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Advanced Drug Delivery Reviews (v.57, #9)
Particulate delivery systems for biodefense subunit vaccines
by Vincent W. Bramwell; Jim E. Eyles; H. Oya Alpar (pp. 1247-1265).
Expanding identification of potentially protective subunit antigens and correlates of protection has provided a basis for the introduction of safer vaccines. Despite encouraging results in animal models, the significant potential of particulate delivery systems in vaccine design has not yet translated into effective vaccines available for use in humans. This review article will focus on the current status of the development of particulate vaccines, mainly liposomes and bio-degradable polymers, against potential agents for biowarfare: plague, anthrax, botulinum, and smallpox; and filoviruses: Marburg and Ebola.
Keywords: Vaccine; Biowarfare; Plague; Anthrax; Botulinum toxin; Smallpox; Filovirus; Liposome; Polylactide; Subunit; PLGA
Molecular basis for improved anthrax vaccines
by Robert N. Brey (pp. 1266-1292).
The current vaccine for anthrax has been licensed since 1970 and was developed based on the outcome of human trials conducted in the 1950s. This vaccine, known as anthrax vaccine adsorbed (AVA), consists of a culture filtrate from an attenuated strain of Bacillus anthracis adsorbed to aluminum salts as an adjuvant. This vaccine is considered safe and effective, but is difficult to produce and is associated with complaints about reactogenicity among users of the vaccine. Much of the work in the past decade on generating a second generation vaccine is based on the observation that antibodies to protective antigen (PA) are crucial in the protection against exposure to virulent anthrax spores. Antibodies to PA are thought to prevent binding to its cellular receptor and subsequent binding of lethal factor (LF) and edema factor (EF), which are required events for the action of the two toxins: lethal toxin (LeTx) and edema toxin (EdTx). The bacterial capsule as well as the two toxins are virulence factors of B. anthracis. The levels of antibodies to PA must exceed a certain minimal threshold in order to induce and maintain protective immunity. Immunity can be generated by vaccination with purified PA, as well as spores and DNA plasmids that express PA. Although antibodies to PA address the toxemia component of anthrax disease, antibodies to additional virulence factors, including the capsule or somatic antigens in the spore, may be critical in development of complete, sterilizing immunity to anthrax exposure. The next generation anthrax vaccines will be derived from the thorough understanding of the interaction of virulence factors with human and animal hosts and the role the immune response plays in providing protective immunity.
Keywords: Anthrax; Bacillus anthracis; Vaccine; Protective antigen; Lethal toxin; Edema toxin; Ames strain; Sterne strain; Lethal factor; Edema factor; Protective immunity; Recombinant PA; Monoclonal antibody; Genetic immunization; Adjuvants; Epitopes
Viral vectors for use in the development of biodefense vaccines
by John S. Lee; Angela G. Hadjipanayis; Michael D. Parker (pp. 1293-1314).
The heightened concerns about bioterrorism and the use of biowarfare agents have prompted substantial increased efforts towards the development of vaccines against a wide range of organisms, toxins, and viruses. An increasing variety of platforms and strategies have been analyzed for their potential as vaccines against these agents. DNA vectors, live-attenuated viruses and bacteria, recombinant proteins combined with adjuvant, and viral- or bacterial-vectored vaccines have been developed as countermeasures against many potential agents of bioterrorism or biowarfare. The use of viruses, for example adenovirus, vaccinia virus, and Venezuelan equine encephalitis virus, as vaccine vectors has enabled researchers to develop effective means for countering the threat of bioterrorism and biowarfare. An overview of the different viral vectors and the threats they counter will be discussed.
Keywords: Abbreviations; Ad; adenovirus; BoNT; botulinum neurotoxin; BWC; Biological and Toxin Weapons Convention; C; capsid; Con; Connaught strain; EBOV; Ebola hemorrhagic fever virus; EBOV(Z); Ebola hemorrhagic fever virus Zaire strain; ELISA; enzyme-linked immunosorbent assay; FDA; Food and Drug Administration; GP; glycoprotein; HA; influenza virus hemagglutinin protein; Hc; carboxy-terminal fragment from the heavy chain of botulinum neurotoxin; HFRS; hemorrhagic fever with renal syndrome; HIV; human immunodeficiency virus; HPS; huntavirus with pulmonary syndrome; HTNV; Hantaan virus; kb; kilobases; kbp; kilobase pairs; KHF; Korean hemorrhagic fever; LSV; Lassa virus; LSGPC or LGP; Lassa virus envelope glycoprotein; LSN or N or LNP; Lassa virus nucleoprotein; MBGV; Marburg virus; mSEB; mutagenized staphylococcal enterotoxin B; NHP; nonhuman primate; NIAID; National Institute of Allergy and Infectious Diseases; NP; nucleoprotein; NYBH; New York Board of Health; OVA; chicken ovalbumin; PA; protective antigen; pfu; plaque forming units; PUUV; Puumala virus; RCN; raccoon poxvirus; RP; replicon particle; RV; rabies virus; RVFV; Rift Valley fever virus; SEB; staphylococcal enterotoxin B; SEOV; Seoul virus; SFV; Semliki Forest virus; SINV; Sindbis virus; TK; thymidine kinase; TRD; Trinidad donkey; UNSCOM; United Nations Special Commission; UTR; untranslated region; VEEV; Venezuelan equine encephalitis virus; VHF; viral hemorrhagic fever; VRP; Venezuelan equine encephalitis virus replicon particle; VSV; vesicular stomatitis virus; VV; vaccinia virusVaccine; Viral vectors; Biodefense; Bioterrorism
The role of particle-mediated DNA vaccines in biodefense preparedness
by Hansi J. Dean; Joel Haynes; Connie Schmaljohn (pp. 1315-1342).
Particle-mediated epidermal delivery (PMED) of DNA vaccines is based on the acceleration of DNA-coated gold directly into the cytoplasm and nuclei of living cells of the epidermis, facilitating DNA delivery and gene expression. Professional antigen-presenting cells and keratinocytes in the skin are both targeted, resulting in antigen presentation via direct transfection and cross-priming mechanisms. Only a small number of cells need to be transfected to elicit humoral, cellular and memory responses, requiring only a low DNA dose. In recent years, data have accumulated on the utility of PMED for delivery of DNA vaccines against a number of viral pathogens, including filoviruses, flaviviruses, poxviruses, togaviruses and bunyaviruses. PMED DNA immunization of rodents and nonhuman primates results in the generation of neutralizing antibody, cellular immunity, and protective efficacy against a broad range of viruses of public health concern.
Keywords: DNA vaccine; Gene gun; Epidermis; Biodefense; Ebola; Marburg; Dengue; Smallpox; Tick-borne encephalitis; Venezuelan equine encephalitis; Hantavirus
DNA vaccines for biodefence
by Helen S. Garmory; Stuart D. Perkins; Robert J. Phillpotts; Richard W. Titball (pp. 1343-1361).
The advantages associated with DNA vaccines include the speed with which they may be constructed and produced at large-scale, the ability to produce a broad spectrum of immune responses, and the ability for delivery using non-invasive means. In addition, DNA vaccines may be manipulated to express multiple antigens and may be tailored for the induction of appropriate immune responses. These advantages make DNA vaccination a promising approach for the development of vaccines for biodefence. In this review, the potential of DNA vaccines for biodefence is discussed.
Keywords: Immunity; Targeting; Co-stimulatory molecules; Delivery; Carriers; Regimens; Viruses; Bacteria
Microencapsulated subunit vaccine approach to enterotoxigenic Escherichia coli and other mucosal pathogens
by Wyatt Byrd; Arthur de Lorimier; Zi-Rong Zheng; Frederick J. Cassels (pp. 1362-1380).
Infections of the intestinal, urogenital, and respiratory tracts are serious health problems worldwide from both a morbidity and mortality perspective. Mucosal pathogens attach to surfaces of mucosa as a prerequisite for colonization and subsequent pathogenesis. By expressing various surface adhesins (colonization factors, CF) they are able to bind to specific mucosal receptors. Enterotoxigenic Escherichia coli (ETEC) can express numerous CF that allow them to attach to a variety of hosts. Mucosal immunity directed against pathogenic microorganisms is critical in host protection with secretory IgA being particularly important in preventing microoganisms from colonizing host cells. M cells likewise have an important immunological function in the small intestines by binding and transporting antigens to lymphocytes and macrophages thus enhancing the immune response. The use of subunit vaccines, such as antigen encapsulated microspheres, can act to effectively deliver specific antigens so as to optimize their immunological response. With the threat of bioterrorism becoming a reality in recent years, the miroencapsulation of antigens from potential bioterrorist agents may be an effective method of delivery so as to induce a level of protection in at risk individuals. The encapsulation of ETEC colonization factors in microspheres and their subsequent administration in small animals and humans has been conducted for many years. Evidence suggests that this type of delivery system for ETEC antigens may enhance their immunogenicity and provide protection against this microorganism.
Keywords: Subunit vaccines; ETEC; Biodegradable microspheres; Mucosal pathogens
Bacterial ghosts as antigen delivery vehicles
by Ulrike Beate Mayr; Petra Walcher; Chakameh Azimpour; Eva Riedmann; Christoph Haller; Werner Lubitz (pp. 1381-1391).
The bacterial ghost system is a novel vaccine delivery system unusual in that it combines excellent natural intrinsic adjuvant properties with versatile carrier functions for foreign antigens. The efficient tropism of bacterial ghosts (BG) for antigen presenting cells promotes the generation of both cellular and humoral responses to heterologous antigens and carrier envelope structures. The simplicity of both BG production and packaging of (multiple) target antigens makes them particularly suitable for use as combination vaccines. Further advantages of BG vaccines include a long shelf-life without the need of cold-chain storage due to their freeze-dried status, they are safe as they do not involve host DNA or live organisms, they exhibit improved potency with regard to target antigens compared to conventional approaches, they are versatile with regards to DNA or protein antigen choice and size, and as a delivery system they offer high bioavailability.
Keywords: Abbreviations; APC; antigen presenting cells; APP; Actinobacillus pleuropneumoniae; BG; bacterial ghosts; CPS; cytoplasmic space; DC; dendritic cells; GFP; green fluorescent protein; IM; inner membrane; LPS; lipopolysaccharide; MBP; maltose binding protein; OM; outer membrane; OMP; outer membrane protein; PBMC; peripheral blood derived monocytic cells; PPS; periplasmic space; StrpA; streptavidin; TA; target antigen; TCP; toxin-co-regulated pili; VCG; Vibrio cholerae; ghostsTarget antigen; Gram-negative bacterial envelope; Particle presentation technology; DNA vaccine; Adjuvant; Delivery system; Bacterial ghosts
Commensal bacteria as a novel delivery system for subunit vaccines directed against agents of bioterrorism
by Rebecca L. Wilson; Dennis E. Hruby (pp. 1392-1402).
Following the anthrax attacks of 2001 and the recent SARS outbreak, concerns about emerging and re-emerging infectious diseases have catalyzed a renewed interest in developing new vaccination strategies that provide rapid and flexible response options to future threats. Because the probability of encountering one of these exotic agents is unknown, it is essential that new vaccine formulations employ methods that provide effective protection and extremely good safety profiles if they are to be used by either military or civilian populations. One approach, which potentially satisfies these criteria, is the use of live recombinant Gram-positive commensal bacteria as expression vectors. This review provides an overview of the system, its advantages and limitations, and details an example of how Gram-positive commensal bacteria are being developed as a fifth generation vaccine against a Class A biowarfare pathogen, namely smallpox.
Keywords: Mucosal immunity; Surface expression; Smallpox; Vaccinia antigens
Vaccination strategies for Francisella tularensis
by Karen E. Isherwood; Richard W. Titball; D. Huw Davies; Phillip L. Felgner; W. John W. Morrow (pp. 1403-1414).
Francisella tularensis is the etiologic agent of tularemia, a severe debilitating disease of humans and animals. The low infectious dose of F. tularensis in humans and the relative ease of culture are probably the properties which originally attracted interest in this bacterium as a bioweapon. Even today, F. tularensis is ranked as one of the pathogens most likely to be used as a biological warfare or bioterrorism agent. A live attenuated vaccine (LVS) has been available for over 50 years, but there are shortcomings associated with its use. This vaccine is not fully licensed and does not offer a high level of protection against respiratory challenge. Nevertheless, this vaccine does demonstrate the feasibility of vaccination against tularemia. Protection against tularemia is likely to be dependent on the induction of cellular and humoral immune responses. These types of responses are induced by the LVS vaccine and could also be induced by a rationally attenuated mutant of F. tularensis. Evoking this range of responses with a sub-unit vaccine may be more difficult to achieve, and will be dependent on the use of suitable vaccine delivery systems.
Keywords: Tularemia; Francisella tularensis; Live vaccine; LVS; TUL4
Production of vaccines against leading biowarfare toxins can utilize DNA scientific technology
by John L. Middlebrook (pp. 1415-1423).
There are a significant number of different natural toxins that are potential biological warfare agents against which a vaccine is needed. DNA science has been a key to the development of potential vaccines against the top threat toxin and should contribute such effects for other toxin's vaccines. Several different DNA technological scientific techniques have been used to accomplish the general goals of (1) cloning of the toxin or large toxin fragments, (2) altering the specific gene sequence to obtain high level expression of vaccine candidate production in alternate species (3) placement of the vaccine gene in very different presentation types of species.
Keywords: Botulinum toxin; Ricin; Protein synthesis inhibition; Immunization; Antibody protection; Aerosol challenge
Vaccines against the category B toxins: Staphylococcal enterotoxin B, epsilon toxin and ricin
by Nicholas J. Mantis (pp. 1424-1439).
The threat of bioterrorism worldwide has accelerated the demand for the development of therapies and vaccines against the Category B toxins: staphylococcal enterotoxin B (SEB), epsilon toxin (ETX) produced by Clostridium perfringens types B and D, and ricin, a natural product of the castor bean. The diverse and unique nature of these toxins poses a challenge to vaccinologists. While formalin-inactivated toxins can successfully induce antibody-mediated protection in animals, their usefulness in humans is limited because of potential safety concerns. For this reason, research is now aimed at developing recombinant, attenuated vaccines based on a detailed understanding of the molecular mechanisms by which these toxins function. Vaccine development is further complicated by the fact that as bioterrorism agents, SEB, ETX and ricin would most likely be disseminated as aerosols or in food/water supplies. Our understanding of the mechanisms by which these toxins cross mucosal surfaces, and importance of mucosal immunity in preventing toxin uptake is only rudimentary.
Keywords: Vaccine; Biodefense; Toxins; Immunity; Mucosal
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