Tuberculosis in Cape Town: An age-structured transmission model

Blaser, Nello; Zahnd, Cindy; Hermans, Sabine; Salazar‐Vizcaya, Luisa; Estill, Janne; Morrow, Carl; Egger, Matthias; Keiser, Olivia; Wood, Robin

doi:10.1016/j.epidem.2015.10.001

Cited by 35 publications

(30 citation statements)

References 41 publications

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“…On the other hand, the lack of relevant immunity markers makes it difficult to develop a protective vaccine. In this regard, broader vaccine effects analysis, including mucosal immunity induction, antibody responses, and nonconventional T-cells responses, might also help to explain some protective conditions [2], such as BCG vaccination [32], latent infection [33,34], and sterile immunity mediated by antibodies [35]. Thus, the registration of TB vaccine candidates after the relevant safety evaluations might be a straightforward way to speed up initiations of post-registration studies of efficiency in specific but efficiently large groups of people.…”

Section: Discussionmentioning

confidence: 99%

First-In-Human Trials of GamTBvac, a Recombinant Subunit Tuberculosis Vaccine Candidate: Safety and Immunogenicity Assessment

et al. 2019

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Tuberculosis is known to be the biggest global health problem, causing the most deaths by a single infectious agent. Vaccine-development efforts are extremely important. This paper represents the results of the first-in-human trial of recombinant subunit tuberculosis vaccine GamTBvac in a Phase I study. GamTBvac is a new BCG booster candidate vaccine containing dextran-binding domain modified Ag85a and ESAT6-CFP10 MTB antigens and CpG ODN adjuvant, formulated with dextrans. Safety and immunogenicity of GamTBvac were estimated in an open-label clinical trial on 60 Mycobacterium tuberculosis uninfected (MTB-uninfected) volunteers previously-vaccinated with Bacillus Calmette—Guérin vaccine (BCG). The candidate vaccine had an acceptable safety profile and was well-tolerated. Three different vaccine doses with a double-immunization scheme were assessed for immunogenicity and induced a significant increase in IFN-γ in-house IGRA response and IgG ELISA analysis. Among them, the half dose vaccine group (containing DBD-ESAT6-CFP10, 12.5 μg; DBD-Ag85a, 12.5 μg; CpG (ODN 2216), 75 μg; DEAE-Dextran 500 kDa, 250 μg; and Dextran 500 kDa, 5 mg) provided high, early and stable in time immune response specific to both protein antigen fusions and is proposed for the further studies.

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Section: Discussionmentioning

confidence: 99%

First-In-Human Trials of GamTBvac, a Recombinant Subunit Tuberculosis Vaccine Candidate: Safety and Immunogenicity Assessment

et al. 2019

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“…However, preventive therapy is only effective in the first two years after infection and fails to reduce TB incidence if applied without risk-stratification 4,44 . Counterintuitively, recent epidemiological data suggest that individuals who have been treated for active TB are more susceptible to re-infection and progress more rapidly following re-infection, suggesting that clearing latent infection with preventive therapy might be counterproductive in a high transmission setting 15,45 .…”

Section: Several Mouse Models Demonstrate That Infection or Inoculatimentioning

confidence: 99%

“…Both historical cohort studies and contemporary epidemiological studies demonstrate that LTBI is protective against re-infection 3,15 . The phenomenon of a low-grade infection protecting against subsequent infections with the same pathogen has led to the development of almost all live vaccines currently in use, including those based on bacteria (BCG) or experimental vaccines against parasites (Leishmania) 16 .…”

Section: Introductionmentioning

confidence: 99%

Latent Mycobacterium tuberculosis infection provides protection for the host by changing the activation state of the innate immune system

Nemeth¹,

Rothchild³

et al. 2019

Preprint

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An efficacious vaccine against adult tuberculosis (TB) remains elusive. Progress is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of TB 1 . Over 90% of people who become infected with Mtb mount an immune response that contains the bacteria indefinitely, leading to a state known as "latent TB infection" (LTBI) 2 . A significant body of epidemiologic evidence indicates that LTBI protects against active TB after re-exposure, offering an intriguing avenue to identifying protective mechanisms 3,4 . We show that in a mouse model, LTBI is highly protective against infection with Mtb for up to 100 days following aerosol challenge. LTBI mice are also protected against heterologous bacterial challenge (Listeria monocytogenes) and disseminated melanoma suggesting that protection is in part mediated by alterations in the activation state of the innate immune system. Protection is associated with elevated activation of alveolar macrophages (AM), the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma upon aerosol challenge. Systems approaches, including transcriptome analysis of both naïve and infected AMs, as well as ex vivo functional assays, demonstrate that LTBI reconfigures the response of tissue resident AMs.. Furthermore, we demonstrate that both LTBI mice and latently infected humans show similar alterations in the relative proportions of circulating innate immune cells, suggesting that the same cellular changes observed in the LTBI mouse model are also occurring in humans. Therefore, we argue that under certain circumstances, LTBI could be beneficial to the host by providing protection against subsequent Mtb exposure. * * CD11b PerCPCy5.5

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“…Factors associated with elevated risk of progression to TB include age, sex, HIV (10,11), and especially being in recent contact with a patient with active pulmonary TB (12,13). A biomarker that identifies household contacts (HHCs) who will progress to TB would provide an opportunity to arrest disease progression through targeted prophylactic intervention (14,15).…”

Section: Tuberculosis (Tb) Caused By Infection Withmentioning

confidence: 99%

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis

Suliman

Thompson

Sutherland

et al. 2018

Am J Respir Crit Care Med

220

226

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Rationale: Contacts of patients with tuberculosis (TB) constitute an important target population for preventive measures because they are at high risk of infection with Mycobacterium tuberculosis and progression to disease.Objectives: We investigated biosignatures with predictive ability for incident TB.Methods: In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, PCR, and the pair ratio algorithm in a training/test set approach. Overall, 79 progressors who developed TB between 3 and 24 months after diagnosis of index case and 328 matched nonprogressors who remained healthy during 24 months of follow-up were investigated. Measurements and Main Results:A four-transcript signature derived from samples in a South African and Gambian training set predicted progression up to two years before onset of disease in blinded test set samples from South Africa, the Gambia, and Ethiopia with little population-associated variability, and it was also validated in an external cohort of South African adolescents with latent M. tuberculosis infection. By contrast, published diagnostic or prognostic TB signatures were predicted in samples from some but not all three countries, indicating site-specific variability. Post hoc meta-analysis identified a single gene pair, C1QC/TRAV27 (complement C1q C-chain / T-cell receptor-a variable gene 27) that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events.Conclusions: Collectively, we developed a simple whole blood-based PCR test to predict TB in recently exposed household contacts from diverse African populations. This test has potential for implementation in national TB contact investigation programs.

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Tuberculosis in Cape Town: An age-structured transmission model

Cited by 35 publications

References 41 publications

First-In-Human Trials of GamTBvac, a Recombinant Subunit Tuberculosis Vaccine Candidate: Safety and Immunogenicity Assessment

First-In-Human Trials of GamTBvac, a Recombinant Subunit Tuberculosis Vaccine Candidate: Safety and Immunogenicity Assessment

Latent Mycobacterium tuberculosis infection provides protection for the host by changing the activation state of the innate immune system

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis

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