Immunologic adjuvant | EPFL Graph Search

In immunology, an adjuvant is a substance that increases or modulates the immune response to a vaccine. The word "adjuvant" comes from the Latin word adiuvare, meaning to help or aid. "An immunologic adjuvant is defined as any substance that acts to accelerate, prolong, or enhance antigen-specific immune responses when used in combination with specific vaccine antigens." In the early days of vaccine manufacture, significant variations in the efficacy of different batches of the same vaccine were correctly assumed to be caused by contamination of the reaction vessels. However, it was soon found that more scrupulous cleaning actually seemed to reduce the effectiveness of the vaccines, and some contaminants actually enhanced the immune response. There are many known adjuvants in widespread use, including aluminium salts, oils and virosomes. Overview Adjuvants in immunology are often used to modify or augment the effects of a vaccine by stimulating the immune system to resp

Engineering the Extra Domain A of fibronectin as a vaccine adjuvant and study of its role in tissue regeneration

Ziad Julier

The extracellular matrix (ECM) protein fibronectin (FN) is a remarkably multifaceted molecule, including numerous fibronectin type III (FNIII) repeats carrying out different functions, which despite being extensively studied for over thirty years still presents certain functions that remain incompletely elucidated. The alternatively spliced FN variant containing the extra domain A (FNIII EDA), located between FNIII 11 and FNIII 12, is expressed in sites of injury, chronic inflammation, and solid tumors. Although its function is not well understood, FNIII EDA is known to agonize Toll-like receptor 4 (TLR4) and appears to be involved in the progression of different skin diseases while studies also suggest that FNIII EDA is involved in tissue repair. The aim of this thesis is thus to better understand some of the immunological and regenerative functions of FNIII EDA and to translate these findings to develop new vaccination strategies based on endogenous proteins. One important task in vaccinology is to develop delivery strategies by which to present antigen, along TLR agonists, so as to induce a desirable adaptive immune response. The use of TLR agonists is associated with sometimes severe constraints and concerns about safety, causing inflammatory responses. Thus, the development of safe and effective vaccines with fewer side effects is a strong need and requires the development of new adjuvants with a correct balance between a strong activation of the immune system and a low toxicity for the patient. Here, by producing various FN fragments containing FNIII EDA, we show that the immunological activity of FNIII EDA depends on its local intramolecular context within the FN chain. N-terminal extension of the isolated FNIII EDA with its neighboring FNIII repeats enhanced its activity in agonizing TLR4, while C-terminal extension abrogated it. In addition, we reveal that an elastase 2 cleavage site is present between FNIII EDA and FNIII 12. Moreover, as FNIII EDA is naturally present within the ECM, we incorporated FNIII EDA bound in a fibrin matrix to mimic the in vivo situation and create an adjuvant-rich microenvironment. Such matrices were shown to induce functional cytotoxic CD8+ T cell responses in two murine cancer models. Furthermore, combinations of specific TLR-agonists have the ability to synergize to induce immune responses that are greater than the sum of their individual effect. Hence, we demonstrate that combination of the TLR9 agonist CpG with FNIII EDA synergizes to induce an efficient immune response while keeping the dose of the toxic CpG at a minimum. Here, the combination of both adjuvants induced a potent immune response sufficient to slow down tumor growth in a murine tumor model as well as to break immune tolerance to eradicate circulating hepatitis B virus (HBV) in a transgenic HBV mouse model. Finally in the last part of this thesis we revealed that FNIII EDA is a growth factor binding domain of FN, with a strong affinity for the platelet-derived growth factor-AA (PDGF-AA). We also demonstrated that FNIII EDA and PDGF-AA have together the ability to enhance fibroblasts proliferation and differentiation into myofibroblasts. In addition, we explored the effects of fibrin matrices functionalized with variants of FNIII EDA on wound closure.

EPFL2016

Redox-Responsive Polycondensate Neoepitope for Enhanced Personalized Cancer Vaccine

Xiaomeng Hu, Li Tang, Lixia Wei, Yu Zhao

A versatile and highly effective platform remains a major challenge in the development of personalized cancer vaccines. Here, we devised a redox-responsive polycondensate neoepitope (PNE) through a reversible polycondensation reaction of peptide neoantigens and adjuvants together with a tracelessly responsive linker-monomer. Peptide-based neoantigens with diverse sequences and structures could be copolymerized with molecular adjuvants to form PNEs of high loading capacity for vaccine delivery without adding any carriers. The redox-responsive PNEs with controlled molecular weights and sizes efficiently targeted and accumulated in draining lymph nodes and greatly promoted the antigen capture and cross-presentation by professional antigen presenting cells. Mice immunized with PNEs showed markedly enhanced antigen-specific T cell response and the protective immunity against the tumor cell challenge.

2020

Immune Engineering Via Differential Antigen Carriers and Co-Stimulatory Molecules

Jackson Eby

There is an increasing clinical need for vaccines capable of enhancing antigen-specific immune responses and treatments that can induce immunological tolerance toward a single antigen. Here we explore two platforms to enhance either immunization or tolerization depending upon the secondary signals involved. First, a poly(ethylene glycol)-bl-poly(propylene sulfide) (PEG-bl-PPS)-based micelle platform capable of conjugating antigen to its surface was developed. Biodistribution studies showed that these micelles (MC) traffic to lymph nodes where they preferentially interact with antigen presenting cells (APC) for over 24 hr. When ovalbumin (Ova)-conjugated micelles (MC-Ova) were delivered intradermally with the adjuvant CpG, they enhanced cytotoxic T cell responses against Ova as well as anti-Ova IgG1 production compared to free Ova with CpG. To change the signals from the MCs to encourage tolerization, hydrophobic corticosteroids capable of preventing APC maturation were incorporated into the PPS core and were shown to be released over the course of 2 days. These vehicles were able to prevent dendritic cell (DC) activation in response to adjuvant both in vitro and in vivo. Ova-conjugated drug-loaded MCs were able to prevent antigen-specific T cell activation in vitro and in vivo as well, but caused an anti-Ova humoral response that was enhanced upon subsequent Ova challenge. Thus, PEG-bl-PPS micelles are valuable tools for enhancing immunization but not tolerization toward exogenous antigens. Second, erythrocytes were labeled in situ for use as apoptotic cell carriers. To enhance immunogenicity, the necrotic signal calreticulin (CRT) was decorated with the erythrocyte- binding peptide ERY (ERY-CRT) and delivered intravenously with ERY-Ova. When combined with chloroquine, this signaling caused production of anti-Ova IgG1 to a level similar to that seen with intradermal MC-Ova + CpG, but showed no cytotoxic T cell response. Because apoptotic cells can be tolerogenic, the Ter119 erythrocyte-binding single- chain antibody fragment (scFv) was used in a fusion with Ova peptides to determine if this technique could delete Ova-recognizing T cells within an immunized repertoire. After immunization with Ova + lipopolysaccharide (LPS), these constructs deleted CD4+ and CD8+ T cell clones specific for Ova without causing adverse reactions from anti-Ova antibodies in circulation. Erythrocytes are therefore encouraging protein-delivery vehicles for induction of both tolerance and humoral immunity.

EPFL2012