Design of tuberculosis vaccine trials under financial constraints

García‐Basteiro, Alberto L.; Rühwald, Morten; Lange, Christoph

doi:10.1080/14760584.2016.1178067

Cited by 7 publications

(7 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consequently, TB vaccine developers rely on large and expensive trials (more than 3,000 subjects) with long follow-up periods to generate proof of concept efficacy data 3, 4 . Therefore there is a relevant push for further research into animal models and correlates, as well as the integration of exploratory immunological projects nested in the clinical trials 5 .…”

Section: Introductionmentioning

confidence: 99%

Optimisation of a murine splenocyte mycobacterial growth inhibition assay using virulent Mycobacterium tuberculosis

Jensen

Holm

Svensson

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

In the absence of a validated correlate of protection or robust animal models for human tuberculosis, Mycobacterial growth inhibition assays (MGIAs) aim to assess vaccines ability to inhibit mycobacterial growth in-vitro. We optimised a reproducible murine splenocyte MGIA based on in-vitro infection with virulent Mycobacterium tuberculosis (M.tb) Erdman. We identified splenocyte viability as a problem in state-of-art MGIA protocols, which can be improved by simple changes in culture conditions (viability increase from 21% to 46% at last day of culture). The growth inhibitory potential in mice immunised with either BCG, H56:CAF01 or H56:CAF01 administered side-by-side with BCG was significantly better compared to placebo in all groups (0.3 log10 CFU [±0.2, p = 0.049], 0.5 [±0.2, p = 0.016] and 0.6 [±0.1, p = 0.0007], respectively) corresponding to the levels of in-vivo protection. Unexpectedly the CAF01 adjuvant control group also induced significant growth inhibition of 0.3 log10 CFU (±0.2, p = 0.047). Finally, we explored vaccine-associated T cell effector functions. Despite presence of high levels of vaccine-specific T cells, we found no increase in CD4+ T cell number or cytokine expression profile, nor a difference in cytokine levels in the supernatant after four days culture with or without M.tb. Spontaneous IFN-γ release correlated with growth inhibition levels (p = 0.02), however the cellular source was not found.

show abstract

Section: Introductionmentioning

confidence: 99%

Optimisation of a murine splenocyte mycobacterial growth inhibition assay using virulent Mycobacterium tuberculosis

Jensen

Holm

Svensson

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Two pivotal trials have shown for the first time that both sustained Mtb infection and progression from Mtb infection to TB disease can be prevented by vaccination of IGRA-negative and IGRA-positive populations, respectively (Nemes et al, 2018a;Van Der Meeren et al, 2018). These encouraging results will stimulate funding to expand the clinical pipeline and accelerate empirical testing of new vaccine candidates (Voss et al, 2018), which has been limited by a lack of market incentives to develop new vaccines for a disease that predominantly affects the inhabitants of resource-limited developing countries (Garcia-Basteiro et al, 2016). The recent results also require important decisions that will shape the next generation of clinical trials to address critical knowledge gaps and unequivocally demonstrate the public health value of new TB vaccination strategies for endemic countries.…”

Section: Resultsmentioning

confidence: 99%

Clinical Development of New TB Vaccines: Recent Advances and Next Steps

2020

View full text Add to dashboard Cite

Mycobacterium tuberculosis (Mtb) kills more people worldwide than any single infectious pathogen, yet the only vaccine licensed against tuberculosis, Bacille Calmette Guerin (BCG) is approaching its centenary. Two recent advances in clinical tuberculosis vaccine development have invigorated the field. BCG revaccination of interferon-gamma release assay (IGRA) negative adolescents provided 45% protection against sustained Mtb infection defined by IGRA conversion; and the protein-subunit vaccine M72/AS01 E provided 50% protection against progression from Mtb infection to tuberculosis disease in IGRA-positive adults. These findings provide encouraging evidence for pre-exposure and post-exposure approaches to vaccination against tuberculosis, both of which may be necessary to rapidly interrupt the cycle of Mtb transmission and sustain long-term impact on global tuberculosis control. New trials are needed to demonstrate efficacy of M72/AS01 E with greater precision, in a wider age range, in diverse epidemic settings, and in populations that include Mtb-uninfected and HIV-infected persons. Modeling the impact of mass campaigns with M72/AS01 E and other fast-follower vaccine candidates will be crucial to make the use case and demonstrate public health value for TB endemic countries. The size and scope of the next generation of efficacy trials, and the need to expand and accelerate the existing clinical development pipeline, will require public and private consortium funding and concerted political will.

show abstract

“…T-cells are considered essential for the immune control of Mtb ; however, it has been difficult to identify a reliable correlate of the protection reflected in the adaptive immune response from the blood 25 26 . This roadblock severely hinders the development of new TB vaccines, as there currently is no alternative to large and very costly efficacy trials 27 . TB vaccine developers determine vaccine immunogenicity by assessing small and transient changes in the vaccine-specific T-cell populations in the blood 28 29 .…”

Section: Discussionmentioning

confidence: 99%

“…However, it is questionable whether the small fraction of circulating antigen-specific T-cells found in the blood is relevant ( i.e. , capable of migrating to the site of an infection and representative of the T-cell-rich microenvironment controlling Mtb ) 27 30 31 .…”

Section: Discussionmentioning

confidence: 99%

A Suction Blister Protocol to Study Human T-cell Recall Responses <em>In Vivo</em>

Holm

Vukmanovic‐Stejic

Blauenfeldt

et al. 2018

JoVE

Self Cite

View full text Add to dashboard Cite

Cutaneous antigen-recall models allow for studies of human memory responses in vivo. When combined with skin suction blister (SB) induction, this model offers accessibility to rare populations of antigen-specific T-cells representative of the cellular memory response as well as the cytokine microenvironment in situ.This report describes the practical procedure of a cutaneous recall, an SB induction, and a harvest of antigen-specific T-cells. To exemplify the method, the tuberculin skin test is used for antigenic recall in individuals who, prior to this study, underwent a Bacillus Calmette-Guérin vaccination against an infection with Mycobacterium tuberculosis. Finally, examples of multiplex and flow cytometric analyses of SB specimens are provided, illustrating high fractions of antigen-specific polyfunctional CD4+ T-cells available by this sampling method compared with cells isolated from the blood.The method described here is safe and minimally invasive, provides a unique opportunity to study both innate and adaptive immune responses in vivo, and may be beneficial to a broad community of researchers working with cell-mediated immunity and human memory responses, in the context of vaccine development.

show abstract

Design of tuberculosis vaccine trials under financial constraints

Cited by 7 publications

References 15 publications

Optimisation of a murine splenocyte mycobacterial growth inhibition assay using virulent Mycobacterium tuberculosis

Optimisation of a murine splenocyte mycobacterial growth inhibition assay using virulent Mycobacterium tuberculosis

Clinical Development of New TB Vaccines: Recent Advances and Next Steps

A Suction Blister Protocol to Study Human T-cell Recall Responses <em>In Vivo</em>

Contact Info

Product

Resources

About