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@#Objective To study the effect of different strains of mice(KM and ICR)immunized with rabies vaccine on thedetection of titer.Methods The rabies vaccine and the national standard for the efficacy verification of rabies vaccine forhuman use(referred to as national standard)were diluted with PBS at the ratios of 1∶25,1∶125,1∶625 and 1∶3 125,and KM and ICR mice with half male and half female were immunized intraperitoneally respectively.Sixteen mice of each strain wereimmunized with 0.5 m L/mouse at each dilution.The immunization was strengthened once every one week at the same dose androute.The mice in each group were weighed 0,7 and 14 d after the initial immunization.After 14 d of the initial immunization,the mice were subjected to intracranial attack with rabies virus(RABV)CVS2(5-100 LD_(50)),0.03 m L/mouse.The numberof mice with death and typical rabies brain symptoms 5 d after the attack was counted.According to the national standard ED_(50),the relative efficacy was calculated by Reed-Muench method.Results The body mass of the two strains of miceshowed an increasing trend during the immunization stage,and the body mass of KM mice increased faster than that of ICRmice.The lgED_(50) values of the national standard in KM mice were all within the expected range of 2.10-2.75,while thevalues in ICR mice were higher than the range.The titers of rabies vaccine in KM mice were all significantly lower than thosein ICR mice(t = 2.887-6.619,each P < 0.05).Conclusion Mouse strains can significantly affect the results of rabies vaccine titer determination,and different standards should be adopted for different strains of mice to ensure the accuracy of vaccine detection results.
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@#Objective To identify the peak 2 protein on the right side of the main peak of size exclusion chromatograghy-high performance liquid chromatography(SEC-HPLC)in freeze-dried human rabies vaccine(Vero cell)stock solution(without human blood albumin),so as to determine the protein composition of the peak and ensure the vaccine quality.Methods The lyophilized human rabies vaccine(Vero cells)stock solution(without human blood albumin)was analyzed by SECHPLC,of which the peak 2 on the right side of the main peak was collected and concentrated by ultrafiltration,then reduced by dithiothreitol(DTT),alkylated by iodoacetamide (IAM) and hydrolyzed by Trypsin. The products were analyzed by nano LC-MS/MS.Results Four proteins were successfully identified in the right peak 2 of SEC-HPLC main peak in lyophilized human rabies vaccine(Vero cell)stock solution(without human blood albumin),and the number of matching peptides for a single protein ranged from 59 to 79. The number of single protein-matching characteristic peptides ranged from 6 to 12. The detection times of single protein-matching characteristic peptide segments ranged from 20 to 36 times. The sequence coverage of the identified proteins ranged from 37. 40% to 64. 31%. A total of 280 peptides participated in the statistics,and the mass spectrum deviation was less than 0. 15 Da.Conclusion The peak 2 on the right side of SEC-HPLC main peak of lyophilized human rabies vaccine(Vero cell)stock solution(without human blood albumin)is derived from rabies strain 4a GV,which is the vaccine particle dissociation.
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@#Objective To compare and analyze two methods for determination of vaccine particle content in freeze-dried human rabies vaccine(Vero cells)bulk and final bulk,and to provide experimental basis for establishing standard detection method for particle content and purity of rabies vaccine products.Methods The samples were subjected to vaccine particle cracking,BCA quantification,and size exclusion chromatograghy-high performance liquid chromatography(SEC-HPLC)analysis. BCA-SEC relative area method and BCA-SEC vaccine particle standard curve method were used to detect the total protein concentration of the bulk and final bulk,separately,and the content of vaccine particles was quantitatively analy-zed. Finally,the detection results of the two methods were compared and analyzed.Results The content of vaccine particles in freeze-dried human rabies vaccine bulk was determined to be within 256-305 μg/mL by the two methods,with an average value of 267-285 μg/mL,and the relative standard deviations(RSDs)ranged from 5. 8% to 10. 2%,with good consistency between two methods. The content of vaccine particles in freeze-dried human rabies vaccine final bulk was determined to be in the range of 149-169 μg/mL by the two methods,with an average value of 152-164 μg/mL,and the two methods showed the RSDs between 0. 9%-4. 7% with good consistency.Conclusion The measured value by BCA-SEC standard curve method deviates less from the expected value and is closer to the actual situation of samples,so it is recommended to use this method as a reference for enterprises.
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@#Objective To evaluate the safety of human purified Vero cell rabies vaccine(PVRV)after exposure in China by Meta-analysis.Methods With rabies,vaccine and safety as key words,a systematic search was performed in PubMed,EMBASE,Cochrane and China National Knowledge Infrastructure(CNKI),supplemented by manual retrieval.A Meta-analysis was performed to analyze the incidence of adverse events of two immunization regimens Zagreb and Essen using Review Manager 5.4 software after literature screening and data extraction according to the inclusion and exclusion criteria.Results A total of 12 studies were included,of which 7 were prospective studies and 5 were retrospective studies.Most included in the studies showed a low risk of bias.The incidence of adverse events in Zagreb regimen was significantly higher than that in Essen regimen[relative risk(RR)= 1.01,95% CI = 0.90 ～ 1.14;I2= 73.00%,P<0.05],but there was a high degree of heterogeneity.The incidence of fever,pain and induration in Zagreb regimen was significantly higher than that in Essen regimen(RR = 1.14,0.92 and 0.86,95% CI = 0.82 ～ 1.60,0.73 ～ 1.14 and 0.29 ～ 2.51;I2= 73.00%,P<0.05],but there was a high degree of heterogeneity.The incidence of fever,pain and induration in Zagreb regimen was significantly higher than that in Essen regimen(RR = 1.14,0.92 and 0.86,95% CI = 0.82 ～ 1.60,0.73 ～ 1.14 and 0.29 ～ 2.51;I2= 81%,65% and 92%,respectively,P<0.01).Conclusion Two regimens of PVRV vaccination after exposure showed good safety.However,when adopting Zagreb regimen,attention should be paid to the physical conditions of children and the elderly with relatively poor immunity to avoid adverse events.
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@#Objective To develop and validate size exclusion column-high performance liquid chromatography(SEC-HPLC)for determination of the purity of bulk material of freeze-dried rabies vaccine for human use.Methods Chromatography column TSK-gel G6000PW_(XL)(7.8 mm × 30 cm,13 μm)was used for the determination(column temperature 30 ℃)with mobile phase of 0.1 mol/L PB buffer(pH 7.8)at a flow rate of 0.5 mL/min.The detection wavelength was 280 nm and injection volume was 20 μL.The method was validated for system suitability,specificity,precision and durability and determined for detection limit and quantitation limit,which was applied to analyze bulk material purity of freeze-dried rabies vaccine for human use of 3 batches of Vero cells and 1 batch of human diploid cells.Results The resolution of target protein spectrum peak of bulk material of reference sample and freeze-dried rabies vaccine for human use prepared with two substrates was more than 1.5 with a tailing factor less than 1.5;The blank solvent showed no absorption peak at the position of target protein peak with no interference in the determination;The RSDs of retention time and peak area in precision verification were both less than 2.0%;The quantitative limit was 10 μg/mL,and the detection limit was 4 μg/mL;The reference sample was injected three times continuously at three different detection wavelengths of 278,280 and 282 nm,and the RSDs of retention time and peak area were also less than 2.0%.The purity of 4 batches of freeze-dried rabies vaccine bulk material for human use was all more than 97%.Conclusion The developed SEC-HPLC for determination of the purity of freeze-dried rabies vaccine bulk material for human use showed good specificity,precision and durability,which provided a reliable method for the quality control of human rabies vaccine.
摘要
Rabies is a zoonosis caused by rabies virus for which no effective treatment is available.The main preventive measure is vaccination with human rabies vaccine before or after rabies exposure.With progress in science and technology,the production process of human rabies vaccine has continually advanced,thereby increasing vaccine quality,and providing a safer,more effective means of rabies prevention and control through increasing human resistance to rabies.New human rabies vac-cines have made breakthroughs in basic research and clinical research.However,the problems of poor vaccine compliance and low vaccination rates must urgently be addressed.China must actively explore effective coping strategies,accelerate the upda-ting of existing immunization procedures,effectively increase the rabies vaccination rate,and achieve the goal of eliminating ra-bies by 2030 as soon as possible.
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@#Objective To develop and verify a qPCR method for the qualitative and quantitative analysis of residual host DNA in human rabies vaccine(Vero cells) stock solution.Methods The qPCR standard curve was established by using the Vero cell DNA quantitative national standard,and the residual host DNA was extracted using magnetic beads.The specificity,repeatability,intermediate precision,accuracy and durability of the method were verified,and the linear range and limit of quantification were determined.The residual DNA of three batches of human rabies vaccine(Vero cells) stock solution was quantitatively analyzed and the fragment size was qualitatively analyzed by using this method.Results The correlation coefficients(R~2) of Vero cell DNA quantitative national standard amplification standard curve were all more than 0.99 by qPCR,and the quantitative range was 0.3 pg/mL～30 ng/mL.The method showed good specificity and repeatability.In the verification of intermediate precision,accuracy and durability,the relative standard deviations(RSD)of detection results of the samples were all less than 10%.The residual DNA content of Vero cells in three batches of stock solution was 0.20～0.77 ng/dose,which met the relevant standard of Chinese Pharmacopoeia(Volume Ⅲ,2020edition).The residual DNA fragments greater than 154 bp accounted for 52%～63%.Conclusion The developed qPCR method for the detection of residual DNA in human rabies vaccine(Vero cells) stock solution had good specificity,repeatability,intermediate precision and durability,and qualitatively and quantitatively analyzed the residual DNA rapidly and accurately,which was of great significance for improving the detection and control of residual DNA content in the production process and final product of human rabies vaccine(Vero cells).
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@#Objective To collaboratively calibrate and finally assign the potency of the 9th national standard for human rabies vaccine for candidate.Methods Qualified laboratories for the production,research and development of human rabies vaccines were organized to determine the potency of candidate national standard for rabies vaccines by using NIH method,with the 7th international standard for rabies vaccines(NIBSC code:16/204)as the reference standard. The detection results were statistically analyzed,and the geometric mean of effective detection values was taken as the final potency value of the candidate standard. According to the requirements of the preparation of national drug reference materials,the candidate standard was destroyed by heat acceleration,and then detected for the glycoprotein antigen to investigate the stability.Results A total of 20 laboratories participated in the collaborative calibration,of which the two laboratories that did not strictly follow the collaborative calibration SOP were excluded,and the data of the remaining collaborative laboratories were valid. After statistical analysis,the final potency of the 9th national standard for rabies vaccine was 11. 4 IU/mL,the 95% confidence limit was 10. 9～11. 9 IU/mL,and the 95% reference range of ED_(50) was 2. 10～2. 75. There was no significant difference in the results of glycoprotein antigen detection under different time conditions(2,4,8 and 16 weeks)at 37 ℃.Conclusion The collaborative calibration research of the 9th national standard for human rabies vaccine(batch number:201906001)has been completed,the potency assignment is scientific and rigorous,the data was reliable,and the thermal stability meets the requirements. At present,this standard has been approved by the National Drug Reference Material Committee,which is of great significance to the quality control of human rabies vaccine,especially the quality control of effectiveness.
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@#Objective To evaluate the safety and immunogenicity of pre-exposure prophylaxis of the approved freeze-dried rabies vaccine(Vero cell)(rabies vaccine in brief)for human use in adults ≥18 years of age.Methods Participants aged ≥18 years in Guizhou and Shanxi provinces from June 2022 to September 2022 were enrolled,vaccinated with 1 dose of rabies vaccine at 0,7,28 d respectively,and collected for 5. 0 mL of venous blood before the first dose and 14 d after the third dose. Immunofluorescence foci assay was used to detect rabies virus neutralizing antibodies,and adverse events were collected 0～7 d after each dose of vaccine.Results A total of 120 participants were enrolled,120 participants received the first dose of rabies vaccine,119 participants received the second dose and 118 participants received the third dose.Before the first dose of rabies vaccine,the seropositive rate of antibody was 2. 54% and the geometric mean concentration(GMC)was 0. 40 IU/mL. After the third dose of rabies vaccine,the seropositive rate and seroconversion rate were 100%,the GMC was 9. 68 IU/mL,and the geometric mean increase(GMI)was 23. 99. The incidence of adverse events 0～7 d after the first,second and third doses of rabies vaccine were 22. 50%,13. 45% and 4. 24%,respectively. The local adverse events were mainly pain,and the systemic adverse events were mainly fever,fatigue/weakness,dizziness,joint pain,and diarrhea.Conclusion Approved rabies vaccine showed good safety and immunogenicity in pre-exposure prophylaxis of people ≥ 18 years old.
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Se relata el nacimiento, auge y decadencia, de la producción de vacunas en el antiguo Instituto Bacteriológico de Chile, desde su fundación en 1929 hasta su fin en 1980, por boca de quien fuera por diecisiete años primero encargado de la fabricación de vacunas bacterianas y luego director de la institución. Las vicisitudes de la vacuna BCG, la introducción del toxoide tetánico, el fin de la vacuna antivariólica y el triunfo de vacuna antirrábica de Fuenzalida y Palacios, se narran a menudo con comentarios de quienes participaron en estos hechos.
The birth, rise and decline, of vaccine production at the Bacteriological Institute of Chile is recounted by mouth of who was for seventeen years first in charge of manufacturing and then director of the institution. The vicissitudes of the BCG vaccine, the introduction of tetanus toxoid, the end of smallpox vaccine, and the triumph of the rabies vaccine are often related with comments from those who participated in the events.
Subject(s)
Humans , History, 20th Century , Bacteriology/history , Communicable Disease Control/history , Vaccine Development/history , Smallpox Vaccine/history , Typhoid-Paratyphoid Vaccines/history , Rabies Vaccines/history , Diphtheria-Tetanus-Pertussis Vaccine/history , Chile , Tuberculosis Vaccines/history摘要
Rabies is an acute viral zoonotic disease that affects all warm-blooded animals including mammals and occurs in more than 150 countries and territories. Although rabies is a 100% fatal disease, it can be pre-vented by the use of potent anti-rabies vaccines (ARV). The present study was a hospital based descrip-tive longitudinal study conducted during February 2019 to July 2020 amongst the animal bite patients attending the Anti -Rabies clinic (ARC) of Vardhman Mahavir Medical College and Safdarjung Hospital (VMMC & SJH), New Delhi, to study the adverse events (vaccine reactions) if any following administra-tion of the ARV. The age of the study participants ranged from 2 to 65 years and the mean age was (29.315.2) years. No severe or serious adverse events were reported. Of the minor reactions, the most commonly reported symptom was pain at the injection site (34; 9.4%) followed by occurrence of tingling sensation (29; 8.1%), headache (22; 6.1%) and itching at the injection site (19; 5.3%). These findings corroborate with those found in previous studies in the literature. It was concluded that although there are possible local or mild or systemic adverse reactions to rabies vaccination, but once initiated, rabies prophylaxis should not be interrupted or discontinued.
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Organ transplant recipients are at a high risk of infection with high hospitalization rate, critical rate and fatality, due to low immune function caused by taking immunosuppressants for a period of long time after organ transplantation. Currently, vaccination is recognized as an effective approach to prevent infection. Organ transplant recipients may be vaccinated according to individual conditions. However, the sensitivity to vaccines may decline in organ transplant recipients. The types, methods and timing of vaccination have constantly been the hot spots of clinical trials. In this article, the general principles, specific vaccines and SARS-CoV-2 vaccines of vaccination in organ transplant recipients were briefly reviewed, aiming to provide reference for the vaccination of organ transplant recipients. Moreover, current status of SARS-CoV-2 vaccination for organ transplant recipients was illustrated under the global outbreak of novel coronavirus pneumonia pandemic.
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Objective:To investigate the effects of different production processes on sensitization responses to human diploid cell rabies vaccines.Methods:This study randomly collected 360 serum samples in clinical trials of four rabies vaccines with different production processes. Total IgE levels at different time points were detected by ELISA. SPSS19.0 software was used for statistical analysis.Results:Total IgE test results showed that the seropositive rate was 20% (6/30) for all four vaccines. The lowest mean value of total IgE was 9 IU/ml and the highest was 210 IU/ml. Repeated measures analysis of variance showed that there was no significant difference in total IgE levels at different sampling time points ( P=0.284), and the total IgE level in people injected with multistep concentrated human diploid cell rabies vaccine was significantly below that in people immunized with Vero cell rabies vaccine ( P=0.024). Conclusions:Increasing the immune dosage of human rabies vaccine could not result in a rise in total IgE. Human diploid cell rabies vaccines had good safety as the production process could remove most of allergenic impurities.
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Aim To study the application of HL-60 monocyte activation test in the pyrogen detection of freeze-dried rabies vaccine for human use.Methods The established HL-60 mononuclear cell activation test (MAT) was transferred between laboratories and the method was verified; referring to the interference test in the photometric method of the bacterial endotoxin test method of the Chinese Pharmacopoeia, HL-60- IL- 6 MAT was used to detect the recovery and pyrogen content of 13 batches of freeze-dried rabies vaccine for human use.Results The linearity of the amount of 1L-6 secreted by HL-60 cells, which stimulated by dif¬ferent concentrations of endotoxin standards was above 0.95; the calculated minimum detection limit was not more than 0.125 EU • mL"1 ; the recovery experiment with a solution containing 0.5 and 1.0 EU • mL"1 of endotoxin was performed to cheek the accuracy of the method.HL-60-IL-6 was used to detect 13 hatches of Freeze-dried rahies vaccine for human use, and the re¬covery of endotoxin was between 50 % to 200%.It was consistent that HL-60-IL-6 with pyrogens and en¬dotoxin test for 4 batches of freeze-dried rabies vaccine for human use which pyrogens and endotoxin test failed and the 3 batches of water for injection.Conclusion The HL-60 MAT using IL-6 as a detection indicator is suitable for the detection of pyrogenic substances in freeze-dried rabies vaccine for human use.
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ObjectiveTo analyze a case of death after inoculation of a freeze-dried rabies vaccine for human use so as to provide reference for the vaccination of the rabies vaccine and the process of investigation and diagnosis involving adverse events following immunization （AEFI） in the future. MethodsData on vaccination， clinical symptoms， treatments， investigation and diagnosis were collected and analyzed. ResultsRabies post-exposure prophylaxis and vaccination were in line with the protocols. On the 3rd day after the inoculation of the rabies vaccine， the patient developed fever， weakness， headache， dizziness， diarrhea and other symptoms. The white blood cell count and neutrophil count increased progressively. At about 17：00 on the same day， the patient suffered a sudden cardiac arrest and died clinically. Autopsy was not carried out. ConclusionThe cause of sepsis /septic shock of the patient is unknown. It is necessary to formulate detailed rabies immunization procedures as well as norms and expert consensus in the field of investigation and diagnosis of AEFI.
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ObjectiveTo analyze a case of death after inoculation of a freeze-dried rabies vaccine for human use so as to provide reference for the vaccination of the rabies vaccine and the process of investigation and diagnosis involving adverse events following immunization （AEFI） in the future. MethodsData on vaccination， clinical symptoms， treatments， investigation and diagnosis were collected and analyzed. ResultsRabies post-exposure prophylaxis and vaccination were in line with the protocols. On the 3rd day after the inoculation of the rabies vaccine， the patient developed fever， weakness， headache， dizziness， diarrhea and other symptoms. The white blood cell count and neutrophil count increased progressively. At about 17：00 on the same day， the patient suffered a sudden cardiac arrest and died clinically. Autopsy was not carried out. ConclusionThe cause of sepsis /septic shock of the patient is unknown. It is necessary to formulate detailed rabies immunization procedures as well as norms and expert consensus in the field of investigation and diagnosis of AEFI.
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Objective To analyze the suspected case of demyelinating myelitis after vaccination with rabies vaccine (Vero cells) in Yichang city, and to provide a clinical basis for reducing or avoiding similar serious, suspected, and abnormal vaccination reactions after inoculation of rabies vaccine (Vero cells). Methods Epidemiological characteristics of a case of demyelinating myelitis after freeze-dried rabies vaccine (Vero cells) inoculation in Yichang City in 2017 were analyzed. Results In 2017, a case of demyelinating myelitis occurred after inoculation of freeze-dried human rabies vaccine (Vero cells) in Yichang city, which was due to the abnormal reaction of vaccination. Conclusion If abnormal signs occur after vaccination, timely medical treatment should be taken to reduce the occurrence of severe diseases and deaths.
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This article referred to the relevant guidelines for vaccine clinical trials and the accumulated experience in the development and review of human rabies vaccines, as well as combined the technical recommendations for human rabies vaccines from major health facilities such as WHO, to discuss the key considerations in the design of clinical trials for human rabies vaccines, including control vaccines, evaluation of efficacy endpoints, clinical subjects, the sample size, immunity persistence, re-exposure immunization schedule and post-marketing study. This article aimed to provide reference for the design of human rabies vaccine clinical trials.
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Background: Atherosclerosis affects multiple vascular beds, accounting for nearly all of coronary heart disease and some proportion of ischemic strokes. Serum lipid levels have an effect on the short-term mortality due to strokes. But in some studies, there was no dyslipidemia in patients who presented with acute stroke. It is important to evaluate the serum lipid levels in both the types of strokes to guide lipid lowering therapy which can reduce incidence of stroke and related mortality. This study is undertaken to evaluate the role of serum lipids in patients of stroke in our centre.Methods: It is a cross sectional study, conducted on 176 patients of stroke, who were assessed by NIHSS stroke scale clinically. Serum lipid profile was measured in all patients. Data was entered in Microsoft Excel and analysed by descriptive statistics. Chi Square test was used for association of qualitative variables. A p value<0.05 was considered statistically significant.Results: In this study conducted on 176 patients, LDL values were deranged more in CVA-bleed group compared to CVA-infarct group. BMI was the best anthropometric measure that correlated with LDL. LDL was also the most common parameter that was deranged in nonsmokers (61.8%) whereas in smokers, total cholesterol (66.3%) was most commonly deranged. Triglyceride and VLDL values were deranged more commonly in diabetic group than in non-diabetic group. A total of 123 out of 145patinets with CVA- infarct, had deranged lipid profile and among patients with CVA- bleed 24 out of 32 had deranged lipid profile.Conclusions: Results of this study shows significant derangement in lipid profile especially in LDL cholesterol levels in both infarct and bleed group, therefore starting statin therapy would prove to be beneficial in preventing recurrence of stroke.
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Complete postexposure prophylaxis with 4 doses of anti-rabies vaccine (ARV) in a previously vaccinated (nonna飗e) individual results in administration of two extra ARV doses resulting in wastages of precious resources comprising vaccine logistics, human resources, physician, and patient time. This cross-sectional study conducted in a secondary care hospital in Delhi among 175 incident animal bite cases observed 39 (22.3%) had an animal-bite history within the previous 5 years. A total of 19 (10.8%) cases reported a history of complete ARV vaccination during a previous animal-bite exposure. However, in the absence of supportive patient medical documentation, all the animal bite cases without exception were prescribed a full course of ARV irrespective of their previous exposure status. Rabies immunoglobulins (anti rabies serum) were also re-administered in 13 (81.2%) cases. National guidelines for rabies prophylaxis should, therefore, consider the inclusion of an explicit decision-making algorithmic mechanism when the health-care provider is confronted with this situation carrying the potential for hidden vaccine wastage.