scholarly journals Induction of Protective Immunity to Anthrax Lethal Toxin with a Nonhuman Primate Adenovirus-Based Vaccine in the Presence of Preexisting Anti-Human Adenovirus Immunity

2005 ◽  
Vol 73 (10) ◽  
pp. 6885-6891 ◽  
Author(s):  
Masahiko Hashimoto ◽  
Julie L. Boyer ◽  
Neil R. Hackett ◽  
James M. Wilson ◽  
Ronald G. Crystal
Keyword(s):  
Nonhuman Primate ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Protective Antigen ◽  
Recombinant Adenovirus ◽  
Lethal Toxin ◽  
Effective Vaccine ◽  
Anthrax Lethal Toxin ◽  
Adenovirus Vaccine

ABSTRACT Prevention or therapy for bioterrorism-associated anthrax infections requires rapidly acting effective vaccines. We recently demonstrated (Y. Tan, N. R. Hackett, J. L. Boyer, and R. G. Crystal, Hum. Gene Ther. 14:1673-1682, 2003) that a single administration of a recombinant serotype 5 adenovirus (Ad) vector expressing anthrax protective antigen (PA) provides rapid protection against anthrax lethal toxin challenge. However, approximately 35 to 50% of humans have preexisting neutralizing antibodies against Ad5. This study assesses the hypothesis that a recombinant adenovirus vaccine based on the nonhuman primate-derived serotype AdC7, against which humans do not have immunity, expressing PA (AdC7PA) will protect against anthrax lethal toxin even in the presence of preexisting anti-Ad5 immunity. Naive and Ad5-immunized BALB/c mice received (intramuscularly) 108 to 1011 particle units (PU) of AdC7PA, Ad5PA (a human serotype Ad5-based vector expressing a secreted form of PA), or AdNull (an Ad5 vector with no transgene). Robust anti-PA immunoglobulin G and neutralizing antibodies were detected by 2 to 4 weeks following administration of AdC7PA to naive or Ad5 preimmunized mice, whereas low anti-PA titers were detected in Ad5-preimmunized mice following administration of Ad5PA. To assess protection in vivo, naive or mice previously immunized against Ad5 were immunized with AdC7PA or Ad5PA and then challenged with a lethal intravenous dose of Bacillus anthracis lethal toxin. Whereas Ad5PA protected naive mice against challenge with B. anthracis lethal toxin, Ad5PA was ineffective in mice that were previously immunized against Ad5. In contrast, AdC7PA functioned effectively not only to protect naive mice but also to protect Ad5-preimmunized mice, with 100% survival after lethal toxin challenge. These data suggest the nonhuman-based vector AdC7PA is an effective vaccine for the development of protective immunity against B. anthracis and importantly functions as a “sero-switch” base for an adenovirus vaccine to function in the context of preexisting anti-Ad immunity.

scholarly journals In Vitro and In Vivo Characterization of Anthrax Anti-Protective Antigen and Anti-Lethal Factor Monoclonal Antibodies after Passive Transfer in a Mouse Lethal Toxin Challenge Model To Define Correlates of Immunity

2007 ◽  
Vol 75 (11) ◽  
pp. 5443-5452 ◽  
Author(s):  
Herman F. Staats ◽  
S. Munir Alam ◽  
Richard M. Scearce ◽  
Shaun M. Kirwan ◽  
Julia Xianzhi Zhang ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Protective Antigen ◽  
Lethal Factor ◽  
Neutralization Assay ◽  
Passive Transfer ◽  
Lethal Toxin ◽  
Significant Protection

ABSTRACT Passive transfer of antibody may be useful for preexposure prophylaxis against biological agents used as weapons of terror, such as Bacillus anthracis. Studies were performed to evaluate the ability of anthrax antiprotective antigen (anti-PA) and antilethal factor (anti-LF) neutralizing monoclonal antibodies (mAbs) to protect against an anthrax lethal toxin (LeTx) challenge in a mouse model and to identify correlates of immunity to LeTx challenge. Despite having similar affinities for their respective antigens, anti-PA (3F11) and anti-LF (9A11), passive transfer of up to 1.5 mg of anti-PA 3F11 mAb did not provide significant protection when transferred to mice 24 h before LeTx challenge, while passive transfer of as low as 0.375 mg of anti-LF 9A11 did provide significant protection. Serum collected 24 h after passive transfer had LeTx-neutralizing activity when tested using a standard LeTx neutralization assay, but neutralization titers measured using this assay did not correlate with protection against LeTx challenge. However, measurement of LeTx-neutralizing serum responses with an LeTx neutralization assay in vitro employing the addition of LeTx to J774A.1 cells 15 min before the addition of the serum did result in neutralization titers that correlated with protection against LeTx challenge. Our results demonstrate that only the LeTx neutralization titers measured utilizing the addition of LeTx to J774A.1 cells 15 min before the addition of sample correlated with protection in vivo. Thus, this LeTx neutralization assay may be a more biologically relevant neutralization assay to predict the in vivo protective capacity of LeTx-neutralizing antibodies.

scholarly journals In Vivo Efficacy of β-Cyclodextrin Derivatives against Anthrax Lethal Toxin

2008 ◽  
Vol 52 (6) ◽  
pp. 2239-2241 ◽  
Author(s):  
Mahtab Moayeri ◽  
Tanisha M. Robinson ◽  
Stephen H. Leppla ◽  
Vladimir A. Karginov
Keyword(s):  
Bacterial Infection ◽  
Rat Model ◽  
Protective Antigen ◽  
Lethal Toxin ◽  
Cyclodextrin Derivatives ◽  
Anthrax Lethal Toxin ◽  
In Vivo Efficacy ◽  
Anthrax Protective Antigen

ABSTRACT We evaluated the in vivo efficacy of three β-cyclodextrin derivatives that block the anthrax protective antigen pore. These compounds were at least 15-fold more potent than previously described β-cyclodextrins in protecting against anthrax lethal toxin in a rat model. One of the drugs was shown to protect mice from bacterial infection.

scholarly journals Inactivation of Rho GTPases by Statins Attenuates Anthrax Lethal Toxin Activity

2008 ◽  
Vol 77 (1) ◽  
pp. 348-359 ◽  
Author(s):  
Aimee M. deCathelineau ◽  
Gary M. Bokoch
Keyword(s):  
Rho Gtpases ◽  
Rho Gtpase ◽  
Protective Antigen ◽  
Biological Effects ◽  
Lethal Factor ◽  
Lethal Toxin ◽  
Mitogen Activated Protein Kinase ◽  
Gtpase Activity ◽  
Anthrax Lethal Toxin ◽  
Reductase Inhibitors

ABSTRACT Anthrax lethal factor (LF), secreted by Bacillus anthracis, interacts with protective antigen to form a bipartite toxin (lethal toxin [LT]) that exerts pleiotropic biological effects resulting in subversion of the innate immune response. Although the mitogen-activated protein kinase kinases (MKKs) are the major intracellular protein targets of LF, the pathology induced by LT is not well understood. The statin family of HMG-coenzyme A reductase inhibitors have potent anti-inflammatory effects independent of their cholesterol-lowering properties, which have been attributed to modulation of Rho family GTPase activity. The Rho GTPases regulate vesicular trafficking, cytoskeletal dynamics, and cell survival and proliferation. We hypothesized that disruption of Rho GTPase function by statins might alter LT action. We show here that statins delay LT-induced death and MKK cleavage in RAW macrophages and that statin-mediated effects on LT action are attributable to disruption of Rho GTPases. The Rho GTPase-inactivating toxin, toxin B, did not significantly affect LT binding or internalization, suggesting that the Rho GTPases regulate trafficking and/or localization of LT once internalized. The use of drugs capable of inhibiting Rho GTPase activity, such as statins, may provide a means to attenuate intoxication during B. anthracis infection.

Trp 346 and Leu 352 Residues in Protective Antigen Are Required for the Expression of Anthrax Lethal Toxin Activity

2001 ◽  
Vol 281 (1) ◽  
pp. 186-192 ◽  
Author(s):  
Smriti Batra ◽  
Pankaj Gupta ◽  
Vibha Chauhan ◽  
Aparna Singh ◽  
Rakesh Bhatnagar
Keyword(s):  
Protective Antigen ◽  
Lethal Toxin ◽  
Anthrax Lethal Toxin

scholarly journals A Universal Dengue Vaccine Elicits Neutralizing Antibodies Against Strains from All Four Dengue Serotypes

2020 ◽  
Author(s):  
Naoko Uno ◽  
Ted M. Ross
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Rhesus Macaques ◽  
Effective Vaccine ◽  
Wild Type ◽  
Monovalent Vaccine ◽  
Viral Particles ◽  
Tropical Areas

Any potential dengue virus (DENV) vaccine needs to elicit protective immunity against strains from all four serotypes to avoid potential antibody dependent enhancement (ADE). In this study, four independent DENV envelope (E) glycoproteins were generated using wild-type E sequences from viruses isolated between 1943 to 2006 using computationally-optimized broadly reactive antigen (COBRA) methodology. COBRA and wild-type E antigens were expressed on the surface of subvirion viral particles (SVPs). Four separate wild-type E antigens were used for each serotype. Mice vaccinated with wild-type DENV SVPs had anti-E IgG antibodies that neutralized serotype specific viruses. COBRA DENV SVPs elicited a broader breadth of antibodies that neutralized strains across all four serotypes. Two COBRA DENV vaccine candidates that elicited the broadest breadth of neutralizing antibodies in mice were used to vaccinate rhesus macaques (Macca mulata) that were either immunologically naïve to any DENV serotype or were had pre-existing antibodies to DENV. Antibodies elicited by COBRA DENV E immunogens neutralized all 12 strains of DENV in vitro, which was comparable to antibodies elicited by a tetravalent wild-type E SVP vaccination mixture. Therefore, using a single DENV COBRA E protein can elicit neutralizing antibodies against strains representing all four serotypes of DENV in both naïve and dengue pre-immune populations. Importance Dengue virus infects millions of people living in the tropical areas of the world. Dengue induced diseases can range from mild to severe with death. An effective vaccine will need to neutralize viruses from all four serotypes of dengue without induced enhanced disease. A dengue E vaccine candidate generated by computationally optimized broadly reactive antigen algorithms elicits broadly neutralizing protection for current circulating strains from all four serotypes regardless of immune status. Most Dengue vaccines in development formulate four separate components based on prM-E from a wild type strain representing each serotype. Designing a monovalent vaccine that elicits protective immunity against all four serotypes is an effective and economical strategy

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