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      A Bacteriophage T4 Nanoparticle-Based Dual Vaccine against Anthrax and Plague

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          Abstract

          Following the deadly anthrax attacks of 2001, the Centers for Disease Control and Prevention (CDC) determined that Bacillus anthracis and Yersinia pestis that cause anthrax and plague, respectively, are two Tier 1 select agents that pose the greatest threat to the national security of the United States. Both cause rapid death, in 3 to 6 days, of exposed individuals. We engineered a virus nanoparticle vaccine using bacteriophage T4 by incorporating key antigens of both B. anthracis and Y. pestis into one formulation. Two doses of this vaccine provided complete protection against both inhalational anthrax and pneumonic plague in animal models. This dual anthrax-plague vaccine is a strong candidate for stockpiling against a potential bioterror attack involving either one or both of these biothreat agents. Further, our results establish the T4 nanoparticle as a novel platform to develop multivalent vaccines against pathogens of high public health significance.

          ABSTRACT

          Bacillus anthracis and Yersinia pestis, the causative agents of anthrax and plague, respectively, are two of the deadliest pathogenic bacteria that have been used as biological warfare agents. Although Biothrax is a licensed vaccine against anthrax, no Food and Drug Administration-approved vaccine exists for plague. Here, we report the development of a dual anthrax-plague nanoparticle vaccine employing bacteriophage (phage) T4 as a platform. Using an in vitro assembly system, the 120- by 86-nm heads (capsids) of phage T4 were arrayed with anthrax and plague antigens fused to the small outer capsid protein Soc (9 kDa). The antigens included the anthrax protective antigen (PA) (83 kDa) and the mutated (mut) capsular antigen F1 and the low-calcium-response V antigen of the type 3 secretion system from Y. pestis (F1mutV) (56 kDa). These viral nanoparticles elicited robust anthrax- and plague-specific immune responses and provided complete protection against inhalational anthrax and/or pneumonic plague in three animal challenge models, namely, mice, rats, and rabbits. Protection was demonstrated even when the animals were simultaneously challenged with lethal doses of both anthrax lethal toxin and Y. pestis CO92 bacteria. Unlike the traditional subunit vaccines, the phage T4 vaccine uses a highly stable nanoparticle scaffold, provides multivalency, requires no adjuvant, and elicits broad T-helper 1 and 2 immune responses that are essential for complete clearance of bacteria during infection. Therefore, phage T4 is a unique nanoparticle platform to formulate multivalent vaccines against high-risk pathogens for national preparedness against potential bioterror attacks and emerging infections.

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          Most cited references44

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          Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense.

          The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals following the use of plague as a biological weapon against a civilian population. The working group included 25 representatives from major academic medical centers and research, government, military, public health, and emergency management institutions and agencies. MEDLINE databases were searched from January 1966 to June 1998 for the Medical Subject Headings plague, Yersinia pestis, biological weapon, biological terrorism, biological warfare, and biowarfare. Review of the bibliographies of the references identified by this search led to subsequent identification of relevant references published prior to 1966. In addition, participants identified other unpublished references and sources. Additional MEDLINE searches were conducted through January 2000. The first draft of the consensus statement was a synthesis of information obtained in the formal evidence-gathering process. The working group was convened to review drafts of the document in October 1998 and May 1999. The final statement incorporates all relevant evidence obtained by the literature search in conjunction with final consensus recommendations supported by all working group members. An aerosolized plague weapon could cause fever, cough, chest pain, and hemoptysis with signs consistent with severe pneumonia 1 to 6 days after exposure. Rapid evolution of disease would occur in the 2 to 4 days after symptom onset and would lead to septic shock with high mortality without early treatment. Early treatment and prophylaxis with streptomycin or gentamicin or the tetracycline or fluoroquinolone classes of antimicrobials would be advised.
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            Anthrax as a biological weapon, 2002: updated recommendations for management.

            To review and update consensus-based recommendations for medical and public health professionals following a Bacillus anthracis attack against a civilian population. The working group included 23 experts from academic medical centers, research organizations, and governmental, military, public health, and emergency management institutions and agencies. MEDLINE databases were searched from January 1966 to January 2002, using the Medical Subject Headings anthrax, Bacillus anthracis, biological weapon, biological terrorism, biological warfare, and biowarfare. Reference review identified work published before 1966. Participants identified unpublished sources. The first draft synthesized the gathered information. Written comments were incorporated into subsequent drafts. The final statement incorporated all relevant evidence from the search along with consensus recommendations. Specific recommendations include diagnosis of anthrax infection, indications for vaccination, therapy, postexposure prophylaxis, decontamination of the environment, and suggested research. This revised consensus statement presents new information based on the analysis of the anthrax attacks of 2001, including developments in the investigation of the anthrax attacks of 2001; important symptoms, signs, and laboratory studies; new diagnostic clues that may help future recognition of this disease; current anthrax vaccine information; updated antibiotic therapeutic considerations; and judgments about environmental surveillance and decontamination.
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              Vaccine technologies: From whole organisms to rationally designed protein assemblies

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                Author and article information

                Contributors
                Role: Editor
                Role: Solicited external reviewer
                Role: Solicited external reviewer
                Role: Solicited external reviewer
                Journal
                mBio
                MBio
                mbio
                mbio
                mBio
                mBio
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                16 October 2018
                Sep-Oct 2018
                : 9
                : 5
                : e01926-18
                Affiliations
                [a ]Department of Biology, The Catholic University of America, Washington, DC, USA
                [b ]Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, USA
                [c ]Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
                [d ]Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
                [e ]Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA
                [f ]Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, Texas, USA
                [g ]Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA
                McGovern Medical School
                University of Colorado Denver
                University of Missouri
                University of North Dakota
                Author notes
                Address correspondence to Ashok K. Chopra, achopra@ 123456utmb.edu , or Venigalla B. Rao, rao@ 123456cua.edu .
                Article
                mBio01926-18
                10.1128/mBio.01926-18
                6191538
                30327445
                802df9fb-25be-4fc9-b301-c2dcb8c11d26
                Copyright © 2018 Tao et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 31 August 2018
                : 6 September 2018
                Page count
                supplementary-material: 1, Figures: 6, Tables: 0, Equations: 0, References: 53, Pages: 13, Words: 9226
                Funding
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;
                Award ID: AI111538
                Award Recipient :
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;
                Award ID: AI064389
                Award Recipient :
                Categories
                Research Article
                Therapeutics and Prevention
                Custom metadata
                September/October 2018

                Life sciences
                anthrax vaccine,bacteriophage t4,biodefense,plague vaccine,small outer capsid protein,vaccine delivery,virus nanoparticles

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