Tuberculosis vaccines — perspectives from the NIH/NIAID Mycobacteria vaccine testing program

Izzo, Angelo A.

doi:10.1016/j.coi.2017.07.008

Cited by 23 publications

(17 citation statements)

References 84 publications

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“…Current strategies to develop next generation BCG vaccines are generally focused on the enhancement of IFNγ production by CD4+ T cells (i.e., Th1 cell-mediated immunity) (Achkar and Casadevall, 2013). Recent attention has been focused toward understanding the role, if any, of vaccine-induced antibodies (Abs) to prevent infection (Izzo, 2017). Various reported mechanisms of Ab-mediated protection against Mtb include direct antimycobacterial activity, opsonization, activation of complement, clearance of immunomodulatory mycobacterial antigens, increase of macrophage Ca2+ signaling, release of oxidants enhancing intracellular killing and other mechanisms of enhancing cell-mediated immunity (Achkar et al, 2014).…”

Section: Tb-specific Protection Conferred By Bcg Vaccinementioning

confidence: 99%

BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny

et al. 2020

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Vaccines have been traditionally developed with the presumption that they exert identical immunogenicity regardless of target population and that they provide protection solely against their target pathogen. However, it is increasingly appreciated that vaccines can have off-target effects and that vaccine immunogenicity can vary substantially with demographic factors such as age and sex. Bacille Calmette-Guérin (BCG), the live attenuated Mycobacterium bovis vaccine against tuberculosis (TB), represents a key example of these concepts. BCG vaccines are manufactured under different conditions across the globe generating divergent formulations. Epidemiologic studies have linked early life immunization with certain BCG formulations to an unanticipated reduction (∼50%) in all-cause mortality, especially in low birthweight males, greatly exceeding that attributable to TB prevention. This mortality benefit has been related to prevention of sepsis and respiratory infections suggesting that BCG induces "heterologous" protection against unrelated pathogens. Proposed mechanisms for heterologous protection include vaccine-induced immunometabolic shifts, epigenetic reprogramming of innate cell populations, and modulation of hematopoietic stem cell progenitors resulting in altered responses to subsequent stimuli, a phenomenon termed "trained immunity." In addition to genetic differences, licensed BCG formulations differ markedly in content of viable mycobacteria key for innate immune activation, potentially contributing to differences in the ability of these diverse formulations to induce TBspecific and heterologous protection. BCG immunomodulatory properties have also sparked interest in its potential use to prevent or alleviate autoimmune and inflammatory diseases, including type 1 diabetes mellitus and multiple sclerosis. BCG can also serve as a model: nanoparticle vaccine formulations incorporating Toll-like receptor 8 agonists can mimic some of BCG's innate immune activation, suggesting that aspects of BCG's effects can be induced with non-replicating stimuli. Overall, BCG represents a paradigm for precision vaccinology, lessons from which will help inform next generation vaccines.

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Section: Tb-specific Protection Conferred By Bcg Vaccinementioning

confidence: 99%

BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny

et al. 2020

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“…Interestingly, 2 of 3 of MVATG18598-expressed latency antigens (Rv2626 and Rv3407) displayed a CTL cytotoxic activity beyond being producers of IFNγ. It would be of interest to dissect the role of immune responses specific to latency antigens in all recombinant therapeutic vaccines developed today containing this class of antigen as stimulating an immune response targeting dormant, metabolically inactive and non-replicating bacteria would be an important endpoint in improvement of MDR management [ 42 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

A multi-antigenic MVA vaccine increases efficacy of combination chemotherapy against Mycobacterium tuberculosis

et al. 2018

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Despite the existence of the prophylactic Bacille Calmette-Guérin (BCG) vaccine, infection by Mycobacterium tuberculosis (Mtb) remains a major public health issue causing up to 1.8 million annual deaths worldwide. Increasing prevalence of Mtb strains resistant to antibiotics represents an urgent threat for global health that has prompted a search for alternative treatment regimens not subject to development of resistance. Immunotherapy constitutes a promising approach to improving current antibiotic treatments through engagement of the host’s immune system. We designed a multi-antigenic and multiphasic vaccine, based on the Modified Vaccinia Ankara (MVA) virus, denoted MVATG18598, which expresses ten antigens classically described as representative of each of different phases of Mtb infection. In vitro analysis coupled with multiple-passage evaluation demonstrated that this vaccine is genetically stable, i.e. fit for manufacturing. Using different mouse strains, we show that MVATG18598 vaccination results in both Th1-associated T-cell responses and cytolytic activity, targeting all 10 vaccine-expressed Mtb antigens. In chronic post-exposure mouse models, MVATG18598 vaccination in combination with an antibiotic regimen decreases the bacterial burden in the lungs of infected mice, compared with chemotherapy alone, and is associated with long-lasting antigen-specific Th1-type T cell and antibody responses. In one model, co-treatment with MVATG18598 prevented relapse of the disease after treatment completion, an important clinical goal. Overall, results demonstrate the capacity of the therapeutic MVATG18598 vaccine to improve efficacy of chemotherapy against TB. These data support further development of this novel immunotherapeutic in the treatment of Mtb infections.

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“…There are currently 14 vaccine candidates in various phases of clinical trials ( Table 1 ) to either prevent latent TB infection (LTBI; Box 1 ) or disease ( WHO, 2020 ). These candidates may prove effective in prophylactic use, assisting chemotherapy ( Box 1 ) or preventing disease relapse ( Izzo, 2017 ). One of the most promising subunit vaccine ( Box 3 ) candidates for children is the modified vaccinia Ankara virus-expressing antigen 85A (MVA85A), the first TB vaccine candidate to enter clinical trials in more than a decade ( McShane and Williams, 2014 ; Tameris et al, 2013 ).…”

Section: Tb Vaccination Development For Pediatric Use – a Brief Overvmentioning

confidence: 99%

Neonatal and infant immunity for tuberculosis vaccine development: importance of age-matched animal models

Ramos

Lunney

Gonzalez-Juarrero

2020

Disease Models &Amp; Mechanisms

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Neonatal and infant immunity differs from that of adults in both the innate and adaptive arms, which are critical contributors to immune-mediated clearance of infection and memory responses elicited during vaccination. The tuberculosis (TB) research community has openly admitted to a vacuum of knowledge about neonatal and infant immune responses to Mycobacterium tuberculosis (Mtb) infection, especially in the functional and phenotypic attributes of memory T cell responses elicited by the only available vaccine for TB, the Bacillus Calmette–Guérin (BCG) vaccine. Although BCG vaccination has variable efficacy in preventing pulmonary TB during adolescence and adulthood, 80% of endemic TB countries still administer BCG at birth because it has a good safety profile and protects children from severe forms of TB. As such, new vaccines must work in conjunction with BCG at birth and, thus, it is essential to understand how BCG shapes the immune system during the first months of life. However, many aspects of the neonatal and infant immune response elicited by vaccination with BCG remain unknown, as only a handful of studies have followed BCG responses in infants. Furthermore, most animal models currently used to study TB vaccine candidates rely on adult-aged animals. This presents unique challenges when transitioning to human trials in neonates or infants. In this Review, we focus on vaccine development in the field of TB and compare the relative utility of animal models used thus far to study neonatal and infant immunity. We encourage the development of neonatal animal models for TB, especially the use of pigs.

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Tuberculosis vaccines — perspectives from the NIH/NIAID Mycobacteria vaccine testing program

Cited by 23 publications

References 84 publications

BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny

BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny

A multi-antigenic MVA vaccine increases efficacy of combination chemotherapy against Mycobacterium tuberculosis

Neonatal and infant immunity for tuberculosis vaccine development: importance of age-matched animal models

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