The effect of various interventions during a typhoid epidemic. Results of a simulation study.

This paper presents an epidemiological model for typhoid fever epidemics or paratyphoid diseases with an enteric course, as well as a deterministic approach for the quantitative representation of this model. The model has been tested against one typhoid and two paratyphoid epidemics which occurred in the Federal Republic of Germany. It was possible to simulate the course of these epidemics with sufficient precision, and to obtain information on the effects of various interventions (e.g. oral vaccination or hygiene measures).

[Para-immunity after oral antigen administration]. / Paramunität nach oraler Antigen-Applikation.

The term "Paramunity" summarizes all non-pathogen specific mechanisms of the defence against infections in man and animal, such as phagocytosis, interference, antibiosis, activation of the lymphopoietic cell system and of lysosomal enzymes, stimulation of humoral factors etc. Examples for the induction of a paramunity are described. After an oral or inhalatory administration of polyvalent vaccines prepared from inactivated bacteria to mice, the rate of phagocytosis of the peritoneal or alveolar macrophages increased significantly. An oral application of inactivated dyspepsia coli bacteria, caused in mice a partial protection against a challenge with a strain of Rous-sarcoma. After a tenfold oral paramunization with the polyvalent vaccine "Dodecoral" consisting of 12 heat-inactivated strains of enterobacteriaceae, mice were protected against an oral infection with the parapoliomyelitis virus Col-SK.

Paramunity after oral immunization.

Previously, we have proposed the term of paramunity which represented the whole nonspecific defence reactions. Now, we experimentally have demonstrated the importance of an oral polybacterial vaccine in the local defence of the intestine against Salmonella or an enterovirus. The role of interferon was also discussed.

[An oral enteritis-vaccine composed of twelve heat-inactivated Enterobacteriaceae 3. Communication: studies on efficacy tests in mice protection tests (author's transl)]. / Ein Enteritis-Oralimpfstoff aus zwölf hitzeinaktivierten Enterobakteriazeen 3. Mitteilung: Wirksamkeitsprüfungen im aktiven Mäuseschutzversuch.

The polyvalent vaccine consists of twelve heat-inactivated species of Enterobacteriaceae (six strains of Salmonellae, two strains of Shigellae, four strains of Dyspepsia coli). The above vaccine is administered orally (6) to man for prophylactic purposes against local infections. The present communication describes the efficacy results of the vaccine obtained for different parameters by the mouse protection test. For this purpose, seven different infection models were used: oral infection with a strain of S. typhimurium and a strain of S. enteritidis, respectively, and intraperitoneal infection with the following five strains: S.l typhimurium, S. panama, S. enteritidis, Sh. flexneri 2a, or E. coli 2380. For 10 days the mice were daily immunized with the twelve-fold vaccine orally administered by means of a probang. On the 10th day after the last orally applied antigen, the animals were challenged with the seven strains mentioned above. The success of vaccination was determined by the difference of mortality between vaccinated and non-vaccinated mice. The results show (Table 1) following the vaccination that a significant effect could be observed and statistically be evaluated for 6 models of infection. Optimal values showing the highest consistency rate were found for the model of intraperitoneal infection with the strain of E. coli 2380. Which is why, studies were made for the following parameters by using the latter mode of infection. The efficacy of the oral immunization depends on the dosage of the vaccine (Table 2). Even at a dilution of 1 : 1000, the effect of the vaccine was still sufficient. Only a dilution of 1 : 10 000 made the vaccination almost ineffective. - The content of humidity of the lyophilized vaccine in a range of 4% to 12% did not influence the immunogenicity (Table 3). - The protection obtained by vaccination was found to last unexpectedly long. The vaccinated mice were still well protected even one year after the oral vaccination (Table 4), which means - when referred to the life-span of mice - that protection is effected for almost a life-time. The lyophilized vaccine does not even loose its immunogenicity after storage at 22 degrees C and 40 degrees C over a period of 3 years (Table 5). These polyvalent lyophilized vaccine are, therefore, storable even under tropical conditions without cooling. This is a further great advantage of this vaccine.

[An oral enteritis-vaccine composed of twelve heat inactivated Enterobacteriaceae. 2. Communication: the immunogenicity after treatment with simulated gastric and intestinal juice proved in an active mouse protection test (author's transl)]. / Ein Enteritis-Oralimpfstoff auz zwölf hitzeinaktivierten Enterobakteriazeen. 2 Mitteilung: Die Immunogenität nach Behandlung mit simuliertem Magen- und Darmsaft geprüft im aktiven Müseschutzversuch.

In the first communication (3), we reported on the conception, the composition, and the efficacy of the polyvalent oral vaccine from 6 strains of salmonellae, 2 strains of shigellae, and 4 strains of dyspepsia coli. The inactivation took place at 100 degrees C/3 min. The question going to be answered in this communication was as follows: Does the immunogenicity of the vaccine decreased during the gastrointestinal passage under influence of acid and enzymes? We allowed the vaccine to react with simulated gastric juice and/or pepsin at pH = 3 and 37 C/60 min on the one hand and with simulated intestinal juice and/or pancreatin at pH = 7 and 37 degrees C/180 min on the other hand either individually or in combination. The vaccinal preparations produced this way were examined for their immunogenicity in the mouse protection test. The mice were orally immunized with the aid of a probang for ten times (total dose = 3.75 x 10(10) germs) and intraperitoneally infected with the virulent enteropathogenic strain of E. coli 2,380 being contained in the twelvefold vaccine on the 10. day after the last oral vaccination. In the main test, 70.4% of 351 non-vaccinated control animals died. 277 mice were immunized with the vaccine having been treated in the strongest way (gastric juice + pepsin + intestinal juice + pancreatin); 4.0% of those died which is an index of efficacy of 94.3. The mice immunized with untreated vaccine served as positive controls and were protected in the same way; 3.1% of 255 mice died (index of efficacy = 95.6). The results show that the simulated gastro-intestinal passage did not have a negative influence upon the immunogenicity of the polyvalent vaccine.

[Animal experiments on combined local immunization against influenza (author's transl)]. / Tierexperimente zur kombinierten lokalen Immunisierung gegen eine Influenzaviruserkrankung.

Mice in ether narcosis were immunized 10 times by means of an inhalation spray with Begrivacs S (Behring-Werke) and then infected nasally with the virulent A/PR8 virus 7 to 12 days after the last immunization. A significant protection was achieved as gauged from the mortality rate. Furthermore, mice were nasally immunized with the polyvalent bacterial lysate vaccine IRS 19 (Sarbach, Chatillon) and subsequently infected nasally with the virulent influenza virus. A significant degree of non-specific protection also developed under these conditions, but was less effective than that after specific immunization. The best protective effect can be gained by applying both vaccines (Begrivac S and IRS 19) in combination. In this case, the mortality rate of the test animals decreases from 68% in the control to 31% in the animals receiving combined vaccination.

[An oral enteritis-vaccine composed of twelve heat inactivated Enterobacteriaceae. 1. Communication: Theoretical and epidemiological considerations (author's transl)]. / Ein Enteritis-Orlimpfstoff aus zwölf hitzeinaktivierten Enterobakteriazeen. 1. Mitteilung: Theoretische und epidemiologische Grundlagen.

The infectious diseases of the human intestinal tract which are caused by bacteria must be distinguished into two groups on account of their different pathogenesis: the cyclic infections (typhoid fever, parathyphoid fever) and the local infections (cholera, dysentery, Salmonella enteritis, dyspepsia coli infections). The local infections of the intestine do not cause a systemic but only a local immunity of the intestinal mucosa. It is necessary therefore to induce local immunity as active immunoprophylaxis by orally administering inactivated antigens. The twelve-fold enteritis vaccine consists of full antigens of 6 Salmonella strains, 2 Shigella strains, and 4 enteropathogenic coli strains pretreated by heat-inactivation (3 min/100 degrees C). The following should be considered as indication to effect active immunoprophylaxis against enteritis: Travelling into tropical and subtropical countries, people in emergency areas, children in developing countries, workers in food industries, secondary hospital infections, and carriers. The active mouse protection test revealed that oral immunization with enterobacteriaceae does not only deliver the well-known specific effect but also a non-specific effect which included the protection against other related enterobacteriaceae. Moreover, the specific component of the combined vaccine is enhanced by heterologous components. The resulting synergism or the adjuvantal effect, respectively, allows to employ a relatively limited number of germs which are selected on the basis of high pathogenicity, good immunogenicity, and great frequency. The first field trial with the twelve-fold vaccine was completed successfully: Following an infection with Salmonella which affected the employees of a fowl slaughtery, eight different species could be demonstrated; the above described polyvalent vaccine was orally administered and proved to be successful. The latter case clearly demonstrates the fast-acting effect of the vaccine on account of the heterologous bacterial antigens contained therein. 51 out of 60 Salmonella carriers excreted germs of a different antigen pattern not contained in the vaccine. However, the good results obtained showed that the species chosen for the vaccine were still sufficiently effective to cover the wide spectrum of other species of related enterobacteriaceae.

Non-specific immunity after local immunization.

The most important advantage of local immunization is the non-specific effect. The active protection test in mice shows an immunity against oral infection with virulent Salmonella typhimurium bacteria after oral immunization with heterologous inactivated enterobacteria. We observed the same non-specific protection in a viral model. After oral immunization with inactivated S. typhimurium bacteria, the mice are protected against oral infection with a virulent parapoliomyelitis virus. In the phagocytosis test after local immunization a non-specific effect is also demonstrated. The rate of phagocytosis of macrophages against streptococci rises significantly after oral immunization or after inhalation with heat-killed S. typhimurium bacteria.