Supramolecular Peptide Nanofiber Vaccines for Eliciting CD8+ T-cell Responses
Chesson, Charles Brent
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CD8+ T cells play a central role in immunity against intracellular pathogens and cancer.Vaccines that elicit robust CD8+ T cell responses are desirable for protection against such infectious diseases and cancers. Subunit vaccines using whole protein or peptide epitopes are becoming increasingly favored due to their superior safety profile compared with live-attenuated or inactive pathogen formulations. The immunogenicity of subunit vaccines often depend heavily on adjuvants. Currently approved clinical adjuvants are chemically heterogeneous mixtures of plant- or pathogen-derived byproducts or formulations of mineral salts, which suffer from toxic side effects. The widely used systemic adjuvant alum is a heterogeneous mixture of aluminum salts whose mechanism of action is still being debated after 80 years of use. These current adjuvants elicit robust humoral responses but fail to elicit robust CD8+ T cell responses. We recently reported that self-assembling peptides that assemble into β-sheet rich nanofibers in physiological buffers could act as self-adjuvanting vaccine carriers. Nanofibers bearing an antigenic peptide epitope from chicken egg ovalbumin (OVA323-339) elicited strong CD4+ T cell-dependent antibody responses, which were detectable for a year. Our report begins with the investigation into whether self-assembling peptide adjuvants can activate CD8+ T cells and elicit protective CTL responses. We conjugated the CD8+ T cell epitope from chicken egg ovalbumin (OVA257-264) via a short linker to a peptide self-assembling domain and investigated immune responses in mice. Our results indicate that OVA257-264-bearing nanofibers can activate CD8+ T cells leading to the production of cytokines, cytolytic markers, and robust antigen-specific CTL responses in vivo. We found that CD8+ specific T-cells populations are significantly higher when immunized with the nanofiber adjuvants compared to clinical adjuvants. Also, CD8+ memory recall responses were enhanced and provided superior protection against an OVA-expressing influenza challenge. Mycobacterium tuberculosis (Mtb) is an opportunistic pathogen that causes nearly 1.4 million deaths and over 8 million new or reactivated infections each year worldwide. It is known that CD4+ and CD8+ T cells are required to mount an effective immune response and IFN- and TNF- are key cytokines in fighting Mtb infection. While IFN- is crucial in the protective immune response to Mtb, it is not sufficient on its own. Multifunctional CD8+ T cells that produce IFN-/ TNF-/IL-2 have been associated with lower risk of reactivation of latent infection and enhanced control of active infection. Building on our report that self-assembling nanofibers bearing a model antigen OVA can stimulate robust CD8+ T cell effector and memory responses, we investigated whether self-assembling peptide (KFE8) nanofibers displaying multiple Mtb epitopes (TB10.4 and AG85B) or toll-like receptor (TLR) agonists (MALP, a TLR-2 agonist) can be co-assembled to generate vaccines capable of eliciting higher levels of IFN-+ CD8+ T cells and multifunctional CD8+ T cells that produce IFN-/TNF-/IL-2. Our data indicates that co-assembled peptide nanofiber vaccines bearing TB10.4 and AG85B elicit significantly higher levels of IFN-+ CD8+ T cells compared to single epitopes. Inclusion of MALP or a CD4+ epitope leads to 8-fold increase in the production of multifunctional CD8+ T cells that produce IFN-/TNF-/IL-2 in mouse models. Mice primed with BCG and then inoculated with a booster dose of peptide nanofiber vaccines had decreased bacterial loads in the lungs. Our data suggests that peptide based nanofibers exhibit desirable qualities as a vaccine carrier and show promising potential as adjuvants for prophylactic vaccines for infectious diseases.