Multidimensional analyses reveal modulation of adaptive and innate immune subsets by tuberculosis vaccines

Virginie Rozot,Muki Shey,Mark Hatherill,William J Fulp ,Ann M Ginsberg,Thomas J Scriba,Sanjay Gurunathan,Lebohang Makhethe,Nicole Bilek,Greg Finak,Munyaradzi Musvosvi,Frances Rantangee,Asma Toefy,David A Hokey,Hennie Geldenhuys,Linda‐Gail Bekker ,Simbarashe Mabwe,Elisa Nemes,Carlos A Diazgranados ,Mzwandile Erasmus,C S S Team

doi:10.1038/s42003-020-01288-3

Abstract

We characterize the breadth, function and phenotype of innate and adaptive cellular responses in a prevention of Mycobacterium tuberculosis infection trial. Responses are measured by whole blood intracellular cytokine staining at baseline and 70 days after vaccination with H4:IC31 (subunit vaccine containing Ag85B and TB10.4), Bacille Calmette-Guerin (BCG, a live attenuated vaccine) or placebo (n = ~30 per group). H4:IC31 vaccination induces Ag85B and TB10.4-specific CD4 T cells, and an unexpected NKTlike subset, that expresses IFN-γ, TNF and/or IL-2. BCG revaccination increases frequencies of CD4 T cell subsets that either express Th1 cytokines or IL-22, and modestly increases IFNγ-producing NK cells. In vitro BCG re-stimulation also triggers responses by donor-unrestricted T cells, which may contribute to host responses against mycobacteria. BCG, which demonstrated efficacy against sustained Mycobacterium tuberculosis infection, modulates multiple immune cell subsets, in particular conventional Th1 and Th22 cells, which should be investigated in discovery studies of correlates of protection.

Highlights

We characterize the breadth, function and phenotype of innate and adaptive cellular responses in a prevention of Mycobacterium tuberculosis infection trial
Vaccine-specific CD4 Th1 cell responses detected in peripheral blood mononuclear cells (PBMCs) and whole blood (WB) are correlated
Frequencies of antigen-specific Th1 cells (i.e. CD4+ T cells producing any combination of IFNγ, IL-2, and/or tumor necrosis factor (TNF)) measured by PBMC and WB-intracellular cytokine staining (ICS) assays correlated significantly (r = 0.59, p < 0,0001, Supplementary Fig. 1a)

Summary

Introduction

Function and phenotype of innate and adaptive cellular responses in a prevention of Mycobacterium tuberculosis infection trial. Responses are measured by whole blood intracellular cytokine staining at baseline and 70 days after vaccination with H4:IC31 (subunit vaccine containing Ag85B and TB10.4), Bacille Calmette-Guerin (BCG, a live attenuated vaccine) or placebo (n = ~30 per group). BCG, which demonstrated efficacy against sustained Mycobacterium tuberculosis infection, modulates multiple immune cell subsets, in particular conventional Th1 and Th22 cells, which should be investigated in discovery studies of correlates of protection. We recently completed a phase IIb randomized, controlled, partially blinded trial (C-040-404), which aimed to determine the safety, immunogenicity, and efficacy of H4:IC31 vaccination or Bacille Calmette-Guerin (BCG) revaccination to prevent QuantiFERON TB Gold In-Tube (QFT) conversion in previously BCG vaccinated, QFT-negative adolescents[2]. The live attenuated, whole-cell BCG vaccine comprises a complex array of lipid, polysaccharide, and protein antigens and has been shown to induce potent MHC-restricted

Methods

Results

Conclusion