Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials

Norrby, Maria; Vesikari, Timo; Lindqvist, L; Maeurer, Markus; Ahmed, Raija; Mahdavifar, Shahnaz; Bennett, Sean; McClain, J. Bruce; Shepherd, Barbara; Li, Daner; Hokey, David A.; Kromann, Ingrid; Hoff, Søren T.; Andersen, Peter; Visser, Adriëtte W. de; Joosten, Simone A.; Ottenhoff, Tom H. M.; Andersson, Jan; Brighenti, Susanna

doi:10.1016/j.vaccine.2017.01.055

Cited by 47 publications

(28 citation statements)

References 38 publications

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“…The highest vaccineinduced CD4+ T-cell response rates were for those recognizing Ag85B in both the H4:IC31 and H56:IC31 vaccinated groups, which were statistically different at day 70 in comparison to baseline and placebo group responses. This was consistent with its presence in both the H4 and H56 immunogens and also with previous studies that have documented its immunodominance [26]. Unsurprisingly, the cytokine co-expression frequencies and patterns of the Ag85B-specific responses were also similar between the two arms.…”

Section: Discussionsupporting

confidence: 91%

A phase 1b randomized study of the safety and immunological responses to vaccination with H4:IC31, H56:IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa

Bekker

Dintwe²,

Fioré-Gartland

et al. 2020

EClinicalMedicine

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Background: Tuberculosis (TB) remains the leading cause of infectious disease-related death. Recently, a trial of BCG revaccination and vaccination with H4:IC31, a recombinant protein vaccine, in South African adolescents (Aeras C-040-404) showed efficacy in preventing sustained QuantiFERON (QFT) conversion, a proxy for Mycobacterium tuberculosis (M.tb) infection. A phase 1b trial of 84 South African adolescents was conducted, concurrent with Aeras C-040-404, to assess the safety and immunogenicity of H4:IC31, H56:IC31 and BCG revaccination, and to identify and optimize immune assays for identification of candidate correlates of protection in efficacy trials. Methods: Two doses of H4:IC31 and H56:IC31 vaccines were administered intramuscularly (IM) 56 days apart, and a single dose of BCG (2À8 £ 10 5 CFU) was administered intradermally (ID). T-cell and antibody responses were measured using intracellular cytokine staining and binding antibody assays, respectively. Binding antibodies and CD4+/CD8+ T-cell responses to H4-and H56-matched antigens were measured in samples from all participants. The study was designed to characterize safety and immunogenicity and was not powered for group comparisons. (Clinicaltrials.gov NCT02378207). Findings: In total, 481 adolescents (mean age 13¢9 years) were screened; 84 were enrolled (54% female). The vaccines were generally safe and well-tolerated, with no reported severe adverse events related to the study vaccines. H4:IC31 and H56:IC31 elicited CD4+ T cells recognizing vaccine-matched antigens and H4-and H56specific IgG binding antibodies. The highest vaccine-induced CD4+ T-cell response rates were for those recognizing Ag85B in the H4:IC31 and H56:IC31 vaccinated groups. BCG revaccination elicited robust, polyfunctional BCG

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Section: Discussionsupporting

confidence: 91%

A phase 1b randomized study of the safety and immunological responses to vaccination with H4:IC31, H56:IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa

Bekker

Dintwe²,

Fioré-Gartland

et al. 2020

EClinicalMedicine

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“…This complexity emphasizes that antigen hierarchy is context dependent and underscore the need for analyzing individual antigen responses in vaccine studies. Comparable observations in the immune hierarchy have been seen for other vaccines such as ID93, H4, and H56 (26,52,53).…”

Section: Discussionmentioning

confidence: 60%

Rescuing ESAT-6 Specific CD4 T Cells From Terminal Differentiation Is Critical for Long-Term Control of Murine Mtb Infection

et al. 2020

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In most cases, Mycobacterium tuberculosis (Mtb) causes lifelong chronic infections, which poses unique challenges for the immune system. Most of the current tuberculosis (TB) subunit vaccines incorporate immunodominant antigens and at this point, it is poorly understood how the CD4 T cell subsets recognizing these antigens are affected during long-term infection. Very little is known about the requirements for sustainable vaccine protection against TB. To explore this, we screened 62 human-recognized Mtb antigens during chronic murine Mtb infection and identified the four most immunodominant antigens in this setting (MPT70, Rv3020c, and Rv3019c and ESAT-6). Combined into a subunit vaccine, this fusion protein induced robust protection both in a standard shortterm model and in a long-term infection model where immunity from BCG waned. Importantly, replacement of ESAT-6 with another ESAT-6-family antigen, Rv1198, led to similar short-term protection but a complete loss of bacterial control during chronic infection. This observation was further underscored, as the ESAT-6 containing vaccine mediated sustainable protection in a model of post-exposure vaccination, where the ESAT-6-replacement vaccine did not. An individual comparison of the CD4 T cell responses during Mtb infection revealed that ESAT-6-specific T cells were more terminally differentiated than the other immunodominant antigens and immunization with the ESAT-6 containing vaccine led to substantially greater reduction in the overall T cell differentiation status. Our data therefore associates long-term bacterial control with the ability of a vaccine to rescue infection-driven CD4T cell differentiation and future TB antigen discovery programs should focus on identifying antigens with the highest accompanying T cell differentiation, like ESAT-6. This also highlights the importance of long-term readouts in both preclinical and clinical studies with TB vaccines.

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“…A number of fusion protein-based subunit vaccines are being tested as boosters to BCG. However, weak immunogenicity of protein/peptide-based vaccines requires a safe and effective adjuvant, which in itself poses issues (19)(20)(21)(22)(23)(24)34).…”

Section: Discussionmentioning

confidence: 99%

“…However, these vaccines would require effective and safe adjuvant to strengthen the immune responses generated. Some of the fusion protein-based vaccines being tested in clinical trials include H56:IC31 [a fusion protein of three M. tuberculosis antigens (85B, ESAT-6 and Rv2660c) formulated in the proprietary adjuvant IC31 R from Valneva], H4:IC31 [a recombinant fusion protein of Mtb antigens 85B and TB10.4 combined with IC31 R adjuvant] and M72 + ASO1E [immunogenic fusion protein (M72) derived from two M. tuberculosis antigens (MTB32A and MTB39A), and the GlaxoSmithKline's proprietary adjuvant AS01E] (19)(20)(21)(22)(23)(24). The efficacy of these experimental vaccines remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Future Path Toward TB Vaccine Development: Boosting BCG or Re-educating by a New Subunit Vaccine

et al. 2018

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Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), kills 5,000 people per day globally. Rapid development and spread of various multi drug-resistant strains of Mtb emphasize that an effective vaccine is still the most cost-effectives and efficient way of controlling and eradicating TB. Bacillus Calmette-Guerin (BCG), the only licensed TB vaccine, still remains the most widely administered human vaccine, but is inefficient in protecting from pulmonary TB in adults. The protective immunity afforded by BCG is thought to wane with time and considered to last only through adolescent years. Heterologous boosting of BCG-primed immune responses using a subunit vaccine represents a promising vaccination approach to promote strong cellular responses against Mtb. In our earlier studies, we discovered lipopeptides of ESAT-6 antigen with strong potential as a subunit vaccine candidate. Here, we have investigated that potential as a booster to BCG vaccine in both a pre-exposure preventive vaccine and a post-exposure therapeutic vaccine setting. Surprisingly, our results demonstrated that boosting BCG with subunit vaccine shortly before Mtb challenge did not improve the BCG-primed immunity, whereas the subunit vaccine boost after Mtb challenge markedly improved the quantity and quality of effector T cell responses and significantly reduced Mtb load in lungs, liver and spleen in mice. These studies suggest that ESAT-6 lipopeptide-based subunit vaccine was ineffective in overcoming the apparent immunomodulation induced by BCG vaccine in Mtb uninfected mice, but upon infection, the subunit vaccine is effective in re-educating the protective immunity against Mtb infection. These important results have significant implications in the design and investigation of effective vaccine strategies and immunotherapeutic approaches for individuals who have been pre-immunized with BCG vaccine but still get infected with Mtb.

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Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials

Abstract: ClinicalTrials.gov, NCT02066428 and NCT02074956.

Cited by 47 publications

References 38 publications

A phase 1b randomized study of the safety and immunological responses to vaccination with H4:IC31, H56:IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa

A phase 1b randomized study of the safety and immunological responses to vaccination with H4:IC31, H56:IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa

Rescuing ESAT-6 Specific CD4 T Cells From Terminal Differentiation Is Critical for Long-Term Control of Murine Mtb Infection

Future Path Toward TB Vaccine Development: Boosting BCG or Re-educating by a New Subunit Vaccine

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