IIBR scientists are designing novel strategies for prophylactics of life-threatening infectious diseases caused by lethal bacterial pathogens such as Bacillus anthracis, Yersinia pestis and Francisella tularensis, which are developed on the basis of extensive studies addressing mechanisms of virulence manifestation. Live attenuated vaccines are variant strains genetically engineered for a substantial decrease in their virulence, while their ability to infect as their virulent parental cognate strains is preserved. Optimal live attenuated vaccine strains exhibit an unaffected ability to elicit an immune response in the host organism, which may protect against a subsequent exposure to the virulent strain. This is exemplified in the Figure by a novel strain of attenuated Bacillus anthracis vaccine, potentially compatible with human use, which is currently evaluated pre-clinically for safety and efficacy in various animal models.
"Development and Evaluation of Live Attenuated Vaccines for Bacillus anthracis "
DoD (US) - MoD (Israel) – IIBR Project agreement NO. DT-PA-IS-12-0002
In this project, we have shown that a chromosomal deletion of the nlpD gene sequence resulted in a drastic reduction of virulence to an LD50 of at least 107 cfu for subcutaneous and airway routes of infection. The high level of attenuation of the Y. pestis nlpD mutant motivated us to evaluate the potential of this defined mutant to serve as a vaccine against plague. In a model of bubonic plague, mice were injected subcutaneously with 1×105 cfu of either the nlpD mutant or the Y. pestis EV76 prototype vaccine strain. Fifty days later, mice were challenged subcutaneously with a high dose of a virulent Y. pestis strain. All mice vaccinated with the nlpD mutant survived the challenge without showing signs of illness whereas EV76 failed to elicit significant protective immunity. In the mouse model of pneumonic plague, a singlesubcutaneous immunization with 1×105-107 cfu of the nlpD mutant or EV76 was followed 50 days later by i.n. challenge of the fully virulent Kimberley53 strain. The challenge dose was 5,500 cfu, which is equivalent to 10 LD50. While all control mice died within 4 days, a protection level of 33% was obtained following immunization with 105 cfu of the nlpD mutant. Higher protection levels of 66% and 82% were obtained by immunization with increasing doses of the mutant (106 cfu and 107 cfu, respectively). In contrast, EV76 was unable to elicit protection following immunization with 105 cfu, and a protection level of 33% was attained only after the immunization dose was increased to 107 cfu. These findings strongly accentuate the potency of the nlpD mutant in establishing effective protective immunity and suggest that it may be a suitable platform for a live vaccine.
The establishment of the adaptive immune response is a relatively slow process requiring several weeks for attaining the amplitude needed for manifestation of its protective value. Since post-exposure prophylactic measures are highly relevant to the cases of acute infections against which mass vaccination is not routinely conducted, we evaluated the efficacy of an anti-plague live vaccine strain in providing rapid protection and characterized the mechanism involved in this innate immune response.
Using the mouse model of plague infection, it was demonstrated that the EV76 live vaccine provides protection against simultaneous challenge with a fully virulent Y. pestis strain. Probing serum samples derived from EV76-immuniezed mice by means of an ex-vivo Y. pestis growth inhibition assay, enabled the identification of a potent systemic antibacterial activity exerted by the host iron- and heme- binding proteins hemopexin and transferrin, early after immunization. The study provides proof of principle for a new concept by which live vaccines have the potential for inducing rapid, broad range iron nutritional immunity against infections. This may prove beneficial for antibiotic resistance scenarios allowing the extension of the time-window required for the development of the acquired immune response.
Identification of key elements involved in the mechanisms of rapid anti-plague immunity
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