Causes of variation in BCG vaccine efficacy: Examining evidence from the BCG REVAC cluster randomized trial to explore the masking and the blocking hypotheses

Barreto, Maurício L.; Pilger, Daniel; Pereira, Susan Martins; Genser, Bernd; Cruz, Álvaro Augusto; Cunha, Sérgio Souza da; Sant’Anna, Clemax Couto; Hijjar, Miguel Aiub; Ichihara, Maria Yuri Travassos; Rodrigues, Laura C.

doi:10.1016/j.vaccine.2014.05.042

Cited by 63 publications

(59 citation statements)

References 34 publications

(52 reference statements)

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“…This may represent an example of masking of the BCG-induced immune response, which has previously been described in children (33). Nevertheless, we demonstrate that BCG is immunogenic, even in the context of prior sensitization, providing evidence against the contrary hypothesis of immunological blocking of the BCG-induced immune response (34). Our study does not address whether these findings have implications for BCG-induced protective immunity.…”

Section: Discussionsupporting

confidence: 44%

Bacillus Calmette–Guérin (BCG) Revaccination of Adults with Latent Mycobacterium tuberculosis Infection Induces Long-Lived BCG-Reactive NK Cell Responses

Suliman

Geldenhuys

Johnson

et al. 2016

The Journal of Immunology

129

139

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One third of the global population is estimated to be latently infected with Mycobacterium tuberculosis (M.tb). We performed a phase 1 randomized, controlled trial of isoniazid preventive therapy (IPT) before re-vaccination with Bacille Calmette-Guerin (BCG) in healthy, tuberculin skin test positive (≥15mm induration), HIV-negative, South African adults. We hypothesised that pre-clearance of latent bacilli with IPT modulates BCG immunogenicity following re-vaccination. Frequencies and co-expression of IFNγ, TNFα, IL-2, IL-17, and/or IL-22 in CD4, and IFNγ-expressing CD8, γδ T, CD3+CD56+ NKT-like and NK cells in response to BCG were measured using whole blood intracellular cytokine staining and flow cytometry. We analyzed 72 participants who were BCG re-vaccinated after IPT (n=33) or without prior IPT (n=39). IPT had little effect on frequencies or cytokine co-expression patterns of M.tb- or BCG-specific responses. Re-vaccination transiently boosted BCG-specific Th1 cytokine-expressing CD4, CD8 and γδ T cells. Despite high frequencies of IFNγ-expressing BCG-reactive CD3+CD56+ NKT-like, CD3−CD56dim and CD3−CD56hi NK cells at baseline, BCG re-vaccination boosted these responses, which remained elevated up to one year after re-vaccination. Such BCG-reactive memory NK cells were induced by BCG vaccination in infants, while in vitro IFN-γ expression by NK cells upon BCG stimulation was dependent on IL-12 and IL-18. Our data suggest that isoniazid pre-clearance of M.tb bacilli has little effect on the magnitude, persistence or functional attributes of lymphocyte responses boosted by BCG re-vaccination. Our study highlights surprising durability of BCG-boosted memory NKT-like and NK cells expressing anti-mycobacterial effector molecules, which may be novel targets for TB vaccines.

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Section: Discussionsupporting

confidence: 44%

Bacillus Calmette–Guérin (BCG) Revaccination of Adults with Latent Mycobacterium tuberculosis Infection Induces Long-Lived BCG-Reactive NK Cell Responses

Suliman

Geldenhuys

Johnson

et al. 2016

The Journal of Immunology

129

139

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“…48 However, it is important to consider that in this older target population vaccination with a BCG replacement vaccine candidate could result in significant masking and blocking effects to vaccination due to preexisting immune responses resulting from previous infection with non-tuberculous environmental mycobacteria. [49][50][51][52] Importantly, a current disadvantage in BCG replacement vaccines is that its administration in a population with compromised immune system could be insecure and even deadly. This important gap can be overcome in future vaccine research by the combined use of different deletions into the same M. tb strain in new candidates for BCG replacement vaccines, improving deletion of M. tb virulence genes.…”

Section: Main Challenges In the Next Yearsmentioning

confidence: 99%

“…Furthermore, a clinical study has being conducted in BCG‐unvaccinated adults living in an area not endemic for TB, to determine the safety of the MTBVAC vaccine . However, it is important to consider that in this older target population vaccination with a BCG replacement vaccine candidate could result in significant masking and blocking effects to vaccination due to preexisting immune responses resulting from previous infection with non‐tuberculous environmental mycobacteria …”

Section: Introductionmentioning

confidence: 99%

Current challenges and opportunities for bacillus Calmette‐Guérin replacement vaccine candidates

Méndez-Samperio¹

2019

Scand J Immunol

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Bacillus Calmette‐Guérin (BCG) remains the only licensed vaccine against human tuberculosis (TB). BCG is a live‐attenuated strain of Mycobacterium bovis, with limitations in efficacy against respiratory TB, the most common form of the disease responsible for transmission. However, continues to be used in the immunization programmes of different countries in the absence of another alternative. In order to improve BCG efficacy against pulmonary TB, in the current clinical TB vaccine pipeline, there are live‐attenuated TB vaccines to replace BCG. This review discusses the current status of the development of live vaccine candidates designed to replace BCG from the rational strategies and immunological challenges to its clinical trial and identify key areas in the next years considered essential to confer improved safety and efficacy over BCG.

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“…MTBVAC) would induce specific long-term immune responses against certain T cell epitopes that are present in M. tuberculosis and absent in BCG and which may be important for protection [38,83]. Moreover, neonatal vaccination with live-attenuated M. tuberculosis vaccines could represent by far the most effective strategy for conferring high-quality protective immunity against TB, as healthy newborns represent the most sensitive and immunologically naïve population without preexisting mycobacterial immunity, which in older age groups can lead to potential masking and blocking effects to vaccination [18,87]. Additionally, considering the similar biological nature of novel live-attenuated M. tuberculosis vaccines and BCG makes one consider that these novel candidates may also possess the inherent nonspecific benefits attributed to BCG and as such, it would be important to consider evaluating them in advanced clinical development trials.…”

Section: Expert Commentarymentioning

confidence: 99%

“…those in the region of difference 1 (RD1) region) in the process of its attenuation by repeated subcultivation passaging in nonstandardized conditions could be one of the reasons [16,17]. Moreover, large number of human clinical trials suggest that revaccination with BCG does not provide additional benefit, which could be due to preexisting heterologous immunity resulting from infection with nontuberculous environmental mycobacteria (NTM), a process known as masking and blocking [18,19].…”

Section: Introductionmentioning

confidence: 99%

MTBVAC from discovery to clinical trials in tuberculosis-endemic countries

Marinova

Gonzalo-Asensio

Aguilo

et al. 2017

Expert Review of Vaccines

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Introduction: BCG remains the only vaccine against tuberculosis (TB) in use today and despite its impressive global coverage, the nature of BCG protection against the pulmonary forms of TB remains subject to ongoing debate. Because of the limitations of BCG, novel TB vaccine candidates have been developed and several have reached the clinical pipeline. One of these candidates is MTBVAC, the first and only TB vaccine in the clinical pipeline to date based on live-attenuated Mycobacterium tuberculosis that has successfully entered clinical evaluation, a historic milestone in human vaccinology. Areas covered: This review describes development of MTBVAC from discovery to clinical development in high burden TB-endemic countries. The preclinical experiments where MTBVAC has shown to confer improved safety and efficacy over BCG are presented and the clinical development plans for MTBVAC are revealed. The search of all supportive literature in this manuscript was carried out via Pubmed. Expert commentary: Small experimental medicine trials in humans and preclinical efficacy studies with a strong immunological component mimicking clinical trial design are considered essential by the scientific community to help identify reliable vaccine-specific correlates of protection in order to support and accelerate community-wide efficacy trials of new TB vaccines. ARTICLE HISTORY

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Causes of variation in BCG vaccine efficacy: Examining evidence from the BCG REVAC cluster randomized trial to explore the masking and the blocking hypotheses

Cited by 63 publications

References 34 publications

Bacillus Calmette–Guérin (BCG) Revaccination of Adults with Latent Mycobacterium tuberculosis Infection Induces Long-Lived BCG-Reactive NK Cell Responses

Bacillus Calmette–Guérin (BCG) Revaccination of Adults with Latent Mycobacterium tuberculosis Infection Induces Long-Lived BCG-Reactive NK Cell Responses

Current challenges and opportunities for bacillus Calmette‐Guérin replacement vaccine candidates

MTBVAC from discovery to clinical trials in tuberculosis-endemic countries

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