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The anthrax vaccine candidate AV7909 is being developed as a next-generation vaccine for post-exposure prophylaxis (PEP) against inhalational anthrax. In clinical studies, two vaccinations with AV7909 administered either two or four weeks apart induced an enhanced immune response compared to BioThrax® (Anthrax Vaccine Adsorbed) (AVA). Anthrax toxin-neutralizing antibody (TNA) levels on Day 70 following initial vaccination that were associated with protection of animals exposed to inhalational anthrax were previously reported for the 0, 4-week AV7909 vaccination regimen. The current study shows that a 0, 2-week AV7909 vaccination regimen protected guinea pigs (GPs) and nonhuman primates (NHPs) against a lethal inhalational anthrax challenge on Days 28 and 70 after the first immunization. An earlier induction of protective TNA levels using a 0, 2-week AV7909 vaccination regimen may provide benefit over the currently approved AVA PEP 0, 2, and 4-week vaccination regimen. [ABSTRACT FROM AUTHOR]

This paper reports the abortion of a male Aberdeen Angus bovine by a vaccine strain of Bacillus anthracis, describing the pathological and microbiological findings and the genome sequence. Necropsy findings included multifocal areas of hemorrhage in different organs. Histologically, various organs showed hemorrhage, fibrin exudation, necrosis associated with countless bacillary bacterial clumps and severe neutrophilic inflammatory infiltrate. In the microbiological examination, numerous rough, nonhemolytic, gray and dry colonies with irregular edges were isolated from liver, lung and abomasum content samples. Gram staining revealed square-ended Gram-positive rods arranged in chains. B. anthracis identification was confirmed by detection of the molecular chromosomal marker Ba813. The genomes from the isolated B. anthracis (named SPV842_15) and from the isolated vaccinal strain (Brazilian vaccinal strain), which was recovered from a commercial vaccine used in the pregnant cow, were sequenced. Genomic comparisons displayed a high level of nucleotide identity in the comparisons between B. anthracis SPV842_15 and the B. anthracis Brazilian vaccinal strain (98,2%). Furthermore, in both strains, only the plasmid pX01 sequence was detected. Although, vaccination against anthrax is characterized by an elevated protective profile and very low residual virulence, immunization with Sterne strains can cause abortion in cattle, presumably by the plasmid pX01 toxins in rare or special situations. [ABSTRACT FROM AUTHOR]

Multiple Anthrax vaccines are licensed or in development for post-exposure prophylaxis in individuals 18 to 65 years of age. No information exists on anthrax vaccines in populations over the age of 65. It is critical that we assess the capacity of anthrax vaccines to generate a protective immune response in older individuals. In this study, we compared BioThrax® to a formulation containing a CpG adjuvant (AV7909). We conducted a Phase 2 clinical study to evaluate safety and immunogenicity of three vaccination schedules of the AV7909 vaccine candidate and one vaccination schedule of BioThrax® vaccine in adults over 65 years of age. A total of 305 subjects were enrolled to assess safety and immunogenicity by seroprotection rates, toxin neutralizing antibody titers, and anti-Protective Antigen ELISA titers. Compared to BioThrax, AV7909 elicited a more robust immune response in older subjects, especially with three doses of AV7909 at Days 1, 15, and 29, or two doses at Days 1 and 29. These trends were true with both seroprotection rates as defined by the percentage of subjects with 50 percent neutralization factors greater than 0.56, and geometric mean antibody titers. The responses to both AV7909 and BioThax were lower in older subjects compared to those aged 18–50. The immunogenicity data suggest that the CpG adjuvant in the AV7909 vaccine helps to elicit a more robust immune response in subjects over the age of 65. Alternative dosing strategies may be considered in this population given the high seroprotection rates with Day 1 and 29, or Day 1, 15, and 29 regimens. Trial Registration : clinicaltrials.gov Identifier: NCT03518125. [ABSTRACT FROM AUTHOR]

Background. Anthrax is globally recognized as an important public health and economic challenge in many agricultural communities. A cross-sectional study was conducted in three subcounties in Arua district to assess the community's awareness, cultural norm, and practices regarding anthrax. This followed a report of active cases of human cutaneous anthrax in the district. Methods. The study was conducted in subcounties of Pawor, Rigbo, and Rhino Camp, Arua district, using focus group discussion. Results. The affected communities had limited knowledge about anthrax, especially its clinical manifestation and modes of transmission both in humans and animals. The community also had no knowledge of the anthrax vaccine or treatment and where they can be accessed from. Poor practices associated with anthrax outbreaks included poor disposal of carcasses and ruminal wastes, occupational hazards (butchers, slaughter men, and herdsmen), consumption of meat from infected animals, communal herding, and cultural norms encouraging consumption of dead animals. Conclusion. This study shows that there is a knowledge gap about anthrax among the people in the affected communities. Key drivers for the anthrax outbreak such as poor cultural beliefs and practices and wildlife-livestock-human interactions were observed in all the three subcounties studied. All these findings could imply a high risk of outbreak of anthrax in Arua and Ugandan agricultural communities where the public health programs are less standardized and less effective. [ABSTRACT FROM AUTHOR]

AV7909 is a next-generation anthrax vaccine candidate indicated for post-exposure prophylaxis of exposure to Bacillus anthracis. AV7909 consists of the Anthrax Vaccine Adsorbed (AVA) bulk drug substance and the immunostimulatory Toll-like receptor 9 agonist oligodeoxynucleotide adjuvant, CPG 7909. Safety testing for pediatric population is warranted to support the potential emergency use of AV7909 in children. This study was conducted to investigate the local tolerance and potential systemic toxicity and their reversibility in juvenile rats by repeat intramuscular injections of the AV7909 vaccine candidate. Animals were dosed on postnatal day (PND) 21 (at weaning), PND 28, and PND 35, with the test article (AV7909), the adjuvant alone (Alhydrogel + CPG 7909), or sterile water for injection. Core group animals were necropsied on PND 37 and recovery group on PND 49. Study end points included survival, clinical observations, injection site observations, body weights, clinical pathology (hematology, coagulation, and clinical chemistry), pro-inflammatory biomarker analysis (alpha-2 macroglobulin [A2M] and alpha-1 acid glycoprotein [AGP]), and anatomic pathology. Immune response to vaccination was measured using the high-throughput anthrax lethal toxin neutralization assay (htpTNA). The AV7909 vaccine candidate produced no apparent systemic or local toxicity. The AGP and A2M levels were elevated in both the adjuvant-alone and AV7909 groups at the end of treatment but were comparable to control levels by the end of the recovery period. All animals in the AV7909 group demonstrated a robust neutralizing antibody response. The results indicate that AV7909 has a favorable safety profile in juvenile rats. [ABSTRACT FROM AUTHOR]

Emerging strains of Bacillus cereus , traditionally considered a self-limiting foodborne pathogen, have been associated with anthrax-like disease in mammals, including humans. The strains have emerged by divergent evolution and, as exchange of genetic material in the Bacillus genus occurs naturally, it is possible that further isolates will be identified in the future. The strains vary in their genotypes and phenotypes, combining traits of both B. cereus and B. anthracis species. Cases of anthrax-like disease associated with these strains result in similar symptoms and mortality rates as those caused by B. anthracis. The strains are susceptible to frontline antibiotics used in the treatment of anthrax and existing vaccines provide protection in animal models. The emergence of these strains has reignited the debate surrounding classification of the B. cereus sensu lato group and serves as a reminder that the field of medical microbiology is constantly changing and remains an important and ongoing area of research. [ABSTRACT FROM AUTHOR]

A 6-year-old Simental-Swiss Brown cross-bred cow, which aborted in the first trimester of the gestation and involuntarily presented anthrax bacilli around the udder, was subjected to this study. The cow was vaccinated with an attenuated anthrax vaccine (Bacillus anthracis 34 F2) 6 months ago and had normal physical examination findings. Samples taken 10 days after the abortion were representative of all possible spaces that could carry the bacteria such as milk, blood, environment, and swabs from rectum, udder and tits of an infected cow. Microbiological examination was carried out by staining the smears with Azure and in vitro culture of the samples on some enriched and selective media such as 7% sheep blood agar (SBA), Brain Heart Infusion (BHI) Broth media with 7% sheep blood, and polymyxin-lysozyme-ethylenediaminetetraacetic acid-thallous acetate (PLET) agar. On a molecular basis, the virulence plasmid-targeted PCR analysis of the isolates was performed. In addition, MLVA-8 and MLVA-25 typing of B. anthracis isolates were conducted. Upon the isolation of B. anthracis with a concentration of 6 × 102 cfu/mL in milk sample and different subtypes obtained from the isolates by MLVA-8 and MLVA-25 typing, the present study enables us to instantiate the presence and unusual spread of bacteria around the udder of cows. [ABSTRACT FROM AUTHOR]

Background: Raxibacumab is a monoclonal antibody against protective antigen, which is the cell-binding part of Bacillus anthracis toxin, and is approved for treatment and postexposure prophylaxis of inhalational anthrax. Anthrax Vaccine Adsorbed (AVA), for anthrax prophylaxis, consists primarily of adsorbed protective antigen. We did a postapproval study to assess the effect of raxibacumab on immunogenicity of AVA.Methods: We did an open-label, parallel-group, randomised non-inferiority study at three centres in the USA. We enrolled healthy volunteers (aged 18-65 years) with no evidence of exposure to protective antigen. Participants were randomly allocated (1:1) according to a pregenerated balanced independent randomisation schedule to either subcutaneous 0·5 mL AVA on days 1, 15, and 29 or raxibacumab intravenous infusion (40 mg/kg) immediately before AVA on day 1, followed by AVA only on days 15 and 29. It was an open-label study to investigators and participants; however, the sponsor remained blinded during the study. The primary outcome was the ratio of geometric mean concentrations (GMCs) of anti-protective antigen antibodies (attributable to the immune response to AVA) between AVA and AVA plus raxibacumab 4 weeks after the first AVA dose in the per-protocol population. The per-protocol population comprised all individuals who received the allocated treatment within the protocol-specified visit window and completed the primary study outcome assessment, without a protocol deviation requiring exclusion. The non-inferiority margin for the ratio of GMCs was predefined (upper limit of 90% CI <1·5). This trial is registered with ClinicalTrials.gov, NCT02339155.Findings: Between Feb 24, 2015, and June 6, 2017, 873 participants were screened for eligibility, of whom 300 were excluded. 573 were randomly allocated either AVA (n=287) or AVA plus raxibacumab (n=286). The per-protocol population comprised 276 individuals assigned AVA and 269 allocated AVA plus raxibacumab. At week 4, the GMC of anti-protective antigen antibodies in participants allocated AVA was 26·5 μg/mL (95% CI 23·6-29·8) compared with 22·5 μg/mL (20·1-25·1) among individuals allocated AVA plus raxibacumab. The ratio between groups was 1·18 (90% CI 1·03-1·35; p=0·0019), which met the predefined non-inferiority margin. Adverse events in the safety population were similar across groups (87 [30%] of 286 in the AVA group vs 80 [29%] of 280 in the AVA plus raxibacumab group) and no treatment-related serious adverse events were reported.Interpretation: Co-administration of raxibacumab with AVA does not negatively affect AVA immunogenicity. This finding suggests that combining raxibacumab with AVA might provide added benefit in postexposure prophylaxis against inhalational anthrax.Funding: US Biomedical Advanced Research and Development Authority, and GlaxoSmithKline. [ABSTRACT FROM AUTHOR]

Aim: Category A classified Bacillus anthracis is highly fatal pathogen that causes anthrax and creates challenges for global security and public health. In this study, development of a safe and ideal next‐generation subunit anthrax vaccine has been evaluated in mouse model. Method and Results: Protective antigen (PA) and BA3338, a surface layer homology (SLH) domain possessing protein were cloned, expressed in heterologous system and purified by IMAC. Recombinant PA and BA3338 with alum were administered in mouse alone or in combination. The humoral and cell‐mediated immune response was measured by ELISA and vaccinated animals were challenged with B. anthracis spores via intraperitoneal route. The circulating IgG antibody titre of anti‐PA and anti‐BA3338 was found significantly high in the first and second booster sera. A significant enhanced level of IL‐4, IFN‐γ and IL‐12 was observed in antigens stimulated supernatant of splenocytes of PA + BA3338 vaccinated animals. A combination of PA and BA3338 provided 80% protection against 20 LD50 lethal dose of B. anthracis spores. Conclusion: Both antigens induced admirable humoral and cellular immune response as well as protective efficacy against B. anthracis spores. Significance and Impact of the Study: This study has been evaluated for the first time using BA3338 as a vaccine candidate alone or in combination with well‐known anthrax vaccine candidate PA. The findings of this study demonstrated that BA3338 could be a co‐vaccine candidate for development of dual subunit vaccine against anthrax. [ABSTRACT FROM AUTHOR]

The article presents the results of the studying of anthrax strains and Bacillus anthracis-like strains on the formation of toxins. We found that anthrax vaccine strains actively produce exotoxins to the culture fluid. The amount of specific protein is different under the same incubation conditions and depends on the individual characteristics of the microorganism population, because of this, different titers of the toxin are registered. Strain B. anthracis K-79 Z (vaccine) with the same number of planting microbial cells and growing on the same culture medium and at the same temperature produces by two orders of magnitude more exotoxin than strains B. anthracis Tsenkovsky II IBM 92Z (virulent), B. anthracis Stern 34F2, (vaccine), B. anthracis 55 (vaccine), B. anthracis SB (vaccine), B. anthracis Tsenkovsky I (vaccine, аpathogenic). The amount of exotoxin may change if the pH of the medium changes. The activity of exotoxin production, when the pH changes, depends on the characteristics of the anthrax strain. [ABSTRACT FROM AUTHOR]

A next-generation anthrax vaccine candidate, AV7909, is being developed for post-exposure prophylaxis (PEP) of inhalational anthrax in combination with the recommended course of antimicrobial therapy. Clinical efficacy studies of anthrax countermeasures in humans are not ethical or feasible, therefore, licensure of AV7909 for PEP is being pursued under the US Food and Drug Administration (FDA) Animal Rule, which requires that evidence of effectiveness be demonstrated in an animal model of anthrax, where results of studies in such a model can establish reasonable likelihood of AV7909 to produce clinical benefit in humans. Initial development of a PEP model for inhalational anthrax included evaluation of post-exposure ciprofloxacin pharmacokinetics (PK), tolerability and survival in guinea pigs treated with various ciprofloxacin dosing regimens. Three times per day (TID) intraperitoneal (IP) dosing with 7.5 mg/kg of ciprofloxacin initiated 1 day following inhalational anthrax challenge and continued for 14 days was identified as a well tolerated partially curative ciprofloxacin treatment regimen. The added benefit of AV7909 vaccination was evaluated in guinea pigs given the partially curative ciprofloxacin treatment regimen. Groups of ciprofloxacin-treated guinea pigs were vaccinated. 1 and 8 days post-challenge with serial dilutions of AV7909, a 1:16 dilution of AVA, or normal saline. A group of untreated guinea pigs was included as a positive control to confirm lethal B. anthracis exposure. Post-exposure vaccination with the AV7909 anthrax vaccine candidate administered in combination with the partially curative ciprofloxacin treatment significantly increased survival of guinea pigs compared to ciprofloxacin treatment alone. These results suggest that the developed model can be useful in demonstrating added value of the vaccine for PEP. [ABSTRACT FROM AUTHOR]

Introduction: Gastrointestinal anthrax is a rare but serious disease. In August 2017, Isingiro District, Uganda reported a cluster of >40 persons with acute-onset gastroenteritis. Symptoms included bloody diarrhoea. We investigated to identify the etiology and exposures, and to inform control measures. Methods: We defined a suspected case as acute-onset of diarrhoea or vomiting during 15–31 August 2017 in a resident (aged≥2 years) of Kabingo sub-county, Isingiro District; a confirmed case was a suspected case with a clinical sample positive for Bacillus anthracis by culture or PCR. We conducted descriptive epidemiology to generate hypotheses. In a case-control study, we compared exposures between case-patients and neighbourhood-matched controls. We used conditional logistic regression to compute matched odds ratios (MOR) for associations of illness with exposures. Results: We identified 61 cases (58 suspected and 3 confirmed; no deaths). In the case-control study, 82% of 50 case-patients and 12% of 100 controls ate beef purchased exclusively from butchery X during the week before illness onset (MOR = 46, 95%CI = 4.7–446); 8.0% of case-patients and 3.0% of controls ate beef purchased from butchery X and elsewhere (MOR = 19, 95%CI = 1.0–328), compared with 6.0% of case-patients and 30% of controls who did not eat beef. B. anthracis was identified in two vomitus and one stool sample. Butchery X slaughtered a sick cow and sold the beef during case-patients' incubation period. Conclusion: This gastrointestinal anthrax outbreak occurred due to eating beef from butchery X. We recommended health education, safe disposal of the carcasses of livestock or game animals, and anthrax vaccination for livestock. Author summary: Gastrointestinal anthrax is one of the forms of anthrax caused by Bacillus anthracis. It is a serious but rarely diagnosed form owing to its presentation being similar to gastroenteritis illness due to other organisms. In this investigation, we ascertained that this was a gastrointestinal anthrax outbreak that was caused by consumption of beef of suspicious origin. Trace back identified the source of this beef as being from one specific butcher. All the case-patients were treated and recovered. The outbreak was controlled at the source through treatment and we provided public education of the masses about the dangers of eating meat of animals that have died of unknown causes. We additionally recommended inspection of meat before sale at butcheries to ensure that it is suitable for human consumption as well as vaccination of the animals in the region. In the long term, anthrax control requires a One-Health approach that is multisectoral, involving ministries of agriculture, animal industries and ministries of health. [ABSTRACT FROM AUTHOR]

The letter to the editor titled "When Does Catholic Social Teaching Imply a Duty to be Vaccinated for the Common Good?" by Stephen M.A. Bow discusses 12 criteria for the duty to vaccinate according to Catholic social teaching. While the criteria are generally good, the fifth criterion stating that "vaccination carries no risk of harm" is slightly overstated. The author argues that while vaccines do carry some risk, the duty to vaccinate still exists because the risks are minimal compared to the risks of not being vaccinated. The author suggests changing the criterion to "vaccination carries minimal risk of harm" or "vaccination carries a proportionally small risk of harm." [Extracted from the article]

Ghana, the world's second-largest cocoa producer, is facing threats to its cocoa industry from illegal mining and smuggling. Illegal mining, known as "galamsey," is a major problem in Ghana, resulting in the destruction of cocoa farms. Farmers are often enticed by lucrative deals to sell off their land for unlawful mining or switch to other crops. The harvest has declined in recent years due to illegal mining, and smuggling of cocoa beans is also a concern. These challenges are impacting Ghana's economy, which is already facing a severe economic crisis. The government has implemented measures to address these issues, including offering cash rewards to whistleblowers. However, more needs to be done to improve prices and living standards for farmers. [Extracted from the article]

• The spatial epidemiology of anthrax can improve disease prevention. • Human anthrax in Vietnam is primarily due to contact with infected livestock/contaminated meat. • Human and livestock anthrax is spatially clustered in Lai Chau province. • Spatial clusters identify key areas for anthrax control in months ahead of high incidence. • Anthrax incidence spikes in humans and livestock in years after livestock vaccine rates drop. Anthrax is reported globally with varying disease intensity and seasonality among countries. In Vietnam, anthrax epidemiology and ecology remain understudied. We used historical data of human and livestock anthrax from 2004 to 2021 in Lai Chau province, to identify spatial clusters of human and livestock anthrax, describe epidemiological characteristics, and compare livestock anthrax vaccine coverage to human and livestock disease incidence. Local Moran's I (LISA) using spatial Bayes smoothed commune-level cumulative incidence (per 10,000) for the study period, epidemiological descriptive statistics, livestock vaccine coverage data, and annual incidence rates (per 10,000) at provincial level were used. LISA identified a human anthrax hotspot (high-high) in the southeast which did not overlap spatially with livestock anthrax hotspots in southeastern and northeastern communes. Most human cases were male, aged 15–59 years, handled sick animals, and/or consumed contaminated meat. Almost all cases were reported by grassroot health facilities with a delay of 6.3 days between exposure and case notification to the national surveillance system. 80 % of human cases were reported from June-October. The increase in disease incidence occurred shortly after livestock anthrax vaccine coverage decreased. This study informs vaccination strategy and targeted surveillance and control measures in newly identified high-risk areas and seasons of anthrax. [ABSTRACT FROM AUTHOR]

We examined the relationship between the association of a vaccine antigen with immune cells in secondary lymphoid organs shortly after immunization and the resulting neutralizing antibody response induced by that antigen using three antigenic forms of anthrax protective antigen (PA) that induce qualitatively different antibody responses. The three PA forms used were wild-type PA, which binds to anthrax toxin receptors and elicits a robust antibody response that includes both neutralizing and non-neutralizing antibodies; a receptor-binding-deficient (RBD) mutant form of PA, which does not bind cellular receptors and elicits only barely detectable antibody responses; and an engineered chimeric form of PA, which binds cholera toxin receptors and elicits a robust total antibody response but a poor neutralizing antibody response. We found that both wild-type PA and the PA chimera associated with immune cells in secondary lymphoid organs after immunization, but the RBD mutant PA exhibited minimal association, revealing a relationship between antigen binding to toxin receptors on immune cells after immunization and subsequent antibody responses. A portion of wild-type PA that bound to immune cells was cell surface-associated and maintained its native conformation. Much lower amounts of conformationally intact PA chimera were associated with immune cells after immunization, correlating with the lower neutralizing antibody response elicited by the PA chimera. Thus, binding of an antigen to receptors on immune cells in secondary lymphoid organs after immunization and maintenance of conformational integrity of the cell-associated antigen help dictate the magnitude of the resulting neutralizing antibody response, but not necessarily the total antibody response.IMPORTANCEMany vaccines protect by the induction of antibodies that neutralize the action of the pathogen. Here, we followed the fate of three antigenic forms of a vaccine antigen in secondary lymphoid organs after immunization to investigate events leading to a robust neutralizing antibody response. We found that the magnitude of the neutralizing antibody response, but not the total antibody response, correlates with the levels of conformationally intact antigen associated with immune cells in secondary lymphoid organs after primary immunization. We believe that these results provide important insights into the genesis of neutralizing antibody responses induced by vaccine antigens and may have implications for vaccine design., Competing Interests: The authors declare no conflict of interest.

Improved methods are needed to prevent wildlife deaths from anthrax. Caused by Bacillus anthracis , naturally occurring outbreaks of anthrax are frequent but unpredictable. The commercially available veterinary vaccine is labeled for subcutaneous injection and is impractical for large-scale wildlife vaccination programs; therefore, oral vaccination is the most realistic method to control and prevent these outbreaks. We reported the induction of an anthrax-specific lethal toxin (LeTx) neutralizing antibody response in mice following oral vaccination with alginate microcapsules containing B. anthracis Sterne strain 34F2 spores, coated with poly-L-lysine (PLL) and vitelline protein B (VpB). We continued evaluating our novel vaccine formulation through this proof-of-concept study in white-tailed deer (WTD; Odocoileus virginianus ; n = 9). We orally vaccinated WTD via needle-free syringe with three formulations of the encapsulated vaccine: 1) PLL-VpB-coated microcapsules with 10 7-8 spores/ml ( n = 5), 2) PLL-VpB-coated microcapsules with 10 9-10 spores/ml ( n = 2), and 3) PLL-coated microcapsules with 10 9-10 spores/ml ( n = 2). Although the limited sample sizes require continued experimentation, we observed an anthrax-specific antibody response in WTD serum following oral vaccination with PLL-coated microcapsules containing 10 9 spores/ ml. Furthermore, this antibody response neutralized anthrax LeTx in vitro, suggesting that continued development of this vaccine may allow for realistic wildlife anthrax vaccination programs.

Outbreaks of anthrax, caused by the soilborne bacterium Bacillus anthracis, are a continuous threat to free-ranging livestock and wildlife in enzootic regions of the United States, sometimes causing mass mortalities. Injectable anthrax vaccines are commercially available for use in livestock, and although hand injection is not a cost- or time-effective long-term management plan for prevention in wildlife, it may provide a tool for managers to target selectively animals of high conservation or economic value. Vaccine-induced anthrax-specific antibody responses have been reported previously in white-tailed deer (Odocoileus virginianus), but the protective nature was not determined. In this study, five white-tailed deer were subcutaneously vaccinated with one dose (1 mL) of the Anthrax Spore Vaccine. Eight blood collections by jugular venipuncture were conducted over 146 d to measure the anthrax-specific antibody response in each deer's serum over time. Antibodies were first detected by ELISA and later with toxin neutralization assays to estimate in vitro protection. Average peak absorbance by ELISA occurred at 14 d postvaccination, whereas average peak in vitro protection occurred at 28 d postvaccination. Observed in vitro protection on average for white-tailed deer after this single-dose vaccination protocol lasted 42-56 d postvaccination, although three individuals still maintained lethal toxin-neutralizing serum antibody titers out to 112 d postvaccination. Vaccination responses were variable but effective to some degree in all white-tailed deer., (© Wildlife Disease Association 2024.)

The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts, meets 3 times per year to develop recommendations for vaccine use in the United States. The group usually has 15 voting members, each of whom is appointed to a 4-year term. ACIP members and Centers for Disease Control and Prevention staff discuss the epidemiology of vaccine-preventable diseases and vaccine research, effectiveness, safety data, and clinical trial results. Representatives from the American Academy of Pediatrics (Y. A. M. and D. W. K.) and the Pediatric Infectious Diseases Society (S. T. O.) are present as liaisons to the ACIP. The ACIP met February 27 to 28, 2019, to discuss hepatitis A (HepA) vaccination of human immunodeficiency virus–infected persons, pneumococcal vaccination among adults aged 65 years or older, influenza vaccine effectiveness and safety, anthrax vaccination in the setting of a mass exposure, human papillomavirus vaccine, zoster vaccines, and Japanese encephalitis vaccine. [ABSTRACT FROM AUTHOR]

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) (Emergent BioSolutions Inc., Lansing, MI) 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. Emergent has produced a thermostable (lyophilized) formulation of AV7909 vaccine utilizing drying technology. The purpose of the study described here was to assess the immunogenicity and efficacy of the lyophilized formulation of the AV7909 vaccine candidate as compared with the liquid formulation in the guinea pig general-use prophylaxis (GUP) model. The study also provides initial information on the relationship between the immune response induced by the thermostable formulation of the vaccine, as measured by the toxin neutralization assay (TNA), and animal survival following lethal anthrax aerosol challenge. Results demonstrated that there were no significant differences in the immunogenicity or efficacy of lyophilized AV7909 against lethal anthrax spore aerosol challenge in the guinea pig model as compared to liquid AV7909. For both vaccine formulations, logistic regression modeling showed that the probability of survival increased as the pre-challenge antibody levels increased. [ABSTRACT FROM AUTHOR]

Anthrax is an acute and highly lethal disease caused by Bacillus anthracis. Protective antigen (PA) is the primary candidate antigen for the anthrax vaccines. However, PA suffers from poor immunogenicity with short-term anti-PA antibody response. High effectiveness, durable immunity, and minimal risk are required for development of an effective anthrax vaccine. In the present study, PA was self-conjugated by 8-arm polyethylene glycol (PEG) and further by thioester chemistry. As a result, 3–5 PA molecules were covalently conjugated and functioned as an antigen delivery system. The conjugate (PA-PEG) could maintain the structural properties of PA and increase the thermal stability of PA. PA-PEG could elicit a robust anti-PA IgG and neutralization antibody response in the magnitude and quality. The antibodies could be largely maintained for 180 days after three immunizations of PA-PEG. PA-PEG effectively stimulated the maturation of dendritic cell and rapidly induced the germinal center (GC) reaction. The percentages of the GC B-cells and T follicular helper (Tfh) cells were thus significantly augmented. The inflammatory response elicited by PA-PEG was comparable to those by PBS and PA. Therefore, PA-PEG is expected as an effective anthrax vaccine candidate with durable immunoprotection against anthrax. [ABSTRACT FROM AUTHOR]

Tremendous efforts are being made to develop an anthrax vaccine with long term protection. The main component of traditional anthrax vaccine is protective antigen (PA) with the trace amount of other proteins and bacterial components. In this study, we developed a recombinant PA-LF chimera antigen of Bacillus anthracis by fusing the PA domain 2-4 with lethal factor (LF) domain 1 and evaluated its protective potential against B. anthracis in mouse model. The anti-PA-LF chimera serum reacted with both PA and LF antigen, individually. The chimera elicited a strong antibody titer in mice with predominance of IgG1 isotype followed by IgG2b, IgG2a and IgG3. Cytokines were assessed in splenocytes of immunized mice and a significant up-regulation in the expression of IL-4, IL-10, IFN-γ and TNF-α was observed. The PA-LF chimera immunized mice exhibited 80% survival after challenge with virulent spores of B. anthracis. Pathological studies showed normal architecture in vital organs (spleen, lung, liver and kidney) of recovered immunized mice on 20 DPI after spore challenge. These findings suggested that PA-LF chimera of B. anthracis elicited good humoral as well as cell mediated immune response in mice, and thus, can be a potent vaccine candidate against anthrax. [ABSTRACT FROM AUTHOR]

Genome editing is an effective tool for the functional examination of bacterial genes and for live attenuated vaccine construction. Here, we report a method to edit the genomic DNA of Bacillus anthracis and Bacillus cereus using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)9 system. Using two prophages in B. anthracis as targets, large-fragment deletion mutants were achieved with rates of 100 or 20%. In B. cereus , we successfully introduced precise point mutations into plcR , with phenotypic assays showing that the resulting mutants lost hemolytic and phospholipase enzyme activities similar to B. anthracis , which is a natural plcR mutant. Our study indicates that CRISPR/Cas9 is a powerful genetic tool for genome editing in the Bacillus cereus group, and can efficiently modify target genes without the need for residual foreign DNA such as antibiotic selection markers. This system could be developed for use in the generation of marker-free live anthrax vaccines or for safer construction of microbiological candidate-based recombinant B. cereus. [ABSTRACT FROM AUTHOR]

Introduction: Anthrax is a dangerous bio-terror agent because Bacillus anthracis spores are highly resilient and can be easily aerosolized and disseminated. There is a threat of deliberate use of anthrax spores aerosol that could lead to serious fatal diseases outbreaks. Existing control measures against inhalation form of the disease are limited. All of this has provided an impetus to the development of new generation vaccines. Areas сovered: This review is devoted to challenges and achievements in the design of vaccines based on the anthrax recombinant protective antigen (rPA). Scientific databases have been searched, focusing on causes of PA instability and solutions to this problem, including new approaches of rPA expression, novel rPA-based vaccines formulations as well as the simultaneous usage of PA with other anthrax antigens. Expert opinion: PA is a central anthrax toxin component, playing a key role in the defense against encapsulated and unencapsulated strains. Subunit rPA-based vaccines have a good safety and protective profile. However, there are problems of PA instability that are greatly enhanced when using aluminum adjuvants. New adjuvant compositions, dry formulations and resistant to proteolysis and deamidation mutant PA forms can help to handle this issue. Devising a modern anthrax vaccine requires huge efforts. [ABSTRACT FROM AUTHOR]

Purpose: Foot-and-mouth disease (FMD) and anthrax are important diseases in sheep. Vaccination is a favorable strategy against both infections. Simultaneous administration of vaccines does generally not impede the immune responses of each other, although there are some exceptions, and it may help reduce the labor and costs of vaccination as well as distress on animals. Although oil adjuvant FMD vaccine has been tried with live anthrax vaccine in cattle, there are no reports on the simultaneous use of both vaccines in sheep. Materials and Methods: In this study, FMD seronegative sheep were used to investigate the impact of the simultaneous vaccination of FMD and anthrax on FMD antibody titers of sheep. Virus neutralization test and liquid phase blocking enzyme-linked immunosorbent assay were used to determine the antibody response to the FMD vaccine. Results: The results demonstrated that both vaccines can be used simultaneously without any interference with the FMD response. Moreover, the simultaneous administration with anthrax vaccine had a stimulating effect on the early (day 7 post-vaccination) virus neutralization antibody response to the FMD vaccine. Conclusion: The simultaneous use of the FMD and anthrax vaccines did not hinder the response to the FMD vaccine in sheep. [ABSTRACT FROM AUTHOR]

• GC1109 is a novel recombinant protective antigen anthrax vaccine. • We evaluate the immunogenicity and safety of GC1109 in healthy adult volunteers. • Participants were randomized to three doses of GC1109 groups or placebo group. • GC1109 was immunogenic after three doses of intramuscular administration. • Although vaccine-related adverse events were frequent, most of them were mild. The demand on effective and safe anthrax vaccine is increasing as a part of the preparedness for possible bioterrorism in the future. We performed a randomized, single-blind, placebo controlled phase II clinical study to evaluate the immunogenicity and safety of a novel recombinant protective antigen (rPA) anthrax vaccine, GC1109, in healthy adult volunteers. Participants were randomized to experiment groups (0.3 mL, 0.5 mL, and 1.0 mL of GC1109) or placebo group (normal saline 0.5 mL) in 2:2:2:1 ratio. They received respective vaccines intramuscularly at 0, 4 and 8 weeks. Immunogenicity was evaluated by seroconversion rate and geometric mean titer (GMT) of lethal toxin neutralizing assay (TNA) and anti-PA IgG by ELISA. Safety was assessed by laboratory tests, and solicited and unsolicited adverse events on diary cards. 30, 29, 30 participants were randomized to 0.3, 0.5, and 1.0 mL of GC1109 groups, respectively, while 15 to placebo group. 92 participants received all three doses. In per-protocol analysis, TNA GMTs at week 12 were 296.5, 285.2, and 433.2 in the three groups, respectively. Seroconversion rates measured by ELISA were 100% at week 12 in the three groups. Local and systemic vaccine-related adverse events were frequent; however, most of them were mild, and no serious events were observed. A new rPA anthrax vaccine GC1109 was immunogenic after three doses of intramuscular administration, and was well-tolerated. [ABSTRACT FROM AUTHOR]

A recombinant protective antigen (rPA) anthrax vaccine candidate (rPA7909) was developed as a next-generation vaccine indicated for postexposure prophylaxis of disease resulting from suspected or confirmed Bacillus anthracis exposure. The lyophilized form of rPA7909-vaccinated candidate contains 75 µg purified rPA, 750 µg aluminum (as Alhydrogel adjuvant), and 250 µg of an immunostimulatory Toll-like receptor 9 agonist oligodeoxynucleotide CpG 7909 in a 0.5 mL phosphate-buffered suspension. General toxicity and local reactogenicity were evaluated in Sprague Dawley rats vaccinated with the full human dose of rPA7909 by intramuscular injection. Animals were immunized on study days 1, 15, and 29. Control groups were administered diluent only or adjuvant control (excipients, CpG 7909, and Alhydrogel adjuvant in diluent) intramuscularly at the same dose volume and according to the same schedule used for rPA7909. Toxicity was assessed based on the results of clinical observations, physical examinations, body weights, injection site reactogenicity, ophthalmology, clinical pathology (hematology, coagulation, and serum chemistry), organ weights, and macroscopic and microscopic pathology evaluation. The immune response to rPA7909 vaccination was confirmed by measuring serum anti-PA immunoglobulin G levels. The rPA7909 vaccine produced no apparent systemic toxicity and only transient reactogenicity at the injection site. The injection site reaction from animals receiving the adjuvant control was very similar to those receiving rPA7909 with respect to the inflammation. The inflammatory response observed in the injection site and the draining lymph nodes was consistent with expected immune stimulation. The overall results indicated a favorable safety profile for rPA7909. [ABSTRACT FROM AUTHOR]

Bacillus anthracis (BA), the etiological agent of anthrax, secretes protective antigen (PA), lethal factor (LF), and edema factor (EF) as major virulence mediators. Amongst these, PA-based vaccines are most effective for providing immunity against BA, but their low shelf life limits their usage. Previous studies showed that B-cell epitopes, ID II and ID III present in PA domain IV possess higher toxin neutralization activity and elicit higher antibody titer than ID I. Moreover, N-terminal region of both LF and EF harbors PA-binding sites which share 100% identity with each other. Here, in this study, we have developed an epitope-based chimeric vaccine (ID–LFn) comprising ID II–ID III region of PA and N-terminal region of LF. We have also evaluated its protective efficacy as well as stability and found it to be more stable than PA-based vaccine. Binding reactivities of ID–LFn with anti-PA/LF/EF antibodies were determined by ELISA. The stability of chimeric vaccine was assessed using circular dichroism spectroscopy. ID–LFn response was characterized by toxin neutralization, lymphocyte proliferation isotyping and cytokine profiling. The protective efficacy was analyzed by challenging ID–LFn-immunized mice with B. anthracis (pXO1+ and pXO2+). ID–LFn was found to be significantly stable as compared to PA. Anti-ID–LFn antibodies recognized PA, LF as well as EF. The T-cell response and the protective efficacy of ID–LFn were found to be almost similar to PA. ID–LFn exhibits equal protective efficacy in mice and possesses more stability as compared to PA along with the capability of recognizing PA, LF and EF at the same time. Thus, it can be considered as an improved vaccine against anthrax with better shelf life. ID-LFn, a novel multiepitope chimeric anthrax vaccine: ID-LFn comprises of immunodominant epitopes of domain 4 of PA and N-terminal homologous stretch of LF and EF. The administration of this protein as a vaccine provides protection against anthrax. [ABSTRACT FROM AUTHOR]

Background: Anthrax is a zoonotic disease caused by Bacillus anthracis and it can be deadly in 6 days. Considerable efforts have been conducted toward developing more effective veterinary and human anthrax vaccines because these common vaccines have several limitations. B. anthracis secretes a tripartite toxin, comprising protective antigen (PA), edema factor (EF), and lethal factor (LF). Several studies have shown important role of PA in protection of anthrax. LF and EF induce production of toxin neutralizing antibodies too. PA in fusion form with LF/EF has synergistic effects as a potential subunit vaccine. Methods: In this study, for the first time, a triple chimeric protein called ELP was modeled by fusing three different domains of anthrax toxic antigens, the N-terminal domains of EF and LF, and the C-terminal domain of PA as a high immunogenic antigen using Modeller 9.19 software. Immunogenicity of the ELP was assessed in guinea pigs using enzyme-linked immunosorbent assay (ELISA) test and MTT assay. Results: Theoretical studies and molecular dynamics (MD) simulation results suggest that the ELP model had acceptable quality and stability. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the purified ELP, its domains, and PA were matched with their molecular size and confirmed by western blotting analysis. In the immune guinea pigs, antibody was produced against all of the ELP domains. It was observed that ELP induced strong humoral response and could protect murine macrophage cell line (RAW 264.7 cells) against anthrax lethal toxin (LeTx). Conclusions: ELP chimeric antigen could be considered as a high immunogenic antigen. [ABSTRACT FROM AUTHOR]

Live genetic engineering anthrax vaccines on the platform of avirulent and probiotic micro-ogranisms are a safe and adequate alternative to preparations based on attenuated Bacillus anthracis strains. Mucosal application results in a direct contact of the vaccine preparations with mucous membranes in those organs and tissues of the macro-organisms, that are exposed to the pathogen in the first place, resulting in a development of local and systemic immune response. Live recombinant anthrax vaccines could be used both separately as well as in a prime-boost immunization scheme. The review focuses on immunogenic and protective properties of experimental live genetic engineering preparations, created based on members ofgeni of Salmonella, Lactobacillus and adenoviruses.

The protective efficacy of human sera from vaccinated individuals with a new recombinant protective antigen anthrax vaccine (GC1109) against lethal spore challenge was evaluated in a mouse model. Eighteen human sera were selected from the vaccinated individuals based on their toxin neutralizing assay (TNA) titer (ED 50 of 55 to 668). The selected sera were diluted and passively transferred to A/J mice and the mice were subsequently challenged with 100 × LD 50 of Bacillus anthracis Sterne spores. The correlation between the survival rate of passively immunized mice and the TNA ED 50 of transferred sera was presented (r = 0.873, P-value < 0.001). The estimated TNA titer for 50% survival rate against lethal challenge was 197 (95% confidence interval of 149 and 260). The result suggest that GC1109 is protective against exposure to B. anthracis and the TNA titer of vaccinated serum can be an indicator for protective efficacy. [ABSTRACT FROM AUTHOR]

Pulmonary anthrax caused by exposure to inhaled Bacillus anthracis , the most lethal form of anthrax disease, is a continued military and public health concern for the United States. The vaccine AV7909, consisting of the licensed anthrax drug substance AVA adjuvanted with CpG7909, induces high levels of toxin neutralizing antibodies in healthy adults using fewer doses than AVA. This study compares the ability of one- or two-dose regimens of AV7909 to induce a protective immune response in guinea pigs challenged with a lethal dose of aerosolized B. anthracis spores 6 weeks after the last vaccine dose. The results indicated that AV7909 was less effective when delivered as a single dose compared to the two-dose regimen that resulted in dose-dependent protection against death. The toxin neutralizing assay (TNA) titer and anti-PA IgG responses were proportional to the protective efficacy, with a 50% TNA neutralizing factor (NF 50 ) greater than 0.1 associated with survival in animals receiving two doses of vaccine. The strong protection at relatively low TNA NF 50 titers in this guinea pig model supports the exploration of lower doses in clinical trials to determine if these protective levels of neutralizing antibodies can be achieved in humans; however, protection with a single dose may not be feasible.

Abstract: The technology for synthesis is described, and the adjuvant properties of CpG oligodeoxynucleotides (CpG-ODNs) are assessed. CpG-ODN sequences were generated according to the available sequences on an automatic synthesizer. The adjuvant activity was evaluated with CpG-ODNs in combination with a recombinant protective antigen and EA1, an S-layer protein of the anthrax agent. It was established that the use of the synthesized adjuvant CpG 2006, along with immunogenic antigens, leads to the development of long-term, high-level immunity in test animals. The synthetic CpG 2006 antigenic product was shown to have an advantage over alhydrogel in terms of adjuvant activity. Experiments on biomodels provided data confirming the absence of toxic and damaging effects of CpG-ODNs on cells and tissues of the macroorganism. Comparison of the cell-mediated immunity (content of CD4+ and CD8+) after immunization by the B. anthracis STI-1 strain or a recombinant anthrax vaccine prototype with CpG 2006 or alhydrogel as an adjuvant is evidence of the activation of the cellular component of the immune system in all of the compared groups. [ABSTRACT FROM AUTHOR]

The recombinant B. anthracis strain 55ΔTPA-1Spo- was used for the development and trial of a method for the simultaneous production of immunogenic anthrax antigens, a protective antigen, and the EA1 protein of the S layer, which are components of a prototype anthrax vaccine. The proposed method includes inoculum preparation, cultivation in liquid medium without antibiotics, sterilizing filtration, concentration, diafiltration, and chromatographic purification on various carriers. This method provides for a high yield of both target products. The purified antigens (alone or in combination with each other) were shown to have no toxic effect on organs and tissues of vaccinated laboratory animals in amounts that were several times higher than immunizing doses. The minor changes revealed by histological examination reflect the adaptation-compensatory reactions of the macroorganism and tend to normalize. The response of immune-competent organs corresponded to moderate development of immunogenesis. The addition of EA1 protein to the recombinant protective antigen resulted in an increase in the expression of the genes determining TLR of innate immunity. Immunization of laboratory animals with the combined preparation caused more pronounced immunobiological alterations in lymphoid organs than the use of only the protective antigen. [ABSTRACT FROM AUTHOR]

The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts, meets 3 times per year to develop recommendations for vaccine use in the United States. The group has 15 voting members, and each member's term is 4 years. ACIP members and Centers for Disease Control and Prevention staff discuss the epidemiology of vaccine-preventable diseases and vaccine research, effectiveness, safety data, and clinical trial results. Representatives from the American Academy of Pediatrics (J. D. C. and D. W. K.) and the Pediatric Infectious Diseases Society (S. T. O.) are present as liaisons to the ACIP. The ACIP met on June 20 and 21, 2018, to discuss influenza vaccine effectiveness and safety, anthrax vaccination in the setting of a mass exposure, human papillomavirus vaccine, mumps vaccine, Japanese encephalitis vaccine, and pneumococcal vaccination among adults. [ABSTRACT FROM AUTHOR]

Abstract Development of recombinant protective antigen (rPA)-based anthrax vaccines has been hindered by a lack of stability of the vaccines associated with spontaneous deamidation of asparagine (Asn) residues of the rPA antigen during storage. In this study, we explored the role that two deamidation-prone Asn residues located directly adjacent to the receptor binding site of PA, Asn713 and Asn719, play in the stability of rPA-based anthrax vaccines. We modified these residues to glutamine (Gln) and generated rPA(N713Q/N719Q), since Gln would not be expected to deamidate on a time scale relevant to vaccine storage. While wild-type rPA vaccine formulated with aluminum hydroxide lost immunogenicity upon storage, as measured by induction of toxin-neutralizing antibodies in mice, the rPA(N713Q/N719Q) vaccine did not exhibit a significant loss in immunogenicity. This finding suggests that modification of Asn713 and Asn719 of rPA to deamidation-resistant amino acids may improve the stability of rPA-based anthrax vaccines. [ABSTRACT FROM AUTHOR]