A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates

PLoS Pathog. 2019 Mar 4;15(3):e1007643. doi: 10.1371/journal.ppat.1007643. eCollection 2019 Mar.

Abstract

Eradication of tuberculosis (TB), the world's leading cause of death due to infectious disease, requires a highly efficacious TB vaccine. Many TB vaccine candidates are in pre-clinical and clinical development but only a few can be advanced to large-scale efficacy trials due to limited global resources. We aimed to perform a statistically rigorous comparison of the antigen-specific T cell responses induced by six novel TB vaccine candidates and the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG). We propose that the antigen-specific immune response induced by such vaccines provides an objective, data-driven basis for prioritisation of vaccine candidates for efficacy testing. We analyzed frequencies of antigen-specific CD4 and CD8 T cells expressing IFNγ, IL-2, TNF and/or IL-17 from adolescents or adults, with or without Mycobacterium tuberculosis (M.tb) infection, who received MVA85A, AERAS-402, H1:IC31, H56:IC31, M72/AS01E, ID93+GLA-SE or BCG. Two key response characteristics were analyzed, namely response magnitude and cytokine co-expression profile of the memory T cell response that persisted above the pre-vaccination response to the final study visit in each trial. All vaccines preferentially induced antigen-specific CD4 T cell responses expressing Th1 cytokines; levels of IL-17-expressing cells were low or not detected. In M.tb-uninfected and -infected individuals, M72/AS01E induced higher memory Th1 cytokine-expressing CD4 T cell responses than other novel vaccine candidates. Cytokine co-expression profiles of memory CD4 T cells induced by different novel vaccine candidates were alike. Our study suggests that the T cell response feature which most differentiated between the TB vaccine candidates was response magnitude, whilst functional profiles suggested a lack of response diversity. Since M72/AS01E induced the highest memory CD4 T cell response it demonstrated the best vaccine take. In the absence of immunological correlates of protection, the likelihood of finding a protective vaccine by empirical testing of candidates may be increased by the addition of candidates that induce distinct immune characteristics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Adolescent
  • Adult
  • Antigens, Bacterial
  • BCG Vaccine
  • CD4-Positive T-Lymphocytes
  • Cytokines
  • Drug Combinations
  • Female
  • Histocompatibility Antigens Class II / immunology
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Immunity, Humoral / immunology
  • Immunity, Humoral / physiology
  • Interferon-gamma
  • Interleukin-17
  • Interleukin-2
  • Lipid A / analogs & derivatives
  • Male
  • Mycobacterium bovis
  • Mycobacterium tuberculosis / immunology*
  • Mycobacterium tuberculosis / pathogenicity
  • Saponins
  • Th1 Cells
  • Tuberculosis / immunology
  • Tuberculosis / metabolism
  • Tuberculosis Vaccines / metabolism*
  • Tuberculosis Vaccines / pharmacology*
  • Tumor Necrosis Factor-alpha
  • Vaccines, DNA

Substances

  • AERAS-402
  • Adjuvants, Immunologic
  • Antigens, Bacterial
  • BCG Vaccine
  • Cytokines
  • Drug Combinations
  • Histocompatibility Antigens Class II
  • IFNG protein, human
  • Interleukin-17
  • Interleukin-2
  • Lipid A
  • MVA 85A
  • Saponins
  • Tuberculosis Vaccines
  • Tumor Necrosis Factor-alpha
  • Vaccines, DNA
  • adjuvant system 01
  • Interferon-gamma

Grants and funding

MR was supported by a scholarship by South African Centre for Epidemiological Modelling and Analysis (www.sacema.org). EN is a Marylou Ingram Scholar of the International Society for Advancement of Cytometry (www.isac-net.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.