Abstract
Heterologous prime–boosting has emerged as a powerful vaccination approach against tuberculosis. However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell responses in BCG-primed mice and investigated its BCG-booster potential. The Apa-specific T-cell response peaked 32–52 weeks after parenteral or mucosal BCG-priming but waned significantly by 78 weeks. A subunit-Apa-boost during the contraction-phase of BCG-response had a greater effect on the magnitude and functional quality of specific cellular and humoral responses compared to a boost at the peak of BCG-response. The cellular response increased following mucosal BCG-prime–Apa-subunit-boost strategy compared to Apa-subunit-prime–BCG-boost approach. However, parenteral BCG-prime–Apa-subunit-boost by a homologous route was the most effective strategy in-terms of enhancing specific T-cell responses during waning in the lung and spleen. Two Apa-boosters markedly improved waning BCG-immunity and significantly reduced Mycobacterium tuberculosis burdens post-challenge. Our results highlight the challenges of optimization of prime–boost regimens in mice where BCG drives persistent immune-activation and suggest that boosting with a heterologous vaccine may be ideal once the specific persisting effector responses are contracted. Our results have important implications for design of prime–boost regimens against tuberculosis in humans.
Highlights
Heterologous prime–boosting has emerged as a powerful vaccination approach against tuberculosis
While Mycobacterium tuberculosis (Mtb) whole cell lysate (WCL) and PPD-specific T cells peak around 12–32 weeks[8,20], native Apa (nApa)-specific total CD4+ T-cell response peaked gradually between 32–52 weeks (Fig. 1a), before waning until 104 weeks, irrespective of the route of Bacille Calmette-Guérin (BCG)-priming
The CD8+ T cells mainly produced IFN-γ(Supplementary Fig. S1b), and exhibited similar expansion and contraction trends in the two groups (Fig. 1a). These results demonstrate that nApa-specific T-cell responses elicited by mucosal or parenteral BCG-priming persist over 1 year and exhibit comparable kinetic patterns in mice
Summary
Heterologous prime–boosting has emerged as a powerful vaccination approach against tuberculosis. The immunological outcomes of boosting during the expansion or peak-phase, when the immune responses are still robust, versus during the contraction-phase of BCG-immunity when the responses wane, have not been systematically studied Another unresolved question is whether the homologous route of prime–boost vaccinations targeting same draining lymph nodes (LNs) provides a more effective boost than the heterologous routes of vaccinations targeting different/distant LNs, as compartmentalization and anatomical localization of T-cell responses differ between mucosal versus parenteral route of BCG-priming[8,13]. We used the mouse model to investigate the boosting potential of a protein-subunit vaccine using Mycobacterium tuberculosis (Mtb) alanine-proline-rich antigen (Apa) as a candidate booster antigen, when administered at the peak versus at the waning of specific BCG-primed response and by altering routes of prime–boost vaccinations
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