Mutated and Bacteriophage T4 Nanoparticle Arrayed F1-V Immunogens from Yersinia pestis as Next Generation Plague Vaccines

Pan Tao, Marthandan Mahalingam, Michelle L. Kirtley, Christina J. van Lier, Jian Sha, Linsey A. Yeager, Ashok Chopra, Venigalla B. Rao

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Pneumonic plague is a highly virulent infectious disease with 100% mortality rate, and its causative organism Yersinia pestis poses a serious threat for deliberate use as a bioterror agent. Currently, there is no FDA approved vaccine against plague. The polymeric bacterial capsular protein F1, a key component of the currently tested bivalent subunit vaccine consisting, in addition, of low calcium response V antigen, has high propensity to aggregate, thus affecting its purification and vaccine efficacy. We used two basic approaches, structure-based immunogen design and phage T4 nanoparticle delivery, to construct new plague vaccines that provided complete protection against pneumonic plague. The NH2-terminal β-strand of F1 was transplanted to the COOH-terminus and the sequence flanking the β-strand was duplicated to eliminate polymerization but to retain the T cell epitopes. The mutated F1 was fused to the V antigen, a key virulence factor that forms the tip of the type three secretion system (T3SS). The F1mut-V protein showed a dramatic switch in solubility, producing a completely soluble monomer. The F1mut-V was then arrayed on phage T4 nanoparticle via the small outer capsid protein, Soc. The F1mut-V monomer was robustly immunogenic and the T4-decorated F1mut-V without any adjuvant induced balanced TH1 and TH2 responses in mice. Inclusion of an oligomerization-deficient YscF, another component of the T3SS, showed a slight enhancement in the potency of F1-V vaccine, while deletion of the putative immunomodulatory sequence of the V antigen did not improve the vaccine efficacy. Both the soluble (purified F1mut-V mixed with alhydrogel) and T4 decorated F1mut-V (no adjuvant) provided 100% protection to mice and rats against pneumonic plague evoked by high doses of Y. pestis CO92. These novel platforms might lead to efficacious and easily manufacturable next generation plague vaccines.

Original languageEnglish (US)
Article numbere1003495
JournalPLoS Pathogens
Volume9
Issue number7
DOIs
StatePublished - Jul 2013

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Plague Vaccine
Yersinia pestis
Bacteriophage T4
Plague
Nanoparticles
Vaccines
Antigens
Aluminum Hydroxide
Subunit Vaccines
T-Lymphocyte Epitopes
Bacterial Proteins
Capsid Proteins
Virulence Factors
Polymerization
Solubility
Communicable Diseases
Calcium
Mortality
Proteins

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Mutated and Bacteriophage T4 Nanoparticle Arrayed F1-V Immunogens from Yersinia pestis as Next Generation Plague Vaccines. / Tao, Pan; Mahalingam, Marthandan; Kirtley, Michelle L.; van Lier, Christina J.; Sha, Jian; Yeager, Linsey A.; Chopra, Ashok; Rao, Venigalla B.

In: PLoS Pathogens, Vol. 9, No. 7, e1003495, 07.2013.

Research output: Contribution to journalArticle

Tao, Pan ; Mahalingam, Marthandan ; Kirtley, Michelle L. ; van Lier, Christina J. ; Sha, Jian ; Yeager, Linsey A. ; Chopra, Ashok ; Rao, Venigalla B. / Mutated and Bacteriophage T4 Nanoparticle Arrayed F1-V Immunogens from Yersinia pestis as Next Generation Plague Vaccines. In: PLoS Pathogens. 2013 ; Vol. 9, No. 7.
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