Summary
"Intestinal bacteria have an enormous influence on health, both in the form of major pathogens and as major constituents of the microbiota. We have demonstrated that high-affinity secretory antibodies (sIgA) offer huge potential to protect from infection and to manipulate microbiota composition. However, designing good oral vaccines to induce high-affinity sIgA is a compound problem. Most protective anti-bacterial sIgA targets bacterial glycans, requiring an understanding of inherently difficult glycan biochemistry. We also need to deliver intact antigen via the highly degradative environment of the intestine. Whole-cell inactivated oral vaccines can induce high-affinity sIgA against some glycan structures, but we have an incomplete picture of what determines the success/failure of these vaccines. By combining advanced biophysical methods (e.g. atomic force spectroscopy), fluorescence and electron microscopy, and synthetic biology, we aim to remove this mystery. Our objectives are:
1) Generate a ""toolbox"" for glycan-binding antibody research: Recombinant antibodies, BCR knock-in mice and defined glycan antigens as purified molecules, on whole bacteria or on virus-like particle will be developed for model antigens: Salmonella Typhimurium O-antigen and the E.coli K100 capsule.
2) Determine the quantitative relationship between glycan antigen sampling into gut-associated lymphoid tissues and particle size, glycan flexibility/structure, digestion resistance and natural IgA binding.
3) Determine how biophysical properties of glycan antigens affect B cell antigen uptake, T cell help and antibody affinity maturation.
4) Combine models of antigen sampling efficiency and anti-glycan antibody affinity maturation to generate a systems-level model of mucosal vaccine efficacy.
This will uncover the fundamental principles governing the induction of high-affinity anti-glycan sIgA, driving urgently required progress in mucosal vaccine design
"
1) Generate a ""toolbox"" for glycan-binding antibody research: Recombinant antibodies, BCR knock-in mice and defined glycan antigens as purified molecules, on whole bacteria or on virus-like particle will be developed for model antigens: Salmonella Typhimurium O-antigen and the E.coli K100 capsule.
2) Determine the quantitative relationship between glycan antigen sampling into gut-associated lymphoid tissues and particle size, glycan flexibility/structure, digestion resistance and natural IgA binding.
3) Determine how biophysical properties of glycan antigens affect B cell antigen uptake, T cell help and antibody affinity maturation.
4) Combine models of antigen sampling efficiency and anti-glycan antibody affinity maturation to generate a systems-level model of mucosal vaccine efficacy.
This will uncover the fundamental principles governing the induction of high-affinity anti-glycan sIgA, driving urgently required progress in mucosal vaccine design
"
Unfold all
/
Fold all
More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/865730 |
| Start date: | 01-07-2020 |
| End date: | 30-06-2025 |
| Total budget - Public funding: | 1 993 750,00 Euro - 1 993 750,00 Euro |
Cordis data
Original description
"Intestinal bacteria have an enormous influence on health, both in the form of major pathogens and as major constituents of the microbiota. We have demonstrated that high-affinity secretory antibodies (sIgA) offer huge potential to protect from infection and to manipulate microbiota composition. However, designing good oral vaccines to induce high-affinity sIgA is a compound problem. Most protective anti-bacterial sIgA targets bacterial glycans, requiring an understanding of inherently difficult glycan biochemistry. We also need to deliver intact antigen via the highly degradative environment of the intestine. Whole-cell inactivated oral vaccines can induce high-affinity sIgA against some glycan structures, but we have an incomplete picture of what determines the success/failure of these vaccines. By combining advanced biophysical methods (e.g. atomic force spectroscopy), fluorescence and electron microscopy, and synthetic biology, we aim to remove this mystery. Our objectives are:1) Generate a ""toolbox"" for glycan-binding antibody research: Recombinant antibodies, BCR knock-in mice and defined glycan antigens as purified molecules, on whole bacteria or on virus-like particle will be developed for model antigens: Salmonella Typhimurium O-antigen and the E.coli K100 capsule.
2) Determine the quantitative relationship between glycan antigen sampling into gut-associated lymphoid tissues and particle size, glycan flexibility/structure, digestion resistance and natural IgA binding.
3) Determine how biophysical properties of glycan antigens affect B cell antigen uptake, T cell help and antibody affinity maturation.
4) Combine models of antigen sampling efficiency and anti-glycan antibody affinity maturation to generate a systems-level model of mucosal vaccine efficacy.
This will uncover the fundamental principles governing the induction of high-affinity anti-glycan sIgA, driving urgently required progress in mucosal vaccine design
"
Status
SIGNEDCall topic
ERC-2019-COGUpdate Date
27-04-2024
Images
No images available.
Geographical location(s)
