Self-adjuvanting nanovaccines boost lung-resident CD4+ T cell immune responses in BCG-primed mice

Abstract

Heterologous vaccine regimens could extend waning protection in the global population immunized with Mycobacterium bovis Bacille Calmette-Guerin (BCG). We demonstrate that pulmonary delivery of peptide nanofibers (PNFs) bearing an Ag85B CD4+ T cell epitope increased the frequency of antigen-specific T cells in BCG-primed mice, including heterogenous populations with tissue resident memory (Trm) and effector memory (Tem) phenotype, and functional cytokine recall. Adoptive transfer of dendritic cells pulsed with Ag85B-bearing PNFs further expanded the frequency and functional repertoire of memory CD4+ T cells. Transcriptomic analysis suggested that the adjuvanticity of peptide nanofibers is, in part, due to the release of damage-associated molecular patterns. A single boost with monovalent Ag85B PNF in BCG-primed mice did not reduce lung bacterial burden compared to BCG alone following aerosol Mtb challenge. These findings support the need for novel BCG booster strategies that activate pools of Trm cells with potentially diverse localization, trafficking, and immune function.

From antigen uptake to immune modulation: the multifaceted potential of peptide nanofibers as vaccine nanocarriers

“…A recent study illustrated the ability of Ag85B delivered using KFE8-based b sheet-forming peptide nanofibers to significantly augment the CD4 + T cell response in Bacillus Calmette-Gue ´rin (BCG)-primed mice following intratracheal administration, suggesting the suitability of the peptide nanofibers for efficient pulmonary vaccination. 23 Current models highlight the need for multivalent tuberculosis vaccines capable of eliciting immune protection from both CD4 + and CD8 + T cells, along with functional B cells and other immune cell populations. Incorporating these components into a vaccine formulation poses a challenge.…”

“…Multiple research endeavours have explored the application of peptide nanofibers as carriers for nano-vaccines, encompassing a spectrum of investigations involving model antigens, antigens sourced from infectious agents, antigens derived from tumours, and/or immune adjuvants. [21][22][23][24][25][26] Concomitantly, in-depth scrutiny has been dedicated to the examination of physicochemical attributes inherent to these nanofibers, including surface charge and mechanisms underpinning immune enhancement. Previous studies have ascertained the pronounced capacity of nanofibers to notably amplify the uptake of antigens by APCs.…”

Leverage biomaterials to modulate immunity for type 1 diabetes

“…No T cell proliferation was observed in the patient’s lesions, but there were abnormal antibody responses to T cell-dependent neoantigens ( 135 ). Bacille Calmette-Guerin (BCG), a derivative of Mycobacterium bovis, induces upregulation of the c-Mcy genes that controls glucose homeostasis and is most commonly used to trigger long-term adjustment of blood sugar levels to near-normal levels in patients with T1D ( 136 , 137 ). In addition, patients with long-term T1D received two doses of BCG for 8 years of follow-up.…”

“…Therefore, it is promising to employ BCG to treat T1D. From the perspective of adjuvant, peptide nanofibers have been used to assist BCG vaccine expansion of CD4 + T cells ( 137 ). It may be possible to extract microvesicles of Mycobacterium bovis and load them with immunosuppressive drugs as a strategy to treat T1D.…”

Fast Self‐Assembly Dynamics of a β‐Sheet Peptide Soft Material

“…[10] The self-assembling KFE8 (Ac-FKFEFKFE-NH 2 ) is a β-sheetforming model peptide currently under extensive investigation for, among other applications, vaccine platforms. [11] The octamer is composed of alternating hydrophobic and hydrophilic amino acid repeats, and depending on conditions such as concentration, pH, and ionic strength, gelation will take place in a time range of seconds to hours. [3] Hydrophobic effects act as a first trigger to start aggregation of the extended β-strands in water.…”