Protection against inhalation anthrax by immunization with Salmonella enterica serovar Typhi Ty21a stably producing protective antigen of Bacillus anthracis

B. Kim Lee Sim, Minglin Li, Manuel Osorio, Yun Wu, Tint T. Wai, Johnny Peterson, Eric R. James, Sumana Chakravarty, Lixin Gao, Rui Xu, Natasha Kc, Richard E. Stafford, William Lawrence, Linsey A. Yeager, Jennifer E. Peel, Satheesh K. Sivasubramani, Ashok Chopra, Svetlana Filippova, Stephen L. Hoffman

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The national blueprint for biodefense concluded that the United States is underprepared for biological threats. The licensed anthrax vaccine absorbed vaccine, BioThrax, requires administration of at least 3-5 intramuscular doses. The anthrax vaccine absorbed vaccine consists of complex cell-free culture filtrates of a toxigenic Bacillus anthracis strain and causes tenderness at the injection site and significant adverse events. We integrated a codon-optimized, protective antigen gene of B. anthracis (plus extracellular secretion machinery), into the chromosome of the licensed, oral, live-attenuated typhoid fever vaccineTy21a to form Ty21a-PA-01 and demonstrated excellent expression of the gene encoding protective antigen. We produced the vaccine in a 10-L fermenter; foam-dried and vialed it, and characterized the dried product. The vaccine retained ~50% viability for 20 months at ambient temperature. Sera from animals immunized by the intraperitoneal route had high levels of anti-protective antigen antibodies by enzyme-linked immunosorbent assay and anthrax lethal toxin-neutralizing activity. Immunized mice were fully protected against intranasal challenge with ~5 LD50 of B. anthracis Sterne spores, and 70% (7/10) of vaccinated rabbits were protected against aerosol challenge with 200 LD50 of B. anthracis Ames spores. There was a significant correlation between protection and antibody levels determined by enzyme-linked immunosorbent assay and toxin-neutralizing activity. These data provide the foundation for achievement of our ultimate goal, which is to develop an oral anthrax vaccine that is stable at ambient temperatures and induces the rapid onset of durable, high-level protection after a 1-week immunization regimen.

Original languageEnglish (US)
Article number17
Journalnpj Vaccines
Volume2
Issue number1
DOIs
StatePublished - Dec 1 2017

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Salmonella typhi
Anthrax Vaccines
Bacillus anthracis
Immunization
Vaccines
Lethal Dose 50
Spores
Enzyme-Linked Immunosorbent Assay
Antigens
Temperature
Antibodies
Typhoid Fever
Aerosols
Codon
Cell Culture Techniques
Chromosomes
Rabbits
Gene Expression
Injections
Inhalation anthrax

ASJC Scopus subject areas

  • Pharmacology
  • Infectious Diseases
  • Immunology
  • Pharmacology (medical)

Cite this

Protection against inhalation anthrax by immunization with Salmonella enterica serovar Typhi Ty21a stably producing protective antigen of Bacillus anthracis. / Sim, B. Kim Lee; Li, Minglin; Osorio, Manuel; Wu, Yun; Wai, Tint T.; Peterson, Johnny; James, Eric R.; Chakravarty, Sumana; Gao, Lixin; Xu, Rui; Kc, Natasha; Stafford, Richard E.; Lawrence, William; Yeager, Linsey A.; Peel, Jennifer E.; Sivasubramani, Satheesh K.; Chopra, Ashok; Filippova, Svetlana; Hoffman, Stephen L.

In: npj Vaccines, Vol. 2, No. 1, 17, 01.12.2017.

Research output: Contribution to journalArticle

Sim, BKL, Li, M, Osorio, M, Wu, Y, Wai, TT, Peterson, J, James, ER, Chakravarty, S, Gao, L, Xu, R, Kc, N, Stafford, RE, Lawrence, W, Yeager, LA, Peel, JE, Sivasubramani, SK, Chopra, A, Filippova, S & Hoffman, SL 2017, 'Protection against inhalation anthrax by immunization with Salmonella enterica serovar Typhi Ty21a stably producing protective antigen of Bacillus anthracis', npj Vaccines, vol. 2, no. 1, 17. https://doi.org/10.1038/s41541-017-0018-4
Sim, B. Kim Lee ; Li, Minglin ; Osorio, Manuel ; Wu, Yun ; Wai, Tint T. ; Peterson, Johnny ; James, Eric R. ; Chakravarty, Sumana ; Gao, Lixin ; Xu, Rui ; Kc, Natasha ; Stafford, Richard E. ; Lawrence, William ; Yeager, Linsey A. ; Peel, Jennifer E. ; Sivasubramani, Satheesh K. ; Chopra, Ashok ; Filippova, Svetlana ; Hoffman, Stephen L. / Protection against inhalation anthrax by immunization with Salmonella enterica serovar Typhi Ty21a stably producing protective antigen of Bacillus anthracis. In: npj Vaccines. 2017 ; Vol. 2, No. 1.
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abstract = "The national blueprint for biodefense concluded that the United States is underprepared for biological threats. The licensed anthrax vaccine absorbed vaccine, BioThrax, requires administration of at least 3-5 intramuscular doses. The anthrax vaccine absorbed vaccine consists of complex cell-free culture filtrates of a toxigenic Bacillus anthracis strain and causes tenderness at the injection site and significant adverse events. We integrated a codon-optimized, protective antigen gene of B. anthracis (plus extracellular secretion machinery), into the chromosome of the licensed, oral, live-attenuated typhoid fever vaccineTy21a to form Ty21a-PA-01 and demonstrated excellent expression of the gene encoding protective antigen. We produced the vaccine in a 10-L fermenter; foam-dried and vialed it, and characterized the dried product. The vaccine retained ~50{\%} viability for 20 months at ambient temperature. Sera from animals immunized by the intraperitoneal route had high levels of anti-protective antigen antibodies by enzyme-linked immunosorbent assay and anthrax lethal toxin-neutralizing activity. Immunized mice were fully protected against intranasal challenge with ~5 LD50 of B. anthracis Sterne spores, and 70{\%} (7/10) of vaccinated rabbits were protected against aerosol challenge with 200 LD50 of B. anthracis Ames spores. There was a significant correlation between protection and antibody levels determined by enzyme-linked immunosorbent assay and toxin-neutralizing activity. These data provide the foundation for achievement of our ultimate goal, which is to develop an oral anthrax vaccine that is stable at ambient temperatures and induces the rapid onset of durable, high-level protection after a 1-week immunization regimen.",
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AU - Wai, Tint T.

AU - Peterson, Johnny

AU - James, Eric R.

AU - Chakravarty, Sumana

AU - Gao, Lixin

AU - Xu, Rui

AU - Kc, Natasha

AU - Stafford, Richard E.

AU - Lawrence, William

AU - Yeager, Linsey A.

AU - Peel, Jennifer E.

AU - Sivasubramani, Satheesh K.

AU - Chopra, Ashok

AU - Filippova, Svetlana

AU - Hoffman, Stephen L.

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