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

Abstract

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...

A Bivalent Anthrax–Plague Vaccine That Can Protect against Two Tier-1 Bioterror Pathogens, Bacillus anthracis and Yersinia pestis

“…The data showed that both the F1mutV-PA and PA vaccines induced high levels of anti-PA antibodies as well as LeTx-neutralizing antibodies at day 20 (Figures 8 C,D). These titers are similar to that reported for the licensed AVA ( 50 , 51 ).…”

Single-Dose Intranasal Administration of AdCOVID Elicits Systemic and Mucosal Immunity against SARS-CoV-2 and Fully Protects Mice from Lethal Challenge

“…In a SARS-CoV-2 challenge model in rhesus macaques, a single intramuscular administration of an adenovectored vaccine candidate was shown to significantly reduce viral load in the bronchoalveolar lavage fluid and lower respiratory tract tissue but the level of viral replication in the nasal cavity was unaffected [ 46 ]. Conversely, nasal administration of replication-deficient human Ad5-vectored vaccines, such as AdCOVID, mimic natural infection of respiratory viruses and stimulate strong protective immunity, both systemically and mucosally, while maintaining an established clinical safety profile [ 47 , 48 , 49 , 50 , 51 ]. Intranasal vaccination stimulates mucosal IgA antibodies, providing a first line of defense at the point of respiratory pathogen inoculation [ 52 ], which correlates well with protection from respiratory infections such as influenza [ 53 , 54 , 55 ].…”

Anti-virulence Therapy Against Bacterial Infections: Mechanisms of Action and Challenges

“…Obiltoxaximab is another monoclonal antibody, which could also neutralize the free PA of B. anthracis and inhibits the lethal effects of anthrax toxins (65). These agents have proven effective in eliminating the inhalational anthrax infection after one treatment intervention conducted on rabbits and monkeys (66).…”