BCG revaccination boosts adaptive polyfunctional Th1/Th17 and innate effectors in IGRA+ and IGRA– Indian adults
Srabanti Rakshit, Asma Ahmed, Vasista Adiga, Bharath K. Sundararaj, Pravat Nalini Sahoo, John Kenneth, George D’Souza, Wesley Bonam, Christina Johnson, Kees L.M.C. Franken, Tom H.M. Ottenhoff, Greg Finak, Raphael Gottardo, Kenneth D. Stuart, Stephen C. De Rosa, M. Juliana McElrath, Annapurna Vyakarnam
Srabanti Rakshit, Asma Ahmed, Vasista Adiga, Bharath K. Sundararaj, Pravat Nalini Sahoo, John Kenneth, George D’Souza, Wesley Bonam, Christina Johnson, Kees L.M.C. Franken, Tom H.M. Ottenhoff, Greg Finak, Raphael Gottardo, Kenneth D. Stuart, Stephen C. De Rosa, M. Juliana McElrath, Annapurna Vyakarnam
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Clinical Research and Public Health Immunology Infectious disease

BCG revaccination boosts adaptive polyfunctional Th1/Th17 and innate effectors in IGRA+ and IGRA– Indian adults

Abstract

BACKGROUND Bacille Calmette-Guérin (BCG) vaccine is protective against Tuberculosis (TB) in children, but its efficacy wanes with age. Consequently, determining if BCG revaccination augments anti-TB immunity in young adults in TB endemic regions is vital.METHODS Two hundred healthy adults, BCG vaccinated at birth, were tested for their IFN-γ release assay (IGRA) status. Of these, 28 IGRA+ and 30 IGRA– were BCG revaccinated, and 24 IGRA+ and 23 IGRA– subjects served as unvaccinated controls. T and innate cell responses to mycobacterial antigens were analyzed by 14-color flow cytometry over 34 weeks.RESULTS IFN-γ and/or IL-2 Ag85A- and BCG-specific CD4+ and CD8+ T cell responses were boosted by revacciantion at 4 and 34 weeks, respectively, and were > 2-fold higher in IGRA+ compared with IGRA– vaccinees. Polyfunctional Ag85A, BCG, and mycobacterium tuberculosis (Mtb) latency Ag–specific (LTAg-specific) CD4+ T cells expressing up to 8 cytokines were also significantly enhanced in both IGRA+ and IGRA– vaccinees relative to unvaccinated controls, most markedly in IGRA+ vaccinees. A focused analysis of Th17 responses revealed expansion of Ag85A-, BCG-, and LTAg-specific total IL-17A+,IL-17F+,IL-22+, and IL-10+ CD4+ T cell effectors in both IGRA+ and IGRA– subjects. Also, innate IFN-γ+ NK/γδ/NKT cell responses were higher in both IGRA+ and IGRA– vaccinees compared with controls. This is the first evidence to our knowledge that BCG revaccination significantly boosts antimycobacterial Th1/Th17 responses in IGRA+ and IGRA– subjects.CONCLUSION These data show that BCG revaccination is immunogenic in IGRA– and IGRA+ subjects, implying that Mtb preinfection in IGRA+ subjects does not impact immunogenicity. This has implications for public health and vaccine development strategies.FUNDING This work was funded principally by DBT-NIH (BT/MB/Indo-US/HIPC/2013).

Authors

Srabanti Rakshit, Asma Ahmed, Vasista Adiga, Bharath K. Sundararaj, Pravat Nalini Sahoo, John Kenneth, George D’Souza, Wesley Bonam, Christina Johnson, Kees L.M.C. Franken, Tom H.M. Ottenhoff, Greg Finak, Raphael Gottardo, Kenneth D. Stuart, Stephen C. De Rosa, M. Juliana McElrath, Annapurna Vyakarnam

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Figure 7

COMPASS heatmaps showing different polyfunctional CD4+ and CD8+ T cell subsets after BCG vaccination.

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COMPASS heatmaps showing different polyfunctional CD4+ and CD8+ T cell s...
Stacked COMPASS heatmaps displaying CD4+ (upper panel) and CD8+ (lower panel) whole blood T cell responses to Ag85A (left panel) and BCG (right panel) in BCG revaccinees (Group 1 [IGRA+, orange] and Group 2 [IGRA–, bright green]) versus unvaccinated controls (Group 3 [IGRA+, light green] and Group 4 [IGRA–,blue]). In the heatmap, columns correspond to the different disjoint cell subsets in which responses were detected and are color-coded in the x-axis legend by the cytokines they express (white, “off”; shaded, “on”; grouped by color, “degree of functionality”) and are displayed in order of increasing functionality from left to right (sky blue to peach). For example, the first column represents CD4+ T cells that produce IFN-γ but none of the other functions. Rows represent study subjects (Group 1, n = 21; Group 2, n = 20; Group 3, n = 18; Group 4 n = 18), which are ordered by the group they belong to and the time point (0 [turquoise] and 4 [pink] weeks for Ag85A and 0 [turquoise] and 34 [pink] weeks for BCG) as shown in the legend at the right. Each cell of the heatmap shows the probability estimated by COMPASS that the observed response is antigen specific in the corresponding subject (row) and cell subset (column), where the probability is color-coded from white (probability, 0) to purple (probability, 1). A probability of 0 indicates certainty that the observed response is background, while a probability of 1 indicates certainty that the observed response is antigen specific. Horizontal lines were added to separate the time points, and red boxes were inserted to highlight the subsets of interest.