T-cell activation is an immune correlate of risk in BCG vaccinated infants

Fletcher, Helen A.; Snowden, Margaret Ann; Landry, Bernard; Rida, Wasima; Satti, Iman; Harris, Stephanie A.; Matsumiya, Magali; Tanner, Rachel; O’Shea, Matthew K.; Dheenadhayalan, Veerabadran; Bogardus, Leah; Stockdale, Lisa; Marsay, Leanne; Chomka, Agnieszka; Harrington-Kandt, Rachel; Manjaly-Thomas, Zita-Rose; Naranbhai, Vivek; Stylianou, Elena; Darboe, Fatoumatta; Penn-Nicholson, Adam; Nemes, Elisa; Hatherill, Mark; Hussey, Gregory; Mahomed, Hassan; Tameris, Michèle; McClain, J. Bruce; Evans, Thomas G.; Hanekom, Willem A.; Scriba, Thomas J.; McShane, Helen

doi:10.1038/ncomms11290

Cited by 221 publications

(298 citation statements)

References 39 publications

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“…In areas with a high incidence of TB, even a small increase in the rate of HIV acquisition would have a major impact on pediatric HIV infections. Importantly, a recently published study reported that higher frequencies of activated CD4 ϩ T cells in BCG-vaccinated human infants from the MVA85A TB vaccine trial had an increased risk for TB disease (82). This is the first report that CD4 ϩ T cell activation is associated not only with higher HIV infection risk but also with predisposition to TB disease.…”

Section: Trained Immunity and Immune Activation Of Tb Vaccinesmentioning

confidence: 71%

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

Jensen

Pena-Ponce

Piatak

et al. 2017

Clin Vaccine Immunol

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Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M. tuberculosis (AMtb)-simian immunodeficiency virus (SIV) vaccine is immunogenic, and although the vaccine did not prevent oral SIV infection, a subset of vaccinated animals was able to partially control virus replication. However, unexpectedly, vaccinated infants required fewer SIV exposures to become infected compared to naive controls. Considering that the current TB vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), can induce potent innate immune responses and confer pathogen-unspecific trained immunity, we hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in AMtb-SIV-vaccinated infants. To address this question, we used archived samples from unchallenged animals from our previous AMtb-SIV vaccine studies and vaccinated additional infant macaques with BCG or AMtb only. Our results show that vaccinated infants, regardless of vaccine strain or regimen, had enhanced myeloid cell responses. However, CD4 ϩ T cells were concurrently activated, and the persistence of these activated target cells in oral and/or gastrointestinal tissues may have facilitated oral SIV infection. Immune activation was more pronounced in BCG-vaccinated infant macaques than in AMtb-vaccinated infant macaques, indicating a role for vaccine attenuation. These findings underline the importance of understanding the interplay of vaccine-induced immunity and immune activation and its effect on HIV acquisition risk and outcome in infants.

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Section: Trained Immunity and Immune Activation Of Tb Vaccinesmentioning

confidence: 71%

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

Jensen

Pena-Ponce

Piatak

et al. 2017

Clin Vaccine Immunol

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“…Although both CD4+ T cells and IFN-γ are required for control of M. tuberculosis infection (Flynn et al, 1993; Green et al, 2013), it has been difficult to establish whether these factors are sufficient to establish protective immunity (Kagina et al, 2010; Fletcher et al, 2016). Recently, the recombinant vaccine strain Modified Vaccinia Ankara virus expressing Ag85A (MVA85A) became the first new TB vaccine candidate to be tested for efficacy in infants in a clinical trial since BCG (Tameris et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

STING-Activating Adjuvants Elicit a Th17 Immune Response and Protect against Mycobacterium tuberculosis Infection

et al. 2018

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SUMMARY There are a limited number of adjuvants that elicit effective cell-based immunity required for protection against intracellular bacterial pathogens. Here, we report that STING-activating cyclic dinucleotides (CDNs) formulated in a protein subunit vaccine elicit long-lasting protective immunity to Mycobacterium tuberculosis in the mouse model. Subcutaneous administration of this vaccine provides equivalent protection to that of the live attenuated vaccine strain Bacille Calmette-Guérin (BCG). Protection is STING dependent but type I IFN independent and correlates with an increased frequency of a recently described subset of CXCR3-expressing T cells that localize to the lung parenchyma. Intranasal delivery results in superior protection compared with BCG, significantly boosts BCG-based immunity, and elicits both Th1 and Th17 immune responses, the latter of which correlates with enhanced protection. Thus, a CDN-adjuvanted protein subunit vaccine has the capability of eliciting a multi-faceted immune response that results in protection from infection by an intracellular pathogen.

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“…BCG-specific CD4 + , CD8 + and γδ T-cell expression of IFN-γ, TNF-α, IL-2, and IL-17 do not seem to correlate with the protection conferred by BCG in infants [111]. However in a more recent study, BCG-specific ELISPOT responses are associated with a reduced risk of disease in BCG-vaccinated South African infants [37]. BCG-specific T-cell ELISPOT antigen specific CD4 + T-cells do not appear to localize to the site of infection in lung tissue until 18–20 days after the establishment of disease, showing that M.tb delays the onset of adaptive Th1 immunity [112].…”

Section: Introductionmentioning

confidence: 89%

“…Recently, higher titres of IgG against Ag85A have been shown to associate with reduced risk of developing active disease in an infant case-control study [37]. This raises the possibility that anti-mycobacterial antibodies assist in the containment of initial infection with M.tb in humans.…”

Section: Introductionmentioning

confidence: 99%

“…These advances may allow mapping of how the antibody response develops during active TB infection, and how it is subverted by M.tb to prevent the formation of any protective antibodies as suggested by the antigenic variation in B-cell epitopes and the lack of surface-binding antibodies. The study of clinical populations who appear to be resistant to acquiring latent infection with M.tb are also of great interest in order to understand immunity against TB [37]. There is strong suggestion that healthy individuals produce high titres of antibodies to PPD and Ag85A upon exposure to mycobacteria, and studies to assess the effect of antibody responses on preventing active or latent infection are a promising avenue of exploration.…”

Section: Introductionmentioning

confidence: 99%

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Antibodies and tuberculosis

et al. 2016

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SummaryTuberculosis (TB) remains a major public health problem internationally, causing 9.6 million new cases and 1.5 million deaths worldwide in 2014. The Bacillus Calmette-Guérin vaccine is the only licensed vaccine against TB, but its protective effect does not extend to controlling the development of infectious pulmonary disease in adults. The development of a more effective vaccine against TB is therefore a pressing need for global health. Although it is established that cell-mediated immunity is necessary for the control of latent infection, the presupposition that such immunity is sufficient for vaccine-induced protection has recently been challenged. A greater understanding of protective immunity against TB is required to guide future vaccine strategies against TB.In contrast to cell-mediated immunity, the human antibody response against M.tb is conventionally thought to exert little immune control over the course of infection. Humoral responses are prominent during active TB disease, and have even been postulated to contribute to immunopathology. However, there is evidence to suggest that specific antibodies may limit the dissemination of M.tb, and potentially also play a role in prevention of infection via mucosal immunity. Further, antibodies are now understood to confer protection against a range of intracellular pathogens by modulating immunity via Fc-receptor mediated phagocytosis. In this review, we will explore the evidence that antibody-mediated immunity could be reconsidered in the search for new vaccine strategies against TB.

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T-cell activation is an immune correlate of risk in BCG vaccinated infants

Cited by 221 publications

References 39 publications

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

STING-Activating Adjuvants Elicit a Th17 Immune Response and Protect against Mycobacterium tuberculosis Infection

Antibodies and tuberculosis

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