosis and their most important immunological aspects. Immune response data generated by these strategies can contribute to the understanding of the immune mechanisms involved in protection against leptospirosis, and consequently, the development of effective vaccines against this disease. This is the first review on leptospiral vaccines focusing on adjuvant aspects.     

Motivation for participating in phase 1 vaccine trials: Comparison of an influenza and an Ebola randomized controlled trial

Introduction/Hypothesis

Recruitment of participants into phase 1 vaccine clinical trials can be challenging since these vaccines have not been used in humans and there is no perceived benefit to the participant. Occasionally, as was the case with a phase 1 clinical trial of an Ebola vaccine in Halifax, Canada, during the 2014–2016 West African Ebola virus outbreak, recruitment is less difficult. In this study, we explored the motivations of participants in two phase 1 vaccine trials that were concurrently enrolling at the same centre and compared the motivations of participants in a high-profile phase 1 Ebola vaccine trial to those in a less high-profile phase 1 adjuvanted seasonal influenza vaccine study.

Current standards and future perspectives in adjuvant treatment for biliary tract cancers

Biliary tract cancer, including cholangiocarcinoma (CCA) and gallbladder cancer (GBC) are rare tumours with a rising incidence. Prognosis is poor, since most patients are diagnosed with advanced disease. Only ~20% of patients are diagnosed with early-stage disease, suitable for curative surgery. Despite surgery performed with potentially-curative intent, relapse rates are high, with around 60–70% of patients expected to have disease recurrence. Most relapses occur in the form of distant metastases, with a predominance of liver spread. In view of high tumour recurrence, adjuvant strategies have been explored for many years, in the form of radiotherapy, chemo-radiotherapy and chemotherapy. Historically, few randomised trials were available, which included a variety of additional tumours (e.g. pancreatic and ampullary tumours); most evidence relied on phase II and retrospective studies, with no high-quality evidence available to define the real benefit derived from adjuvant strategies.Since 2017, three randomised phase III clinical trials have been reported; all recruited patients with resected biliary tract cancer (CCA and GBC) who were randomised to observation alone, or chemotherapy in the form of gemcitabine (BCAT study; included patients diagnosed with extrahepatic CCA only), gemcitabine and oxaliplatin (PRODIGE-12/ACCORD-18; included patients diagnosed with CCA and GBC) or capecitabine (BILCAP; included patients diagnosed with CCA and GBC). While gemcitabine-based chemotherapy failed to show an impact on patient outcome (relapse-free survival (RFS) or overall survival (OS)), the BILCAP study showed a benefit from adjuvant capecitabine in terms of OS (pre-planned sensitivity analysis in the intention-to-treat population and in the per-protocol analysis), with confirmed benefit in terms of RFS. Based on the BILCAP trial, international guidelines recommend adjuvant capecitabine for a period of six months following potentially curative resection of CCA as the current standard of care for resected CCA and GBC. However, BILCAP failed to show OS benefit in the intention-to-treat (non-sensitivity analysis) population (primary end-point), and this finding, as well as some inconsistencies between studies has been criticised and has led to confusion in the biliary tract cancer medical community.This review summarises the adjuvant field in biliary tract cancer, with evidence before and after 2017, and comparison between the latest randomised phase III studies. Potential explanations are presented for differential findings, and future steps are explored.     

Fertility preservation in patients of childbearing age treated for breast cancer: A nationwide cohort study

BackgroundApproximately 7% of breast cancers are diagnosed in women under 40. Question of subsequent fertility has become fundamental. We aimed to evaluate the rate of fertility preservation (FP) by oocyte retrieval (OR) after ovarian stimulation in patients of childbearing age, managed for breast cancer with adjuvant chemotherapy in France, reuse rate of frozen gametes and live births rate (LBR) after treatment.MethodsWe included 15,774 women between 18 and 40 years old, managed by surgery and adjuvant chemotherapy for breast cancer, between January 2011 and December 2020 from a French health registry. Patients with OR after breast surgery and before chemotherapy were considered as FP group; those with no OR as no FP group. To compare LBR with French population independently of age, we calculated Standardized Incidence Rates (SIR) of live births using indirect standardization method.ResultsFP rate increased gradually since 2011, reaching 17% in 2019. A decrease in use was observed in 2020 (13,9%). Among patients with at least 2 years of follow-up, gamete reuse rate was 5,6%. Births after cancer were mostly from spontaneous pregnancies. Among patients with at least 3 years of follow-up, LBR was 19,6% in FP group, 3,9% in second group. SIR of live births was of 1,05 (95% CI = 0.91–1.19) and 0.33 (95% CI = 0.30–0.36) in FP and no FP group respectively.ConclusionOncofertility activity increased until 2019 in France, reaching 17%. Gamete reuse rate was low. Births resulted mainly from spontaneous pregnancies. SIR of live births was lower in no FP group.     

78例胃窦癌的治疗分析

自１９８８年２月至１９９２年８月期间手术治疗的７８例胃窦癌患者进行了回顾性分析，手术后肿瘤复发的情况，与十二指肠断端有无癌细胞残存密切相关，并发现于幽门环下切断十二指肠少于３ｃｍ者有癌细胞残存达３４％，切除十二指肠达３ｃｍ者，无论肿瘤分化程度如何，恶性程度高低，切除断端均无癌细胞残存，手术后辅以化疗，对于病人的预后有一定提高。本组随访到的５９例病人中，接受化疗的３３例，在２年３个月至６年１个月内死亡７例（２１．２％），未接受化疗的２６例，在５个月至３年８个月内死亡的２６例，在５个月至３年８个月内死亡９例（３５％）。     

Centralisation of services for the management of ovarian cancer: arguments for

The recommendation in 1999, by the National Health Service Executive (NHSE) that the management of gynaecological cancer be centralised, led to a reorganisation of services for women with gynaecological malignancies. Debate has continued about the feasibility and benefits of ovarian cancer centralisation particularly because its insidious presentation can make it difficult to identify women with ovarian cancer before surgery. Despite this, there is clear evidence that centralisation is advantageous to women in terms of quality of life, morbidity and survival.     

CpG ODN增强乙肝疫苗在老年小鼠中的免疫应答

目的：探讨CpG ODN对老年小鼠的体液和细胞免疫应答的增强作用。方法：选用老年C57BL／6小鼠，将乙肝疫苗和10μg、20μg CpG ODN同时或单独肌注到小鼠体内，两周后以同样剂量加强免疫一次，再过3周后摘除眼球取血，用EILSA方法检测抗HBs16；抗体和IL-12；无菌取脾脏作HE染色，观察脾脏淋巴细胞变化。结果：10μg和20μg CpG ODN与疫苗同时注射组产生的抗体绝对量分别是单独注射疫苗组的3倍和4倍；产生的IL-12水平较对照组有明显升高，且20μg比10μCpG组产生的IL-12水平更高。光镜下各组的脾脏淋巴细胞的变化如下：正常老年鼠组脾脏淋巴细胞较正常青年鼠组明显稀少；老年鼠 10μgCpG组脾脏淋巴细胞较正常老年鼠组有了明显增加，且细胞核也明显增大；20μgCpG组增加的更加明显。结论：CpG ODN能增强乙肝疫苗在老年小鼠中的体液和细胞免疫应答。     

Th免疫反应在以壳聚糖为佐剂的幽门螺杆菌疫苗免疫保护中的作用

目的：探讨以壳聚糖为佐剂的脚疫苗的免疫保护作用及其机理。方法：BALB／c小鼠随机分为7组：空白对照组、壳聚糖酸溶液组、壳聚糖颗粒组、却抗原组、脚抗原＋壳聚糖酸溶液组、却抗原＋壳聚糖颗粒组和脚抗原＋CT组，各组于第0、7、14和21天灌胃各免疫1次，末次免疫后4周给予SS1Hp菌攻击，隔日1次，共2次。在攻击前后分批处死小鼠，取胃黏膜检测坳和Th1、Th2细胞因子含量，同时检测血清中抗Hp IgG2a和IgG1含量。结果：①以壳聚糖为佐剂的坳疫苗的免疫保护率达60％，与以CT为佐剂的印疫苗的免疫保护率（58．33％）相似，显著高于单纯脚抗原组及其他不含Hp抗原组（P〈0．001～0．05）。②却攻击后胃黏膜内IFN-γ、IL-2和IL-12含量在含佐剂组显著高于无抗原和无佐剂组（P〈0．001～0．05）；③坳攻击后胃黏膜内IL-4含量在以壳聚糖颗粒为佐剂组显著高于以CT为佐剂组（P〈0．05），以壳聚糖溶液为佐剂组显著高于对照组、无佐剂组及佐剂中含CT组（P〈0．001～0．05）。结论：以壳聚糖为佐剂的坳疫苗对脚感染具有免疫保护作用，同时可促进Th1和Th2的混合免疫反应。