Host immunity to <i>Bacillus anthracis</i> lethal factor and other immunogens: implications for vaccine design

Altmann, Daniel M.

doi:10.1586/14760584.2015.981533

Cited by 12 publications

(11 citation statements)

References 43 publications

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“…For example, 7.5% of AVA recipients with anti-PA IgG titers ≥ 1:1000 had LT neutralization activity that was indistinguishable from unvaccinated controls [29]. Initiatives to develop less reactogenic and more effective anthrax vaccines resulted in development of recombinant PA [17–20] and consideration of additional vaccine targets including LF [30]. …”

Section: Discussionmentioning

confidence: 99%

Lethal factor antibodies contribute to lethal toxin neutralization in recipients of anthrax vaccine precipitated

Dumas

Garman

Cuthbertson

et al. 2017

Vaccine

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A major difference between two currently licensed anthrax vaccines is presence (United Kingdom Anthrax Vaccine Precipitated, AVP) or absence (United States Anthrax Vaccine Adsorbed, AVA) of quantifiable amounts of the Lethal Toxin (LT) component Lethal Factor (LF). The primary immunogen in both vaccine formulations is Protective Antigen (PA), and LT-neutralizing antibodies directed to PA are an accepted correlate of vaccine efficacy; however, vaccination studies in animal models have demonstrated that LF antibodies can be protective. In this report we compared humoral immune responses in cohorts of AVP (n=39) and AVA recipients (n=78) matched 1:2 for number of vaccinations and time post-vaccination, and evaluated whether the LF response contributes to LT neutralization in human recipients of AVP. PA response rates (≥95%) and PA IgG concentrations were similar in both groups; however, AVP recipients exhibited higher LT neutralization ED50 values (AVP: 1464.0 ± 214.7, AVA: 544.9 ± 83.2, p<0.0001) and had higher rates of LF IgG positivity (95%) compared to matched AVA vaccinees (1%). Multiple regression analysis revealed that LF IgG makes an independent and additive contribution to the LT neutralization response in the AVP group. Affinity purified LF antibodies from two independent AVP recipients neutralized LT and bound to LF Domain 1, confirming contribution of LF antibodies to LT neutralization. This study documents the benefit of including an LF component to PA-based anthrax vaccines.

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Section: Discussionmentioning

confidence: 99%

Lethal factor antibodies contribute to lethal toxin neutralization in recipients of anthrax vaccine precipitated

Dumas

Garman

Cuthbertson

et al. 2017

Vaccine

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“…The toxin proteins are in general B. anthracis specific, whereas homologs of the capsule genes have been found reasonably commonly in other closely related species. The toxin proteins have as a consequence been under development by a number of commercial groups as sub-unit vaccine candidates for Anthrax infection (Brey, 2005 ; Splino et al, 2005 ; Comer and Peterson, 2009 ; Friedlander and Little, 2009 ; Altmann, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Whole genome protein microarrays for serum profiling of immunodominant antigens of Bacillus anthracis

et al. 2015

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A commercial Bacillus anthracis (Anthrax) whole genome protein microarray has been used to identify immunogenic Anthrax proteins (IAP) using sera from groups of donors with (a) confirmed B. anthracis naturally acquired cutaneous infection, (b) confirmed B. anthracis intravenous drug use-acquired infection, (c) occupational exposure in a wool-sorters factory, (d) humans and rabbits vaccinated with the UK Anthrax protein vaccine and compared to naïve unexposed controls. Anti-IAP responses were observed for both IgG and IgA in the challenged groups; however the anti-IAP IgG response was more evident in the vaccinated group and the anti-IAP IgA response more evident in the B. anthracis-infected groups. Infected individuals appeared somewhat suppressed for their general IgG response, compared with other challenged groups. Immunogenic protein antigens were identified in all groups, some of which were shared between groups whilst others were specific for individual groups. The toxin proteins were immunodominant in all vaccinated, infected or other challenged groups. However, a number of other chromosomally-located and plasmid encoded open reading frame proteins were also recognized by infected or exposed groups in comparison to controls. Some of these antigens e.g., BA4182 are not recognized by vaccinated individuals, suggesting that there are proteins more specifically expressed by live Anthrax spores in vivo that are not currently found in the UK licensed Anthrax Vaccine (AVP). These may perhaps be preferentially expressed during infection and represent expression of alternative pathways in the B. anthracis “infectome.” These may make highly attractive candidates for diagnostic and vaccine biomarker development as they may be more specifically associated with the infectious phase of the pathogen. A number of B. anthracis small hypothetical protein targets have been synthesized, tested in mouse immunogenicity studies and validated in parallel using human sera from the same study.

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“…Other routes of exposure could occur through deliberate release, acts of bioterrorism, or injection of contaminated drugs by intravenous drug users [3, 27, 30]; in these contexts, especially the threat of bioterrorist use, there has long been a perceived need to have an effective anthrax vaccination programme available. Three major vaccines have been in use in various parts of the world since the Cold War, with various recombinant subunit vaccine candidates in trial for rollout [31, 32]. Interestingly however, compared to many other bacterial pathogens, the immunology and immunogenetics underpinning any clear understanding of correlates of protection (CoP) are poorly delineated for anthrax [33].…”

Section: Discussionmentioning

confidence: 99%

HLA class II polymorphism influences the immune response to protective antigen and susceptibility to Bacillus anthracis

Altmann

Ascough

Ingram

et al. 2019

Preprint

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The causative agent of anthrax, Bacillus anthracis, evades the host immune response and establishes infection through the production of binary exotoxins composed of Protective Antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define HLA-DR-restricted and HLA-DQ-restricted CD4+ T cell responses to the immunodominant epitopes of PA. This was correlated with the binding affinities of epitopes to HLA class II molecules, as well as the responses of two human cohorts: individuals vaccinated with the Anthrax Vaccine Precipitated (AVP) vaccine (which contains PA and trace amounts of LF), and patients recovering from cutaneous anthrax infections. The infected and vaccinated cohorts expressing different HLA types were found to make CD4+ T cell responses to multiple and diverse epitopes of PA. The effects of HLA polymorphism were explored using transgenic mouse lines, which demonstrated differential susceptibility, indicating that HLA-DR1 and HLA-DQ8 alleles conferred protective immunity relative to HLA-DR15, HLA-DR4 and HLA-DQ6. The HLA transgenics enabled a reductionist approach, allowing us to better define CD4+ T cell epitopes. Appreciating the effects of HLA polymorphism on the variability of responses to natural infection and vaccination will be vital in planning protective strategies against anthrax.Author SummaryThe bacterium responsible for causing the disease anthrax, Bacillus anthracis, produces a binary toxin composed of Protective Antigen (PA) and either Lethal Factor (LF) or Edema Factor (EF). Previous vaccination strategies have focused upon the antibody response to the PA subunit. However, within the field of bacterial immunity, there is a growing appreciation of the importance of the adaptive immune response, specifically led by CD4+ T cells. We identified long-term CD4+ T cell responses to PA epitopes following cutaneous human anthrax infection and vaccination, indicating that this toxin component is a principle B. anthracis antigen. To characterise the impact of polymorphism in HLA class II alleles at DR and DQ loci, we used transgenic mice to map the immunodominant epitopes from PA. This was correlated with survival in the transgenic lines following live anthrax challenge. We were able to demonstrate the differential impact of HLA class II alleles upon the CD4+ T cell immunodominant epitopes which shaped the immune hierarchy and therefore susceptibility to anthrax infection.

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Host immunity to Bacillus anthracis lethal factor and other immunogens: implications for vaccine design

Cited by 12 publications

References 43 publications

Lethal factor antibodies contribute to lethal toxin neutralization in recipients of anthrax vaccine precipitated

Lethal factor antibodies contribute to lethal toxin neutralization in recipients of anthrax vaccine precipitated

Whole genome protein microarrays for serum profiling of immunodominant antigens of Bacillus anthracis

HLA class II polymorphism influences the immune response to protective antigen and susceptibility to Bacillus anthracis

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