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Evaluation of the safety and immunogenicity of two antigen concentrations of the Mtb72F/AS02(A) candidate tuberculosis vaccine in purified protein derivative-negative adults.

ABSTRACT: Tuberculosis (TB) remains a major cause of illness and death worldwide, making a new TB vaccine an urgent public health priority. Purified protein derivative (PPD)-negative adults (n = 50) were equally randomized to receive 3 doses at 1-month intervals (at 0, 1, and 2 months) of one of the following vaccines: Mtb72F/AS02(A) (10 or 40 ?g antigen), Mtb72F/saline (10 or 40 ?g antigen), or AS02(A). Mtb72F/AS02(A) recipients received an additional dose 1 year after the first dose to evaluate if the elicited immune response could be boosted. Mtb72F/AS02(A) vaccines were locally reactogenic but clinically well tolerated, with transient adverse events (usually lasting between 1 and 4 days) that resolved without sequelae being observed. No vaccine-related serious adverse events were reported. Vaccination with Mtb72F/AS02(A) induced a strong Mtb72F-specific humoral response and a robust Mtb72F-specific CD4(+) T-cell response, both of which persisted at 9 months after primary immunization and for 1 year after the booster immunization. There was no significant difference between the magnitude of the CD4(+) T-cell response induced by the 10-?g and 40-?g Mtb72F/AS02(A) vaccines. The Mtb72F-specific CD4(+) T cells predominantly expressed CD40L; CD40L and interleukin-2 (IL-2); CD40L and tumor necrosis factor alpha (TNF-?); CD40L, IL-2, and TNF-?; and CD40L, IL-2, TNF-?, and gamma interferon (IFN-?). Serum IFN-?, but not TNF-?, was detected 1 day after doses 2 and 3 for the Mtb72F/AS02(A) vaccine but did not persist. Vaccine-induced CD8(+) T-cell responses were not detected, and no immune responses were elicited with AS02(A) alone. In conclusion, Mtb72F/AS02(A) is clinically well tolerated and is highly immunogenic in TB-naïve adults. The 10- and 40-?g Mtb72F/AS02(A) vaccines show comparable safety and immunogenicity profiles.

SUBMITTER: Leroux-Roels I

PROVIDER: S-EPMC2976103 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Evaluation of the safety and immunogenicity of two antigen concentrations of the Mtb72F/AS02(A) candidate tuberculosis vaccine in purified protein derivative-negative adults.

Leroux-Roels Isabel I Leroux-Roels Geert G Ofori-Anyinam Opokua O Moris Philippe P De Kock Els E Clement Frédéric F Dubois Marie-Claude MC Koutsoukos Marguerite M Demoitié Marie-Ange MA Cohen Joe J Ballou W Ripley WR

Clinical and vaccine immunology : CVI 20100922 11

Tuberculosis (TB) remains a major cause of illness and death worldwide, making a new TB vaccine an urgent public health priority. Purified protein derivative (PPD)-negative adults (n = 50) were equally randomized to receive 3 doses at 1-month intervals (at 0, 1, and 2 months) of one of the following vaccines: Mtb72F/AS02(A) (10 or 40 μg antigen), Mtb72F/saline (10 or 40 μg antigen), or AS02(A). Mtb72F/AS02(A) recipients received an additional dose 1 year after the first dose to evaluate if the e ...[more]

PMID: 20861328

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Project description:BackgroundRequisites for an efficacious tuberculosis (TB) vaccine are a minimal genomic diversity among infectious Mycobacterium tuberculosis strains for the selected antigen, and the capability to induce robust T-cell responses in the majority of human populations. A tool in the identification of putative T-cell epitopes is in silico prediction of major histocompatibility complex (MHC)-peptide binding. Candidate TB vaccine antigen Mtb72F and its successor M72 are recombinant fusion proteins derived from Mtb32A and Mtb39A (encoded by Rv0125 and Rv1196, respectively). Adjuvanted Mtb72F and M72 candidate vaccines were shown to induce CD4(+) T-cell responses in European, US, African and Asian populations.MethodsSequence conservation of Mtb32A, Mtb39A, Mtb72F and M72 among 46 strains (prevalent Mycobacterium strains causing human TB disease, and H37Ra) was assessed by multiple alignments using ClustalX. For Mtb32A, Mtb39A and Mtb72F, 15-mer human leukocyte antigen (HLA)-class II-binding peptides were predicted for 158 DRB1 alleles prevailing in populations with high TB burden, 6 DRB3/4/5, 8 DQ and 6 DP alleles, using NetMHCII-pan-3.0. Results for 3 DRB1 alleles were compared with previously published allele-matched in vitro binding data. Additional analyses were done for M72. Nonameric MHC class I-binding peptides in Mtb72F were predicted for three alleles representative of class I supertypes A02, A03 and B07, using seven prediction algorithms.ResultsSequence identity among strains was ≥98 % for each protein. Residue changes in Mtb39A comprised primarily single residue or nucleotide insertions and/or deletions in repeat regions, and were observed in 67 % of strains. For Mtb72F, 156 DRB1, 6 DRB3/4/5, 7 DQ and 5 DP alleles were predicted to contain at least one MHC class II-binding peptide, and class I-binding peptides were predicted for each HLA-A/B allele. Comparison of predicted MHC-II-binding peptides with experimental data indicated that the algorithm's sensitivity and specificity were variable among alleles.ConclusionsThe sequences from which Mtb72F and M72 are derived are highly conserved among representative Mycobacterium strains. Predicted putative T-cell epitopes in M72 and/or Mtb72F covered a wide array of HLA alleles. In silico binding predictions for class I- and II-binding putative epitopes can be complemented with biochemical verification of HLA binding capacity, processing and immunogenicity of the predicted peptides.

Project description:BACKGROUND:Purified protein derivative (PPD) has been used for more than half a century as an antigen for the diagnosis of tuberculosis infection based on delayed type hypersensitivity. Although designated as "purified," in reality, the composition of PPD is highly complex and remains ill-defined. In this report, high resolution mass spectrometry was applied to understand the complexity of its constituent components. A comparative proteomic analysis of various PPD preparations and their functional characterization is likely to help in short-listing the relevant antigens required to prepare a less complex and more potent reagent for diagnostic purposes. RESULTS:Proteomic analysis of Connaught Tuberculin 68 (PPD-CT68), a tuberculin preparation generated from M. tuberculosis, was carried out in this study. PPD-CT68 is the protein component of a commercially available tuberculin preparation, Tubersol, which is used for tuberculin skin testing. Using a high resolution LTQ-Orbitrap Velos mass spectrometer, we identified 265 different proteins. The identified proteins were compared with those identified from PPD M. bovis, PPD M. avium and PPD-S2 from previous mass spectrometry-based studies. In all, 142 proteins were found to be shared between PPD-CT68 and PPD-S2 preparations. Out of the 354 proteins from M. tuberculosis-derived PPDs (i.e. proteins in either PPD-CT68 or PPD-S2), 37 proteins were found to be shared with M. avium PPD and 80 were shared with M. bovis PPD. Alignment of PPD-CT68 proteins with proteins encoded by 24 lung infecting bacteria revealed a number of similar proteins (206 bacterial proteins shared epitopes with 47 PPD-CT68 proteins), which could potentially be involved in causing cross-reactivity. The data have been deposited to the ProteomeXchange with identifier PXD000377. CONCLUSIONS:Proteomic and bioinformatics analysis of different PPD preparations revealed commonly and differentially represented proteins. This information could help in delineating the relevant antigens represented in various PPDs, which could further lead to development of a lesser complex and better defined skin test antigen with a higher specificity and sensitivity.

Dataset Information

Evaluation of the safety and immunogenicity of two antigen concentrations of the Mtb72F/AS02(A) candidate tuberculosis vaccine in purified protein derivative-negative adults.

Publications

Evaluation of the safety and immunogenicity of two antigen concentrations of the Mtb72F/AS02(A) candidate tuberculosis vaccine in purified protein derivative-negative adults.

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