Correlation between anthrax lethal toxin neutralizing antibody levels and survival in guinea pigs and nonhuman primates vaccinated with the AV7909 anthrax vaccine candidate

Abstract

The anthrax vaccine candidate AV7909 is being developed as a next generation vaccine for a post-exposure prophylaxis (PEP) indication against anthrax. AV7909 consists of the Anthrax Vaccine Adsorbed (AVA, BioThrax®) bulk drug substance adjuvanted with the immunostimulatory oligodeoxynucleotide (ODN) compound, CPG 7909. The addition of CPG 7909 to AVA enhances both the magnitude and the kinetics of antibody responses in animals and human subjects, making AV7909 a suitable next-generation vaccine for use in a PEP setting. The studies described here provide initial information on AV7909-induced toxin-neutralizing antibody (TNA) levels associated with the protection of animals from lethal Bacillus anthracis challenge. Guinea pigs or nonhuman primates (NHPs) were immunized on Days 0 and 28 with various dilutions of AV7909, AVA or a saline or Alhydrogel + CPG 7909 control. Animals were challenged via the inhalational route with a lethal dose of aerosolized B. anthracis (Ames strain) spores and observed for clinical signs of disease and mortality. The relationship between pre-challenge serum TNA levels and survival following challenge was determined in order to calculate a threshold TNA level associated with protection. Immunisation with AV7909 induced a rapid, highly protective TNA response in guinea pigs and NHPs. Surprisingly, the TNA threshold associated with a 70% probability of survival for AV7909 immunized animals was substantially lower than the threshold which has been established for the licensed AVA vaccine. The results of this study suggest that the TNA threshold of protection against anthrax could be modified by the addition of an immune stimulant such as CPG 7909 and that the TNA levels associated with protection may be vaccine-specific.

A serological survey of Bacillus anthracis reveals widespread exposure to the pathogen in free-range and captive lions in Zimbabwe.

“…Though technically demanding, TNA confirms previous exposure toB. anthracis in animals and is species-independent (Ngundi, Meade, Lin, Tang, & Burns, 2010;Omland et al, 2008;Savransky et al, 2017). On the other hand the ELISA assay detects antibodies to PA antigen in sera of infected individuals and is less demanding but well correlated with the TNA (Arciniega & Domínguez-Castillo, 2011;Ndumnego, Crafford, Beyer, & van Heerden, 2013;Parreiras, Sirota, Wagner, Menzies, & Arciniega, 2009).…”

Repeat-Dose Toxicity Study of a Lyophilized Recombinant Protective Antigen-Based Anthrax Vaccine Adjuvanted With CpG 7909

“…Studies in guinea pigs and in non-human primates reported a correlation between anthrax lethal toxin neutralizing antibody levels and survival in animals vaccinated with Anthrax Vaccine Adsorbed (AVA) adjuvanted with CpG 7909 and challenged with B anthracis spores. 16 The AVA adjuvanted with CpG 7909 induced a rapid, highly protective immune response with the relatively low toxin neutralizing antibody levels associated with the high level of protection indicating that, in addition to antibodies, protection is also conferred by the B- and T-cell repertoire and other aspects of the immune response that are stimulated during immunization and restimulated upon challenge. In a phase 1 study, the addition of CpG 7909 to AVA increased the antibody response by 6- to 8-fold at peak and accelerated the response by 3 weeks when administered intramuscularly (IM) compared to the unadjuvanted vaccine.…”

Nonhuman primate species as models of human bacterial sepsis

“…Cynomolgus macaques inoculated with nebulized B. anthracis experienced significantly improved survival after receiving the novel tetracycline class antibiotic TP-271 88 . Survival of inhalational anthrax in this primate species was also significantly improved by administering a post-exposure prophylaxis vaccine, AV7909 89 . The combination of both post-exposure treatments was tested in rhesus macaques where antibiotics (ciprofloxacin × 14 days) and vaccine therapy (anthrax vaccine adsorbed, AVA) significantly improved post-exposure survival compared to antibiotics alone, likely due to delayed germination of anthrax spores occurring after completion of antibiotics leading to anthrax infection 90 .…”

“…Other studies using rhesus or cynomolgus macaques administered aerosolized B. anthracis spores via nose- or head-only exposure chambers 88–90 . Animals developed a moribund, disseminated anthrax infection with sepsis and respiratory failure over several days 88,89 . The inhalational model mimics the likely mechanism of exposure to B. anthracis (airborne dispersion) in a possible terrorist attack and is therefore invaluable to researchers developing novel anthrax therapies for such a public health emergency 90,91 .…”