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Die i. m. Applikation eines trivalenten Poliomyelitisvirus Antigens, das von uns auf die Abwesenheit von vermehrungsfahigem Virus gepruft war, rief unabhangig von der Immunitatslage bei 22 von 27 Probanden neutralisierende und komplementbindende Antikorper gegen den Typ 1 des Poliomyelitisvirus hervor. Das beobachtete, serologische Verhalten spricht fur weitgehend vergleichbare Reaktionen des Organismus auf inaktives Virusantigen wie auf Infektion durch aktives Virus.

In der vorliegenden Arbeit wurdenγ-Al(OH)3 undγ-Al2O3 vergleichend auf ihre adsorptiven Eigenschaften untersucht. Es stellte sich im wesentlichen folgendes heraus: 1. Influenzavirus wird sowohl vonγ-Al(OH)3 als auch vonγ-Al2O3 gesetzmasig adsorbiert. 2. Die Adsorption ist bei beiden Adsorbentien einmal viruskonzentrations-, zum anderen adsorbenskonzentrationsabhangig. 3. Die Adsorption mit beiden Adsorbentien folgt beim Influenzavirus und ebenfalls beim Methamoglobin der Adsorptionsisotherme vonFreundlich. 4. γ-Al(OH)3 ist bezuglich seiner Oberflachenstruktur stabil, was in einer quantitativ gleichbleibenden Adsorptionsfahigkeit zum Ausdruck kommt. 5. γ-Al(OH)3-Chargen verschiedener Provenienz zeigten, das die Herstellung von gleichwertigen Al(OH)3-Praparationen seit Jahren zum Stand der Herstellungstechnik gehort. 6. γ-Al(OH)3 ist in seinem quantitativen Bindungsvermogen demγ-Al2O3 nachFricke (Gluhtemperatur 2 Std 600° C) um mehr als das Zehnfache uberlegen. Das geringere Adsorptionsvermogen desγ-Al2O3 erklart sich aus seinem geringeren Zerkluftungsgrad, der eine kleinere adsorptiv wirksame Oberflache des Aluminiumoxyds bedingt.

Das Problem der Konkurrenz der Antigene wurde an Tetanus-, Diphtherie-, Pertussis- und Poliomyelitis-Antigen experimentell im Tierversuch gepruft. Fur die Auswertung fanden die vorgeschriebenen quantitativen Methoden Anwendung. Die Experimente ergaben, das eine gegenseitige Beeinflussung der Antigene erfolgt. In den meisten Fallen ausert sich diese als eine Steigerung der antikorperbildenden Fahigkeit der Antigene. Bei der Auswertung des Poliomyelitis-Antigens lies sich nachweisen, das die Art der gegenseitigen Beeinflussung von der verwendeten Tierspecies abhangt. In der Auswertung am Affen und Kuken wurden Steigerungen durch Kombination, in der Auswertung am Meerschweinchen dagegen eine Unterdruckung der Poliomyelitis-Komponente beobachtet. Die Bedeutung der Befunde fur die Antikorperbildung wird diskutiert.

Die vorgelegten Untersuchungen zeigen, das Gamma-Al(OH)3-haltige inaktivierte Poliomyelitisimpfstoffe in gleichformiger Qualitat von mehr als zweijahriger Haltbarkeit und langer Wirkungsdauer produziert wurden. Die Befunde sind statistisch gesichert.

During 1970 to 1977 adverse reactions after pertussis vaccination were reported for 149 persons, 56% male and 44% female. Their symptoms permitted to divide the vaccinees into 2 groups, the first with more severe (S) and the second with other symptoms (O). No differences were observed in age and sex among the two groups. The interval between vaccination and appearance of first symptoms was longer for the O than for the S group. While less than one quarter of the reactions in the O group occurred after primovaccination, more than half of the S side effects were seen after the first vaccination. Further analysis of the S group revealed that all but two of their symptoms (fever and encephalopatht) corresponded to the hypoglycaemic syndrome. The consequences hereof are discussed with regard to prevention and therapy.

The epidemiologic background on which the efficacy of vaccines has to be considered shows that the mortality of infectious diseases in the first seventy years of our century was reduced to an extent which goes far beyond all other diseases. This trend is similar in all countries of comparable status of zivilization. Trends in morbidity may be different, but no sufficient documentation is available for morbidity of infectious diseases in this country. Developments of new vaccines for industrialized countries will show a change compared with the present vaccines. After introduction of vaccines against the big killers until 1950 disabling diseases were the more recent target of immunoprophylaxis such as poliomyelitis, measles, rubella, mumps. Vaccine efficiency was greatly increased by vaccination campaigns for which strategies and tactics were developed in an almost military fashion. Analysis of the future vaccines reveals a further change not only by additional antigens but by new target groups of the population to be protected. Not only will more vaccines be developed for adults but also for certain risk groups. More knowledge of immune-defence mechanisms in such groups will be needed for the final success of such vaccines. Moreover immunoprophylaxis may even enable immunotherapy in future. The most dramatic effect of immunoprophylaxis is to be expected in the coming decades in the non-industrialized world. This will be effectuated not by the newer vaccines, but by products which we know already. It is the decision of WHO to include an "Expanded program of vaccination" into their help for developing countries. Here new technologies are under investigation which will procure a new round in vaccination tactics. Vaccination is planned by WHO not only to help to develop countries but to play a decisive role in the problem of over-population. Such expectations are based on the fact that in the industrialized world the birthrate fell while the infant survival rates rose. Vaccination then would be more than immunoprophylaxis; vaccination would have a place then among man's many intelligent answers to mankind's many natural problems.

Guinea pigs of inbred strain 2 were vaccinated with BCG 1331 Copenhagen (K-Nr. 240-1) six to seven weeks before intradermal application of about 10(5) leukocytes from a highly leukemic animal in mixture with 10(7) colony forming units (CFU) of BCG. This presensitization with BCG totally abolished or strongly reduced the antitumor activity of L2C-cells adjoining BCG. Increase of bacterial mass applied from 1 X 10(7) to 2 X 10(8) CFU did not restore the antileukemic effect of BCG as observed in unvaccinated guinea pigs by a significant delay of death in a portion of animals and by the occurrence of long-term survivors. Since local reaction to BCG occurred much earlier in presensitized than in unvaccinated animals, we speculate that the destruction of tumor cells and hence the antigenic stimulus was too premature in presensitized animals to build up a BCG-mediated antitumor immunity.

During 1970 to 1977 adverse reactions after pertussis vaccination were reported for 149 children, 56% male and 44% female. Their symptoms permitted to divide the vaccinees into 2 groups: one with more severe (S) and the second with other symptoms (0). No differences were observed in age and sex among the two groups. The interval between vaccination and appearance of first symptoms was longer for the 0 than for the S group. While less than one quarter of the reactions in the 0 group occurred after primovaccination, more than half of the S side effects were seen after the first vaccination. Further analysis of the S group revealed, that all but two of their symptoms (fever and encephalopathy) corresponded to the hypoglycaemic syndrome. The consequences hereof are discussed with regard to prevention and therapy.

Developments are based on past experience and lead to the future. With vaccines, success in the past will show what can be expected for the future. This paper tries to demonstrate what factors are to be considered for a reliable prediction for developments in vaccines. The factors studied are: feasibility of manufacture of vaccines quality requirements target populations epidemiological considerations costs consequences

Sixteen cases of parotitis and 2 cases of diabetes mellitus after mumps vaccination have been reported since the introduction of the live attenuated mumps vaccine in the F. R. Germany in the fall of 1976. Due to the post-vaccination incubation of 7 to 10 days, support is given to the assumption that these cases are vaccine induced and not coincidental wild virus infections. The diabetes mellitus cases, however, are too few to be included in this rational.

A rabies vaccine prepared in human diploid cell strains was purified by continuous-flow sucrose density gradient centrifugation. The peak fractions containing 35-40% sucrose were diluted with a stabilizer consisting of degraded gelatine in a Tris-EDTA-buffer, and then inactivated with beta-propiolactone and freeze-dried to a residual moisture of approximately 2.5%. This vaccine was stable as proved by accelerated stability tests.

Continuous-flow isopycnic banding of rabies virus in sucrose gradient was used to purify the antigen for the preparation of a human diploid cell rabies vaccine. Prior to the addition of the stabilizer, the average specific potency of several vaccine batches was 234 antigenic values per 1.0 mg of protein. Further data regarding potency and stability of this vaccine are presented.

A collaborative assay was conducted by 9 laboratories on 31 samples of human albumin which were in clinical use. It was the object of the study to establish test systems which would differentiate between albumins of venous or placental origin. The properties examined for this purpose were: appearance, total protein, haem, polymers, alkaline phosphatase and blood group substances. Additional tests such as for beta-thromboglobulin and citrate were included; pyrogenicity, however, was excluded because this was under study for all plasma proteins at that time. Results obtained were in satisfactory agreement both between laboratories and between samples. They, therefore, enabled the verification of a number of correlations in the test systems. The evaluation did not allow, however, the differentiation of the samples in relation to their origin. The results were, therefore, regarded as a tool to define the upper limits of acceptance for human albumins corresponding to the quality prescribed by the European Pharmacopoeia.

In order to reduce the risk of allergic reactions, a purified human diploid cell culture rabies vaccine was developed. Pitman-Moore strain of rabies was propagated in WI-38 or MRC-5 cells. Both cell strains were found to be equally suitable for pro agation of rabies virus. The virus was purified and concentrated by continuous-flow sucrose density gradient ultracentrifugation. Virus peak fractions were diluted with a stabilized and then inactivated with BPL and freeze-dried. According to the standard NIH test for potency, the vaccine proved to be very potent and stable. The results of initial clinical applications of the vaccine will be presented.

Influenza vaccines (split, adsorbed, low nitrogen) of two different antigen concentrations (commercial production) were administered to 1,111 adult persons of both sexes. Up to five previous vaccinations had been given to the population under observation. Their reactions both local and general were not different in primo-vaccinees or boostered persons. Increasing numbers of previous vaccinations were not reflected by increasing rates of complaints. Disregarding immunization history, the group given the higher concentrated vaccine showed a lower rate of side effects while the lower antigen concentration produced a higher rate. The relevance of the observation that no sensitizing effect occurred in persons with up to five vaccinations may be a characteristic of split adsorbed influenza vaccines of high purity.

In order to improve the tolerance of rabies vaccine from human diploid cell cultures, the rabies virus antigen is purified in the sucrose density gradient by means of a flow ultracentrifuge. The purified virus has a specific infectiosity of 10(9) LD50 and a speicific activity of 250 units "relative activity" per 1 mg protein. The purified vaccine has been shown to be well tolerated, effective and stable.

Inactivation of Polioviruses has been studied extensively in the 1950s and 1960's. It was shown that, to a certain extent, the kinetics of inactivation depend on the viral structure with which the inactivating agents react. Polio-RNA will loose its capacity for multiplication after one hit of an appropriate agent, thus being inactivated in a first order reaction. Multiple hits on the viral protein are needed to render the virus non-proliferate, which is characterized by a second order reaction. Examples for both types of reaction are given. While the "classical" inactivating chemicals are still in use for poliovaccines, other RNA viruses have successfully been treated with other agents and experimentally yet different substances have been described. Aiming for the highest possible antigenicity, the least harmful procedure seems essential. Since the inactivation procedure includes factors other than chemicals, such as temperature, time, pH etc., they too are part of the discussion evaluating the benefits and the shortcomings of the various technologies.

The first vaccines were obtained from animals infected with the vaccine viruses. Bacterial vaccines were derived from culture media prepared from animal tissues. In some cases the principles of manufacture remained unchanged for more than a century, the methods only were refined. Animal cell culture was not introduced into vaccine production until the second half of of this century. After more than 25 years the search for non-animal substrates and their improvement still goes on. Control of vaccines lagged behind this progress. After a period of no control for the early vaccines, animal tests enabled immunologists to measure safety and potency, thus eliminating the disasters attributable to unsafe products or failures in protection. In vitro methods of control led to a better understanding of the immunology of vaccines. Replacement of animals in manufacture is now to be paralleled by their replacement in control. This will require courage from both the manufacturer and the controller.

A BCG vaccine prepared from strain 1331 Copenhagen was given to newborns and infants in four logarithmically decreasing doses (expressed in VU = viable units): 25 X 10(4), 11 X 10(4), 5 X 10 (4), and 2.2 X 10(4). The efficacy of the vaccine was determined through the conversion rate (tuberculin skin test) with 2 and 10 T. U. of RT 23, AND 10 AND 50 I. U. of GT (Hoechst). The results indicated that the conversion rate is a function of the dose of VU of the vaccine, as well as of the units of tuberculin used for testing.

1405 neonates and infants were vaccinated with BCG Vaccine (strain 1331 Copenhagen) at five clinics in the Federal Republic of Germany. Doses in logarithmic increments from 22000 to 250000 VU (viable units)/0.1 ml were given by strictly intradermal injection. Carrying out the post-vaccinal tuberculin test by the MENDEL-MANTOUX technique, the dose-effect relationship could be demonstrated (Fig. 3). Conversion rates raised from 43% to 76% (Tab. 1); they are furthermore depending from the tuberculin dose and the assessment of the skin reaction. Tests with up to 50 I.U. of purified tuberculin were resulting in conversion rates over 90% for vaccination doses of 100 000 VU and more, any palpable infiltration regarding as a positive result (Fig. 4). The vaccine showed good safety in all concentrations employed concerning reactions at the site of injection. Lympnode enlargement, palable even 12 weeks postvacc., was common. In the course of the trial there was one case of suppurative lymphadenitis among the 262 children who were given the vaccine in the highest concentration (250000 VU). Subsequent trials revealed a rate of this complication in the 1:1000 range. The approval for the vaccine with 100000-300000 VU/dose has subsequently been given by the Federal Bureau for Sera and Vaccines.

Medical indications for the use of human albumin (HA) by the clinician have been described in the past. They were invariably based on the knowledge of the function of the HA molecule and its feasible role in circulation. So these indications in fact became recommendations to the clinician. In recent years various authorities were faced with the necessity to review requirements for HA, wherever they existed, or to define new requirements, where none were considered before. IABS was, therefore, asked to find out if and how the recommended indications were accepted by physicians of various disciplines. Using a questionnaire more than 800 replies were received. These answers and their evaluation permitted the statement that the clinical use of HA is not limited to the recommended one, but used for additional and newer indications with obvious success. In addition it was noted that present requirements by control authorities do not seem to cover sufficiently the needs of the patients.

Due to the similarity of symptoms, 22 cases of mono- and polyneuritis after tetanus vaccination from our own records covering the years 1970--1977, as well as 6 additional cases taken from existing literature, are being analyzed. As expected, the number of male vaccinees exceede that of female vaccinees, the former being younger than the latter and women generally received less previous tetanus vaccination than men. Three out of four cases occurred during the summer season. The interval between vaccination and the first symptoms was shorter in mononeuritis than in polyneuritis. The prognosis of most cases was benign, irrespective of age, sex and tetanus vaccination history. Cases with delayed recovery only occurred during the summer months. In cases of polyneuritis it seems that the longer the interval between vaccination and the first symptoms, the slower the recovery. It has to be emphasized that the discussed cases of neuritis have to be viewed as extremely rare complications due to tetanus vaccine.

In different experiments 46 guinea pigs of inbred strain 2 were inoculated intradermally with a lethal dose of about 10(5) gelatine purified L2C leukocytes per animal in mixture with 10(7) colony forming units (CFU) of BCG Copenhagen 1331. From these animals 58% showed a significant (p = 0.05) delay of death from leukemia in comparison to 38 animals not treated with BCG all perishing of leukemia with an average life time of 22.7 days (+/- 4.1 S.D.) after tumor cell inoculation. In 15% of the animals BCG caused long term survivors, still alive more than three months after L2C application. Twelve of them were challenged with nearly 10(5) L2C leukocytes; nine animals remained healthy demonstrating strong acquired resistance against L2C leukemia. Fresh submers cultured and lyophilized pellicle grown preparations of BCG Copenhagen 1331 were equally effective in antitumor activity. Using the same CFU dosage the lyophilized Copenhagen 1331 preparation was compared with two other commercial BCG vaccines and was found equivalent or better in efficacy against L2C leukemia.

In vitro parameters of BCG vaccine, such as colony-forming units or bacterial weight, are significant with respect to efficacy and occurrence of side effects only for vaccines which are made by one manufacturer according to one method and tested in one laboratory. With respect to colony-forming units from different products, widely varying doses must be applied to gain comparable effects. Similar effects can be expected from the human dose, recommended for each particular product. These conclusions, derived from experiences in vaccination against tuberculosis can also be considered essential for comparative immunotherapy with BCG vaccines.

The safety of the vaccine could be assessed by three different investigations: a) During the dose finding study (part I) the vaccine showed good safety in all concentrations employed concerning reactions at the site of injection; palpable lymph node enlargement was common. There was one case of suppurative lymphadenitis amond the 262 children who were given the vaccine in the highest concentration (25 X 10(4) VU). b) Subsequent trials in the course of 21 months, when high risk persons could be vaccinated, revealed a rate of this complication in the 1:1,000 range, no case was reported among older persons. c) After the official approval of the vaccine (10 - 30 X 10(4) VU/ml) in the FRG 1 supp. lymphadenitis among 5,000 vaccinated newborns can be calculated.

A BCG vaccine was produced from strain 1331 to replace a vaccine from strain Goteborg that had been in use in the Federal Republic of Germany for approximately 20 years. The latter vaccine neither corresponded to international nor to national requirements, whereas the former did so. The ‘new’ vaccine contained less viable units and had less dry weight than the ‘old’ vaccine. Field trials with the ‘new’ vaccine in schoolchildren and newborns resulted in satisfactory conversion rates. Although schoolchildren tolerated the ‘new’ formula well, it caused four times more lymphadenitis in newborns than did the Goteborg vaccine. One case of suppurative lymphadenitis after the ‘new’ vaccine was statistically indistinguishable from the absence of such a case after the ‘old’ vaccine. Adverse reactions after general use correlated in their frequency with the number of viable units in the vaccine but there was no such correlation with the dry weight. Among the in vitro and in vivo tests a correlation was found between viable units and skin reactivity in guinea-pigs. Within the licensed limits in routine manufacture no correlation between viable units and dry weight was observed, while in lower than licensed ranges both parameters correlated. In consequence it appears decisive for the manufacture and control of BCG vaccines that: 1. (i) the parameters to be included in the method of manufacture be shown to correlate within the licensed range and 2. (ii) field trials be performed to prove the dose-response relationship both for efficacy and safety before the vaccine is given a general release.

Requirements for human serum albumin (HSA) asked for by physicians in six countries were analyzed. Compilation of data obtained by a questionnaire revealed differences of opinion that could be traced to the frequency of HSA therapy in the respective country. Where albumin was used frequently clinical and experimental evidence for the efficacy of this therapy was high too, and so was the interest in the binding capacity of HSA for a number of substances. In contrast, negative attitudes towards HSA therapy were reported predominantly from countries where the frequency of use of albumin was low. Since the request to obtain more information on the binding capacity of HSA was strongly expressed by responding physicians, this wish should be considered for future quality control preferably in the process of manufacture.

Jedes Gesprach uber Kombinations-Vaccinen wie uberhaupt uber Vaccinen mus die zwei Seiten des Problems berucksichtigen, namlich den Impfstoff und den Impfling. In dieser Aufzahlung ist keine Reihenfolge enthalten, es handelt sich vielmehr, wie sich im weiteren Verlauf dieser Erorterung zeigen lassen wird, um ein dauerndes Wechselspiel zwischen Impfstoff und Impfling, dessen Ergebnis fur die Beurteilung des Erfolgs masgebend ist.

Die Gruppe der Myxoviren umfast eine Anzahl von Virusarten, welche in ihrer atiologischen Bedeutung fur Erkrankungen von Menschen und Tieren sehr stark voneinander abweichen. Die verschiedenen hierin zusammengefasten Viren gleichen sich jedoch in einer Reihe von Eigenschaften so sehr, das nicht nur diese Virusgruppe gegenuber anderen klar abgrenzbar ist, sondern das auch die Beschreibung der Gruppencharakteristika so erfolgen kann, das fur die einzelnen Virusarten der Gruppe nur noch wenige besondere Merkmale nachzutragen sein werden. Die nachfolgende Darstellung dieser intensiv durchforschten Virusgruppe soll sich nicht darauf beschranken, den Stand der Kenntnisse wiederzugeben, der in Hand- und Lehrbuchern zu finden ist; sie will vielmehr auch die offenen Fragen anschneiden, deren Bedeutung erst in jungster Zeit durch verfeinerte Untersuchungsmethoden zu Tage trat. Das die Grenzen unseres Wissens auf diesem Gebiet oft sehr schnell erreicht sind, wird den Fachmann nicht verwundern, dem Anfanger soll damit jedoch das Verstandnis fur neuere Forschungsrichtungen erleichtert werden.

Obwohl das Krankheitsbild, welches das Mumpsvirus beim Menschen verursacht, keinerlei Ahnlichkeit mit demjenigen von Influenzavirus aufweist, gehort das Mumpsvirus wegen seiner virologischen Eigenschaften ebenfalls zu den Myxoviren. Als Erreger der Parotitis epidemica hat es klinische Bedeutung vornehmlich in der Kinderheilkunde, ferner wegen seines Auftretens bei Erwachsenen und den vielfaltigen Manifestationen der Infektion in der gesamten Medizin. Der Mumps (Parotitis epidemica) last sich als Infektionskrankheit so lange zuruckverfolgen, wie sich in der Menschheitsgeschichte medizinische Aufzeichnungen finden. Wegen seines Vorkommens zu allen Zeiten und wegen seines gleichbleibenden Charakters kann der Mumps als die stabilste Seuche des Menschen bezeichnet werden. Der englische Ausdruck fur die Krankheit (to mump = Fratzen schneiden) hat sich in den deutschen Sprachgebrauch eingefuhrt, weil die Kenntnis uber das schon im Altertum beschriebene Krankheitsbild durch englische Autoren des 18. und 19. Jahrhunderts auf den Stand gebracht werden konnte, welcher erst durch die Ara der atiologischen Untersuchungen erweitert wurde. Es liegt auch durch die verbesserten virusdiagnostischen Moglichkeiten bisher kein eindeutig gesicherter Grund zu der Annahme vor, das sich der Charakter der Krankheit gewandelt habe.