Safety and immunogenicity of the M72/AS01 E candidate tuberculosis vaccine in adults with tuberculosis: A phase II randomised study

Gillard, Paul; Yang, Pan‐Chyr; Danilovitš, Manfred; Su, Wei‐Juin; Cheng, Shih-Lung; Pehme, Lea; Bollaerts, Anne; Jongert, Erik; Moris, Philippe; Ofori-Anyinam, Opokua; Demoitié, Marie-Ange; Castro, Marcela

doi:10.1016/j.tube.2016.07.005

Cited by 65 publications

(56 citation statements)

References 43 publications

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“…This vaccine has decreased bacterial loads and elicited CD4 ϩ and CD8 ϩ multifunctional T-cell responses in mice infected with multidrug-resistant TN5904 as well as H37Rv (41). Mtb72F, developed by GSK, contains PPE18, which was produced from the H37Rv strain (40,42). Several genetic variations, including SNPs in PPE18, have been observed in clinical isolates and result in alteration of amino acid sequences even in T-cell epitopes (43).…”

Section: Discussionmentioning

confidence: 99%

Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice

Kim

Hur

et al. 2017

Clin Vaccine Immunol

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The aim of this study was to evaluate the protective efficacy of MTBK_ 24820, a complete form of PPE39 protein derived from a predominant Beijing/K strain of Mycobacterium tuberculosis in South Korea. Mice were immunized with MTKB_24820, M. bovis Bacilli Calmette-Guérin (BCG), or adjuvant prior to a high-dosed Beijing/K strain aerosol infection. After 4 and 9 weeks, bacterial loads were determined and histopathologic and immunologic features in the lungs and spleens of the M. tuberculosis-infected mice were analyzed. Putative immunogenic T-cell epitopes were examined using synthetic overlapping peptides. Successful immunization of MTBK_24820 in mice was confirmed by increased IgG responses (P Ͻ 0.05) and recalled gamma interferon (IFN-␥), interleukin-2 (IL-2), IL-6, and IL-17 responses (P Ͻ 0.05 or P Ͻ 0.01) to MTBK_24820. After challenge with the Beijing/K strain, an approximately 0.5 to 1.0 log 10 reduction in CFU in lungs and fewer lung inflammation lesions were observed in MTBK_24820-immunized mice compared to those for control mice. Moreover, MTBK_24820 immunization elicited significantly higher numbers of CD4 ϩ T cells producing protective cytokines, such as IFN-␥ and IL-17, in lungs and spleens (P Ͻ 0.01) and CD4 ϩ multifunctional T cells producing IFN-␥, tumor necrosis factor alpha (TNF-␣), and/or IL-17 (P Ͻ 0.01) than in control mice, suggesting protection comparable to that of BCG against the hypervirulent Beijing/K strain. The dominant immunogenic T-cell epitopes that induced IFN-␥ production were at the N terminus (amino acids 85 to 102 and 217 to 234). Its vaccine potential, along with protective immune responses in vivo, may be informative for vaccine development, particularly in regions where the M. tuberculosis Beijing/K-strain is frequently isolated from TB patients.

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Section: Discussionmentioning

confidence: 99%

Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice

Kim

Hur

et al. 2017

Clin Vaccine Immunol

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“…2). The M72 vaccine sponsored by GSK (47) and originally developed by Corixa (48) contains PPE 18 also known as Mtb39a (Rv1196; Fig. 2).…”

Section: Clinical Studies Of Tb Vaccines Containing Ppesmentioning

confidence: 99%

The Enigmatic PE/PPE Multigene Family of Mycobacteria and Tuberculosis Vaccination

Brennan

2017

Infect Immun

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The genome of Mycobacterium tuberculosis, the bacterium responsible for the disease tuberculosis, contains an unusual family of abundant antigens (PE/PPEs). To date, certain members of this multigene family occur only in mycobacteria that cause disease. It is possible that the numerous proteins encoded by these mycobacterial genes dictate the immune pathogenesis of this bacterial pathogen. There is also evidence that some of these antigens are present at the cell surface and that they affect the pathology and immunology of the organism in many ways. Also, they elicit both antibodies and T cells, they may be involved in antigenic variation, and they may be good candidates for vaccines and drugs. However, since they are plentiful and extremely homologous, these PE/PPEs are very challenging to study, and it is difficult to be certain what role(s) they have in the pathogenesis of tuberculosis. Consequently, how to develop treatments like vaccines using these antigens as candidates is complex.

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“…While the biological consequences are not completely understood, these findings imply that these epitopes are conserved because they fulfill an important biological role, and that immune recognition of MTBC may favor the pathogen . One of the proteins in a polypeptide candidate TB vaccine, M72/AS0E1, which recently yielded acceptable safety results in a phase II trial , contains a sequence from a PE protein discussed in previous sections. High sequence variability among MTBC clinical isolates has been observed in these specific proteins .…”

Section: Translational Implications Of Mtbc Lineage Associated Variatmentioning

confidence: 99%

Immunological consequences of strain variation within the Mycobacterium tuberculosis complex

et al. 2017

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In 2015, there were an estimated 10.4 million new cases of tuberculosis (TB) globally, making it one of the leading causes of death due to an infectious disease. TB is caused by members of the Mycobacterium tuberculosis complex (MTBC), with human disease resulting from infection by M. tuberculosis sensu stricto and M. africanum. Recent progress in genotyping techniques, in particular the increasing availability of whole genome sequence data, has revealed previously under appreciated levels of genetic diversity within the MTBC. Several studies have shown that this genetic diversity may translate into differences in TB transmission, clinical manifestations of disease, and host immune responses. This suggests the existence of MTBC genotype‐dependent host–pathogen interactions which may influence the outcome of infection and progression of disease. In this review, we highlight the studies demonstrating differences in innate and adaptive immunological outcomes consequent on MTBC genetic diversity, and discuss how these differences in immune response might influence the development of TB vaccines, diagnostics and new therapies.

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Safety and immunogenicity of the M72/AS01 E candidate tuberculosis vaccine in adults with tuberculosis: A phase II randomised study

Cited by 65 publications

References 43 publications

Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice

Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice

The Enigmatic PE/PPE Multigene Family of Mycobacteria and Tuberculosis Vaccination

Immunological consequences of strain variation within the Mycobacterium tuberculosis complex

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