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The role of antibodies in tuberculosis diagnosis, prophylaxis and therapy: a review from the ESGMYC study group

Solomon Tibebu Melkie, Lilibeth Arias, Chiara Farroni, Mateja Jankovic Makek, Delia Goletti, Cristina Vilaplana
European Respiratory Review 2022 31: 210218; DOI: 10.1183/16000617.0218-2021
Solomon Tibebu Melkie
1Experimental Tuberculosis Unit (UTE), Fundació Institut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona (UAB), Badalona, Spain
2UCBL, UnivLyon, Université Claude Bernard Lyon 1 (UCBL1), Villeurbanne, France
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Lilibeth Arias
1Experimental Tuberculosis Unit (UTE), Fundació Institut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona (UAB), Badalona, Spain
3Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
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Chiara Farroni
4Translational Research Unit, National Institute for Infectious Diseases-IRCCS L. Spallanzani, Rome, Italy
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Mateja Jankovic Makek
5Dept for Respiratory Diseases, University Clinical Centre Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia
6ESCMID (European Society on Clinical Microbiology and Infectious Diseases) study group on mycobacterial infections, Basel, Switzerland
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Delia Goletti
4Translational Research Unit, National Institute for Infectious Diseases-IRCCS L. Spallanzani, Rome, Italy
6ESCMID (European Society on Clinical Microbiology and Infectious Diseases) study group on mycobacterial infections, Basel, Switzerland
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Cristina Vilaplana
1Experimental Tuberculosis Unit (UTE), Fundació Institut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona (UAB), Badalona, Spain
3Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
6ESCMID (European Society on Clinical Microbiology and Infectious Diseases) study group on mycobacterial infections, Basel, Switzerland
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  • For correspondence: cvilaplana@igtp.cat
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    FIGURE 1

    Potential mechanisms of action of antibodies in tuberculosis: a) antibodies enhance phagocytosis of Mycobacterium tuberculosis (MTB) by neutrophils and macrophage via FcR binding; b) antibodies also enhance the fusion of phagosome and lysosome; c) antibodies activate CD4+ T-cells; d) antibodies enhance killing of infected macrophages by activating natural killer (NK) cells; e) antibodies facilitate direct neutralisation of the bacilli; f) antibodies block the binding of MTB to epithelial cells and prevent extrapulmonary dissemination of the bacteria. ADCP: antibody-dependent cellular phagocytosis; CMI: cell-mediated immunity; ADCC: antibody-dependant cellular cytotoxicity; Ag: antigen; Ab: antibody; TCR: T-cell receptor; MHC: major histocompatibility complex.

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  • TABLE 1

    List of antibodies for the diagnosis of active tuberculosis (TB), latent TB infection (LTBI) and treatment monitoring

    Antibodies and MTB antigenResults and relevanceReferences
    Sen and SpTPP status
    Antibodies for diagnosis of active TB
     IgG against 11 antigens (Rv3881, Rv0934, Rv2031c, Rv1886c, Rv1860, Rv3874, Rv2875, Rv3841, Rv1926c, MEMH37Rv and Rv1984)#Sen: for dx of smear positive PTB, 95%Moderately comparable to the target (≥98%)[18]
    Sen: for dx of smear negative PTB, 88%Met the optimal value needed (≥68%)
    Sp: in COPD patients 96% and healthy controls 91%Moderately comparable to the target (>98%)
     IgG against 8 antigens (Ag85B, Ag85A, Ag85C, Rv0934-P38, Rv3881, BfrB, Rv3873 and Rv2878c)#Sen: for screening active TB: 90.6%Met the minimal value for TB screening (>90%)[19]
    Sp: 88.6%Met the optimal target for TB screening test (>70%)
     IgG against 6 antigens and fusion proteins from these antigens (Rv0934, Rv3874, Rv2875, Rv2031, Rv2032 and Rv0831)¶Sen: for dx of smear positive PTB, 93%Moderately comparable to the target (≥98%)[23]
    Sp: 96%Moderately met the optimal value needed (>98%)
     IgG against 7 antigens (PstS1, Rv0831c, FbpA, EspB, bfrB, HspX and ssb)+Sen: for dx of PTB, 74–90%Slightly comparable to target (>98%)[24]
    Sp: 96–100%Met the optimal value (>98%)
     IgG against Rv0220, Rv2958c, Rv2994 and Rv3347c§Sen: 80.4–91.3%Slightly comparable to the optimal value (≥98%)[25]
    Sp: 91.7–98.3%Moderately comparable
     Anti-TB-LTBI IgG, anti-Tpx IgG and anti-MPT64 IgA.  TB-LTBI: (antigen cocktail composed of Tpx and L16)ƒSen: for dx of active TB, 95.2%Moderately comparable to the optimal value (≥98%)[5]
    Sp: 97.6%Comparable to the target (≥98%)
     Anti-LAM IgA, anti-LAM IgG, anti-Tpx IgA, anti-HSP16.3 IgG and anti-HSP20 IgA##Sen: 81%Slightly comparable to the optimal value (≥98%)[21]
    Sp: for dx of non-TB cases, 94%Moderately comparable to the target (≥98%)
     IgG against A60 (commercial test)¶¶Sen: 91.2%Moderately comparable[26]
    Sp: 92%Moderately comparable
     IgG against 38-kDa, 16-kDa, and 6-kDa (commercial test)#Sen: 78.1%Slightly comparable to the optimal value (≥98%)[29]
    Specificity: 100%Met the optimal value (>98%)
    Antibodies for diagnosis of LTBI
     IgG against ESAT6 and MDP1IgG against ESAT6 and MDP1 were significantly higher in recent LTBI compared to remote LTBI (Sen and Sp data not available)[17]
     IgG against PPE17Sen for dx of LTBI 87%, for dx of active TB (95%) (Sp data not available)[4]
     IgG against PPDSera from LTBI has less fucose and more galactose and sialic acid compared to active TB patient[13]
    Antibodies for treatment monitoring
     IgG against 14 kDaIncreased following treatment, and decreased after 3 years[33]
     IgG against 38 kDa and LAMIncreased at month 2 and month 8 following treatment[34]
     IgG against Rv2626c and ESAT6Decreased following treatment
     Anti-16 kDa IgA and IgMDecreased following treatment[5]
     IgG against LAM and TB – LTBIIncreased at month 6 of anti-TB treatment completion
     Anti-Tpx IgG and anti-ESAT-6 IgAPredicated slow responders with an accuracy of 90.5%[32]
     Anti-16 kDa IgGIncreased following TB treatment[6]
     Anti-ESAT-6 and CFP-10 IgGHigher before treatment, and increased following treatment

    Recent LTBI: <2 years since infection; remote LTBI: >2 years since infection. MTB: Mycobacterium tuberculosis; Sen: sensitivity; Sp: specificity; TTP: targeted product profiles; PTB: pulmonary TB; LAM: Lipoarabinomannan; dx: diagnosis. #: IgG against multiple antigens (measured individually, analysed in combination); ¶: IgG against multiple antigens and fusion protein (measured individually, analysed in combination); +: IgG against multiple antigens and antigen cocktails (measured individually, analysed in combination); §: IgG against novel single or multiple antigens; ƒ: multiple antibodies (IgG, IgM, IgA) against multiple antigens and antigen cocktail (measured individually, analysed in combination); ##: multiple antibodies against multiple antigens (measured individually, analysed in combination); ¶¶: IgG against single protein (multiantigen complex).

    • TABLE 2

      Descriptions of the Mycobacterium tuberculosis (MTB) antigens included in this review

      AntigensSynonymsDescriptions and biological activitiesReferences
      esxARv3875, ESAT-66 kDa early secretory antigenic target of unknown function. Elicits high level of INF-γ from memory effector cells during the first phase of a protective immune response. Component of QuantiFERON test, and absent in BCG strain.[17, 77]
      esxBRv3874, CFP1010 kDa culture filtrate antigen of unknown function.[77]
      esxWRv3620Putative ESAT-6 like protein 10 of unknown function.[77]
      esxVRv3619Putative ESAT-6 like protein 1 of unknown function.[77]
      Rv1813cRv1813cA conserved hypothetical protein of unknown function.[78]
      LAMComponents of MTB-cell wall. Inhibit IFN-γ mediated macrophage activation; T-cell proliferation, IL-12 production, neutrophil recruitment, DC activation.[79]
      fbpARv3804c, Ag85aFibronectin binding protein A and components of Ag85 complex (Ag85a), possesses a mycolyltransferase activity (85A) required for the biogenesis of trehalose dimycolate (cord factor), main component for maintaining cell wall integrity.[77]
      fbpBRv1886c, Ag85bFibronectin binding protein B and components of Ag85 complex (Ag85b). Secreted antigen acts as mycolyltransferase (85B), which is involved in cell wall mycoloylation.[77, 80]
      fbpCRv0129c, Ag85cFibronectin binding protein C and components of Ag85 complex (Ag85c). Secreted antigen acts as mycolyltransferase (85C), which is involved in cell wall mycoloylation.[77]
      espBRv3881cSecreted ESX-1 substrate protein B, EspB. A conserved alanine and glycine-rich protein of unknown function.[77]
      mpt70Rv2875Major secreted immunogenic protein of unknown function.[77]
      AcgRv2032Acg (acr-coregulated gene). Conserved protein of unknown function.[77]
      Rv0831Rv0831A conserved protein of unknown function.[77]
      bfrBRv3841Bacterioferritin. Intracellular molecule involved in iron storage.[77]
      Rv0831cRv0831cA conserved protein of unknown role.[77]
      HspXRv2031c, 16/14 kDaHeat shock protein (alpha-crystallin homolog). Stress protein induced by anoxia. Proposed role in long-term survival of the bacilli during latent infections.[77, 79]
      PstS1Rv0934, 38kDaPeriplasmic phosphate-binding lipoprotein (PBP-1). Immunodominant antigen involved in active transport of inorganic phosphate across the membrane.[34, 77]
      SsbRv0054Helix-destabilising protein involved in DNA replication, recombination and repair.[77]
      lipCRv0220Probable esterase LipC with unknown function. A lipolytic enzyme probably active in cellular metabolism.[77]
      Rv2958cRv2958cPossible glycosyl transferase with unknown function. Probably involved in cellular metabolism and has a role in resistance to killing by human macrophages.[77]
      Rv2994Rv2994Probable conserved integral membrane protein with unknown function; could be involved in efflux system.[77]
      Rv1813cRv1813cA conserved hypothetical protein of unknown function.[81, 82]
      A60Located in the cytosol, macromolecular antigen complex, conserved in typical and atypical mycobacteria, main component of commercial ELISA kit (Anda Biologicals, Strasbourg, France).[26]
      HbhARv0475Protein regulated by iron that promotes extrapulmonary dissemination and facilitates adherence to epithelial cells. Induces mycobacterial aggregation.[79]
      TpxRv1932Probable thiol peroxidase with antioxidant activity. Could remove peroxides or H2O2.[77]
      ApaRv1860, MPT-32
      45/47kDa
      Alanine- and proline-rich secreted protein (fibronectin attachment protein). Could mediate bacterial attachment to host cells.[77]
      AcrA1Rv3391Multifunctional enzyme with acyl-CoA-reductase activity. Possibly involved in cellular metabolism.[77]
      hrp1Rv2626cHypoxic response protein 1 of unknown function.[77]
      PPE17Rv1168cPPE of unknown function. Induces strong B-cell responses.[4, 77]
      PPE42Rv2608PPE family protein of unknown function.[77]
      PPE55Rv3347cPPE family protein of unknown function.[77]
      MDP1A histone-like nucleoid associated protein expressed by many mycobacterial species. Could play a role in long-term survival of mycobacteria.[17]

      INF: interferon; BCG: bacille Calmette–Guérin; LAM: lipoarabinomannan; IL: interleukin; DC: dendritic cell; MDP1: mycobacterial DNA-binding protein 1; HbhA: heparin binding haemagglutinin (adhesin); Ssb: single-strand binding protein; H2O2: hydrogen peroxide; PPE: proline-proline-glutamic acid.

      • TABLE 3

        The protective antibodies in tuberculosis (TB) upon passive transfer of polyclonal and monoclonal antibodies

        AntibodyDescriptionProtective effectsReferences
        Polyclonal antibodies in TB
         Human IVIgTreatment in MTB-infected miceSignificant reduction in bacterial load in spleen and lung[43]
         Human IVIgIntact versus deglycosylated IVIg in murine models of progressive TBIntact IVIg reduced bacillary load in the lung[42]
         Human IgGIntranasal inoculation 2 h before MTB infection in miceSignificant reduction in pulmonary bacterial load lasting for 2 months[41]
         Hyperimmune sera (RUTI)Protection against post-chemotherapy relapse TB infection in SCID miceSignificant reduction in bacillary load, less granuloma and less pneumonia compared to the control sera[44]
         Human seraAntibodies from LTBI and active TB in aerosol MTB challenge in miceAntibodies from LTBI showed moderate protection[40]
         Human IgG against PPDIgG from LTBI showed higher sialic acid and galactoseAnti-inflammatory activity[13]
        Monoclonal antibodies in TB
         Human mAb (2E9IgA1) against AcrIntranasal inoculation in transgenic miceReduced the bacterial burden
        Dependant on CD98 (FcαRI)
        [39]
         mAbs IgA (TBA61) against AcrIntranasal inoculation in mice10-fold reduction in CFU[45]
         Coating of BCG mAbs against HBHAIntranasal infection in micePrevents extrapulmonary dissemination[47]
         mAbs (SMITB14) anti-LAM IgG1Intranasal administration in miceImproved survival, reduced CFU, reduced weight loss[48]

        IVIg: intravenous immunoglobulin; MTB: Mycobacterium tuberculosis; SCID: severe combined immunodeficiency; LTBI: latent TB infection; mAb: monoclonal antibody; Acr: alpha crystalline; LAM: lipoarabinomannan; CFU: colony-forming unit; HBHA: heparin-binding haemagglutinin adhesin.

        • TABLE 4

          Antibody responses in current tuberculosis (TB) vaccine candidates

          TB vaccineCurrent stage#Evidence of humoral immunityReferences
          Antibodies in BCG vaccines
           BCGIgG against AM enhanced phagolysosome fusion and intracellular growth inhibition[51]
           BCGIgG against LAM enhanced cell and innate immunity, enhanced phagocytosis[52]
           BCGIgG against mycobacterial cell lysate elevated post-BCG[53]
          Antibodies in subunit TB vaccines
           M72/AS01EIIbAnti-M72 IgG in humans correlated with protection and persisted for 3 years[56]
           H56:IC31IIbInduced H56-specific IgG in phase I trial[61]
           (H4:IC31, H56:IC31 and BCG revaccination)IInduced anti-H4 and anti-H56 IgG1 and IgG3[59]
           ID93/GLA-SEIIaID93-specific IgG induced in phase I trials[62]
           AM-Ag85AProtective anti-AM and anti-Ag85A antibodies in preclinical study[63]
          Antibodies in viral vector-based TB vaccines
           MVA85AIIAg85A-specific CD4 T-cell failed to show protection while anti-Ag85A IgG was protective[12]
           MVA85A-IMX313 and MVA85AInduced IgG specific to Ag85A in phase I trials[66]
           ChAdOx185A/MVA85AIPrime vaccination induced anti-Ag85A IgG, and IgG levels increased by a booster vaccine[67]
          Antibodies in whole-cell TB vaccines
           VPM1002 (rBCG)Live/IIHigher anti-PPD antibodies in human in phase II compared to BCG[68]
           DAR-901Killed/IIbInduced humoral immunity in mouse model of infection[69]
           RUTIKilled/IIaMixed Th1 and Th2 response with antigen-specific antibodies[70]

          BCG: bacille Calmette–Guérin; AM: arabinomannan; LAM: lipoarabinomannan; Th: T-helper cell. #: the stages of the current TB vaccines included in the table refer to clinical development stages and are based on the TuBerculosis Vaccine Initiative [54].

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          The role of antibodies in tuberculosis diagnosis, prophylaxis and therapy: a review from the ESGMYC study group
          Solomon Tibebu Melkie, Lilibeth Arias, Chiara Farroni, Mateja Jankovic Makek, Delia Goletti, Cristina Vilaplana
          European Respiratory Review Mar 2022, 31 (163) 210218; DOI: 10.1183/16000617.0218-2021

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          The role of antibodies in tuberculosis diagnosis, prophylaxis and therapy: a review from the ESGMYC study group
          Solomon Tibebu Melkie, Lilibeth Arias, Chiara Farroni, Mateja Jankovic Makek, Delia Goletti, Cristina Vilaplana
          European Respiratory Review Mar 2022, 31 (163) 210218; DOI: 10.1183/16000617.0218-2021
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          • Article
            • Abstract
            • Abstract
            • Introduction
            • The role of antibodies in TB diagnosis and treatment monitoring
            • The role of antibodies in TB prophylaxis and therapy
            • Antibody response in TB vaccines
            • Mechanism of antibody-mediated protection
            • Studies not showing the protective functions of antibodies
            • Conclusion and perspectives
            • Supplementary material
            • Footnotes
            • References
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