Nanoscale Peptide Self-assemblies Boost BCG-primed Cellular Immunity Against Mycobacterium tuberculosis

Abstract

Bacillus Calmette-Guerin (BCG) is the only vaccine against TB and has limited protection efficacy, which wanes past adolescence. Multifunctional CD8+ T cells (IFN-γ+/TNF-α+/IL-2+) are associated with lower reactivation risk and enhanced control of active Mtb infection. Since boosting with BCG is contraindicated, booster vaccines that augment T cell immunity in the lungs of BCG-vaccinated individuals are urgently needed. We developed a vaccination strategy based on self-assembling peptide nanofibers presenting Mtb-specific CD8+ or CD4+ T cell epitopes that induce high frequency and antigen-specific effector memory T cells producing IFN-γ and IL-2. Intranasal immunization with peptide nanofibers was well tolerated in mice leading to increased antigen-specific CD8+ T cell population in the lungs. Co-assembled nanofibers of CD8+ T cell epitopes and toll-like receptor 2 (TLR2) agonists induced a 8-fold expansion in multifunctional CD8+ T cell populations in the lungs of vaccinated mice. Aerosol challenge with Mtb in BCG-primed and nanofiber-boosted mice provided an additional 0.5-log CFU reduction in lung bacterial load and indicating enhanced protection compared to BCG alone. Together, these data suggest that heterologous prime-boost with BCG and peptide nanofiber vaccines induces cell mediated immunity in the lung, reduces bacterial burden, and is a potentially safer alternative for boosting BCG-primed immunity.

A single dose polyanhydride-based nanovaccine against paratuberculosis infection

“…Recently, nano-peptide based adjuvant enhanced BCG primed immune response by induction of a robust polyfunctional CD8 + T cells. 60 Overall, the presented analyses (Figs 3, 4) clearly indicated robust induction of polyfunctional T cell responses in mice immunized by the nanovaccines as depicted by higher triple and double cytokine producing CD8 + T cells when compared with non-vaccinated (PBS) and Mycopar®-vaccinated mice. It is noteworthy to mention here that for M. tuberculosis vaccines, polyfunctional T cells were mainly CD4 + unlike the predominantly CD8 + population observed in animals vaccinated with the PAN-Cf group.…”

Incorporation of the Tat cell‐penetrating peptide into nanofibers improves the respective antitumor immune response

“…According to results from previous studies (Chesson et al, 2018;Rudra, Sun et al, 2012;Rudra, Tian, Jung, & Collier, 2010;Si et al, 2018), peptide-based nanofibers when used as a (Rudra, Khan et al, 2017;Si et al, 2018). Furthermore, J.…”

“…They have emerged as the most promising platform, as short peptides of interest can be integrated into a nanovaccine in tandem with SAPs such as Q11 (J. Chen et al, 2013; Chesson et al, 2014; Pompano et al, 2014), or KFE8 that assembles into β‐sheet rich nanofibers in physiological buffer (Mora‐Solano et al, 2017; Rudra, Ding et al, 2016). In addition, SAP‐based nanofibers can be generated bearing different epitopes via noncovalent self‐assembly of SAP that are synthesized in tandem with defined epitopes (Chesson et al, 2018; Pompano et al, 2014). SAP‐based nanofibers have recently gained increased attention as vaccine platform for the application in infectious and noninfectious diseases (Mora‐Solano et al, 2017; Rudra, Ding et al, 2016; Si et al, 2018; Trent et al, 2015).…”

Advancements in prophylactic and therapeutic nanovaccines

“…Mice vaccinated with coassembly of nanofibers containing CD8 + T cell epitopes and TLR2 agonists in the lungs increased the expansion of multi-functional cytotoxic T cell population. On further challenge with Mtb, significant reduction in lung bacterial load was observed in comparison to BCG primed mice [67] . In another study, Mtb lipid-based nanovaccines were used wherein chitosan nanoparticles bound with Mtb lipids induced cell-mediated and antibody-mediated immunity by secretion of immunoglobulins (IgG, IgM) and prominent Th1 and Th2 cytokines in lymph node and spleen cells [136] .…”

“…Such peptide sequences undergo assembly into fibrils with the antigenic epitope sticking outward from the fibril surface [6] . These fibrils have been assembled with various epitopes of Plasmodium falciparum [66] , Mycobacterium tuberculosis [67] , Streptococcus aureus [68] , T-helper cells epitope PADRE [68] and OVA epitopes [69] . Conjugation of E2EP3 immunogenic epitope of Chikungunya virus E2 glycoprotein with β-sheet self-adjuvanted amyloid assemblies showed cytocompatibility with enhanced macrophage uptake and robust IgG response against E2EP3 epitope [70] .…”