[On the characteristics of epitheloid granuloma in vaccination with plague vaccines].
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The median lethal dose (MLD) of a pathogenic strain of Yersinia pestis was established by three routes of administration in three strains of mouse. There was no significant difference between the MLDs in the different strains of mouse. The MLD by the subcutaneous route in Balb/C and an outbred line was approximately 1 c.f.u.; the MLD following intraperitoneal administration was tenfold higher. There were significant differences in the mean times to death after administration of the challenge by different routes. The relative efficacy of a live attenuated vaccine strain of Y. pestis (EV76) was compared with that of the formaldehyde-killed vaccine (Plague vaccine, USP). EV76 protected against high challenge doses (up to 5.75 x 10(6) MLD), though immunized animals showed side effects of varying severity. The killed vaccine was less effective in terms of dose-protection (deaths occurred after challenge with 4000 MLD) and several of the vaccinated animals suffered sub-lethal, plague-related sequelae to the challenge.
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The effectiveness of some vaccine preparations for the revaccination of hamadryas baboons after their primary immunization with live plague vaccine " NIIS " administered in the form of aerosol was studied. The study was carried out under the conditions of the aerosol challenge of the animals with Y. pestis. The subcutaneous injection of plague vaccine " NIIS " was found to have advantages over its aerosol administration. Revaccination with Y. pestis fraction I, absorbed, was found to be 8 times more effective than the administration of plague vaccine " NIIS " by inhalation and not inferior to the subcutaneous injection of this vaccine. Y. pestis lipopolysaccharide, when injected simultaneously with fraction I, produced an immunosuppressive effect. The development of chemical plague vaccine on the basis of fraction I, intended for revaccination, was shown to have good prospects.
Killed plague vaccines prepared from avirulent strains A1122 and EV76S of Yersinia pestis were more effective in mouse potency tests than samples of Plague Vaccine, USP, prepared from killed Y. pestis of the virulent strain 195/P. Manufacture of vaccine from avirulent Y. pestis would obviate requirements for the large containment facilities that are currently needed for producing Plague Vaccine, USP.
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Evaluation of the immunity produced by plague vaccines was made by measurement of the reactions in the body fluids of man and different animals to demonstrate altered refractoriness. Four serological methods were used: the agglutination test, the complement-fixation test, the passive mouse-protection test, and the haemagglutination test. Results showed that the majority of animal and human hosts, in response to injections of Pasteurella pestis, vigorously develop antibodies which may persist in the peripheral blood serum for several months.Critical tests to establish the correlation between antibody response following inoculation with plague antigens or vaccines and resistance to infection showed that inoculation of 30mug of Fraction I antigen consistently protected mice against P. pestis infection and that there is a definite correlation between the appearance of serum antibodies and the immunity state of the mice. There is a similar correlation in guinea-pigs, although the immunogenicity of antigens and vaccines for these animals is very variable. Primates are rendered resistant to massive infection with 1,000,000,000 to 2,000,000,000 viable P. pestis by suspensions of formalin-killed bacilli and by heat- or chemically-killed broth vaccine administered in the customary human dose; basic immunization with Fraction I renders approximately 60% of monkeys immune.Evidence from experiments carried out on groups of human volunteers points to the conclusion that any plague vaccine containing 2-3 mg of Fraction I or capable of producing that amount when inoculated into the body will favourably alter the susceptibility of 50% of inoculated persons. But, to alter favourably the responsiveness of a greater percentage and to enhance the moderately effective immunity, re-inoculation at intervals of 3-6 months is essential.
A fully recombinant sub-unit vaccine comprising the protein antigens rF1 + rV has been demonstrated to protect immunised guinea pigs against exposure to 10(5) colony-forming units (CFU) of virulent Yersinia pestis. Additionally, IgG purified from rF1 + rV-immunised guinea pig serum, protected the mouse by passive immunisation against challenge with Y. pestis whereas IgG purified from the serum of guinea pigs immunised with a licensed killed whole cell (KWC) vaccine for plague, protected less well. Guinea pigs immunised with the licensed killed whole cell vaccine developed an IgG titre for fraction 1 (F1) but not for V antigen. The differential in protection conferred on the mouse by passive immunisation with guinea pig IgG, was abrogated by the use of IgG purified from guinea pigs immunised with killed whole cell vaccine supplemented with V antigen. These findings indicate that the reduced efficacy of the licensed killed whole cell vaccine formulation previously observed in the mouse can be attributed to lack of the V antigen. Cross-protection of the mouse with guinea pig IgG suggests that the recognition of neutralising epitopes in the F1 and V proteins is conserved between these two species.
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Vaccines against bioterrorism agents offer the prospect of providing high levels of protection against airborne pathogens. However, the diversity of the bioterrorism threat means that it may be necessary to use several vaccines simultaneously. In this study we have investigated whether there are changes to the protective immune response to a recombinant sub-unit plague vaccine when it is co-administered with other sub-unit or live attenuated vaccines. Our results indicate that the co-administration of these vaccines did not influence the protection afforded by the plague vaccine. However, the co-administration of the plague sub-unit vaccine with a live vaccine resulted in markedly increased levels of IgG2a subclass antibodies, and markedly reduced levels of IgG1 subclass antibodies, to the plague sub-unit vaccine. This finding might have implications when considering the co-administration of other vaccine combinations.
Dry live plague vaccine EB was examined under microscope; it appeared that in the mentioned preparation the bacterial cells were enclosed in the artificial sucrose-gelatin capsule of the stabilizer which apparently maintained the vital activity of the microorganisms in the state of anabiosis by forming a stable bond with the bacterial body.
Yersinia pestis, the causative agent of plague, is an emerging threat as a means of bioterrorism. Accordingly, the Working Group on Civilian Biodefense, as well as the Centers for Disease Control and Prevention, has specified Y. pestis as a prime candidate for use in bioterrorism. As the threat of bioterrorism increases, so does the need for an effective vaccine against this potential agent. Experts agree that a stable, non-invasive vaccine would be necessary for the rapid large-scale immunization of a population following a bioterrorism attack. Thus far, live Salmonella-based oral vaccines show the most potential for this purpose. When delivered via a mucosal route, Salmonella-based plague vaccines show the ability to protect against the deadly pneumonic form of plague. Also, mass production, distribution, and administration are easier and less costly for attenuated Salmonella-based plague vaccines than for plague vaccines consisting of purified proteins. Most attenuated Salmonella-based plague vaccines have utilized a plasmid-based expression system to deliver plague antigen(s) to the mucosa. However, these systems are frequently associated with plasmid instability, an increased metabolic burden upon the vaccine strain, and highly undesirable antibiotic resistance genes. The future of Salmonella-based plague vaccines seems to lie in the use of chromosomally encoded plague antigens and the use of in vivo inducible promoters to drive their expression. This method of vaccine development has been proven to greatly increase the retention of foreign genes, and also eliminates the need for antibiotic resistance genes within Salmonella-based vaccines.
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While the safety of the available live plague vaccine EV 76 (Paris) continues to be the subject of further study, the USP formol-killed, virulent Pasteurella pestis (Yersinia pestis) suspension capable of protecting 60% of non-human primates, particularly Hanuman langurs (Presbytis entellus), warrants further clinical tests and field trials. Inoculated in a dosage of 2x10(9) killed plague bacilli (1 ml), followed by a booster of 400 million organisms (0.2 ml) in 1-3 months, this vaccine stimulates the appearance of passive mouse-protection antibodies (below an index of 10) and passive haemagglutinins in 60%-65% of human subjects. Recent experiences in Viet-Nam demonstrate that personnel vaccinated with the USP vaccine, although frequently exposed, enjoy almost complete freedom from the disease. One of the 4 known and confirmed cases of bubonic plague in North Americans occurred in an unvaccinated individual. Among individuals inoculated with the USP vaccine, 2 confirmed cases of pneumonic plague and 1 case of asymptomatic pharyngeal plague have been recorded. The incidence of plague in the Republic of Viet-Nam during the past 3 years is estimated at 13 263 cases in a population in part vaccinated with a live plague which exhibited inadequate immunogenic efficacy in experimental tests.