scholarly journals Efficacy of a Vaccine Based on Protective Antigen and Killed Spores against Experimental Inhalational Anthrax

2008 ◽  
Vol 77 (3) ◽  
pp. 1197-1207 ◽  
Author(s):  
Yves P. Gauthier ◽  
Jean-Nicolas Tournier ◽  
Jean-Charles Paucod ◽  
Jean-Philippe Corre ◽  
Michèle Mock ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Protective Immunity ◽  
Protective Antigen ◽  
Virulent Strain ◽  
Neutralizing Antibody ◽  
Cutaneous Anthrax ◽  
Anthrax Vaccines ◽  
Mucosal Secretions ◽  
Highly Virulent ◽  
Lethal Doses

ABSTRACTProtective antigen (PA)-based anthrax vaccines acting on toxins are less effective than live attenuated vaccines, suggesting that additional antigens may contribute to protective immunity. Several reports indicate that capsule or spore-associated antigens may enhance the protection afforded by PA. Addition of formaldehyde-inactivated spores (FIS) to PA (PA-FIS) elicits total protection against cutaneous anthrax. Nevertheless, vaccines that are effective against cutaneous anthrax may not be so against inhalational anthrax. The aim of this work was to optimize immunization with PA-FIS and to assess vaccine efficacy against inhalational anthrax. We assessed the immune response to recombinant anthrax PA fromBacillus anthracis(rPA)-FIS administered by various immunization protocols and the protection provided to mice and guinea pigs infected through the respiratory route with spores of a virulent strain ofB. anthracis. Combined subcutaneous plus intranasal immunization of mice yielded a mucosal immunoglobulin G response to rPA that was more than 20 times higher than that in lung mucosal secretions after subcutaneous vaccination. The titers of toxin-neutralizing antibody and antispore antibody were also significantly higher: nine and eight times higher, respectively. The optimized immunization elicited total protection of mice intranasally infected with the virulentB. anthracisstrain 17JB. Guinea pigs were fully protected, both against an intranasal challenge with 100 50% lethal doses (LD50) and against an aerosol with 75 LD50of spores of the highly virulent strain 9602. Conversely, immunization with PA alone did not elicit protection. These results demonstrate that the association of PA and spores is very much more effective than PA alone against experimental inhalational anthrax.

scholarly journals Anthrax Spores Make an Essential Contribution to Vaccine Efficacy

2002 ◽  
Vol 70 (2) ◽  
pp. 661-664 ◽  
Author(s):  
Fabien Brossier ◽  
Martine Levy ◽  
Michèle Mock
Keyword(s):  
Guinea Pigs ◽  
Protective Antigen ◽  
Humoral Response ◽  
Anthrax Toxin ◽  
Experimental Animals ◽  
Challenge Strain ◽  
Anthrax Spores ◽  
Acellular Vaccines ◽  
Essential Contribution ◽  
Anthrax Vaccines

ABSTRACT Anthrax is caused by Bacillus anthracis, a gram-positive spore-forming bacterium. Septicemia and toxemia rapidly lead to death in infected mammal hosts. Currently used acellular vaccines against anthrax consist of protective antigen (PA), one of the anthrax toxin components. However, in experimental animals such vaccines are less protective than live attenuated strains. Here we demonstrate that the addition of formaldehyde-inactivated spores (FIS) of B. anthracis to PA elicits total protection against challenge with virulent B. anthracis strains in mice and guinea pigs. The toxin-neutralizing activities of sera from mice immunized with PA alone or PA plus FIS were similar, suggesting that the protection conferred by PA plus FIS was not only a consequence of the humoral response to PA. A PA-deficient challenge strain was constructed, and its virulence was due solely to its multiplication. Immunization with FIS alone was sufficient to protect mice partially, and guinea pigs totally, against infection with this strain. This suggests that spore antigens contribute to protection. Guinea pigs and mice had very different susceptibilities to infection with the nontoxigenic strain, highlighting the importance of verifying the pertinence of animal models for evaluating anthrax vaccines.

scholarly journals Oral Spore Vaccine Based on Live Attenuated Nontoxinogenic Bacillus anthracis Expressing Recombinant Mutant Protective Antigen

2005 ◽  
Vol 73 (7) ◽  
pp. 4043-4053 ◽  
Author(s):  
R. Aloni-Grinstein ◽  
O. Gat ◽  
Z. Altboum ◽  
B. Velan ◽  
S. Cohen ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Guinea Pigs ◽  
Protective Antigen ◽  
De Novo ◽  
Oral Vaccine ◽  
Humoral Response ◽  
Neutralizing Antibody ◽  
Threshold Level ◽  
Oral Immunization ◽  
Secretory Iga

ABSTRACT An attenuated nontoxinogenic nonencapsulated Bacillus anthracis spore vaccine expressing high levels of recombinant mutant protective antigen (PA), which upon subcutaneous immunization provided protection against a lethal B. anthracis challenge, was found to have the potential to serve also as an oral vaccine. Guinea pigs immunized per os with the recombinant spore vaccine were primed to B. anthracis vegetative antigens as well as to PA, yet only a fraction of the animals (30% to 50%) mounted a humoral response to all of these antigens. Protective immunity provided by per os immunization correlated with a threshold level of PA neutralizing antibody titers and was long-lasting. Protection conferred by per os immunization was attained when the vaccine was administered in the sporogenic form, which, unlike the vegetative cells, survived passage through the gastrointestinal tract. A comparison of immunization of unirradiated spores with immunization of γ-irradiated spores demonstrated that germination and de novo synthesis of PA were prerequisites for mounting an immune protective response. Oral immunization of guinea pigs with attenuated B. anthracis spores resulted in a characteristic anti-PA immunoglobulin isotype profile (immunoglobulin [G1 IgG1] versus IgG2), as well as induction of specific anti-PA secretory IgA, indicating development of mucosal immunity.

scholarly journals Search for Correlates of Protective Immunity Conferred by Anthrax Vaccine

2001 ◽  
Vol 69 (5) ◽  
pp. 2888-2893 ◽  
Author(s):  
Shaul Reuveny ◽  
Moshe D. White ◽  
Yaakov Y. Adar ◽  
Yaron Kafri ◽  
Zeev Altboum ◽  
...  
Keyword(s):  
Antibody Titer ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Protective Antigen ◽  
Surrogate Marker ◽  
Neutralizing Antibody ◽  
Enzyme Linked Immunosorbent Assay ◽  
Lethal Challenge ◽  
Anthrax Spores ◽  
Antibody Titers

ABSTRACT Vaccination by anthrax protective antigen (PA)-based vaccines requires multiple immunization, underlying the need to develop more efficacious vaccines or alternative vaccination regimens. In spite of the vast use of PA-based vaccines, the definition of a marker for protective immunity is still lacking. Here we describe studies designed to help define such markers. To this end we have immunized guinea pigs by different methods and monitored the immune response and the corresponding extent of protection against a lethal challenge with anthrax spores. Active immunization was performed by a single injection using one of two methods: (i) vaccination with decreasing amounts of PA and (ii) vaccination with constant amounts of PA that had been thermally inactivated for increasing periods. In both studies a direct correlation between survival and neutralizing-antibody titer was found (r 2 = 0.92 and 0.95, respectively). Most significantly, in the two protocols a similar neutralizing-antibody titer range provided 50% protection. Furthermore, in a complementary study involving passive transfer of PA hyperimmune sera to naive animals, a similar correlation between neutralizing-antibody titers and protection was found. In all three immunization studies, neutralization titers of at least 300 were sufficient to confer protection against a dose of 40 50% lethal doses (LD50) of virulent anthrax spores of the Vollum strain. Such consistency in the correlation of protective immunity with anti-PA antibody titers was not observed for antibody titers determined by an enzyme-linked immunosorbent assay. Taken together, these results clearly demonstrate that neutralizing antibodies to PA constitute a major component of the protective immunity against anthrax and suggest that this parameter could be used as a surrogate marker for protection.

scholarly journals Immunization with Truncated Recombinant Protein SpaC of Erysipelothrix rhusiopathiae Strain 715 Serovar 18 Confers Protective Immunity against Challenge with Various Serovars

2010 ◽  
Vol 17 (12) ◽  
pp. 1991-1997 ◽  
Author(s):  
Ho To ◽  
Shuichi Someno ◽  
Shinya Nagai ◽  
Tomohiro Koyama ◽  
Tetsuji Nagano
Keyword(s):  
Protective Immunity ◽  
Protective Antigen ◽  
Protective Efficacy ◽  
Statistical Significance ◽  
Effective Vaccine ◽  
Erysipelothrix Rhusiopathiae ◽  
Helical Domain ◽  
First Time ◽  
Highly Virulent ◽  
Spa Proteins

ABSTRACTPreviously, we showed that surface protective antigen (Spa) proteins ofErysipelothrix rhusiopathiaecan be classified into three molecular species—SpaA, SpaB, and SpaC—and that SpaC is the most broadly cross-protective antigen among the three Spa proteins. In this study, we examined the ability of the α-helical domain, which comprises the N-terminal half of SpaC, to elicit cross-protective immunity in mice and pigs. Mice actively immunized with the full-length protein (rSpaC664) or the α-helical domain (rSpaC427), but not the C-terminal domain (rSpaC253), were protected against challenge withE. rhusiopathiaeserovars 1a, 2, 6, 19, and 18 expressing heterologous (SpaA or SpaB) and homologous (SpaC) Spas. The α-helical domain seemed to provide better protection than rSpaC664, although the differences did not reach statistical significance. Similarly, mice passively immunized with rabbit anti-rSpaC664 or anti-rSpaC427 sera, but not anti-rSpaC253 serum, were protected from challenge with various serovars. Pigs immunized with SpaC427 also developed specific antibodies against Spa proteins and were protected from challenge with the highly virulent heterologousE. rhusiopathiaestrain Fujisawa (serovar 1a). Taken together, these results demonstrate for the first time the striking protective efficacy of the α-helical domain-mediated immunization in both mice and pigs, thereby highlighting its utility as the most promising candidate for the development of a safe and effective vaccine against erysipelas.

scholarly journals Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane-penetrating loop

2021 ◽  
Vol 77 (9) ◽  
Author(s):  
F. Hoelzgen ◽  
R. Zalk ◽  
R. Alcalay ◽  
S. Cohen-Schwartz ◽  
G. Garau ◽  
...  
Keyword(s):  
Pore Formation ◽  
Protective Antigen ◽  
Neutralizing Antibody ◽  
Anthrax Toxin ◽  
Structural Basis ◽  
Severe Illness ◽  
Central Component ◽  
Important Target ◽  
Anthrax Infection ◽  
Anthrax Vaccines

Anthrax infection is associated with severe illness and high mortality. Protective antigen (PA) is the central component of the anthrax toxin, which is one of two major virulence factors of Bacillus anthracis, the causative agent of anthrax disease. Upon endocytosis, PA opens a pore in the membranes of endosomes, through which the cytotoxic enzymes of the toxin are extruded. The PA pore is formed by a cooperative conformational change in which the membrane-penetrating loops of PA associate, forming a hydrophobic rim that pierces the membrane. Due to its crucial role in anthrax progression, PA is an important target for monoclonal antibody-based therapy. cAb29 is a highly effective neutralizing antibody against PA. Here, the cryo-EM structure of PA in complex with the Fab portion of cAb29 was determined. It was found that cAb29 neutralizes the toxin by clamping the membrane-penetrating loop of PA to the static surface-exposed loop of the D3 domain of the same subunit, thereby preventing pore formation. These results provide the structural basis for the antibody-based neutralization of PA and bring into focus the membrane-penetrating loop of PA as a target for the development of better anti-anthrax vaccines.

scholarly journals Salmonella enterica Serovar Typhimurium Expressing a Chromosomally Integrated Copy of the Bacillus anthracis Protective Antigen Gene Protects Mice against an Anthrax Spore Challenge

2003 ◽  
Vol 71 (7) ◽  
pp. 3831-3836 ◽  
Author(s):  
Helen S. Garmory ◽  
Richard W. Titball ◽  
Kate F. Griffin ◽  
Ulrike Hahn ◽  
Reinhard Böhm ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Salmonella Enterica ◽  
Protective Immunity ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Protective Antigen ◽  
Signal Sequence ◽  
Auxotrophic Mutant ◽  
Serovar Typhimurium ◽  
Export System ◽  
Lethal Doses

ABSTRACT Protective immunity against infection with Bacillus anthracis is almost entirely based on a response to the protective antigen (PA), the binding moiety for the two other toxin components. We cloned the PA gene into an auxotrophic mutant of Salmonella enterica serovar Typhimurium as a fusion with the signal sequence of the hemolysin (Hly) A gene of Escherichia coli to allow the export of PA via the Hly export system. To stabilize the export cassette, it was also integrated into the chromosome of the live Salmonella carrier. When S. enterica serovar Typhimurium with the chromosomally integrated PA gene was given intravenously to A/J mice, they developed high levels of antibody to PA. These mice were protected against intraperitoneal challenge with 100 or 1,000 50% lethal doses of B. anthracis strain STI. This work contributes to the development of a Salmonella-based orally delivered anthrax vaccine.

scholarly journals HEMOLYTIC STREPTOCOCCUS LYMPHADENITIS IN GUINEA PIGS

1939 ◽  
Vol 70 (4) ◽  
pp. 347-359 ◽  
Author(s):  
C. V. Seastone
Keyword(s):  
Guinea Pigs ◽  
Virulent Strain ◽  
Cervical Lymphadenitis ◽  
Non Invasive ◽  
Naturally Occurring ◽  
Precipitin Reaction ◽  
Bactericidal Antibody ◽  
Pure Cultures ◽  
Highly Virulent ◽  
Infective Agent

A group of guinea pigs carrying a chronic streptococcus cervical lymphadenitis has been studied. The chronic disease may be transmitted with pure cultures of streptococci isolated from the naturally occurring abscesses. Its probable mode of transmission under natural conditions was shown to be the ingestion of the infective agent. The spontaneous appearance of an acutely fatal variant was observed. Infection with the chronic strains protected animals against the highly virulent strain. Such immunity could not be passively transferred to either mice or guinea pigs, nor could any opsonizing, precipitating, or bactericidal antibody be associated with it. The presence of allergy could not be correlated with this immunity. The dissociation of the chronic and acute strains was investigated and non-invasive phases isolated. No precipitin reaction attributable to an antigenic virulence factor could be demonstrated. No protection was obtained with vaccines or aggressins.

scholarly journals Mucosal or Parenteral Administration of Microsphere-Associated Bacillus anthracis Protective Antigen Protects against Anthrax Infection in Mice

2002 ◽  
Vol 70 (4) ◽  
pp. 2022-2028 ◽  
Author(s):  
Helen C. Flick-Smith ◽  
Jim E. Eyles ◽  
Richard Hebdon ◽  
Emma L. Waters ◽  
Richard J. Beedham ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Protective Efficacy ◽  
Dose Schedule ◽  
Mucosal Immune Response ◽  
Parenteral Administration ◽  
Routes Of Administration ◽  
Anthrax Infection ◽  
Anthrax Vaccines ◽  
Lethal Doses

ABSTRACT Existing licensed anthrax vaccines are administered parenterally and require multiple doses to induce protective immunity. This requires trained personnel and is not the optimum route for stimulating a mucosal immune response. Microencapsulation of vaccine antigens offers a number of advantages over traditional vaccine formulations, including stability without refrigeration and the potential for utilizing less invasive routes of administration. Recombinant protective antigen (rPA), the dominant antigen for protection against anthrax infection, was encapsulated in poly-l-lactide 100-kDa microspheres. Alternatively, rPA was loosely attached to the surfaces of microspheres by lyophilization. All of the microspheric formulations were administered to A/J mice with a two-dose schedule by either the intramuscular route, the intranasal route, or a combination of these two routes, and immunogenicity and protective efficacy were assessed. An intramuscular priming immunization followed by either an intramuscular or intranasal boost gave optimum anti-rPA immunoglobulin G titers. Despite differences in rPA-specific antibody titers, all immunized mice survived an injected challenge consisting of 103 median lethal doses of Bacillus anthracis STI spores. Immunization with microencapsulated and microsphere-associated formulations of rPA also protected against aerosol challenge with 30 median lethal doses of STI spores. These results show that rPA can be encapsulated and surface bound to polymeric microspheres without impairing its immunogenicity and also that mucosal or parenteral administration of microspheric formulations of rPA efficiently protects mice against both injected and aerosol challenges with B. anthracis spores. Microspheric formulations of rPA could represent the next generation of anthrax vaccines, which could require fewer doses because they are more potent, are less reactogenic than currently available human anthrax vaccines, and could be self-administered without injection.

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