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A novel live attenuated anthrax spore vaccine based on an acapsular Bacillus anthracis Sterne strain with mutations in the htrA, lef and cya genes.
Vaccine 2017; 35(44):6030-6040V

Abstract

We recently reported the development of a novel, next-generation, live attenuated anthrax spore vaccine based on disruption of the htrA (High Temperature Requirement A) gene in the Bacillus anthracis Sterne veterinary vaccine strain. This vaccine exhibited a highly significant decrease in virulence in murine, guinea pig and rabbit animal models yet preserved the protective value of the parental Sterne strain. Here, we report the evaluation of additional mutations in the lef and cya genes, encoding for the toxin components lethal factor (LF) and edema factor (EF), to further attenuate the SterneΔhtrA strain and improve its compatibility for human use. Accordingly, we constructed seven B. anthracis Sterne-derived strains exhibiting different combinations of mutations in the htrA, cya and lef genes. The various strains were indistinguishable in growth in vitro and in their ability to synthesise the protective antigen (PA, necessary for the elicitation of protection). In the sensitive murine model, we observed a gradual increase (ΔhtrA<ΔhtrAΔcya<ΔhtrAΔlef<ΔhtrAΔlefΔcya) in attenuation - up to 108-fold relative to the parental Sterne vaccine strain. Most importantly, all various SterneΔhtrA derivative strains did not differ in their ability to elicit protective immunity in guinea pigs. Immunisation of guinea pigs with a single dose (109 spores) or double doses (>107spores) of the most attenuated triple mutant strain SterneΔhtrAlefMUTΔcya induced a robust immune response, providing complete protection against a subsequent respiratory lethal challenge. Partial protection was observed in animals vaccinated with a double dose of as few as 105spores. Furthermore, protective immune status was maintained in all vaccinated guinea pigs and rabbits for at least 40 and 30weeks, respectively.

Authors+Show Affiliations

Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel. Electronic address: theodorc@iibr.gov.il.Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28342664

Citation

Chitlaru, Theodor, et al. "A Novel Live Attenuated Anthrax Spore Vaccine Based On an Acapsular Bacillus Anthracis Sterne Strain With Mutations in the htrA, Lef and Cya Genes." Vaccine, vol. 35, no. 44, 2017, pp. 6030-6040.
Chitlaru T, Israeli M, Rotem S, et al. A novel live attenuated anthrax spore vaccine based on an acapsular Bacillus anthracis Sterne strain with mutations in the htrA, lef and cya genes. Vaccine. 2017;35(44):6030-6040.
Chitlaru, T., Israeli, M., Rotem, S., Elia, U., Bar-Haim, E., Ehrlich, S., ... Shafferman, A. (2017). A novel live attenuated anthrax spore vaccine based on an acapsular Bacillus anthracis Sterne strain with mutations in the htrA, lef and cya genes. Vaccine, 35(44), pp. 6030-6040. doi:10.1016/j.vaccine.2017.03.033.
Chitlaru T, et al. A Novel Live Attenuated Anthrax Spore Vaccine Based On an Acapsular Bacillus Anthracis Sterne Strain With Mutations in the htrA, Lef and Cya Genes. Vaccine. 2017 10 20;35(44):6030-6040. PubMed PMID: 28342664.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel live attenuated anthrax spore vaccine based on an acapsular Bacillus anthracis Sterne strain with mutations in the htrA, lef and cya genes. AU - Chitlaru,Theodor, AU - Israeli,Ma'ayan, AU - Rotem,Shahar, AU - Elia,Uri, AU - Bar-Haim,Erez, AU - Ehrlich,Sharon, AU - Cohen,Ofer, AU - Shafferman,Avigdor, Y1 - 2017/03/23/ PY - 2016/12/22/received PY - 2017/01/24/revised PY - 2017/03/08/accepted PY - 2017/3/28/pubmed PY - 2018/3/15/medline PY - 2017/3/27/entrez KW - Anthrax KW - Anthrax toxins KW - Bacillus anthracis KW - HtrA KW - Live attenuated vaccine SP - 6030 EP - 6040 JF - Vaccine JO - Vaccine VL - 35 IS - 44 N2 - We recently reported the development of a novel, next-generation, live attenuated anthrax spore vaccine based on disruption of the htrA (High Temperature Requirement A) gene in the Bacillus anthracis Sterne veterinary vaccine strain. This vaccine exhibited a highly significant decrease in virulence in murine, guinea pig and rabbit animal models yet preserved the protective value of the parental Sterne strain. Here, we report the evaluation of additional mutations in the lef and cya genes, encoding for the toxin components lethal factor (LF) and edema factor (EF), to further attenuate the SterneΔhtrA strain and improve its compatibility for human use. Accordingly, we constructed seven B. anthracis Sterne-derived strains exhibiting different combinations of mutations in the htrA, cya and lef genes. The various strains were indistinguishable in growth in vitro and in their ability to synthesise the protective antigen (PA, necessary for the elicitation of protection). In the sensitive murine model, we observed a gradual increase (ΔhtrA<ΔhtrAΔcya<ΔhtrAΔlef<ΔhtrAΔlefΔcya) in attenuation - up to 108-fold relative to the parental Sterne vaccine strain. Most importantly, all various SterneΔhtrA derivative strains did not differ in their ability to elicit protective immunity in guinea pigs. Immunisation of guinea pigs with a single dose (109 spores) or double doses (>107spores) of the most attenuated triple mutant strain SterneΔhtrAlefMUTΔcya induced a robust immune response, providing complete protection against a subsequent respiratory lethal challenge. Partial protection was observed in animals vaccinated with a double dose of as few as 105spores. Furthermore, protective immune status was maintained in all vaccinated guinea pigs and rabbits for at least 40 and 30weeks, respectively. SN - 1873-2518 UR - https://www.unboundmedicine.com/medline/citation/28342664/A_novel_live_attenuated_anthrax_spore_vaccine_based_on_an_acapsular_Bacillus_anthracis_Sterne_strain_with_mutations_in_the_htrA_lef_and_cya_genes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0264-410X(17)30339-0 DB - PRIME DP - Unbound Medicine ER -