Intramuscular Delivery of Adenovirus Serotype 5 Vector Expressing Humanized Protective Antigen Induces Rapid Protection against Anthrax That May Bypass Intranasally Originated Preexisting Adenovirus Immunity

Wu, Shipo; Zhang, Zhe; Yu, Rui; Zhang, Jun; Liu, Ying; Song, Xiaohong; Yi, Shaoqiong; Liu, Ju; Chen, Jianqin; Yin, Ying; Xu, Junjie; Hou, Lihua; Chen, Wei

doi:10.1128/cvi.00560-13

Cited by 10 publications

(13 citation statements)

References 33 publications

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“…Frequently, one or more of the E3 gene products are also deleted in order to abolish the immunosuppressive activities of some E3 gene products (9) and to allow for insertion of larger or multiple transgenes. As vaccines, adenoviral expression vectors possess distinct advantages compared to protein-based vaccines, including intracellular expression of the immunogen leading to induction of robust cellular and humoral immunity, the ability to administer the vaccine through a variety of routes, including intranasal (10,11), topical (12), oral (13), and traditional intramuscular routes (14,15), and improved vaccine stability profiles. Intranasal administration of adenoviral-vectored vaccines is a simple, noninvasive method of vaccination that also has the potential to induce mucosal immunity at the site of vaccination to provide first-line defense against pathogens that enter the body through the respiratory tract (11,16,17).…”

mentioning

confidence: 99%

Efficacy and Immunogenicity of Single-Dose AdVAV Intranasal Anthrax Vaccine Compared to Anthrax Vaccine Absorbed in an Aerosolized Spore Rabbit Challenge Model

Krishnan¹,

Andersen²,

Shoemaker³

et al. 2015

Clin. Vaccine Immunol.

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cAdVAV is a replication-deficient adenovirus type 5-vectored vaccine expressing the 83-kDa protective antigen (PA83) from Bacillus anthracis that is being developed for the prevention of disease caused by inhalation of aerosolized B. anthracis spores. A noninferiority study comparing the efficacy of AdVAV to the currently licensed Anthrax Vaccine Absorbed (AVA; BioThrax) was performed in New Zealand White rabbits using postchallenge survival as the study endpoint (20% noninferiority margin for survival). Three groups of 32 rabbits were vaccinated with a single intranasal dose of AdVAV (7.5 ؋ 10 7 , 1.5 ؋ 10 9 , or 3.5 ؋ 10 10 viral particles). Three additional groups of 32 animals received two doses of either intranasal AdVAV (3.5 ؋ 10 10 viral particles) or intramuscular AVA (diluted 1:16 or 1:64) 28 days apart. The placebo group of 16 rabbits received a single intranasal dose of AdVAV formulation buffer. All animals were challenged via the inhalation route with a targeted dose of 200 times the 50% lethal dose (LD 50 ) of aerosolized B. anthracis Ames spores 70 days after the initial vaccination and were followed for 3 weeks. PA83 immunogenicity was evaluated by validated toxin neutralizing antibody and serum anti-PA83 IgG enzyme-linked immunosorbent assays (ELISAs). All animals in the placebo cohort died from the challenge. Three of the four AdVAV dose cohorts tested, including two single-dose cohorts, achieved statistical noninferiority relative to the AVA comparator group, with survival rates between 97% and 100%. Vaccination with AdVAV also produced antibody titers with earlier onset and greater persistence than vaccination with AVA. Bacillus anthracis is a Gram-positive, rod-shaped, spore-forming bacterial pathogen and is the etiological agent of anthrax disease. Inhalation of the B. anthracis spores is associated with high levels of mortality in exposed individuals and has led to the use of aerosolized B. anthracis spores as a bioterror weapon (1-3). Following spore inhalation, B. anthracis undergoes a transformation from quiescent spores into a vegetative state associated with active growth and release of two binary toxins that mediate the majority of the pathological effects of anthrax disease. These toxins, lethal toxin and edema toxin, are formed through the interaction of lethal factor (LF) and edema factor (EF) with protective antigen (PA) (4). Vaccines against anthrax are not intended to inhibit B. anthracis vegetative growth but rather are directed against PA and the central role this protein plays in the pathogenesis of anthrax disease. Previous studies have shown that neutralizing antibody to PA is correlated with protection from anthrax disease (5-8).Vaccines derived from replication-deficient adenoviral vectors are deleted in E1 gene function, ensuring that replication can only be supported in specialized cell lines that provide the essential E1 function in trans. Frequently, one or more of the E3 gene products are also deleted in order to abolish the immunosuppressive activities of some E3 ge...

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confidence: 99%

Efficacy and Immunogenicity of Single-Dose AdVAV Intranasal Anthrax Vaccine Compared to Anthrax Vaccine Absorbed in an Aerosolized Spore Rabbit Challenge Model

Krishnan¹,

Andersen²,

Shoemaker³

et al. 2015

Clin. Vaccine Immunol.

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“…PA expressed in an adenovirus vector has been tested in rodents with 100% protection against anthrax challenge after a single intranasal or i.m. immunization in mice or rats, respectively (50, 51). However, pre-existing intranasally-induced immunity to Ad5 did inhibit subsequent i.m.…”

Section: Discussionmentioning

confidence: 99%

A CpG-Ficoll Nanoparticle Adjuvant for Anthrax Protective Antigen Enhances Immunogenicity and Provides Single-Immunization Protection against Inhaled Anthrax in Monkeys

Kachura

Hickle

Kell

et al. 2016

The Journal of Immunology

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Nanoparticulate delivery systems for vaccine adjuvants, designed to enhance targeting of secondary lymphoid organs and activation of APCs, have shown substantial promise for enhanced immunopotentiation. We investigated the adjuvant activity of synthetic oligonucleotides containing CpG-rich motifs (CpG-ODN) linked to the sucrose polymer Ficoll, forming soluble 50 nm particles (DV230-Ficoll), each containing over 100 molecules of the TLR9 ligand, DV230. DV230-Ficoll was evaluated as an adjuvant for a candidate vaccine for anthrax using a recombinant form of protective antigen (rPA) from Bacillus anthracis. A single immunization with rPA plus DV230-Ficoll induced 10-fold higher titers of toxin-neutralizing antibodies in cynomolgus monkeys at 2 weeks compared with animals immunized with equivalent amounts of monomeric DV230. Monkeys immunized either once or twice with rPA plus DV230-Ficoll were completely protected from challenge with 200 LD50 aerosolized anthrax spores. In mice, DV230-Ficoll was more potent than DV230 for the induction of innate immune responses at the injection site and draining lymph nodes. DV230-Ficoll was preferentially co-localized with rPA in key antigen-presenting cell populations and induced greater maturation marker expression (CD69 and CD86) on these cells and stronger germinal center B and T cell responses, relative to DV230. DV230-Ficoll was also preferentially retained at the injection site and draining lymph nodes and produced fewer systemic inflammatory responses. These findings support the development of DV230-Ficoll as an adjuvant platform, particularly for vaccines such as for anthrax, for which rapid induction of protective immunity and memory with a single injection is very important.

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“…We previously purified and preserved anthrax protective protein (PA) in our laboratory . TLR4 agonist monophosphoryl lipid A (MPLA), Al(OH) 3 ‐based alum adjuvant (Alhydrogel) and squalene oil‐in‐water (o/w) emulsion (AddaVax) were obtained from InvivoGen (San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Ad5‐based anthrax vaccine (Ad5‐PA) was previously purified and preserved in our laboratory . Briefly, the anthrax PA cassette was cloned into a shuttle vector and then into E1/E3‐deleted adenoviral molecular clones.…”

Section: Methodsmentioning

confidence: 99%

Toll‐like receptor 4 signalling regulates antibody response to adenoviral vector‐based vaccines by imprinting germinal centre quality

Liu

et al. 2018

Immunology

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Adenoviral vectors (AdV) are considered promising candidates for vaccine applications. A prominent group of Toll-like receptors (TLRs) participate in the adenovirus-induced adaptive immune response, yet there is little information regarding the role of TLR4 in AdV-induced immune responses in recent literature. We investigated the function of TLR4 in both adaptive and innate immune responses to an AdV-based anthrax vaccine. By immunizing wild-type and TLR4 knockout (TLR4-KO) mice, we revealed the requirement of TLR4 in AdV-induced innate responses. We also showed that TLR4 functions are required for germinal centre responses in immunized mice, as expression of the apoptosis-related marker Fas was down-regulated on germinal centre B cells from TLR4-KO mice. Likewise, decreased expression of inducible costimulator on follicular T helper cells was observed in immunized TLR4-KO mice. Moreover, a potent protective antigen-specific humoral immune response was mimicked using an adjuvant system containing the TLR4 agonist monophosphoryl lipid A. Overall, our findings showed that very rapid antigen-specific antibody production is correlated with the TLR4-imprinted germinal centre response to AdV-based vaccine. These results provide additional evidence for the use of the AdV and a TLR agonist to induce humoral responses. Our findings offer new insights into rational vaccine design.

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Intramuscular Delivery of Adenovirus Serotype 5 Vector Expressing Humanized Protective Antigen Induces Rapid Protection against Anthrax That May Bypass Intranasally Originated Preexisting Adenovirus Immunity

Cited by 10 publications

References 33 publications

Efficacy and Immunogenicity of Single-Dose AdVAV Intranasal Anthrax Vaccine Compared to Anthrax Vaccine Absorbed in an Aerosolized Spore Rabbit Challenge Model

Efficacy and Immunogenicity of Single-Dose AdVAV Intranasal Anthrax Vaccine Compared to Anthrax Vaccine Absorbed in an Aerosolized Spore Rabbit Challenge Model

A CpG-Ficoll Nanoparticle Adjuvant for Anthrax Protective Antigen Enhances Immunogenicity and Provides Single-Immunization Protection against Inhaled Anthrax in Monkeys

Toll‐like receptor 4 signalling regulates antibody response to adenoviral vector‐based vaccines by imprinting germinal centre quality

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