Understanding Typhoid Disease After Vaccination: a Single Centre, Randomised, Doubleblind, Placebo Controlled Study to Evaluate M01ZH09 in a Healthy Adult Challenge Model, Using Ty21a Vaccine as a Positive Control.

Using an established model of human typhoid infection, whereby healthy adults are deliberately infected with typhoid-causing bacteria, the investigators will determine how effective a new oral typhoid vaccine (M01ZH09) is in preventing infection. A previously licensed oral typhoid vaccine (Ty21a) will be used to make sure the challenge model used works properly.

开始日期2011-10-07

申办/合作机构

University of Oxford

[+2]

NCT00679172 / Completed临床2期

A Randomised, Double-blind, Placebo-controlled, Single Dose, Dose Escalation Study to Determine the Immunogenicity, Safety and Tolerability of S. Typhi (Ty2 aroC-ssaV-) ZH9 at Doses of 5.0 x 10E9 CFU, 7.5 x 10E9 CFU, 1.1 x 10E10 and 1.7 x 10E10 CFU and 1.7 x 10E10 CFU, Following Oral Administration to Healthy, Typhoid Vaccine naïve Subjects in the USA.

This study is to investigate the safety, tolerability and immunogenicity of the typhoid fever vaccine candidate M01ZH09 manufactured at commercial scale, at a new manufacturing facility. The vaccine will be delivered as a single oral dose to healthy, typhoid vaccine-naïve adults.

开始日期2008-05-01

申办/合作机构

Emergent BioSolutions, Inc.

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项与伤寒疫苗(Emergent BioSolutions, Inc.) 相关的文献（医药）

2024-12-01·Vaccine

Fatal ascending paralysis after typhoid vaccine: Guillain and Barré's description of the very first case

Article

作者: Wijdicks, Eelco F.M. ; Wijdicks, Eelco F M

BACKGROUNDAlbeit rare, Guillain - Barré syndrome (GBS) has been associated with several vaccines. Surveys of these associations have not looked before 1950. Herein, I revisit the first described case of vaccine-associated GBS, manifesting during the Great War and to prevent typhoid.METHODSReview of primary and secondary source material. Description of a landmark case.RESULTSReview of a report of a 31-year-old brigadier who was revaccinated with "vaccin TAB" (a triple antityphoid-paratyphoid vaccine A and B) which days later was followed by rapid progression of limb weakness, oropharyngeal weakness and fatal neuromuscular respiratory weakness. Cerebrospinal fluid showed mild pleocytosis and increased protein (albumen). There was a normal brain and spinal cord at autopsy.CONCLUSIONThis is the first reported case of a vaccine-associated GBS.

2024-11-01·The Lancet Global Health

The effect of BCG revaccination on the response to unrelated vaccines in urban Ugandan adolescents (POPVAC C): an open-label, randomised controlled trial

Article

作者: Kiwudhu, Fred ; Cose, Stephen ; Amongin, Rebecca ; Tumwesige, Pius ; van Dam, Govert J ; Akello, Mirriam ; Mutebe, Alex ; Wajja, Anne ; Oduru, Gloria ; Kaleebu, Pontiano ; Nsubuga, Denis ; Kukundakwe, Christine ; Nkangi, Ronald ; Kiwanuka, Samuel ; Nakazibwe, Esther ; Katushabe, Charity ; Kabagenyi, Joyce ; Namusobya, Loyce ; Kabuubi, Prossy N ; Corstjens, Paul L A M ; Akurut, Hellen ; Kabali, Joel ; Kakande, Ayoub ; Kizindo, Robert ; Nassuuna, Jacent ; Driciru, Emmanuella ; Nassanga, Beatrice ; Sewankambo, Moses ; Tumusiime, Josephine ; Nyanzi, Ruth ; Kayiwa, John ; Zirimenya, Ludoviko ; Walusimbi, Bridgious ; Nkurunungi, Gyaviira ; Kizza, Moses ; Kabami, Grace ; Natukunda, Agnes ; Nayebare, Doreen ; Onen, Caroline ; Elliott, Alison M ; Webb, Emily L ; Zziwa, Christopher ; Apule, Barbara ; Akello, Florence A ; Namutebi, Milly ; Ninsiima, Caroline ; Nankabirwa, Christine ; Amongi, Susan ; Serubanja, Joel

BACKGROUNDImmune responses induced by several important vaccines differ between populations, with reduced responses in low-income and rural settings compared with high-income and urban settings. BCG immunisation boosts immune responses to some unrelated vaccines in high-income populations. We aimed to test the hypothesis that BCG revaccination can enhance responses to unrelated vaccines in Ugandan schoolchildren.METHODSWe conducted an open-label, randomised controlled trial to compare the effects of BCG revaccination versus no BCG revaccination on the immunogenicity of subsequent unrelated vaccines among adolescents aged 13-17 years who are participants in an urban Ugandan birth cohort study, in which BCG vaccination was documented at birth. Participants were excluded if they had received any of the trial vaccines or related agents when aged 5 years or older. Computer-generated 1:1 randomisation was implemented in REDCap. Participants were excluded if they were concurrently enrolled in other trials; had a clinically significant history of immunodeficiency, or serious psychiatric conditions or moderate to severe acute illnesses; were taking immunosuppressive medications; had allergies to vaccine components, a predisposition towards developing keloid scarring; positive HIV tests or pregnancy tests; were female participants who were lactating; or if they planned to use investigational drugs, vaccines, blood products, or any combination thereof. Trial participants assigned to the BCG revaccination group received the live parenteral BCG-Russia vaccine (Serum Institute of India, Pune, India; 0·1 mL intradermally, right upper arm) at week 0. All participants received yellow fever vaccine (YF-17D; Sanofi Pasteur, Lyon, France; 0·5 mL intramuscularly, left upper arm), live oral typhoid vaccine (Ty21a; PaxVax, London, UK; one capsule per day taken for three alternate days), and quadrivalent virus-like particle human papillomavirus (HPV) vaccine (Merck, Rahway, NJ, USA; 0·5 mL intramuscularly, left upper arm) at week 4; and toxoid vaccines (tetanus-diphtheria; Serum Institute of India; 0·5 mL intramuscularly, left upper arm) and an HPV booster at week 28. An additional HPV vaccination at week 8 was provided to female participants older than 14 years who had not previously been vaccinated. The primary outcomes were yellow fever neutralising antibody titres at 4 weeks post-YF-17D vaccination, Salmonella enterica serovar Typhi (henceforth S Typhi) O-lipopolysaccharide (O:LPS)-specific IgG concentration at 4 weeks post-Ty21a vaccination, and HPV-16 and HPV-18 L1 protein-specific IgG concentration at 4 weeks post-HPV vaccination. Primary outcome assays were conducted at week 8, and at week 52 for tetanus-diphtheria. We conducted an intention-to-treat analysis comparing log-transformed outcomes between trial groups, with results back-transformed to geometric mean ratios (GMRs). The safety population comprised all randomly allocated participants. The trial was registered at the ISRCTN Registry (ISRCTN10482904) and is complete.FINDINGSBetween Aug 31 and Oct 12, 2020, we screened 376 potential participants for eligibility. We enrolled and randomly allocated 300 participants to the two groups (151 [50%] to the BCG group and 149 [50%] to the no BCG group). 178 (59%) of 300 participants were male and 122 (41%) were female. 142 (91%) of 151 participants in the BCG group and 139 (93%) of 149 in the no BCG group completed follow-up. There was no effect of BCG revaccination, compared with no BCG revaccination, on the response observed for any vaccine. Yellow fever plaque reduction neutralising reference tests (PRNT₅₀) titres (the reciprocal of the last plasma dilution that reduced by 50%) had a GMR of 0·95 (95% CI 0·75-1·19; p=0·62) and PRNT₉₀ (reciprocal of the last plasma dilution that reduced by 90%) had a GMR of 0·94 (0·74-1·19; p=0·60); IgG to S Typhi O:LPS was 0·99 (0·80-1·23; p=0·94); IgG to HPV-16 was 0·97 (0·69-1·35; p=0·85) and to HPV-18 was 1·03 (0·76-1·40; p=0·83); and toxoid-specific IgG for tetanus was 1·13 (0·87-1·47; p=0·36) and was 1·00 (0·87-1·16; p=0·97) for diphtheria. There were no serious adverse events in either group.INTERPRETATIONWe found no evidence that BCG revaccination is an effective strategy to improve immunogenicity of other vaccines in this low-income, urban setting.FUNDINGUK Medical Research Council.TRANSLATIONFor the Luganda translation of the abstract see Supplementary Materials section.

2024-11-01·The Lancet Global Health

The effect of intermittent preventive treatment for malaria with dihydroartemisinin–piperaquine on vaccine-specific responses among schoolchildren in rural Uganda (POPVAC B): a double-blind, randomised controlled trial

Article

作者: Tumwesige, Pius ; Kizindo, Robert ; Kiwanuka, Samuel ; Ninsiima, Caroline ; Kabami, Grace ; Kiwudhu, Fred ; Kabagenyi, Joyce ; Kaleebu, Pontiano ; Nassuuna, Jacent ; Webb, Emily L ; Mutebe, Alex ; Natukunda, Agnes ; Amongin, Rebecca ; Nkangi, Ronald ; Nsubuga, Denis ; Kabuubi, Prossy N ; Katushabe, Charity ; Zirimenya, Ludoviko ; Nakazibwe, Esther ; Onen, Caroline ; Namusobya, Loyce ; Staedke, Sarah G ; Nkurunungi, Gyaviira ; Amongi, Susan ; Nassanga, Beatrice ; Cose, Stephen ; Corstjens, Paul L A M ; Serubanja, Joel ; Nyanzi, Ruth ; Kukundakwe, Christine ; Akello, Florence A ; Kizza, Moses ; Kayiwa, John ; Zziwa, Christopher ; Nankabirwa, Christine M ; Driciru, Emmanuella ; Walusimbi, Bridgious ; Wajja, Anne ; Kabali, Joel ; Namusobya, Loyce K ; Apule, Barbara ; Nayebare, Doreen ; van Dam, Govert J ; Namutebi, Milly ; Elliott, Alison M ; Akello, Mirriam ; Oduru, Gloria ; Sewankambo, Moses ; Kakande, Ayoub ; Akurut, Hellen ; Nankabirwa, Christine ; Tumusiime, Josephine

BACKGROUNDSeveral important vaccines differ in immunogenicity and efficacy between populations. We hypothesised that malaria suppresses responses to unrelated vaccines and that this effect can be reversed-at least partially-by monthly malaria intermittent preventive treatment (IPT) in high-transmission settings.METHODSWe conducted an individually randomised, double-blind, placebo-controlled trial of the effect of malaria IPT with dihydroartemisinin-piperaquine on vaccine responses among schoolchildren aged 9-17 years in Jinja district, Uganda. Participants were recruited from two schools and did not have exposure to vaccines of interest after the age of 5 years, with the exception of human papillomavirus (HPV). Computer-generated 1:1 randomisation was implemented in REDCap. 3-day courses of dihydroartemisinin-piperaquine (dosage by weight) or placebo were administered monthly, including twice before the first vaccination. Trial participants were vaccinated with the live parenteral BCG vaccine (Serum Institute of India, Pune, India) at week 0; yellow fever vaccine (YF-17D; Sanofi Pasteur, Lyon, France); live oral typhoid vaccine (Ty21a; PaxVax, London, UK), and quadrivalent virus-like particle HPV vaccine (Merck, Rahway, NJ, USA) at week 4; and toxoid vaccines (tetanus-diphtheria; Serum Institute of India) and an HPV booster at week 28. An additional HPV vaccination at week 8 was provided to female participants older than 14 years who had not previously been vaccinated, and a tetanus-diphtheria booster was given after completion of the trial at week 52. Primary outcomes were vaccine responses at week 8 and, for tetanus-diphtheria, at week 52, and analysis was done in the intention-to-treat population. Malaria parasite prevalence at enrolment and during follow-up was determined retrospectively by PCR. The safety population comprised all randomly allocated participants. The trial was registered at the ISRCTN Registry (ISRCTN62041885) and is complete.FINDINGSBetween May 25 and July 14, 2021, we assessed 388 potential participants for eligibility. We enrolled and randomly allocated 341 participants to the two groups (170 [50%] to dihydroartemisinin-piperaquine and 171 [50%] to placebo); 192 (56%) were female and 149 (44%) participants were male. 145 (85%) participants in the dihydroartemisinin-piperaquine group and 140 participants (82%) in the placebo group were followed up until the week 52 endpoint. At enrolment, 109 (64%) of all participants in the dihydroartemisinin-piperaquine group and 99 (58%) of 170 participants in the placebo group had malaria; this reduced to 6% or lower at all follow-up visits in the dihydroartemisinin-piperaquine group. There was no effect of dihydroartemisinin-piperaquine versus placebo on primary outcomes: BCG-specific IFNγ ELISpot response had a geometric mean ratio (GMR) of 1·09 (95% CI 0·93-1·29), p=0·28; yellow fever neutralising antibody was 1·19 (0·91-1·54), p=0·20 for plaque reduction neutralising reference tests (PRNT₅₀) titres (the reciprocal of the last plasma dilution that reduced by 50%) and 1·24 (0·97-1·58), p=0·09 for PRNT₉₀ titres (reciprocal of the last plasma dilution that reduced by 90%); and IgG to Salmonella enterica serovar Typhi O-lipopolysaccharide was 1·09 (0·81-1·46), p=0·58, HPV-16 was 0·72 (0·44-1·77), p=0·19, HPV-18 was 0·71 (0·47-1·09), p=0·11; tetanus toxoid was 1·22 (0·91-1·62), p=0·18, and diphtheria toxoid was 0·97 (0·83-1·13), p=0·72. There was some evidence that dihydroartemisinin-piperaquine reduced waning of the yellow fever response.INTERPRETATIONIPT for malaria with dihydroartemisinin-piperaquine did not improve peak vaccine responses, despite reducing malaria prevalence. Possible longer-term effects on response waning should be further explored.FUNDINGUK Medical Research Council.TRANSLATIONFor the Luganda translation of the abstract see Supplementary Materials section.

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2024-04-06

·生物制品圈

疫苗的“前世今生”，一段波澜壮阔的历史

疫苗一词是“疫苗之父”巴斯德( Louis Pasteur) 为纪念先驱者琴纳( Edward Jenner) 发明牛痘苗( vaccine) 而创造，指由减毒或灭活微生物制成、能够针对疾病产生免疫力的生物制品。疫苗作为人类与疾病斗争的有力武器，消灭或控制了许多传染病。脊髓灰质炎、鼠疫、麻疹、狂犬病、百日咳、破伤风、乙型病毒性肝炎(乙肝) 等发病率也通过接种疫苗大幅降低。自 18 世纪天花疫苗诞生至今，疫苗研发经历了数百年的发展其技术发展经历了 3 次革命。第一次始于 19 世纪末，巴斯德研制成功鸡霍乱疫苗、羊炭疽疫苗和狂犬疫苗，并利用生物传代和物理化学方法处理病原体，得到减毒和灭活疫苗; 第二次发生在 20 世纪 80 年代，其标志是以酵母制造乙肝疫苗。这一阶段，以重组 DNA 技术为代表的分子生物学技术的发展，使疫苗的研究从整体病原体水平进阶到分子水平; 第三次是 20 世纪 90 年代研制成功核酸疫苗，该技术最早由美国的沃夫( Wolff) 等发明。人类使用疫苗预防疾病已有200多年的历史，疫苗作为人类与疾病斗争的有力武器，消灭或控制了许多传染病。今天我们就来回顾一下，疫苗经历了怎样的发展轨迹？疫苗发展历程梳理一、萌芽期疫苗的横空出世首先得从天花病毒说起。天花是一种烈性传染病，不论什么人，一旦与患者接触，几乎都会传染，并且死亡率极高。但是在长时间的医疗中发现，有两种人是对天花有抵抗力的：一是从天花中康复的人，二是曾经护理过天花病的人。我们的前人在这种现象的启发下，研究出了用人痘接种预防天花的方法。该方法是将沾有疤浆患者的衣服给正常儿童穿戴，或将天花愈合后局部皮肤组织研磨成细粉，经鼻使儿童吸入。我们的前人在这种现象的启发下，研究出了用人痘接种预防天花的方法。该方法是将沾有疤浆患者的衣服给正常儿童穿戴，或将天花愈合后局部皮肤组织研磨成细粉，经鼻使儿童吸入。不过因为风险太大，这个技术一直没有推广开来，但这个技术的发展却给了人们很大的启发，让他们找到了对抗天花的方法。在18世纪末，一名英国的乡下大夫爱德华-琴纳接待一名妇女，她患有发烧、腰疼、呕吐等症状，他从中意识到接种牛痘可以预防天花。为了证实这一设想，他于1796年5月14日从一名正患牛痘的挤奶女工身上的脓疤里取少量脓液注射至八岁男孩詹姆斯费普臂内。六周后，男孩的牛痘反应消退，所以正如琴纳所说：“尽管假性天花接种小孩手臂出现类似的脓疤，除此之外几乎不可觉察。”琴纳为了证实其效果，先后多次给费普接种，但费普却安然无恙。2个月后，再接种天花患者来源的痘液，费普仅局部手臂出现疤疹，未引起全身天花。据此，琴纳于1798年出版其专著《探究》，称此技术为疫苗接种。在琴纳那个时代，人们根本不知道天花是由一种病毒引起的，也不知道种痘能让身体产生一种对抗天花的免疫。但是，经过他的实际观察，经过试验，确定了一种新的疫苗接种法，它不仅安全，而且很有效，是一个划时代的发明。琴纳（公元1749年—公元1823年）二、第一次疫苗革命这一阶段疫苗的发展归功于路易·巴斯德于19世纪末在疫苗研制领域的先锋作用和卓越贡献。被誉为疫苗之父的巴斯德的伟大贡献在于：他选用免疫原性强的病原微生物经培养，用物理或化学方法将其灭活后，再经纯化制成。灭活疫苗使用的毒种一般是强毒株，但使用减毒的弱毒株也有良好的免疫原性，如用萨宾减毒株生产的脊髓灰质炎灭活疫苗。减毒活疫苗是采用人工定向变异的方法，或从自然界筛选出毒力高度减弱或基本无毒的活的微生物制成疫苗，并以此给人接种而达到预防传染病的目的。在19世纪末，科赫发明了在固体培养基上分离细菌培养物的方法，该法为巴斯德研制疫苗奠定了基础。巴斯德首次发现，长期在人工培养基上，如将鸡霍乱弧菌置于两个星期后，这种菌种对雏鸡不会造成致病性。还有一点很重要：即使再次给这些被注射过的雏鸡注射了霍乱，他们也不会感染。巴斯德提出，这可能是因为在老的培养基中，鸡霍乱弧菌的毒性降低，但是其免疫原性保持不变，从而导致雏鸡对霍乱弧菌有了免疫力。以此理论巴斯德将炭疽杆菌在42~43℃的环境下培养两周后，制成人工减毒炭疽活疫苗。在巴斯德光辉成就的启发下，1908年卡麦特和古林将一株牛型结核杆菌在含有胆汁的培养基上连续培养13年213代，终于在1921获得减毒的卡介苗(BCG)。最初卡介苗为口服，20世纪20年代末改为皮内注射，卡介苗在新生儿抵御粟粒性肺结核和结核性脑膜炎方面具有很好的效果。自1928年至今，卡介苗仍在全世界广泛地被用于儿童计划免疫接种，已有40多亿人接种过卡介苗。这一阶段疫苗革命中还包括白喉、破伤风类毒素、鼠疫疫苗、伤寒疫苗和黄热病等30多种疫苗的成功研制。巴斯德三、第二次疫苗革命第二次疫苗革命主要是从分子水平上制备基因工程亚单位疫苗。由于分子生物技术、生物化学、遗传学和免疫学的迅速发展，使得研制新疫苗和改进旧疫苗的工作能够在分子水平上进行。以酵母制备乙肝疫苗作为二次疫苗革命的分水岭。采用重组DNA技术、蛋白质化学技术开创了疫苗研制的第二次革命。1.重组核酸技术美国斯坦福大学于1972年提出重组核酸技术，并以迅雷不及掩耳之势风靡世界，开创了生命科学的新局面，其中包括疫苗的研制。基因重组技术的运用，为疫苗的研发提供了一条崭新的道路。该技术不仅可以获得几乎所有的免疫原，还可以让病原微生物的研究者和疫苗的接种者变得更加安全。例如，乙肝疫苗最初是从人乙型肝炎表面抗原(HBsAg)携带者血浆中提取，对健康人来说，其接种的危险性显而易见。20世纪80年代，又有研究报道了 HBsAg的基因在酵母和真核细胞中的表达，该方法既可获得类似于血液疫苗的免疫效果，又可获得简单、快速、廉价、高效的 HBsAg的抗体，对接种人群具有较高的安全性。当前，在不改变疫苗抗原性的前提下，利用重组核酸技术，以病毒、细菌作为载体，将目标基因导入到疫苗菌株及其质粒的基因组中，从而在不改变其抗原性的情况下，实现对疫苗菌株的高表达。所以，该疫苗对人体所起到的免疫作用是双向的。例如，第一次疫苗革命产生的卡介苗，现在采用重组核酸技术将γ-干扰素(IFN-γ)、白细胞介素2(IL-2)等细胞因子基因导入卡介苗中，成为重组卡介苗(γBCG)。重组卡介苗不仅保留传统卡介苗的特性，同时还分泌γ-干扰素和白细胞介素2，这样重组卡介苗既可用于结核病的预防，又能用于肿瘤或其他免疫性疾病的治疗。2.蛋白质化学和化学技术由于疫苗中的保护性抗原大部分为蛋白质，所以要得到特异性的蛋白质抗原，必须先对其进行分离纯化，由此可见蛋白质化学技术的发展对疫苗的研制起着重大作用。另外，可根据骨髓依赖性(B)淋巴细胞表位或胸腺依赖性(T)淋巴细胞表位直接采用蛋白质化学和化学技术合成多肤抗原，用来制备多肤疫苗。四、第三次疫苗革命核酸疫苗的开发研制，标志着第三次疫苗革命的到来。1995年美国纽约科学院召开专门研讨核酸疫苗会议，称之为疫苗学的新纪元和疫苗的第三次革命。1.核酸疫苗的发现和研制沃夫等人偶然的研究成果以及阿瑟的基因递送体系，为发展新型核酸疫苗奠定了基础。20世纪80年代后期，90年代初期，人们利用表达基因的核酸进行基因疗法，发现不经任何处理的裸露基因，可以在肌肉细胞内表达蛋白质，并且可以在肌肉细胞内持续两个月，引起人体产生免疫反应，由此引发了一场核酸疫苗的研发。在最初的动物实验中有两个令人欣喜的结果:第一是A型流感病毒核酸疫苗注射给小鼠，结果诱发了小鼠产生抗体和细胞毒性T细胞。然后用A型流感(PR/8) 攻击，100%小鼠健康存活，而对照组100%在9天后死亡。几乎同时，费南(Fynan)等人使用基因枪和编码红细胞凝集素的核酸，其结果也使小鼠获得保护性免疫应答。另一个重要的研究结果是乙肝表面抗原的核酸疫苗。该疫苗不但能诱导动物产生相应的抗体，还能让转基因动物体内的 HBV表面抗原呈阴性。因此，可以用核酸疫苗来预防和治疗疾病，特别是对乙型肝炎的核酸疫苗。该结果对目前国内乙型肝炎疫苗的研发具有一定的指导意义。2.核酸疫苗的应用前景核酸疫苗的研究进展令人鼓舞，核酸疫苗因其独特的优势，在免疫防治中发挥了重要作用。因此，自1994年以来，美国 FDA先后批准了包括 AIDS，流感，乙肝，单纯疤疹，疟疾，Cancer在内的几种核酸疫苗的临床试验。欧美各国都投入了大量的人力物力，对核酸疫苗进行了研发。核酸疫苗已用于淋巴瘤、黑色素瘤、结肠癌及前列腺癌的临床前治疗研究。据统计，1989年至2004年，全球得到认可的基因治疗临床试验共9987例，仅肿瘤治疗占66%。然而，由于其高致死率，迄今尚无针对肝癌 DNA疫苗进行临床研究的相关报道。因此，开展肝癌核酸疫苗临床应用的研究具有重要意义。核酸疫苗也被广泛应用于基因缺陷导致的免疫缺陷疾病的治疗，其中以 ADA基因为代表的基因治疗是目前最有效的一种。mRNA 疫苗技术在新冠疫情应对中市场前景得到较大提升。2020年是 mRNA 技术平台的突破元年，新冠 mRNA 疫苗的推出和广泛使用极大提升了mRNA 疫苗的融资和市场活力。目前开发中的 mRNA 制剂有3个主要应用：预防性疫苗、治疗性疫苗和治疗药物。复星与拜恩泰科研发的mRNA新冠疫苗样品人类在200多年前就开始应用疫苗，它为我们构筑了一道强有力的生物屏障，使我们免受病毒的攻击。在这次疫情之后，疫苗是人类的“保护神”，这一点是毋庸置疑的。随着技术的进步，经过科学家们的不懈努力，将会有更多的治疗性和预防性疫苗被研制出来。疫苗对于人体的作用，无论怎样夸张也不为过，因为每一种新型疫苗的出现，都代表着一场人类对某种疾病的胜利！参考：[1]许丽丽,陈艳,陈征宇等.疫苗的发展与创新：从天花疫苗到新型冠状病毒疫苗[J].医药导报,2021,40(07):876-881.[2]贾冰冰,李卫国.疫苗技术发展的历史与展望[J].生物学通报,2016,51(06):1-3.[3]https://www.nobelprize.org/prizes/lists/all-nobel-prizes/[4]https://www.nature.com/immersive/d42859-020-00005-8/index.html识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

疫苗

2024-03-24

·生物制品圈

不止打麻将，打疫苗也能预防老年痴呆？

疫苗对老年群体的益处，不仅仅是预防“疫苗可预防的疾病(VPD)”所致身体的损害，可能还有心智上的额外获益——老年人接种VPD疫苗可能降低痴呆症风险的研究早已屡见不鲜。这些研究既有涉及流感疫苗、带状疱疹疫苗，也有关于狂犬病疫苗和乙肝疫苗。既有队列研究也有病例对照研究和荟萃分析，既有动物试验也有试验性研究，证据不可谓不广泛。01 流感疫苗降低了老年痴呆风险3月初，Nature子刊npj vaccines发表了一项中国学者开展、评估接种流感疫苗对老年痴呆影响的为期12年的前瞻性队列研究。研究利用英国生物库人口数据，纳入70938名60岁以上老年人，其中54%的老年人接种过流感疫苗。研究结果很积极，结论下的也很谨慎——接种流感疫苗与社区居住的成年人痴呆症发病风险的降低有显著相关性（HR=0.83；95% CI，0.72-0.95）。有意思的是，尽管研究谨慎性地只下了相关性结论并未表明因果关系，但却发现了流感疫苗与痴呆症之间的剂量-反应关系——接种流感疫苗频次更高的老年人老年痴呆患病率更低。接种流感疫苗的平均频次＞0.8剂/年，患痴呆症的风险更低02 这些疫苗或许也能“降”痴呆除了流感疫苗，去年10月BMC刊载了另一项关于接种流感疫苗和带状疱疹疫苗与痴呆症风险降低有关的回顾性、大样本队列研究发现，接种带状疱疹疫苗的预防效果似乎要比流感疫苗更好，包括更低的痴呆症、阿尔茨海默病和其他类型的痴呆风险。ps：可能由于两款疫苗保护效果的差异带来的差异？疫苗起预防作用的机制，是否因为它保护了老年人群免受病原感染？近日一项纳入了6项队列研究、涉及538531名带状疱疹患者的最新荟萃分析显示：带状疱疹患者与痴呆风险之间存在显著的直接关联，接受抗病毒治疗的带状疱疹患者与痴呆风险呈负相关（HR：0.68,95% CI：0.59-0.77，p < 0.001）。图示为带状疱疹患者和痴呆之间的关系去岁斯坦福大学学者在知名医学研究预印本medRxiv的一项述论似乎也已经发现了接种带状疱疹疫苗可降低老年痴呆的因果效应。除了流感疫苗和带状疱疹疫苗外，一项荟萃分析揭示了常规接种其他成人VPD疫苗或许都可以显著降低平均约35%的痴呆风险（HR=0.65，95%CI:0.60-0.71），包括狂犬疫苗、乙肝疫苗、甲肝疫苗、百白破疫苗，甚至伤寒疫苗。（如下图，整个感觉就是制药打疫苗，别管什么疫苗，都能降低老年痴呆的风险）03 这个被忽视的疫苗可能也有“妙用”成人VPD疫苗算起来并不太多，而适合老年人群常规接种的VPD疫苗仅有流感疫苗、肺炎疫苗、带状疱疹疫苗和戊型肝炎疫苗4种，其中戊肝疫苗经常被忽略。多项研究数据显示，年龄和男性不仅是痴呆症的两个关键危险因素，同样也是戊型肝炎的关键危险因素——戊肝患者的平均年龄约为50岁（发病高峰），且随着年龄增长暴露风险可累积。戊肝患者的男女比例与痴呆症患者也很相似，都约为2:1。图源于：中国2011-2021年戊型病毒性肝炎发病趋势和时空聚集性[J].中国疫苗和免疫,2022.一项发表在知名感染病学杂志、由西班牙学者开展的对照研究发现，抗-HEV IgG阳性（既往暴露）与老年人神经病理损伤和AD诊断率较高有关（aOR=1.97;p=0.006；aOR=1.84; p=0.022）。图示为神经病理性损伤（左）和阿尔茨海默（右）的风险而病因研究的证据也不少，其中发表于知名学术期刊PNAS的一项由弗吉尼亚大学开展的动物实验研究显示：HEV可通过直接感染脑微血管内皮细胞侵入中枢神经系统，随后感染神经元细胞导致中枢神经系统损伤。是否可以推测——暴露于HEV的老年人有更高的老年痴呆风险？上述带状疱疹的研究似乎也可以佐证该猜想。04 老年痴呆可能由于病原感染由于疫苗素养属于一种比较关键的健康素养，所以尽管有这些发现，但我们也只能猜测——是疫苗保护了老年人免受病毒对神经系统的损害（因果关系），还是接种疫苗的老年人健康素养间接避免了患老年痴呆的风险（偏倚因素）？要解决这个疑问，可能还需要探讨另一个问题——如果老年人暴露于这些病毒或疾病，是否会导致神经系统损伤。其实越来越多的研究支持散发性AD的病原感染假说（AD中较为常见但病因不明的一种），特别是几种疱疹病毒（HHV1-7 、VZV、EBV、MCV）、黄病毒（即寨卡病毒、登革热病毒、日本脑炎病毒）、HIV病毒、5种常见的肝炎病毒及SARS-CoV2等可能会增加患AD的风险。2023年Cell子刊Neuron也做了这样一项研究——基于FinnGen数据库和英国生物银行（UKB）的数据分析发现，流感、肺炎与其中5种神经退行性疾病（AD、ALS、痴呆、PD和VAS）显著相关。05 接种疫苗的另一个意外好处除了老年痴呆外，也有研究显示，定期接种流感疫苗对急性冠状动脉综合征和中风有一致的、剂量依赖性的保护效果，同时接种流感疫苗和肺炎球菌疫苗与降低某些心血管事件（中风、充血性心力衰竭、缺血性心脏病和心肌梗死）的风险相关。可能的保护机制有4种：预防感染引起的并发症；减少炎症反应并改善血管功能、降低血栓形成的风险；疫苗免疫反应可能有助于减轻或防止感染引起的炎症和免疫激活；抗体可以与氧化低密度脂蛋白（oxLDL）发生交叉反应，而oxLDL是动脉粥样硬化斑块的组成部分。06 是否可以宣传这些额外获益考虑以上研究证据，建议老年人群常规接种流感疫苗、肺炎疫苗、带状疱疹疫苗和戊型肝炎疫苗。流感、肺炎等疾病的“知名度”显然无法与老年痴呆相比，宣传这些额外获益或许更能调动老年人群的接种积极性（毕竟老年人是“买送”项目的主要拥趸），但如何做好尺度监管又是一个问题。去年加拿大学者就刊文呼吁——流感疫苗可以预防心血管疾病的证据越来越多，《加拿大免疫指南》应当考虑更新并纳入该影响，以便让更多人知道后去积极接种疫苗。参考资料：NPJ Vaccines. 2024 Mar 2;9(1):51.BMC Public Health. 2023 Oct 2;23(1):1903.Front Immunol. 2022 May 3;13:872542.Health Sci Rep. 2024 Mar 13;7(3):e1941.Ageing Res Rev. 2023 Nov;91:102068.Neuron. 2023 Apr 5;111(7):1086-1093.e2.中国疫苗和免疫,2022,28(04):417-421.J Infect Dis. 2023 Apr 12;227(7):873-877.PNAS. 2022 Jun 14;119(24):e2201862119.doi: 10.1101/2023.05.23.23290253.Geroscience. 2023 Dec;45(6):3419-3447.识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

疫苗临床结果

2024-02-26

·Pharmaceutical Technology

SK bioscience’s typhoid vaccine receives WHO prequalification

SK bioscience developed the SKYTyphoid vaccine along with the International Vaccine Institute (IVI). Credit: SK bioscience. SK bioscience has achieved a significant milestone with its typhoid conjugate vaccine, SKYTyphoid, receiving prequalification (PQ) certification from the World Health Organization (WHO). This is the fourth WHO PQ for the company, following certifications for two influenza vaccines and a varicella vaccine. The WHO PQ system is a rigorous process that ensures the safety and efficacy of vaccines by assessing their manufacturing process, quality and clinical trial data. The development of SKYTyphoid was a collaborative effort with the International Vaccine Institute (IVI) and received support from the Bill & Melinda Gates Foundation. SKYTyphoid employs the purified Vi polysaccharide-diphtheria toxoid conjugate method, which is safe for infants and children aged six months to two years. See Also: Neurocrine Biosciences sees highest patent filings and grants during December in Q4 2023 Caribou Biosciences sees highest patent filings and grants during November in Q4 2023 It provides comparable immunogenicity and long-term protection with a single dose, as against current oral live or polysaccharide typhoid vaccines. In 2022, SKYTyphoid obtained an export licence from the Korean Ministry of Food and Drug Safety, following a global clinical trial. The Phase III study involved 2,160 subjects aged six months to 45 years in Nepal, showcasing a favourable immunogenicity and safety profile. The results indicated that SKYTyphoid’s performance was on par with another WHO PQ-certified polysaccharide-protein conjugate typhoid vaccine. SK bioscience CEO Jaeyong Ahn stated: “We are pleased that our global collaboration to address the global vaccine supply imbalance and improve public health has been recognised by the WHO PQ certification. “We will make every effort to rapidly supply SKYTyphoid by obtaining approvals in countries.” With the WHO PQ designation, SK bioscience is set to target global markets, focusing on public procurement in typhoid-endemic countries with high demand. IVI director general Dr Jerome Kim stated: “Typhoid fever is more prevalent in warmer temperatures, and climate change and the worrying rise of antimicrobial resistance are only adding to the threat of the disease. Vaccination is critical to effective prevention and control of the disease. In collaboration with SK bioscience and other partners, IVI will continue endeavours to make this vaccine accessible to people who need it the most.”

疫苗临床3期临床结果

100 项与伤寒疫苗(Emergent BioSolutions, Inc.) 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D06261	-	-	-

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
伤寒	临床2期	-	Prokarium Ltd.	-
伤寒	临床2期	-	Prokarium Ltd.	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00679172 (CTgov)	临床2期	伤寒	187	Placebo (Cohorts 1-4 pooled)+Dose of 5.0 x 10^9 CFU (Cohort 1) (M01ZH09 Vaccine Candidate Cohort 1)	鑰築醖選鹹衊鏇簾齋願(醖鏇願糧築襯遞願餘鏇) = 築齋蓋膚鏇築選繭鑰築製鏇簾膚觸選餘鏇淵憲 (範艱積網齋憲簾夢觸構, 鬱糧蓋鏇範蓋製構簾襯 ~ 窪鏇網積願餘範壓壓齋) 更多	-	2017-06-07
				Placebo (Cohorts 1-4 pooled)+Dose of 7.5 x 10^9 CFU (Cohort 2) (M01ZH09 Vaccine Candidate Cohort 2)	鑰築醖選鹹衊鏇簾齋願(醖鏇願糧築襯遞願餘鏇) = 蓋鏇鬱鏇鏇壓憲製衊憲製鏇簾膚觸選餘鏇淵憲 (範艱積網齋憲簾夢觸構, 夢築餘顧鏇糧觸憲齋簾 ~ 積鹹艱範築鏇窪齋壓憲) 更多
NCT01405521 (Pubmed \| PLoS Negl Trop Dis)	临床2期	-	99	M01ZH09	願願顧選壓繭簾築齋壓(膚壓壓憲憲簾鬱鏇餘觸) = 獵襯觸艱齋夢餘選獵製獵壓蓋衊壓築願夢襯糧 (窪築衊壓獵窪齋糧醖窪, 39.1 ~ 75.5) 更多	不佳	2016-08-01
				Placebo	願願顧選壓繭簾築齋壓(膚壓壓憲憲簾鬱鏇餘觸) = 夢衊餘窪積獵鑰範願顧獵壓蓋衊壓築願夢襯糧 (窪築衊壓獵窪齋糧醖窪, 47.2 ~ 87.2)
NCT00679172 (Pubmed \| Vaccine)	临床2期	伤寒	187	M01ZH09	網鑰觸憲簾壓膚遞繭觸(鏇壓顧鏇遞製憲襯製觸) = One subject had a transient low-grade fever 獵鬱膚選窪憲獵製願膚 (積鑰鹹獵簾製製淵製繭 )	-	2010-04-30