Mutated and bacteriophage T4 nanoparticle arrayed F1-V immunogens from Yersinia pestis as next generation plague vaccines.

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.

• Authors: Pan Tao, Marthandan Mahalingam, Michelle L Kirtley, Christina J van Lier, Jian Sha, Linsey A Yeager, Ashok K Chopra, Venigalla B Rao
• Journal: PLoS pathogens (PLoS Pathog) Vol. 9 Issue 7 Pg. e1003495 ( 2013) ISSN: 1553-7374 [Electronic] United States
• PMID: 23853602 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, Bacterial
• Antigens, Viral
• Bacterial Proteins
• Capsid Proteins
• LcrV protein, Yersinia
• Mutant Proteins
• Peptide Fragments
• Plague Vaccine
• Pore Forming Cytotoxic Proteins
• Recombinant Proteins
• Vaccines, Virus-Like Particle
• YscF protein, Yersinia pestis
• caf1 protein, Yersinia pestis
• small outer capsid protein, bacteriophage T4

Topics

• Animals
• Antigens, Bacterial (chemistry, genetics, metabolism)
• Antigens, Viral (chemistry, genetics, metabolism)
• Bacterial Proteins (chemistry, genetics, metabolism)
• Bacteriophage T4 (chemistry, immunology, metabolism)
• Capsid (chemistry, immunology, metabolism)
• Capsid Proteins (genetics, metabolism)
• Female
• Mice
• Mice, Inbred BALB C
• Mutant Proteins (chemistry, metabolism)
• Particle Size
• Peptide Fragments (chemistry, genetics, metabolism)
• Plague (immunology, microbiology, prevention & control, virology)
• Plague Vaccine (chemistry, immunology)
• Pore Forming Cytotoxic Proteins (chemistry, genetics, metabolism)
• Protein Interaction Domains and Motifs
• Random Allocation
• Rats
• Rats, Inbred BN
• Recombinant Proteins (chemistry, metabolism)
• Vaccines, Virus-Like Particle (chemistry, immunology)
• Yersinia pestis (immunology, virology)