冻干Vero细胞狂犬病纯化疫苗在120例门诊病人中的临床效果

目的:观察国产冻干非洲绿猴肾传代细胞(Vero细胞)为基质制备的狂犬病纯化疫苗临床应用的免疫效果和安全性。方法:选择门诊部就诊的犬致伤者240例,分为试验组和对照组。试验组接种冻干Vero细胞狂犬病纯化疫苗,对照组接种地鼠肾狂犬病纯化疫苗。2组人群均按照狂犬病疫苗暴露后常规免疫程序进行接种,于全程接种后15d测定中和抗体,并观察不良反应。结果:试验组抗体阳性率为96.7%,明显高于对照组的90.0%,P<0.05;不良反应发生率为10.8%,明显低于对照组的21.7%,P<0.05。结论:Vero细胞纯化疫苗抗体阳转率高、不良反应发生率低,临床应用优于地鼠肾纯化疫苗,适宜推广使用。     

Rabies antibody seroprotection rates among travelers in Nepal: "rabies seroprotection in travelers"

BACKGROUND: Rabies preexposure immunization is recommended for international travelers who are at risk for exposure to rabid animals, especially in areas where postexposure treatment may be limited. Rabies antibody seroprotection rates among international travelers has not been previously investigated. OBJECTIVE: To assess preexisting rabies seroprotection among travelers presenting to a health clinic in Nepal. METHODS: A prospective convenience sample of international travelers evaluated at a health center in Kathmandu, Nepal during a 2-month period. Subjects were eligible for inclusion if they had received rabies preexposure vaccination within the previous 5 years. Demographic information and vaccination records of rabies preexposure prophylaxis were obtained. Consenting subjects provided serum for rabies antibody measurement measured using the rapid fluorescent focus inhibition test. A dilution greater than or equal to 1:5 (0.5 IU/mL) was considered positive. Data were analyzed using chi-squares and two-sample t-tests with unequal variances. RESULTS: A total of 43 patients consented to enroll. Complete data were available for 38 patients. Subjects had received human diploid cell vaccine (HDCV) or purified Vero cell rabies vaccine (PVRV) vaccine, either via the intradermal or intramuscular route. All patients had adequate antibody titers except one, who had a titer below 0.5 IU/mL. There was no statistically significant relationship between antibody titer and type of vaccine, route of administration, time since vaccination, number of vaccinations, or patient age. CONCLUSIONS: Among 38 travelers to Nepal who had received documented preexposure rabies HDCV or PVRV vaccination series, 37 demonstrated adequate titers of > or =0.5 IU/mL and would be considered boostable if exposed to rabies virus. One traveler had a titer of <0.5 IU/mL. Type of vaccine, method of administration, number of vaccinations, and time since vaccination did not influence rabies antibody titer. Rabies vaccination with HDCV and PVRV vaccine was effective in stimulating adequate seroprotection in this sample of travelers.     

Peripheral neuropathy following administration of nerve tissue antirabies vaccine

In 1997, two patients were admitted to Tikur Anbessa Hospital with complaints of ascending paralysis in all extremities following administration of sheep brain tissue anti-rabies vaccine following a rabies exposure. The paralysis had started after 14 daily subcutaneous injections of the Fermi type nerve tissue vaccine. After an eight week stay in the hospital with supportive care and physiotherapy, the patients showed remarkable improvement. They received a booster dose of vaccine while in the hospital, with no deterioration in their neurological status and were discharged.     

A lowered probability of pregnancy in females in the USA aged 25–29 who received a human papillomavirus vaccine injection

Birth rates in the United States have recently fallen. Birth rates per 1000 females aged 25–29 fell from 118 in 2007 to 105 in 2015. One factor may involve the vaccination against the human papillomavirus (HPV). Shortly after the vaccine was licensed, several reports of recipients experiencing primary ovarian failure emerged. This study analyzed information gathered in National Health and Nutrition Examination Survey, which represented 8 million 25-to-29-year-old women residing in the United States between 2007 and 2014. Approximately 60% of women who did not receive the HPV vaccine had been pregnant at least once, whereas only 35% of women who were exposed to the vaccine had conceived. For married women, 75% who did not receive the shot were found to conceive, while only 50% who received the vaccine had ever been pregnant. Using logistic regression to analyze the data, the probability of having been pregnant was estimated for females who received an HPV vaccine compared with females who did not receive the shot. Results suggest that females who received the HPV shot were less likely to have ever been pregnant than women in the same age group who did not receive the shot. If 100% of females in this study had received the HPV vaccine, data suggest the number of women having ever conceived would have fallen by 2 million. Further study into the influence of HPV vaccine on fertility is thus warranted.     

FDA《狂犬病：为暴露后预防的被动免疫成分研制单克隆抗体鸡尾酒供企业用指导原则》介绍

狂犬病是由狂犬病毒引起的急性传染病,及时给予暴露后预防（PEP）可阻止临床症状出现。PEP由清洗伤口、给予狂犬病疫苗和在伤口内和周围给予抗狂犬病病毒免疫球蛋白（RIG）3部分构成。由于多种原因限制了RIG的使用,其全球使用率不到狂犬病病毒暴露的2%。因此,抗狂犬病病毒单克隆抗体鸡尾酒正被开发为PEP被动免疫成分RIG的替代品。美国食品药品监督管理局（FDA）于2021年7月发布了《狂犬病：为暴露后预防的被动免疫成分研制单克隆抗体鸡尾酒供企业用指导原则》,旨在促进抗狂犬病病毒单克隆抗体鸡尾酒的开发,并对抗狂犬病病毒单克隆抗体鸡尾酒的研究提出了详细而具体的建议,其中包括临床和非临床研究的要点以及临床III期疗效试验设计。详细介绍该指导原则主要内容,期望对中国在此方面的研究和监管提供帮助,对《抗狂犬病病毒单克隆抗体新药临床试验技术指导原则（征求意见稿）》的修订有所启示。     

Survey of rabies preexposure and postexposure prophylaxis among missionary personnel stationed outside the United States

BACKGROUND: Of the 36 cases of human rabies that have occurred in the United States since 1980, 12 (33%) were presumed to have been acquired abroad. In the United States, it is recommended that international travelers likely to come in contact with animals in canine rabies-enzootic areas that lack immediate access to appropriate medical care, including vaccine and rabies immune globulin, should be considered for preexposure prophylaxis. In 1992, the death of an American missionary who had contracted rabies while stationed in Bangladesh highlighted this high-risk group. METHODS: To assess their knowledge of rabies risk, rabies exposures, and compliance with preventive recommendations, we asked 695 missionaries and their family members to complete questionnaires about their time stationed abroad. RESULTS: Of the 293 respondents stationed in countries where rabies is endemic, 37% reported prior knowledge of the presence of rabies in their country of service. Only 28% of the personnel stationed in rabies-endemic countries received preexposure prophylaxis. Having preexposure prophylaxis specifically recommended increased the likelihood of actually receiving it (O.R. 15.6, 95%CI 7.4 - 34.9). There were 38 reported exposures (dogs = 66%, another human = 20%), proven or presumed to be rabid. Three of the people exposed received rabies immune globulin and vaccine; 11 received vaccine alone; 8 received only basic first aid, and 16 received no treatment. CONCLUSIONS: Although American missionaries stationed abroad are at an increased risk for exposure to rabies, compliance with established preventive measures was low. Prior to being stationed abroad, an educational rabies-prevention briefing, including encouragement to receive preexposure prophylaxis, could be an effective intervention for missionaries to decrease their risk of rabies.     

Use of neutralizing murine monoclonal antibodies to rabies glycoprotein in passive immunotherapy against rabies

Passive immunization is an important parameter of post exposure rabies prophylaxis. Two types of rabies immunoglobulin (RIGs) are currently available for Passive immunization against rabies i.e., human rabies immunoglobulin (HRIG) and equine rabies immunoglobulin (ERIG). The former is very expensive and not easily available and the latter causes side effects because of which its utility is limited. In the present study we have produced murine monoclonal antibodies (Mabs) to rabies glycoprotein (G) and studied their utility in passive immunization against rabies using animal models. Their efficacy was compared to commercially available ERIG both in terms of neutralizing titer and effective protein concentration. The neutralizing titers of these Mabs ranged from 1650-75,000 IU/mL by RFFIT. They belonged to the IgG 2 a subclass. The Mabs were able to protect 70-100% of mice and guinea pigs inoculated with rabies viruses, depending on the strain of the virus. These Mabs were found to be 2,000 times more potent than commercial ERIG in terms of effective protein concentration and neutralizing titer. Further studies are required to study their utility in humans exposed to rabies.     

Economic issues in postexposure rabies treatment

Rabies remains a worldwide public health problem even though means to control this disease are known. Logistic problems and cultural barriers for effective dog control in many countries and the high cost of human postexposure treatment, account for much of the remaining worldwide human toll. Efforts to make vaccines, with effective and safe tissue or avian culture products and immune globulin, more affordable have been only marginally successful. Second generation rabies vaccines (purified Vero-, chick and duck embryo cell products) are effective, safe and less expensive than human diploid cell rabies vaccine. Reduced dose intradermal postexposure vaccination works, is affordable, and has helped abolish the use of dangerous and poorly immunogenic brain tissue-derived vaccines in Thailand, the Philippines, and Sri Lanka. The use of purified equine rabies immune globulin has been found to be safe and cost-effective. It is, unfortunately, in short supply worldwide. Preexposure rabies vaccination for travelers to endemic regions is recommended and should be administered by the intramuscular route whenever possible.     

Generation and characterization of the human neutralizing antibody fragment Fab091 against rabies virus

Aim:

To transform the human anti-rabies virus glycoprotein (anti-RABVG) single-chain variable fragment (scFv) into a Fab fragment and to analyze its immunological activity.

Methods:

The Fab gene was amplified using overlap PCR and inserted into the vector pComb3XSS. The recombinant vector was then transformed into E coli Top10F'' for expression and purification. The purified Fab was characterized using SDS-PAGE, Western blotting, indirect ELISA, competitive ELISA, and the fluorescent antibody virus neutralization test (FAVN), respectively, and examined in a Kunming mouse challenge model in vivo.

Results:

A recombinant vector was constructed. The Fab was expressed in soluble form in E coli Top10F''. Specific binding of the Fab to rabies virus was confirmed by indirect ELISA and immunoprecipitation (IP). The neutralizing antibody titer of Fab was 10.26 IU/mL. The mouse group treated with both vaccine and human rabies immunoglobulin (HRIG)/Fab091 (32 IU/kg) showed protection against rabies, compared with the control group (P<0.05, Logrank test).

Conclusion:

The antibody fragment Fab was shown to be a neutralizing antibody against RABVG. It can be used together with other monoclonal antibodies for post-exposure prophylaxis of rabies virus in future studies.     

Assessing the relationship between antigenicity and immunogenicity of human rabies vaccines. Results of a meta-analysis

A meta-analysis was done to study the relationship between antigenecity and immunogenecity of human rabies vaccines. The data of ten cell culture human rabies vaccine studies conducted at a single centre during 1993-2004 were used in the study. The vaccines studied included Purified Chick Embryo Cell Vaccine (Kaketsuken, Japan and Rabipur, India), Purified Vero cell Rabies Vaccine (Verorab, France), Human Diploid Cell Vaccine (MIRV, France and Rabivax, Adsorbed and Lyophilized, India) and Rhesus Diploid Rabies Vaccine (adsorbed, USA). Interestingly, it was revealed that an higher antigenecity of rabies vaccines viz. potency of > or = 5 IU per single intramuscular dose did not result in significantly higher immunogenecity, as measured by rabies virus neutralizing antibody (RVNA) titers in the vaccinees, both on day 14 (t = 0.42, p > 0.66, GMR = 1.06, 95% CI of GMR = 0.82, 1.37) and day 90 (t = 0.80, p > 0.43, GMR = 1.15, 95% CI of GMR = 0.74, 1.14). However, as there are no reports of meta-analysis of cell culture human rabies vaccine trials, to confirm this observation the authors recommend further studies in this regard.     

Immunogenicity of rabies postexposure booster injections in subjects who had previously received intradermal preexposure vaccination

BACKGROUND: Preexposure rabies vaccination is recommended using the full dose intramuscular or less expensive reduced dose intradermal method. The reliability of the reduced dose intradermal preexposure regimen is still controversial. The objective of this study was to determine whether it will mount a predictable accelerated immune response after a simulated rabies exposure. METHOD: One hundred and thirty-eight veterinary students received intradermal or intramuscular preexposure vaccination using a potent batch of purified chick embryo rabies vaccine. They then received booster injections one year later. RESULTS: Subjects who received intradermal rabies preexposure vaccination, using 0.1 mL of a potent tissue culture vaccine on days 0, 7, and 28, had a lower postexposure booster antibody response 1 year later than subjects given the preexposure series intramuscularly. A significant number showed an unsatisfactory early anamnestic response. Residual neutralizing antibodies, 1 year after the intramuscular preexposure series, were also significantly higher in the intramuscular than in the 0.1 mL dose intradermal group. However, all study subjects had antibody titers above the minimum recommended level of 0.5 IU/mL by day 14. CONCLUSIONS: We conclude that not all subjects who received an intradermal preexposure vaccine series may be fully protected during the first 5 days after an exposure. Rabies immune globulin, injected into bite wounds and followed by a complete postexposure vaccine series, may be indicated if such a patient experiences a severe rabies exposure.     

Immunogenicity of two modern tissue culture rabies vaccines in pre-exposure prophylaxis

Pre-exposure prophylaxis was given to employees supposed to be involved in rabies vaccine production in India. Prior to availability of the manufacturer's own human diploid cell (HDC) vaccine (Rabivax), immunization was executed with a chick embryo cell (CEC) vaccine (Rabipur). This constellation gave an opportunity to compare retrospectively immunogenicity of these two vaccines. The data was collected by retrospective analysis over more than three years at the clinic of Serum Institute of India Ltd. As per the standard protocol, persons with negative rabies vaccination history receive a dose of 1 ml of rabies vaccine intramuscularly on day 0, 7 and 28, and the virus anti-glycoprotein antibodies are measured one month after the third dose. The antibody levels > or =0.5 IU/ml are considered protective. The CEC and HDC vaccines were used during the analysis period. In all, 43 individuals received the CEC vaccine, 106 the HDC vaccine. The mean age of recipients was 33 years five months (Rabipur) and 30 years three months (Rabivax). All subjects in both groups were males. Five commercial batches of the CEC vaccine (129 doses) and seven batches of the HDC vaccine (318 doses) were used. Ninety-nine percent of the HDC and 93% of the CEC vaccine recipients were protected after the standard three dose schedule. Geometric mean titre was significantly greater for the HDC than CEC vaccine, being 5.05 IU/ml and 2.90 IU/ml, respectively (p = 0.0002). The HDC vaccine showed a good lot-to-lot consistency with respect to GMT both by ANOVA test and Nonparametric ANOVA test. On the other hand, the CEC vaccine demonstrated a variation in titres, when the lots were compared. Three out of four low-responders accepted a booster vaccination, and regardless of whether Rabipur or Rabivax was used, all three responded well one month after the booster. The Indian HDC vaccine compares well with the CEC vaccine in terms of immunogenicity. With HDC vaccines, cost has been an issue. However, since the new HDC vaccine has a comparable cost to the CEC vaccine, it may be possible to use it in large-scale vaccinations.     

乙肝疫苗联合免疫球蛋白在阻断乙肝母婴传播中的临床疗效观察

目的探讨分析乙肝疫苗联合免疫球蛋白在乙肝母婴传播途径阻断中的作用效果。方法选取从2010年1月至2012年11月在我院进行产前检查的住院分娩的200例HBsAg阳性孕妇及脐血为研究对象,所有孕妇的肝功能均正常。按照平均随机抽样的原则平均分为对照组和干预组,各为100例孕妇。对照组的新生儿在出生后24 h内接种乙肝疫苗联合免疫球蛋白100IU;干预组的孕妇在孕周为28、32和36周时,分别注射200IU的免疫球蛋白各1次,其新生儿在出生后的处理与对照组相同。所有病例均进行成功随访,观察接种后12个月两组新生儿乙肝五项检查情况。结果干预组和对照组的12个月新生儿HBsAg和HBsAb阳性率分别为1%、94%和6%、75%,两组间的差异均有有统计学意义(P<0.05)。结论对新生儿肌内注射免疫球蛋白联合乙肝疫苗接种对乙肝母婴阻断中的作用效果显著,尤其是在分娩前进行免疫球蛋白产前干预具有良好的免疫阻断作用,降低了新生儿感染乙肝的概率安全有效,值得临床推广应用。     

冻干人用狂犬病疫苗(MRC-5细胞)非临床安全性研究

目的 对冻干人用狂犬病疫苗(MRC-5细胞)进行全身主动过敏试验、肌肉刺激性、单次给药毒性和溶血性评价,以考察其安全性.方法 本研究起止时间为2014年3月至2016年10月.按照确定的工艺和质量标准,使用人二倍体细胞MRC-5培养狂犬病固定毒株,灭活、纯化后制备冻干人用狂犬病疫苗,质量检定合格后,用于开展全面的动物毒...     

人用精制狂犬病疫苗不良反应与免疫学效果

目的 :观察人用精制狂犬病疫苗(PHKCRV)的免疫学效果及不良反应。方法 :选择332例健康者 ,按预防性免疫接种程序接种组 2 72人 ,其中PHKCRV 2 4 2人 ,用法国维尔博狂犬病疫苗 (PVCRV ) 30人。按应急性免疫接种程序接种PHKCRV的 6 0人中进行不同剂量 [全量 (1.0mL)组和半量 (0 .5mL)组 ,每组各 30人 ]接种。结果 :　PHKCRV不良反应率为 2 3% (7/ 30 )低于PVCRV的 33% (10 / 30 )。 2种疫苗中和抗体阳转率均为 10 0 %。中和抗体水平预防性接种组为 (10± 5)kU·L- 1,应急性接种组中全量组为 (9± 3)kU·L- 1;半量组为 (7.3± 2 .5)kU·L- 1。结论 :说明该疫苗不仅不良反应轻微而且免疫原性良好     

Rabies postexposure prophylaxis in returned injured travelers from France, Australia, and New Zealand: a retrospective study

BACKGROUND. There is little published information available describing rabies pre- and postexposure prophylaxis (PEP) in tourists returning to their home country and seeking care for animal-associated injuries, especially those associated with a rabies risk. METHOD. We analyzed 261 travelers seeking care on returning to their home country following an animal-related injury acquired abroad. Information on individual cases of rabies (PEP) including preexposure status, type of contact with a potentially rabid animal, type of animal, and the nature of rabies PEP was collected by retrospectively analyzing records from May 1997 to May 2005. RESULTS. The majority of injuries were acquired in South-east Asia and North Africa. Only 6.8% of injured patients were previously vaccinated against rabies, while 75.4% of the cohort experienced a severe injurious contact with animals (World Health Organization category III). Of travelers who sustained a high-risk injury, only 24% received both vaccination and rabies immune globulin,(RIG) while 76% received vaccination only. Of the travelers who did not receive RIG, 43% had received a first dose of vaccine more than 7 days after return and before presenting to a clinic in their home country. CONCLUSIONS. This study highlights important deficiencies in rabies PEP for travelers who acquire high-risk, animal-associated injuries in rabies-endemic countries, with the majority not receiving adequate PEP or experiencing a substantial delay before receiving rabies vaccination.     

我院人用狂犬病疫苗及狂犬病人免疫球蛋白使用情况分析

目的：总结分析2015-2017年我院人用狂犬病疫苗及狂犬病人免疫球蛋白（HRIG）的使用情况,为科学、合理地制定采购计划及储备管理提供依据。方法：通过医院信息管理系统调取2015-2017年我院人用狂犬病疫苗及HRIG的相关使用数据,计算其月占比、季节指数等数据,对我院2015-2017年人用狂犬病疫苗及HRIG的使用情况进行分析。结果：2015-2017年我院人用狂犬病疫苗共使用484166支,分别为145140支、154818支、184208支,使用总量逐年增加。其中5-10月使用量最大,季节指数均超过100%;12月至来年3月接种量使用量相对较小,季节指数均不超过80%。3年间HRIG的使用总量也逐年明显增加,季节指数的变化与人用狂犬病疫苗相似。结论：2015-2017年我院人用狂犬病疫苗及HRIG的使用量基本呈现夏秋季多、冬春季少的规律,具有典型的季节性。根据时间序列方程式计算得到的2018年人用狂犬病疫苗预测使用数量与实际使用数量并不相符,误差率较大,易受外界因素影响。因此,还是要根据季节及实际使用情况的变化,动态地进行人用狂犬病疫苗及HRIG的库存管理。人用狂犬病疫苗在使用中发现的不良反应多为局部反应,但我院近年来也偶发非常严重的不良反应,因此要加强观察,提高重视。     

Endemic existence of rabies in Ethiopia

The study on the prevalence of rabies was conducted on a retrospective data gathered from EHNRI rabies diagnostic laboratory Addis Ababa, in the years 1979-1987. During this period a total of 8036 animals were brought to the rabies diagnostic laboratory. Ninety one percent (7329) of these animals were dogs. The remaining 8.8% (707) comprised of cats, domestic animals (donkeys, cows, sheep) and wild animals (monkeys, jackals and hyenas). Out of 7329 dogs examined 832 were positive for rabies. Dogs accounted for the majority of animal rabies (94.01% of the total positive animals). The remaining 5.99% (53) of the animals diagnosed with rabies-comprised of cats, domestic animals and some wild animals. A total of 15,940 people were given post exposure anti-rabies prophylaxis treatment that came from different parts of the country in the years 1979-1987. The prevalence rates of rabies were found to be higher soon after dogs' breeding seasons. Such an observation indicates that among dogs infection, transmission through biting is significant during the breeding season. However, despite the high incidence of rabies in Ethiopia, only 320 people were reported to have died of rabies in the years 1979-1984. This supports, the hypothesis that there is a lack of appropriate reporting system on prevalence of rabies and its impact on humans in Ethiopia.     

拉米夫定在阻断母婴传播慢性乙型肝炎中的临床观察

目的拉米夫定能有效地阻断母婴垂直传播乙型肝炎。方法对87例HBsAg、HBeAg阳性的孕妇进行随机分组,分为治疗组(A)45例与对照组(B)42例,A组45例在妊娠24周口服拉米夫定100mg,每日1次至分娩后停药。B组42例孕妇在28周、32周、36周各肌肉注射100U乙肝免疫球蛋白。两组中所生的新生儿在分娩2小时肌肉注射乙肝免疫球蛋白100U,6小时接种重组酵母乙肝疫苗5μg,并且在分娩后1、6个月按时接种重组酵母乙肝疫苗5μg。结果A组45例孕妇所生的1岁婴儿中外周血清检测1例HBsAg阳性,阻断率97.78%。B组42例孕妇所生的新生儿的1岁婴儿中外周血清检测6例HBsAg阳性,阻断率85.71%。结论A组阻断率明显高于B组,拉米夫定能降低母婴传播乙型肝炎的风险。     

Immunogenicity and efficacy of Fermi-type nerve tissue rabies vaccine in mice and in humans undergoing post-exposure prophylaxis for rabies in Ethiopia

Rabies is an acute viral encephalitis that is invariably fatal following the manifestations of clinical signs. To subvert the course of the disease, rabies post-exposure prophylaxis (PEP) is widely utilized. The immunogenicity and efficacy of Fermi-type rabies vaccine produced in Ethiopia was determined in mice subjected to intracranial challenge with rabies virus, and in humans undergoing rabies PEP in Ethiopia. Mice were randomly assigned into 5 groups. Group 1 received 0.25 ml each of phenolized saline intraperitoneally for 14 consecutive days. Mice in groups 2-5 received 0.25 ml of rabies vaccine for human PEP for the same period of time. Blood samples were drawn from the retro-orbital vein of all mice on designated days for the determination of rabies virus neutralizing antibody (VNA) using the mouse serum neutralization test. Mice were subsequently challenged intracranially with rabies virus at a concentration of 64 MICLD50 90 days post initial vaccination. Rabies neutralizing antibody titers in the sera of immunized mice ranged from 4.6 to 25 IU/ml. Booster vaccine doses did not seem to induce significant increases in the immune response of vaccinated mice, all of whom withstood intracranial challenge with rabies virus. Rabies VNA was further determined in 12 patients vaccinated in accordance with the prescribed dosage of Fermi-type vaccine for human rabies PEP. Most had > 0.5 IU/ml of rabies VNA by day 14, and none detectable at day 1. In contrast to mice, booster doses of vaccine may contribute to slightly higher rabies VNA titers in humans but our small sample size, on top of significant defaulter rates in the study participants, limits our interpretation of the effects of booster vaccine doses. The results of this study are the first documentation of the efficacy and immunogenicity of the Ethiopian Fermi type nerve tissue vaccine in both humans and mice.