Exploiting Pre-Existing CD4+ T Cell Help from Bacille Calmette–Guérin Vaccination to Improve Antiviral Antibody Responses

Abstract

The continuing emergence of viral pathogens and their rapid spread into heavily populated areas around the world underscore the urgency for development of highly effective vaccines to generate protective antiviral Ab responses. Many established and newly emerging viral pathogens, including HIV and Ebola viruses, are most prevalent in regions of the world in which Mycobacterium tuberculosis infection remains endemic and vaccination at birth with M. bovis bacille Calmette–Guérin (BCG) is widely used. We have investigated the potential for using CD4+ T cells arising in response to BCG as a source of help for driving Ab responses against viral vaccines. To test this approach, we designed vaccines comprised of protein immunogens fused to an immunodominant CD4+ T cell epitope of the secreted Ag 85B protein of BCG. Proof-of-concept experiments showed that the presence of BCG-specific Th cells in previously BCG-vaccinated mice had a dose-sparing effect for subsequent vaccination with fusion proteins containing the Ag 85B epitope and consistently induced isotype switching to the IgG2c subclass. Studies using an Ebola virus glycoprotein fused to the Ag 85B epitope showed that prior BCG vaccination promoted high-affinity IgG1 responses that neutralized viral infection. The design of fusion protein vaccines with the ability to recruit BCG-specific CD4+ Th cells may be a useful and broadly applicable approach to generating improved vaccines against a range of established and newly emergent viral pathogens.

CD4+ T Cells Induced by Tuberculosis Subunit Vaccine H1 Can Improve the HIV-1 Env Humoral Response by Intrastructural Help

“…Although the model of ISH presented here is based on a vaccine system currently investigated in clinical trials, a recent report by Ng et al also indicates a possible clinical applicability of ISH with the licensed tuberculosis vaccine BCG [ 60 ]. The authors demonstrate that a fusion protein of an immunogen and two BCG peptides (one of which was similar to this study) is able to recruit BCG-induced T helper cells, leading to an isotype switch to the IgG2c subtype.…”

Biomaterial engineering strategies for B cell immunity modulations

“…Leveraging pre-existing T cells can accelerate GC formation and amplify the magnitude of GC responses, 212–215 but the expansion on antigen-specific B cells appears to be minimal in other studies. 216 Additionally, while the enhancement effect is clearly T cell epitope dependent, the exact phenotype of the effector T cells involved in this process remains unclear.…”

“…Wallis et al subsequently developed liposomal vaccine particles that displayed ErbB-2 and encapsulated OVA 323-339 peptides to improve antibodies against the cancer surface protein ErbB-2, also known as HER-2. 211 Leveraging pre-existing T cells can accelerate GC formation and amplify the magnitude of GC responses, [212][213][214][215] but the expansion on antigen-specific B cells appears to be minimal in other studies. 216 Additionally, while the enhancement effect is clearly T cell epitope dependent, the exact phenotype of the effector T cells involved in this process remains unclear.…”

Designing Anti-Viral Vaccines that Harness Intrastructural Help from Prior BCG Vaccination

“…There is currently just a handful of FDA-approved adjuvants available for vaccine formulation in humans [ 8 ], and many of these do not elicit protective immune responses when formulated with subunit vaccines and require adjustments in dose and formulation to be compatible with different antigens [ 9 ]. We have studied the possibility of using the activities of pre-existing mycobacteria-specific helper T cells (Th) to address this problem [ 10 ]. Our previous studies took advantage of BCG Th cells, which are already present in BCG-vaccinated individuals, and increased the immunogenicity of the subunit vaccine, in this case, an Ebola virus glycoprotein, by adding BCG CD4 + T cell (Th) epitopes to the immunogen.…”