Prime-boost vaccination strategy with bacillus Calmette–Guérin (BCG) and liposomized alpha-crystalline protein 1 reinvigorates BCG potency

Abstract

Summary Bacillus Calmette–Guérin (BCG) remains the only available and most widely administered vaccine against Mycobacterium tuberculosis (Mtb), yet it fails to protect vaccinated individuals either from primary infection or reactivation of latent tuberculosis (TB). Despite BCG's variable efficacy against TB, the fact remains that BCG imparts protection in children against the disease, indicating that BCG possesses a wide protective antigenic repertoire. However, its failure to impart protection in adulthood can be linked to its failure to generate long‐lived memory response and elicitation of an inadequate immune response against latency‐associated antigens. Therefore, to improve the protective efficacy of BCG, a novel vaccination strategy is required. Consequently, in the present study, we have exploited the vaccination potential of liposomized α‐crystalline 1 (Acr1L), a latency‐associated antigen to induce enduring protective immunity against Mtb in BCG‐primed animals. It is noteworthy that an increase in the multi‐functional [interferon (IFN)‐γhi/tumour necrosis factor (TNF)‐αhi] CD4 and CD8 T cells were observed in BCG‐primed and Acr1L‐boosted (BCG‐Acr1L) animals, compared to BCG alone. Further, substantial expansion of both central memory (CD44hi/CD62Lhi) and effector memory (CD44hi/CD62Llo) populations of CD4 and CD8 T cells was noted. Importantly, BCG‐Acr1L exhibited significantly better protection than BCG, as evidenced by a reduction in the bacterial burden and histopathological data of the lungs. In essence, BCG‐Acr1L could be a potent future vaccination strategy to reinvigorate BCG potency.

A lipidated peptide of Mycobacterium tuberculosis resuscitates the protective efficacy of BCG vaccine by evoking memory T cell immunity

“…Nevertheless, BCG efficacy wanes with age, which indicates its failure to elicit life-long immunity [32]. In this context, several approaches are being tried to boost BCG ability to generate enduring memory T cells and protection against TB [8, 9].…”

“…Memory inducing cytokines like IL-7 and IL-15 have been shown to sufficiently augment the BCG induced memory T cells [8]. Furthermore, booster dose of Mtb antigen Acr1 entrapped in fusogenic-liposomes generated long-term memory T cells and improved BCG potency [9]. Thus, it implies that the protective efficacy of BCG can be boosted through antigen-priming.…”

Strategies to Improve BCG Vaccine Efficacy

“…Consistent with this idea, priming with rBCG-CMX followed by a booster vaccination with the same strain showed increased efficacy in reducing lung bacterial load in mice [18]. In another study, mice were first primed with BCG and then boosted with liposome-encapsulated α-crystalline 1 (Acr1L), a latency-associated BCG antigen, which enhanced protection against M. tuberculosis infection [19]. This also resulted in an expansion of IFN-γ hi tumor necrosis factor (TNF)-α hi CD4 + and CD8 + T cells, as well as T CM (CD44 hi CD62L hi ) and T EM (CD44 hi CD62L lo ) CD4 + and CD8 + T cells [19].…”

“…In another study, mice were first primed with BCG and then boosted with liposome-encapsulated α-crystalline 1 (Acr1L), a latency-associated BCG antigen, which enhanced protection against M. tuberculosis infection [19]. This also resulted in an expansion of IFN-γ hi tumor necrosis factor (TNF)-α hi CD4 + and CD8 + T cells, as well as T CM (CD44 hi CD62L hi ) and T EM (CD44 hi CD62L lo ) CD4 + and CD8 + T cells [19]. In a clinical study, BCG-vaccinated children were boosted with a modified vaccinia virus Ankara (MVA) vaccine, MVA85A, carrying the Ag85A antigen of M. tuberculosis [20].…”

Mycobacterium tuberculosis host cell interaction: Role of latency associated protein Acr-1 in differential modulation of macrophages

“…It has been found that Mycobacterium heat shock protein Acr-1 based vaccine can activate the host immune responses that protect host from subsequent Mycobacterium onslaught [ 43 ]. The prophylactic role of Acr-1 has been attributed to its potential to modulate MΦs and also to its capacity to trigger M .…”