Joel H. Collier

Chronic inflammation driven by sustained interleukin-1 beta (IL-1β) signaling disrupts the resolution phase of tissue repair by orchestrating dysregulated immune activity. As a key upstream mediator, IL-1β prolongs the activation of pro-inflammatory myeloid cells and establishes an environment that prevents the transition to tissue repair. Here, we developed an active immunotherapy against IL-1β using the self-assembling peptide nanofiber Coil29, which elicits robust and specific IL-1β-targeted immune responses in both wild-type and diabetic mice, without inducing systemic immunosuppression. In a chronic wound model, the therapy accelerated re-epithelialization and enhanced overall tissue regeneration, outperforming anti-IL-1β monoclonal antibodies. This therapy suppressed macrophage activity, promoted their M2-like polarization, enhanced pro-healing cytokine secretion and enriched the injury site with anti-IL-1β antibodies. In vitro, we found that antibodies from immunized mice reprogrammed M1 macrophages toward an M2-like phenotype, suggesting that antibody-mediated modulation of IL-1β activity may drive the enhanced wound re-epithelization seen in immunized animals. Altogether, these findings highlight a targeted, regenerative therapy for the healing of chronic wounds.

Focusing antibody responses towards known neutralizing epitopes is a major strategy for protective immunization. Targeting flexible antigenic regions represents a unique challenge because functional antibodies must be able to bind the epitope of interest in multiple conformations. The fusion peptide (FP) of HIV-1 is a flexible peptide critical to viral entry of host cells for which broadly neutralizing antibodies have been identified. Because elicitation of potent, functional antibodies toward this epitope remains an unmet challenge in HIV-1 vaccination, we introduce a designed immunogen platform capable of raising anti-FP-antibodies with increased conformational tolerance relative to a traditional carrier protein. Antibodies induced by these immunogens bind heterologous FP sequences when elicited in mice and infant non-human primates. This platform shows promise for preclinical development to prime antibody responses toward FP of the HIV-1 envelope and can likely be translated to peptide immunofocusing for other viral pathogens.

Biomaterials are increasingly sought as central components of new medical technologies for inflammatory conditions because they serve a range of functions from inert carriers of anti-inflammatory molecules to active engagers of the immune system. Unique challenges presented by diseases of mucosal tissues necessitate biomaterial designs that can circumvent the mucosal barrier and engage tissue-specific immune cells. This review will describe recent advances in biomaterials for treating specific mucosal inflammatory diseases.

Therapeutic allergen vaccine immunogens can trigger IgE-mediated mast cell activation, resulting in allergic reactions. Here, we report on a mode of hypoallergenic immunogen design that enables immunization against IgE-reactive peptide B cell epitopes by optimizing the distance between epitopes. Using DNA-based model immunogens, we show that mast cells and B cells exhibit idiosyncratic sensitivity to interepitope spacing, with mast cell activation being dampened by high interepitope spacing while B cells remain responsive to identical immunogen configurations. To exploit this finding, we construct hypoallergenic immunogens based on supramolecular peptide nanofibers with ultralow epitope density that, when used as an allergen vaccine, raise protective allergen-neutralizing IgG antibody responses. This study provides a proof-of-concept for a mode of hypoallergenic immunogen design based on nanoscale control of the distances between IgE-reactive epitopes, which may enable allergen vaccination against IgE-reactive epitope targets in the absence of allergic reactogenicity.

Mucosal immune responses to vaccination are essential for achieving full protection against pathogens entering their host at mucosal sites. However, traditional parenteral immunization routes commonly fail to raise significant mucosal immunity. Sublingual immunization is a promising alternative delivery route to raise robust immune responses both systemically and at mucosal sites, and nanomaterial‐based subunit vaccine platforms offer opportunities for raising epitope‐specific responses. Here, sublingual immunization is reported using the Coil29 platform of coiled‐coil self‐assembling peptide nanofibers. The successful immunization with epitopes of varying physicochemical properties by including mucus‐modulating components – namely sequences of proline, alanine, and serine (PAS) is demonstrated. PASylation is shown to decrease mucin complexation and increase epithelial penetration in vitro, enabling sublingual immunization against a variety of selected peptide epitopes in vivo. Coil29 fibers are also readily formed into tablets for solid‐state dosing formulations and maintain their immunogenicity in this state. Previous sublingual peptide nanofiber immunotherapies have been based on different structures, such as highly stable β‐sheets. The present work demonstrates that alternatively folded structures such as α‐helical nanofibers can also be rendered sublingually immunogenic, enabling immunization with a variety of peptide epitopes and offering additional ways to specify mucus interactions, delivery state, dosing, and formulation.

The anaphylatoxins C3a and C5a are products of the complement cascade that play important and interrelated roles in health and disease. Both are potential targets for anti‐inflammatory active immunotherapies in which a patient's own immune system is stimulated to produce therapeutic immune responses against problematic self‐molecules. However, the complex and time‐dependent interrelations between the two molecules make dual targeting challenging. To investigate a dual‐target active immunotherapy against C3a and C5a and to systematically study the effect of varied degrees of responses against both targets, the study employed self‐assembled peptide immunogens capable of displaying a broad range of epitope compositions and Design‐of‐Experiments (DoE) approaches. Peptide nanofibers contained B‐cell epitopes of C3a and C5a in defined quantities, and intranasal immunization raised systemic and mucosal immunity against each target. In a lipopolysaccharide‐induced model of sepsis, increasing anti‐C5a responses are protective, whereas increasing anti‐C3a responses are detrimental, and survival rates are negatively correlated with anti‐C3a/anti‐C5a IgG titer ratio. This work highlights the interplay between the two molecules by making use of a modular, defined, and easily adjusted biomaterial‐based active immunotherapy platform.

IL‐1β is a principal proinflammatory cytokine underlying multiple local and systemic chronic inflammatory conditions including psoriasis, rheumatoid arthritis, inflammatory bowel disease, and type 2 diabetes. Passive immunotherapies and biologic drugs targeting IL‐1β, while offering significant clinical benefit, nevertheless have limitations such as significant non‐response rates, induction of anti‐drug antibodies, and high costs. Here, an active immunotherapy raising antibody responses against IL‐1β employing self‐assembling peptide nanofibers is described. The nanofibers contain defined quantities of B‐cell epitopes from IL‐1β and exogenous T helper epitopes and employ the Q11 self‐assembling peptide platform. Without adjuvant, the nanofibers raised durable anti‐IL‐1β antibody responses that inhibit IL‐1β activity in vitro and in vivo. In a mouse model of imiquimod‐induced psoriasis, prophylactic immunizations with the nanofibers diminished symptoms of epidermal thickening. This therapeutic effect is associated with biasing the immune response toward an anti‐inflammatory IgG1/Th2 phenotype and a lowered expression of proinflammatory genes in the skin. Further, anti‐IL‐1β nanofibers induced therapeutic immunosuppressive CD62L+ Treg cells. This technology represents a potential alternative for passive immunotherapies and other biologics for treating chronic inflammatory conditions.

Nanomaterials are becoming important tools for vaccine development owing to their tunable and adaptable nature. Unique properties of nanomaterials afford opportunities to modulate trafficking through various tissues, complement or augment adjuvant activities, and specify antigen valency and display. This versatility has enabled recent work designing nanomaterial vaccines for a broad range of diseases, including cancer, inflammatory diseases, and various infectious diseases. Recent successes of nanoparticle vaccines during the coronavirus disease 2019 (COVID-19) pandemic have fueled enthusiasm further. In this review, the most recent developments in nanovaccines for infectious disease, cancer, inflammatory diseases, allergic diseases, and nanoadjuvants are summarized. Additionally, challenges and opportunities for clinical translation of this unique class of materials are discussed.

Oral immunization is a promising strategy for preventing and treating gastrointestinal (GI) infections and diseases, as it allows for direct access to the disease site. To elicit immune responses within the GI tract, however, there are many obstacles that oral vaccines must surmount, including proteolytic degradation and thick mucus barriers. Here, we employed a modular self-assembling peptide nanofiber platform to facilitate oral immunization against both peptide and small molecule epitopes. Synthesizing nanofibers with d-amino acids rendered them resistant to proteases in vitro, whereas l-amino acid nanofibers were rapidly degraded. Additionally, the inclusion of peptide sequences rich in proline, alanine, and serine (PAS), increased nanofiber muco-penetration, and accelerated nanofiber transport through the GI tract. Oral immunization with PASylated nanofibers and mucosal adjuvant generated local and systemic immune responses to a peptide epitope but only for l-amino acid nanofibers. Further, we were able to apply this design to also enable oral immunization against a small molecule epitope and illustrated the therapeutic and prophylactic effectiveness of these immunizations in mouse models of colitis. These findings demonstrate that supramolecular peptide self-assemblies have promise as oral vaccines and immunotherapies.