Toward safer and more efficient pertussis vaccines.
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Biomedical subjects
Publications and source records attributed to A Wegmann.
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The high immunogenicity of the liposomal hepatitis A vaccine (Epaxal Berna) after a single dose and after a booster dose one year later has been confirmed in several studies with healthy adult volunteers: 95-100% and 96-100% seroconversion (> or = 20 mIE/ml) after 1 and 12 months respectively, as well as a booster effect in 100% of the cases after revaccination. The tolerability of this new, alum-free vaccine has been excellent with 6-25% local and 0-13% mild systemic reactions after a dose of 0.5 ml. Stability testing with and without detergent indicated partial internalization of the hepatitis A virions in the phospholipid bilayer of the liposome vesicles with storage. Immunization of 10 healthy adult volunteers with vaccine stored for 32 months at 4 degrees C showed, however, that the duration of storage has no influence on immunogenicity and tolerability of the vaccine.
A previously well 24-year-old man complained of persistent epigastric pain after a session of intensive muscle building exercise especially of the abdominal muscles. The abdomen was diffusely tender without guarding. There was an increased concentration of bilirubin (64.7 mumol/l), GOT (117 U/l), GPT (529 U/l) and alkaline phosphatase (150 U/l). Ultrasound examination showed a widening of the choledochal duct to 11 mm without signs of gallstones. Endoscopic retrograde cholangiography additionally revealed contrast-medium extravasation from the left hepatic duct. Computed tomography, performed immediately afterwards, confirmed the extravasation, while liver and pancreas were unremarkable. Laparoscopy revealed a 5 mm tear in the left hepatic duct, close to the hepatic duct bifurcation with bile effusion into the peritoneal cavity. The latter was rinsed endoscopically with Ringer's solution and drains were placed in the omental bursa and subhepatically in the region of the bile leak. To relax the sphincter Oddi glycerol trinitrate was administered postoperatively, for the first five days 72 mg/24 h intravenously, then for nine days twice daily 20 mg by month. No more bile drained as early as the second postoperative day and the patient was free of symptoms 2 weeks later.
Ultrasonography (US) is the method of choice for evaluation of gallbladder stones with an accuracy of 96%. Number, size and calcification can be assessed by virtue of US reflection and attenuation. If more than five stones are present, the accuracy decreases. To determine the calcium content of stones more precisely, computed tomography can be used. This allows an assessment of the success rate of lithotripsy and chemolysis. Oral cholecystography is an alternative method of similar accuracy as US. It provides additional information about the patency of the cystic duct. In the presence of ductal stones, the accuracy of US decreases to 30%, mainly because of overlying bowel gas. Since 8 to 16% of all cases of cholecystolithiasis are accompanied by choledocholithiasis and since this entails a change in treatment, intravenous cholecystocholangiography with an accuracy of more than 90% is the method of choice in this case. Additionally, it provides knowledge on the biliary anatomy preoperatively. It does not, however, replace US, because opacification of the gallbladder is limited with this method. If intravenous cholecystocholangiography fails in case of impaired liver function, transcholecystic cholangiography or, in cases of dilated ducts, percutaneous transhepatic cholangiography can be used. Plain film radiography is not a suitable technique, since only 10 to 15% of all gallstones calcify.
O-specific polysaccharide (O-PS) isolated from serotype 18 Escherichia coli lipopolysaccharide (LPS) was covalently coupled to either Pseudomonas aeruginosa toxin A (TA) or or cholera toxin (CT). The conjugates were nontoxic and nonpyrogenic. The conjugates were well tolerated on parenteral administration to human volunteers, with only mild, transient local reactions reported. Immunization engendered an IgG antibody response to both the O-PS and carrier protein. Anti-LPS antibody promoted the uptake and killing of an E. coli O18 strain bearing the K1 capsule by human polymorphonuclear leukocytes, which was complement dependent. Antibody to carrier protein neutralized the activity of native TA or CT in cell culture assays. Passively transferred IgG isolated from the serum of immunized donors provided a significant (P less than .01) degree of protection against fatal experimental E. coli O18 sepsis in mice. This study illustrates the potential use of such conjugates as vaccines against E. coli extraintestinal infections.
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The rabies antibody content of each of ten lots of human rabies immunoglobulin was titrated by both the mouse neutralization test and the rapid fluorescent focus inhibition test. The two tests did not give comparable results, the antibody titres obtained by the mouse neutralization test being 1.4-9.6 times higher than those obtained by the rapid fluorescent focus inhibition test. This titre difference was associated with a consistently lower antibody response in human volunteers who had received post-exposure rabies vaccine treatment which included the administration of RIG assayed by the RFFIT.
Lipid A-free polysaccharide (PS) isolated from Pseudomonas aeruginosa immunotype 5 lipopolysaccharide (LPS) was covalently coupled to toxin A via reductive amination. The PS-toxin A conjugate was comprised of 29.8% PS and 70.2% toxin A, possessed a molecular weight of greater than 1 X 10(6), was nontoxic for animals and was nonpyrogenic for rabbits at a dose of 50 micrograms/kg body wt when administered intravenously. The conjugate evoked only mild, transient reactions upon subcutaneous administration to human volunteers. Vaccination engendered immunoglobulin G (IgG) antibody, which neutralized the cytotoxic effect of toxin A and promoted the uptake and killing of P. aeruginosa in the presence of human polymorphonuclear leukocytes. Passively transferred IgG isolated from the serum of immunized donors was far more effective at preventing fatal P. aeruginosa burn wound sepsis than paired preimmunization serum. These studies establish the potential usefulness of such a PS-toxin A conjugate as a vaccine against P. aeruginosa.
Tolerance, clinical effects and kinetics of an unmodified immunoglobulin preparation for intravenous use were investigated in 4 patients with advanced chronic lymphocytic leukemia. Previously, good tolerance of the preparation had been found in 49 immunologically normal patients. The four patients with secondary humoral immunodeficiency received doses of 140-360 mg IgG/kg per infusion as outpatients at monthly intervals. With one exception, no acute infections (pneumonitis), as commonly seen before, were observed during the observation time of 24 to 68 weeks, and the pre-existing chronic infections (bronchitis, sinusitis etc.) remained compensated without antibiotics. In all four patients tolerance of the preparation was good. In all cases of hypogammaglobulinemia a dose-dependent increase in the serum IgG concentration was observed immediately after the infusion. However, persistence of the serum IgG increase showed considerable interindividual differences. The half life of the tetanus and HBs antibodies (21.7 to 34.4 and 19.7 to 25.7 days respectively) found in 4 healthy volunteers is within the biological range. This indicates an unmodified structure of the antibodies of the IgG class contained in the preparation used.
The encephalitogenic potential of rabies vaccines prepared from nervous tissue is a result of the presence of myelin basic protein. Vaccines prepared from duck embryos are economical and efficient, but, occasionally, cases of allergic encephalomyelitis have been reported. An improved rabies vaccine has been developed that contains the classical Pitman Moore strain of rabies virus grown in embryonated duck eggs. This vaccine has been highly purified and enriched in immunologically effective rabies virus glycoprotein antigen. We have searched for the presence of myelin basic protein using sensitive radioimmunological and immunoblotting techniques. Whereas the classical duck embryo rabies vaccine contained small amounts of myelin basic protein, in the improved purified duck embryo rabies vaccine, none could be detected.
The combined Measles-Mumps-Rubella vaccines commercially available for use are safe, highly immunogenic, and protective. But the acceptance rate of these vaccines by the public and also by the general practitioners in most part of Europe is not a very high one. One of the reasons for this low acceptance-rate is the fear of side-reactions. In spite of that only exceptional cases of dangerous allergic reactions induced by such vaccines, especially the lay population can be scared by the contraindications mentioned in the "physician circular-patent product information". Therefore it was worthwhile to test a new trivalent vaccine produced exclusively on human tissue without using any avian protein or animal protein extracts or antibiotics. Under double-blind conditions 120 children aged between 15 and 24 months received either the new vaccine or the commercially available M-M-R-II vaccine produced by MSD. Measles and Rubella antibodies were tested by hemagglutination-inhibition tests, Mumps by the immuno-fluorescence technique. No reports of major side-effects were received from the 12 physicians participating in the trial. The seroconversion rates recorded 6 to 8 weeks after vaccination were high (95-100%) and there was no statistically significant difference between the two vaccines with regard to immunogenic potency.
A new, live attenuated mumps vaccine virus strain for human diploid cells has been developed at the Swiss Serum and Vaccine Institute, Berne. The Rubini virus was derived from a child of the same name possessing typical clinical signs and symptoms of mumps infection. Attenuation of the wild virus was performed by isolation and serial passage in WI-38 human diploid cells, specific pathogen-free hens' eggs and MRC-5 human diploid cells. The attenuated virus has been examined in respect of identity, freedom from adventitious agents and growth potential in MRC-5 cells. Furthermore, it does not evoke any clinical reactions in either baby or adult monkeys. It is characterized by the production in Vero cells of smaller plaques than are elicited by either the Jeryl Lynn or Urabe mumps virus strains. The reactogenicity and immunogenicity of the Rubini virus for man was studied by administering a monovalent vaccine to 13 adult male volunteers and a trivalent human diploid cell Rubini, measles (Edmonston-Zagreb-19 virus strain) and rubella (RA 27/3 virus strain) vaccine to 60 children ranging in age from 15 to 24 months. No reactions were observed. Seroconversion was obtained in 95% of the vaccinees, who developed a mean 50% neutralizing antibody titre of 1:64 after 6-8 weeks. Sensitization to avian and other animal proteins and antibiotics which may follow the use of most of the currently available measles-mumps-rubella vaccines, either single or combined, may be expected to be eliminated when this new vaccine is used. Its use in persons already sensitized to such products should furthermore induce no anaphylactic reactions.
The further attenuated Enders (FAE) measles vaccine strain and the Edmonston B-Zagreb (EZ) measles vaccine strain were compared. In VERO-cells plaque sizes of FAE varied between 0.5 and 1 mm, those of EZ between 1 and 2 mm in diameter. The lots available in Switzerland during a 2 year period showed virus titers of 10(3.1) to 10(4.0) TCID50 per dose in the one vaccine (FAE) and of 10(3.1) to 10(4.5) TCID50 per dose in the other (EZ). Clinical investigations were performed with FAE and EZ monovalent and trivalent (measles + mumps + rubella) vaccine preparations. The virus titers of the vaccine lots used were 10(3.1) to 10(4.0) TCID50 per dose. The overall seroconversion rates of 96% to 100% indicate that both types of vaccine have comparable immunization properties. Stability tests demonstrated good stability of both the FAE and the EZ vaccines. Thus conservation at 37 degrees C was possible for 2 and 4 weeks, respectively, and at 41 degrees C for 6 and 6 days, respectively, without undue loss of live virus content (less than 1 log 10). Since the EZ vaccine is derived from human diploid cells, it is particularly suitable for the vaccination of persons with a history of allergy to avian proteins.
At the Swiss Serum and Vaccine Institute, Berne, a highly purified rabies vaccine presenting a high content of effective rabies virus glucoprotein antigen has been developed. The new vaccine is derived from embryonated duck eggs (PDEV). Immunizations performed according to the post-exposure schedule recommended for potent rabies vaccines by the WHO (6 injections on days 0, 3, 7, 14, 28 and 90) already induce protective antibody titers on day 14 (greater than 1 IU/ml). Use of the latest radioimmunological methods did not reveal the presence of myelin basic protein in the new rabies vaccine. Due to improvements of its preparation the rabies vaccine PDEV is an economical and highly efficient vaccine involving only a very remote risk of post-vaccinal encephalitis.
The results of a field trial with a novel, live attenuated human diploid cell vaccine (HDCV) against measles, mumps and rubella are described. The study was performed double blind and included 120 children aged 15 to 24 months. 60 children received the new vaccine and a control group of another 60 children were vaccinated with M-M-RR II. The seroconversion rates found 6 to 8 weeks after the vaccination were high without exception (95% to 100%). The multiple chi 2-test revealed no statistically significant difference in immunogenic efficacy between the two vaccines (p greater than 0.05). No reports of side effects were received from the 12 physicians participating in the study. It is pointed out that all components of the new vaccine are highly attenuated and that the vaccine is free of avian protein, animal protein extracts and antibiotics. This excludes all theoretical and practical contraindications due to the corresponding hypersensitivities.