Mutant MERS RBD Vaccine Antigen to Prevent DPP4 Epitope Masking
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Solution Overview
Problem
Existing MERS-CoV vaccines face challenges in inducing robust neutralizing antibody responses due to high levels of DPP4 in human serum, which masks the receptor binding domain (RBD) of the spike protein, impairing B cell recognition and antibody maturation, particularly in subjects with elevated DPP4 levels.
Innovation Solution
Development of a mutant receptor-binding domain (MERS-mRBD) and mutant spike protein (MERS-mSpike) with reduced binding strength to DPP4 and sialic acid, utilizing specific mutations to prevent epitope masking and enhance antibody generation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild type MERS-CoV spike protein or RBD is used as vaccine antigen, then the antigen can bind to DPP4 receptor with high affinity, but this causes epitope masking by soluble DPP4 in serum, impairing B cell recognition and antibody maturation
Solution Approach 1:
The patent applies the 'Blessing in disguise' principle by introducing mutations that reduce DPP4 binding affinity, which converts the harmful effect of epitope masking into a beneficial outcome. By deliberately weakening the interaction between the vaccine antigen and DPP4 receptor, the patent prevents soluble DPP4 from masking critical epitopes, thereby allowing B cells to properly recognize and generate neutralizing antibodies against the RBD and spike protein.
2Object-affected harmful factors
If mutations are introduced to reduce DPP4 binding affinity, then epitope masking is prevented and antibody generation is enhanced, but the binding strength to the natural receptor is reduced
Solution Approach 1:
The patent applies the 'Parameter changes' principle by systematically modifying amino acid residues at the DPP4 binding interface of the RBD and spike protein. Specific mutations (such as L140R, G172E/K, V189Y/W, and combinations thereof) are introduced to alter the binding parameters, reducing the affinity for DPP4 receptor while preserving the immunogenicity and epitope accessibility. This parameter modification allows the vaccine to function effectively despite reduced natural receptor binding.
3Ease of operation
If existing MERS-CoV vaccines (ChAdOx1, GLS-5300, MVA-MERS-S) are used, then vaccination can be administered, but neutralizing antibody responses are relatively weak and detected in only 44-79% of vaccinated participants
Solution Approach 1:
The patent applies the 'Taking out' principle by extracting and isolating the critical DPP4 binding interface region (RBD) from the complete spike protein, and further by removing the high-affinity binding capability through targeted mutations. This extraction approach allows the vaccine to focus on presenting immunogenic epitopes without the confounding effect of strong DPP4 binding that masks these epitopes, thereby improving neutralizing antibody responses compared to whole spike protein vaccines.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The mutated MERS-mRBD and MERS-mSpike vaccines elicit a highly efficient immune response even in the presence of high DPP4 levels, promoting the production of RBD- and spike-binding antibodies, thereby enhancing protective immunity against MERS-CoV.
Implementation Method 1
having a reduced binding strength to the RBD-receptor DPP4 (dipeptidylpeptidase 4) of MERS-CoV compared to the wild type receptor-binding domain of MERS-CoV
Data Source
AI summary
The present invention relates to a mutant receptor-binding domain (MERS-mRBD) of MERS-CoV (middle east respiratory syndrome coronavirus) or a fragment thereof and/or a mutant spike protein (MERS-mSpike) of MERS-CoV or a fragment thereof having a reduced binding strength to the RBD-receptor DPP4 (dipeptidylpeptidase 4) of MERS-CoV compared to the wild type receptor-binding domain of MERS-CoV (MERS-wtRBD) and/or having a reduced binding strength to sialic acid compared to a wild type spike of MERS-CoV (MERS-wtSpike). Furthermore, the present invention relates to and a nucleic acid comprising a nucleotide sequence encoding for the MERS-mRBD or the fragment thereof or the MERS-mSpike or the fragment thereof and a vaccine composition comprising one or more MERS-mRBDs or fragments thereof, one or more MERS-mSpikes, one or more polypeptides or proteins and/or one or more nucleic acids according to the present invention, as well as methods for prevention and/or treatment of diseases caused by MERS-CoV in a subject.