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

PLoS Pathogens

Pan Tao¹  Marthandan Mahalingam¹  Jian Sha²  Venigalla B. Rao²  Michelle L. Kirtley²  Christina J. van Lier²  Ashok K. Chopra³  Linsey A. Yeager⁴ 

[1] Department of Biology, The Catholic University of America, Washington, District of Columbia, United States of America;Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, United States of America;Galveston National Laboratory, The University of Texas Medical Branch, Galveston, Texas, United States of America;Institute of Human Infections and Immunity, The University of Texas Medical Branch, Galveston, Texas, United States of America

关键词: Vaccines;    Plagues;    Antigens;    Yersinia pestis;    Bacteriophages;    Antigen encapsulation;    Viral packaging;    Enzyme-linked immunoassays;   

DOI  :  10.1371/journal.ppat.1003495

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY