Tuberculosis Subunit Vaccination Provides Long-Term Protective Immunity Characterized by Multifunctional CD4 Memory T Cells

Abstract

Improved vaccines capable of promoting long-term cellular immunity are urgently required for a number of diseases that remain global health problems. In the present study, we demonstrate that a tuberculosis subunit vaccine, Ag85B-ESAT-6/CAF01 (where ESAT-6 is early secreted antigenic target of 6 kDa and CAF01 is cationic adjuvant formulation 01), induces very robust memory CD4 T cell responses that are maintained at high levels for >1 year postvaccination. This long-term, vaccine-induced memory response protects against a challenge with Mycobacterium tuberculosis at levels that are comparable to or better than those of bacillus Calmette-Guérin. Characterization of the CD4 memory T cells by multicolor flow cytometry demonstrated that the long-lived memory population consisted almost exclusively of TNF-α+IL-2+ and IFN-γ+TNF-α+IL-2+ multifunctional T cells. In addition, memory cells isolated >1 year postvaccination maintained a strong, vaccine-specific proliferative potential. Long-term memory induced by the BCG vaccine contained fewer multifunctional T cells and was biased toward effector cells mainly of the TNF-α+IFN-γ+-coexpressing subset. Ag85B-ESAT-6/CAF01 vaccination very efficiently sustained multifunctional CD4 T cells that accumulated at the site of infection after M. tuberculosis challenge, whereas the response in unvaccinated animals was characterized by CD4 effector T cells. Our data demonstrate that adjuvanted subunit vaccines can promote long-term protective immune responses characterized by high levels of persisting multifunctional T cells and that the quality and profile of this response is sustained postinfection.

Tuberculosis vaccine with high predicted population coverage and compatibility with modern diagnostics

“…It has previously been shown that in mice vaccinated with BCG, the T cells are primarily effector or effector-memory T cells 6 mo after vaccination (32). In contrast we have shown that 1 y after vaccination with a fusion protein (H1) formulated in the same adjuvant used in this study, the T cells are primarily central memory T cells (33). In HIV-infected individuals, polyfunctional CD4 T cells are a characteristic feature observed in HIV controllers, and an inverse correlation has been shown with viral load, whereas noncontrollers elicit responses dominated by IFN-γ single-positive CD4 T cells (34).…”

Mucosal delivery of antigen‐coated nanoparticles to lungs confers protective immunity against tuberculosis infection in mice

“…Cells from mice immunised with BCG and boosted with Nano-Ag85B (without HBHA) also produced multiple cytokines (75% produced three and 25% two cytokines), suggesting that nanoparticles play a major role in inducing the polyfunctional T-cell responses. Several recent studies have established a link between multifunctional memory CD4 + T cells, i.e.secreting IFN-γ, TNF-α and IL-2, and protection against MTB [29][30][31].In conclusion, we show here that targeting a TB Ag to lung epithelial surfaces by means of fusion with HBHA is an effective way of inducing mucosal and systemic immune responses, particularly for boosting BCG-induced immunity. Formulating HBHAderived hybrid proteins with nanoparticles further enhanced the immune responses and conferred a significantly improved protection against MTB infection, suggesting that this novel mucosal vaccination approach merits further studies, particularly in respect of longevity of the protection and understanding of the cellular and molecular mechanisms involved.…”

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

“…These multifunctional memory CD4 T‐cells are found following vaccination or infection in animal models and in humans 24, 25, 26, 27, 28, 29. In infection models of Leishmania major and Mycobacterium tuberculosis , multifunctional CD4 T‐cells provide the most effective immune protection, and in humans they correlate with successful recovery from infection with Japanese encephalitis virus 25, 27, 29…”