Cross-species prediction of human survival probabilities for accelerated anthrax vaccine absorbed (AVA) regimens and the potential for vaccine and antibiotic dose sparing

Stark, Gregory V.; Sivko, Gloria S.; VanRaden, Mark; Schiffer, Jarad; Taylor, Katherine A.; Hewitt, J.; Quinn, Conrad P.; Nuzum, Edwin O.

doi:10.1016/j.vaccine.2016.06.041

Cited by 12 publications

(15 citation statements)

References 15 publications

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“…Cessation of antimicrobial treatment at Day 28 would reduce the schedule duration by 32 days. Cross species modeling may be applied to estimate predicted probability of survival in humans receiving schedules matched with the NHP studies [13–15]. …”

Section: Discussionmentioning

confidence: 99%

“…In rhesus macaques vaccinated with a three dose priming series of AVA [20] and in this study [15], the anti-PA IgG level at the time of challenge was determined to be the most accurate single measure for determining the probability of survival against an inhalation anthrax challenge, with peak response being the next best alternative. In an extensive analysis of data from multiple studies in several species, Fay, et al [13] found that the TNA measurement could also be used to predict survival.…”

Section: Discussionmentioning

confidence: 99%

“…These data may be applied to the parallel designed human clinical trial [11] using logistic regression models of cross-species immune responses to generate predicted survival probabilities in humans administered either a half-dose accelerated AVA regimen or full-dose accelerated AVA regimen [11;15]…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of early immune response-survival relationship in cynomolgus macaques after Anthrax Vaccine Adsorbed vaccination and Bacillus anthracis spore challenge

Sivko

Stark

Tordoff

et al. 2016

Vaccine

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Anthrax vaccine adsorbed (AVA, BioThrax) is approved by the US Food and Drug Administration for post-exposure prophylaxis (PEP) of anthrax in adults. The PEP schedule is 3 subcutaneous (SC) doses (0, 14 and 28 days), in conjunction with a 60 day course of antimicrobials. The objectives of this study were to understand the onset of protection from AVA PEP vaccination and to assess the potential for shortening the duration of antimicrobial treatment (http://www.phe.gov/Preparedness/mcm/phemce/Documents/2014-phemce-sip.pdf). We determined the efficacy against inhalation anthrax in nonhuman primates (NHP) of the first two doses of the PEP schedule by infectious challenge at the time scheduled for receipt of the third PEP dose (Day 28). Forty-eight cynomolgus macaques were randomized to five groups and vaccinated with serial dilutions of AVA on Days 0 and 14. NHP were exposed to Bacillus anthracis Ames spores on Day 28 (target dose 200 LD50 equivalents). Anti-protective antigen (PA) IgG and toxin neutralizing antibody (TNA) responses to vaccination and in post-challenge survivors were determined. Post-challenge blood and selected tissue samples were assessed for B. anthracis at necropsy or end of study (Day 56). Pre-challenge humoral immune responses correlated with survival, which ranged from 24–100% survival depending on vaccination group. Surviving, vaccinated animals had elevated anti-PA IgG and TNA levels for the duration of the study, were abacteremic, exhibited no apparent signs of infection, and had no gross or microscopic lesions. However, survivors had residual spores in lung tissues. We conclude that the first two doses of the PEP schedule provide high levels of protection by the scheduled timing of the third dose. These data may also support consideration of a shorter duration PEP antimicrobial regimen.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Evaluation of early immune response-survival relationship in cynomolgus macaques after Anthrax Vaccine Adsorbed vaccination and Bacillus anthracis spore challenge

Sivko

Stark

Tordoff

et al. 2016

Vaccine

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“…In addition to the ECL method used to determine the treatment trigger, a PA ELISA directly quantifying the PA in serum was performed retrospectively on frozen serum samples for the quantification of circulating PA on days 1, 2, and 3; immediately pretreatment; and on days 7, 14, 28, and 56, as previously described (32). Toxinneutralizing antibodies and anti-PA IgG titers were monitored by the TNA and the ELISA, respectively, on days 10, 14, 21, 28, 42, and 56 and on each of the 3 days after the last treatment, as previously described (33,34).…”

Section: Methodsmentioning

confidence: 99%

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Bacillus anthracis Infection in BALB/c Mice and Cynomolgus Macaques

Grossman

Anderson

Drabek

et al. 2017

Antimicrob Agents Chemother

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The fluorocycline TP-271 was evaluated in mouse and nonhuman primate (NHP) models of inhalational anthrax. BALB/c mice were exposed by nose-only aerosol to Ames spores at a level of 18 to 88 lethal doses sufficient to kill 50% of exposed individuals (LD). When 21 days of once-daily dosing was initiated at 24 h postchallenge (the postexposure prophylaxis [PEP] study), the rates of survival for the groups treated with TP-271 at 3, 6, 12, and 18 mg/kg of body weight were 90%, 95%, 95%, and 84%, respectively. When 21 days of dosing was initiated at 48 h postchallenge (the treatment [Tx] study), the rates of survival for the groups treated with TP-271 at 6, 12, and 18 mg/kg TP-271 were 100%, 91%, and 81%, respectively. No deaths of TP-271-treated mice occurred during the 39-day posttreatment observation period. In the NHP model, cynomolgus macaques received an average dose of 197 LD of Ames spore equivalents using a head-only inhalation exposure chamber, and once-daily treatment of 1 mg/kg TP-271 lasting for 14 or 21 days was initiated within 3 h of detection of protective antigen (PA) in the blood. No (0/8) animals in the vehicle control-treated group survived, whereas all 8 infected macaques treated for 21 days and 4 of 6 macaques in the 14-day treatment group survived to the end of the study (56 days postchallenge). All survivors developed toxin-neutralizing and anti-PA IgG antibodies, indicating an immunologic response. On the basis of the results obtained with the mouse and NHP models, TP-271 shows promise as a countermeasure for the treatment of inhalational anthrax.

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“…The only licensed anthrax vaccine, Anthrax Vaccine Absorbed (AVA, BioThrax ® ), is advisable for active immunization in humans 18-65 years of age at high risk of exposure. The primary immunogen in AVA is PA. AVA induces immunity primarily by stimulating the production of antibodies against PA. Anti-PA antibodies directly neutralize the toxin, inhibiting spore germination, and improve the spore phagocytosis by macrophages [60,61].…”

Section: Bacillus Anthracismentioning

confidence: 99%

Dangerous Pathogens as a Potential Problem for Public Health

et al. 2020

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Pathogens are various organisms, such as viruses, bacteria, fungi, and protozoa, which can cause severe illnesses to their hosts. Throughout history, pathogens have accompanied human populations and caused various epidemics. One of the most significant outbreaks was the Black Death, which occurred in the 14th century and caused the death of one-third of Europe’s population. Pathogens have also been studied for their use as biological warfare agents by the former Soviet Union, Japan, and the USA. Among bacteria and viruses, there are high priority agents that have a significant impact on public health. Bacillus anthracis, Francisella tularensis, Yersinia pestis, Variola virus, Filoviruses (Ebola, Marburg), Arenoviruses (Lassa), and influenza viruses are included in this group of agents. Outbreaks and infections caused by them might result in social disruption and panic, which is why special operations are needed for public health preparedness. Antibiotic-resistant bacteria that significantly impede treatment and recovery of patients are also valid threats. Furthermore, recent events related to the massive spread of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an example of how virus-induced diseases cannot be ignored. The impact of outbreaks, such as SARS-CoV-2, have had far-reaching consequences beyond public health. The economic losses due to lockdowns are difficult to estimate, but it would take years to restore countries to pre-outbreak status. For countries affected by the 2019 coronavirus disease (COVID-19), their health systems have been overwhelmed, resulting in an increase in the mortality rate caused by diseases or injuries. Furthermore, outbreaks, such as SARS-CoV-2, will induce serious, wide-ranging (and possibly long-lasting) psychological problems among, not only health workers, but ordinary citizens (this is due to isolation, quarantine, etc.). The aim of this paper is to present the most dangerous pathogens, as well as general characterizations, mechanisms of action, and treatments.

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Cross-species prediction of human survival probabilities for accelerated anthrax vaccine absorbed (AVA) regimens and the potential for vaccine and antibiotic dose sparing

Cited by 12 publications

References 15 publications

Evaluation of early immune response-survival relationship in cynomolgus macaques after Anthrax Vaccine Adsorbed vaccination and Bacillus anthracis spore challenge

Evaluation of early immune response-survival relationship in cynomolgus macaques after Anthrax Vaccine Adsorbed vaccination and Bacillus anthracis spore challenge

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Bacillus anthracis Infection in BALB/c Mice and Cynomolgus Macaques

Dangerous Pathogens as a Potential Problem for Public Health

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