Simultaneous Immunization with B.C.G., Diphtheria-tetanus,and Oral Poliomyelitis Vaccines in Children Aged 13-14

The simultaneous administration of B.C.G. vaccine, diphtheria-tetanus toxoid aluminium hydroxide adsorbed vaccine, and oral poliovaccine was studied in 628 children aged 13-14 years between 1966 and 1969 in Newham, London. The efficacy of these vaccines was unaffected by administering them at the same time; routine simultaneous administration is considered justified when organizational difficulties prevent the attainment of high immunization rates with the vaccines given separately. No adverse reactions to B.C.G. or oral poliomyelitis vaccines took place, but 8% of children had moderately severe local reactions after diphtheria-tetanus aluminium hydroxide adsorbed vaccine, which were attributed to diphtheria toxoid.Serological studies showed the need for immunization against diphtheria, tetanus, and poliomyelitis at 13-14 years of age. Because of the adverse reactions to diphtheria toxoid, however, simultaneous administration of tetanus toxoid aluminium hydroxide adsorbed, oral poliomyelitis, and B.C.G. vaccines only is recommended at present.An “adult type” diphtheria-tetanus toxoid might overcome the problem of reactions, though in two to three years'' time most children aged 13-14 years will have received diphtheria-tetanus-pertussis vaccine in infancy and reinforcement might then be accomplished by a small intradermal dose of the currently available fluid diphtheria-tetanus vaccine.Continued serological studies of diphtheria and tetanus antitoxins and polio antibody are necessary to determine the future need for reinforcement of immunity; such studies should become an essential part of the surveillance of the community immunization programme.     

Comparative clinical trial of vaccines against avian influenza

Scientic-production association "Microgen" has finished 1st phase of clinical trials of candidate vaccines against avian influenza in order to assess their reactogenicity, safety, and immunogenicity. Two vaccines constructed from NIBRG-14 vaccine strain [A/Vietnam/1 194/2004 (H5N1)], obtained from World Health Organization, were studied: "OrniFlu" (inactivated subunit influenza vaccine adsorbed on aluminium hydroxide) and inactivated polymer-subunit influenza vaccine with polyoxydonium (IPSIV). Clinical trial of the vaccines with different quantity of antigen (15, 30, and 45 mcg of H5N1 virus hemagglutinin) was carried out in Influenza Research Institute (St. Petersburg) and in Mechnikov Research Institute of Vaccines and Sera (Moscow). Analysis of results allowed to conclude that both vaccines were safe, well tolerated and characterized by low reactogenicity. Two-doses vaccination schedule was needed to meet required seroconversion and seroprotection rates (> or =1:40 in > or =70% of vaccinated volunteers). "Orni-Flu" vaccine containing 15 mcg of hemagglutinin and optimal quantity of aluminium hydroxide (0.5 mg) in one dose as well as IPSIV containing 45 mcg of hemagglutinin and 0.75 mg of polyoxydonium in one dose were most immunogenic after 2 doses - seroprotection rates in microneutralization assay were 72.2% and 77.0% respectively. Marked influence of aluminium hydroxide content on immunogenicity of the "OrniFlu" vaccine was confirmed in the study. Optimal quantity of adjuvant was 0.5 mg per dose. According to basic concept of vaccine development, preference is given to vaccine that under minimal quantity of antigen induces sufficient specific immune response and is safe in volunteers. "OrniFlu" vaccine containing 15 mcg of H5N1 virus hemagglutinin and optimal quantity of aluminium hydroxide (0.5 mg) corresponded to these requirements that allowed researchers to recommend it for clinical trials of 2nd phase.     

乙型肝炎疫苗中游离抗原对免疫效果的影响

将按《生物制品规程》制备除氢氧化铝吸附方式不同外,其余所有过程均一致的疫苗各１０批,在ＨＢｓＡｇ含量相同前提下,于５００公升大罐内吸附制备的疫苗中游离抗原含量比在１０公升瓶内吸附制备的疫苗高４倍,两者均数分别为３０４．１ｎｇ／ｍｌ和７３．１ｎｇ／ｍｌ,吸附率分别为９７．９５％和９９．５１％;用ＲＰＨＡ测定游离抗原滴度前者也比后者高２倍;动物免疫效价（ＥＤ５０）高４７％。在上述吸附率范围内,游离抗原含量与ＥＤ５０呈正相关（ｒ＝０．７１７９Ｐ＜０．００１）。     

Results of a study of new preparations of inactivated whole-virion influenza vaccines for the protection of children in the USSR

The safety, reactogenic properties and antigenic potency of inactivated whole-virion influenza vaccines produced in the USSR were studied on 1,117 schoolchildren in limited coded clinico-immunological observations. Inactivated chromatographic influenza vaccine obtained from strain A/Texas/1/77 (H3N2) and a variant of this vaccine, developed specially for children and obtained from strains A/Texas/1/77 and B/Leningrad/76, were used for immunization. Both preparations were introduced intradermally in a single injection in a volume of 0.1-0.2 ml by means of bi-3 jet injector. The content of hemagglutinin in this volume varied from 3.0 to 8.0 micrograms. Clinico-laboratory investigations demonstrated the safety of mono- and bivalent inactivated whole-virion influenza vaccine administered intradermally in a single injection to children of school age. The vaccines showed low reactogenicity and high antigenic potency in children aged 7-10 and 11-14 years, and the optimal doses of the preparations were selected for children of different age groups. The distinct prophylactic effectiveness of inactivated chemical chromatographic influenza vaccines in children aged 11-14 years was revealed 11 months after immunization, the index of immunological effectiveness being 1.7.     

Stability of cholera and typhoid vaccines

Fluid plain and adsorbed and freeze-dried cholera and tyhpoid vaccines of different composition were examined for thermostability by potency testing (by active mouse protection tests) after exposure to 37 degrees C for 1, 2, 3, 4, 8 and 12 weeks. Loss of potency was evaluated by comparison with samples stored at 4 degrees C. The fluid plain cholera vaccine remained fully potent for 1--3 weeks, the adsorbed vaccine for at least 4 weeks. The fluid typhoid vaccines showed greater thermosensitivity than the fluid plain cholera vaccine. The freeze-dried cholera and typhoid vaccines were both very stable, retaining fully potency after at least 12 weeks' exposure to 37 degrees C. It should be emphasized that the above results apply exclusively to vaccines prepared by the methods used by the authors and formulated to identical compositions.     

Comparative study of the safety, reactogenicity and antigenic activity of chemical and live brucellosis vaccines in a controlled epidemiological trial

The complex evaluation of the reactogenicity characteristics revealed that after immunization with chemical brucellosis vaccine systemic reactions observed in most of the vaccinees were mildly pronounced and local reactions, mildly and moderately pronounced, their duration not exceeding 48-72 hours. During 4 months after immunization the antigenic and immunogenic potency of chemical brucellosis vaccine was no different from that of live brucellosis vaccine; seropositive persons immunized with chemical and live brucellosis vaccines showed no statistically significant differences in the geometric mean of their antibody titers, as determined in a number of serological tests, for a year after immunization. The examination of the vaccinees 4 and 12 months after immunization revealed that the sensitizing activity of chemical brucellosis vaccine was, respectively, 12.2 and 2.5 times lower than the allergenic action of live brucellosis vaccine.     

Studies on live rubella vaccine. V. Quantitative aspects of interference between rubella, measles and mumps viruses in their trivalent vaccine

Rubella vaccine combined with measles and mumps vaccines was administered in a single injection to children of 1 to 5 years of age. All three vaccines were serologically effective, and the clinical reactions caused by measles vaccine were considerably alleviated, when 6 x 10(3) PFU of rubella and 10(4) TCD50 per dose of mumps vaccines were combined with 5 x 10(4) TCD50 of measles vaccine. When a larger amount of mumps vaccine (3 x 10(5) TCD50/dose) was used, it caused interference with the rubella and measles viruses, i.e., the antibody response to rubella virus became poor and the incidence of clinical reactions to measles virus decreased. On the other hand, when 5 x 10(5) TCD50/dose of measles vaccine was combined with 10(4) TCD50/dose of mumps vaccine, the clinical reactions to measles virus were decreased but were almost the same as those induced by this vaccine alone.     

Feasibility of the use of ELISA in an immunogenicity-based potency test of anthrax vaccines

Complexities of lethal challenge animal models have prompted the investigation of immunogenicity assays as potency tests of anthrax vaccines. An ELISA was used to measure the antibody response to protective antigen (PA) in mice immunized once with a commercially available (AVA) or a recombinant PA vaccine (rPAV) formulated in-house with aluminum hydroxide. Results from the anti-PA ELISA were used to select a single dose appropriate for the development of a potency test. Immunization with 0.2 mL of AVA induced a measurable response in the majority of animals. This dose was located in the linear range of the vaccine dose–antibody response curve. In the case of rPAV, practical limitations prevented the finding of the best single dose for the potency testing of purified vaccines. In additional immunogenicity experiments neither the magnitude of the response to a single dose of vaccine, nor the estimation of the dose necessary to induce a measurable response were able to consistently detect brief exposure of vaccines to potentially damaging temperatures. However, differences detected for rPAV in the proportion of mice responding to the same dose of treated and untreated vaccine suggested that further assay development to increase the sensitivity of the latter design may be warranted.     

不同粒径氢氧化铝佐剂对白喉类毒素免疫效果的影响

研究不同粒径的氢氧化铝[Al(OH)3]对白喉类毒素的吸附效果,用于指导疫苗生产,提高疫苗质量。用透射电镜测得的不同粒径的Al(OH)3分别吸附白喉类毒素及用絮状单位测定法和疫苗效价测定法对其吸附效果作比较,并经统计学处理。试验结果显示,粒径为210nm的Al(OH)3对白喉类毒素吸附效果及对白喉疫苗效力的免疫增强作用明显好于粒径600nm的Al(OH)3。实验证实,Al(OH)3佐剂的粒径大小与白喉类毒素的吸附效果及疫苗的免疫原性密切相关。     

The choice of adjuvants in Mycoplasma vaccines

The use of adjuvants in vaccine production is an important aspect of potent vaccines. This investigation was concerned with finding the most efficient adjuvants for use in Mycoplasma vaccines produced in Nigeria. Four different vaccines were produced from the Gladysdale strain of Mycoplasma mycoides subspecies mycoides. They differed depending on the type of adjuvants used. Each vaccine was used to vaccinate eight cattle using a dose of 1 ml. Two other groups of eight cattle were used as controls. One of the two groups received 1 ml dose of inactivated Gladysdale vaccine without adjuvant while the second group received 1 ml dose of saline. The number of cattle that had the peak complement fixing (CF) antibody titres of 1/80 in each group of cattle was four for vaccine containing aluminium hydroxide gel, eight for vaccine containing liquid paraffin, one for vaccine containing sodium alginate and one for vaccine without adjuvant. Seven cattle from the group vaccinated with vaccine containing Freund's incomplete adjuvant had peak CF antibody titres of 1/80 or higher. The two groups vaccinated with vaccine containing liquid paraffin and Freund's incomplete adjuvant survived challenge at 6 months post vaccination. Freund's incomplete adjuvant and liquid paraffin containing 10% Arlacel A are the most efficient adjuvants.     

Immunological responses to recombinant cysteine synthase A of Brucella abortus in BALB/c mice

Brucellosis is a worldwide zoonotic disease. No Brucella vaccine is available for use in humans, and existing animal vaccines have limitations. There is a need to develop a safe and effective vaccine against human and animal brucellosis. In the present study, we generated recombinant cysteine synthase A (rCysK) of Brucella abortus in Escherichia coli and purified it up to homogeneity by metal affinity chromatography. The immunogenicity and protective efficacy of purified rCysK were evaluated in BALB/c mice with Freund’s adjuvant, aluminium hydroxide gel or without any adjuvant. High titres of anti-rCysK IgG antibody predominated by IgG1 were observed in all immunized mice. After stimulation with rCysK, the spleen lymphocytes of mice immunized with CysK formulated with aluminium hydroxide gel produced significant levels of IFN-γ. Protection against challenge with virulent B. abortus strain 544 was determined in BALB/c mice, and significant protection was observed in all CysK immunized groups when compared with PBS control. Among all the CysK vaccine groups, comparatively better protection was observed in mice immunized with aluminium hydroxide gel (1.064 units of protection). Overall, the results of the study suggest that rCysK induces primarily Th2 type of immune response and provides partial protection against B. abortus challenge.     

Immune response of noninbred mice to subvirion influenza vaccines with various antigen and sorbent loads

The variants of splitted and subunit influenza monovaccines from virus strains A/Leningrad/385/80R (H3N2) and A/Kiev/59/79R (H1N1), adsorbed on aluminium hydroxide and having the varying content of hemogglutinin and the carrier, have been studied. The immune response of noninbred mice to a single and double injections of these vaccines have been evaluated, the concentrations of the antigen and the carrier inducing a high response in the animals, have been determined. Differences in the immunological potency of hemagglutinins H1 and H3 have been noted.     

Potency of pertussis component in the DTP vaccine--an overview of three decade study in Poland.

In Poland, similar to many highly immunized Western countries, a recent increase in cases of pertussis has been observed. This study aims to evaluate the level of potency fluctuations of the pertussis component of Polish-produced DTP vaccine due to the changes having occurred in production and potency testing procedures. We compared the potency of the pertussis component of DTP vaccine lots produced and evaluated in similar periods and with similar production and testing procedures. Records of Kendrick test results performed over a 30-year period were available for analysis. This study confirms the role of different manufacturers, changes in vaccine strain compositions, in-house reference preparations used as reference vaccines in the Kendrick tests, and in mice of single strain sources in the potency values obtained. In addition, the comparisons performed revealed a downtrend in potency levels since 1992. Potency decrease in vaccine lots produced during 1992-1997 has been positively correlated to the lowering of the number of IOU/dose. Strain compositions of the DTP vaccine pertussis component and in-house references have been found to be associated with the fluctuation in potency estimations, and confirmed their crucial role in ensuring vaccine efficacy. Our study reveals that relative efficacy of the DTP vaccine produced in 1992-1997 might be lower than that of vaccines produced in other periods. This might in turn explain the increase in pertussis cases among children aged 5-15 years which is presently being observed in Poland.     

Evaluation of the potential use of inactivated influenza centrifuged vaccines with various hemagglutinin levels for immunizing schoolchildren

The safety, reactogenic properties and immunogenic potency of inactivated influenza centrifuged vaccines with different hemagglutinin content were studied in observations on children aged 11-15 and 7-10 years. According to the results of clinico-laboratory investigations, commercial influenza vaccine and its variant with hemagglutinin content reduced by half were found to be safe and showed faintly pronounced reactogenic properties in children. After vaccination hyperemia developed at the site of injection, moderate in 5% of the vaccinees aged 7-10 years and mild in other vaccinees of both age groups. The immunogenic potency of the preparations was determined by the specific features of influenza virus strains: strain A (H1N1) induced seroconversion in 62-94% and strain A (H3N2), in 67-96% of children.     

Relative Stability of Pertussis Vaccine Preserved with Merthiolate, Benzethonium Chloride, or the Parabens

When stored at 4 C, or heated at 22 or 35 C followed by storage at 4 C, the potency of pertussis vaccines preserved with Merthiolate was more stable than the potency of vaccines preserved with benzethonium chloride or the parabens (methyl- and propyl-p-hydroxybenzoate). Without preservative, potency was more stable than in the presence of benzethonium chloride or the parabens, but less stable than when Merthiolate was present. The histamine-sensitizing factor of the vaccines likewise decreased with the loss of potency. The deleterious effect of benzethonium chloride and the absence of the stabilizing effect of Merthiolate were contributing factors, if not the sole cause, for the instability of pertussis vaccine in quadruple antigen vaccine (diphtheria and tetanus toxoids and pertussis and poliomyelitis vaccines).     

Reactions after pertussis vaccine: a manufacturer's experiences and difficulties since 1964

Pertussis vaccines vary in quality, safety, and efficacy according to the production strains of Bordetella pertussis, the method of manufacture, and quality control procedures. It is therefore not justifiable to combine information on the incidence, nature, and severity of reactions after all manufacturers'' pertussis vaccines as if they were a single product. Attempts were made to collect information on all suspected cases of severe reactions that occurred after administration of about 15 million doses of Wellcome pertussis vaccines in the United Kingdom and Northern Ireland from 1964 to mid-1977. Altogether six deaths, six neurological reactions with sequelae, and 17 convulsions without sequelae were reported, but some were clearly not attributable to the vaccine, while, in other cases, the available information was inadequate for assessing the role of vaccination. Neurological disorders, similar to those reported in a few children after pertussis vaccination, occur unexpectedly in apparently healthy infants at the recommended age for immunisation, so chance association between vaccination and these events can be expected in some children. The Joint Committee on Vaccination and Immunisation has made several recommendations aimed at reducing severe reactions after pertussis vaccination. These include replacing plain vaccine with aluminium-adsorbed vaccine, but there is no clear evidence that the aluminium-adsorbed vaccine produces fewer reactions than the plain.There are difficulties enough in deciding the cause of events that occur after vaccination, since these reactions often occur naturally in children of vaccination age. The task is made even harder by the assumption that various manufacturers'' vaccines are the same and the lack of information available to manufacturers about cases in which their vaccine has been implicated. Information on vaccines administered is entered on immunisation records cards; it should be used and referred to if reactions occur.     

Investigation of an Aerosol Challenge Model as Alternative to the Intracerebral Mouse Protection Test for Potency Assay of Whole Cell Pertussis Vaccines

The current potency test for whole cell pertussis vaccines, the intracerebral mouse protection test, is still the only assay which has shown a correlation with protection in children. However, it has considerable disadvantages as it uses a severe challenge procedure and the results tend to show significant intra- and inter-laboratory variation. An alternative assay based on non-lethal aerosol challenge of mice has been investigated as a replacement for the current intracerebral mouse protection test. Evaluation of this indicated that the aerosol system allowed consistent inoculation of bacteria into mice and gave good reproducibility. The protective capacity of different vaccine preparations was distinguished by this assay. Furthermore, the viable counts of Bordetella pertussis in the lungs of challenged mice were immunisation dose-dependent, which allowed the relative potency of vaccines to be calculated. Comparison of potency of five batches of vaccine from different manufacturers assayed by both the intracerebral and the aerosol challenge methods ranked the vaccines in identical order. The results suggest that this method has potential for use as a potency test for whole cell pertussis vaccine which would result in a great reduction in the number of animals used. It would also replace the lethal challenge by a non-lethal procedure and thereby avoid the use of the severe intracerebral challenge procedure.     

重组乙型肝炎疫苗(CHO细胞)鉴别试验的方法研究

目的：建立重组乙型肝炎疫苗(CHO细胞)鉴别试验的方法。方法：取重组乙型肝炎疫苗(CHO细胞)以1：10比例加入lmol/L盐酸调节pH值,采用ELISA双抗体夹心法检测,同时设以氢氧化铝、未处理的重组乙型肝炎疫苗、狂犬疫苗、出血热疫苗,以及试剂盒的阴、阳性作为对照。结果：狂犬疫苗、出血热疫苗及氢氧化铝对照为阴性,直接检测重组乙型肝炎疫苗(CHO细胞)呈弱阳性,加入盐酸调节pH值后原倍样品呈弱阳性,10倍稀释后呈强阳性。采用该方法检测5批疫苗均呈强阳性。组内平行试验,组间重复试验。结论：将重组乙型肝炎疫苗(CHO细胞)调节pH值后10倍稀释,用ELISA双抗体夹心法检测呈阳性,而且稳定可靠,该方法可用于该疫苗的鉴别试验。     

Evaluation of the reactogenicity and immunogenic potency of combined vaccine "Bubo-Kok" in the immunization of children against diphtheria, tetanus, pertussis and viral hepatitis B

Combined vaccine "Bubo-Kok" is characterized by safety and high immunological activity. The number of postvaccinal reactions in children aged 1 and 2 years, immunized with vaccine "Bubo-Kok", was not statistically different from those in groups of children immunized with adsorbed DPT vaccine, as well with such vaccine in combination with vaccine against hepatitis B. After the completion of the primary course of immunization 100% of children had protective antibody titers against diphtheria, tetanus and hepatitis B. Antibody titers against pertussis, equal to or exceeding protective titers, were found in more than 70% of immunized children. The immunogenic potency of vaccine "Bubo-Kok" with respect to all its components was not inferior to that of adsorbed DPT vaccine and vaccine against hepatitis B, when introduced simultaneously in different areas of the body. Vaccine "Bubo-Kok" successfully passed state trials and was recommended for registration.     

The measurement and full statistical analysis including Bayesian methods of the aluminium content of infant vaccines

BackgroundAluminium salts are the most common adjuvants in infant vaccines. The aluminium content of a vaccine is provided by the manufacturer and is indicated on the patient information leaflet. There is no independent verification, for example by the European Medicines Agency, of the aluminium content of infant vaccines.MethodsWe have measured the aluminium content of thirteen infant vaccines using microwave-assisted acid and peroxide digestion followed by transversely heated graphite furnace atomic absorption spectrometry. Our data are compared with manufacturer’s data using full statistical analyses including Bayesian methods.ResultsWe found that only three vaccines contained the amount of aluminium indicated by the manufacturer. Six vaccines contained a statistically significant (P < 0.05) greater quantity while four vaccines contained a statistically significant (P < 0.05) lower quantity. The range of content for any single vaccine varied considerably, for example, from 0.172 to 0.602 mg/vaccine for Havrix.ConclusionsThe data have raised specific questions about the significance of the aluminium content of vaccines and identified areas of extremely limited information. Since aluminium is a known toxin in humans and specifically a neurotoxin, its content in vaccines should be accurate and independently monitored to ensure both efficacy and safety.