Zika Antibody Isolation via B Cell Sorting for Cross-Neutralization
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Solution Overview
Problem
Current studies on Zika virus (ZIKV) antibodies lack understanding of responses in flavivirus-naïve individuals and the impact of prior DENV exposure on ZIKV vaccination, with existing vaccine development not addressing how to elicit potent neutralizing antibodies in individuals with pre-existing DENV immunity.
Innovation Solution
Isolation of eleven neutralizing antibodies from convalescent rhesus macaques using a unique B cell sorting strategy, which identified four new classes targeting cross-protomer antigenic epitopes on the viral envelope, and the characterization of a potent antibody, MZ4, that neutralizes ZIKV and DENV-2 with a novel site of vulnerability, elicited by a single immunization with ZPIV vaccination.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If monoclonal antibodies are isolated from individuals with prior flavivirus exposure, then cross-neutralizing activity against multiple flaviviruses is achieved, but antibody specificity to Zika virus is reduced due to original antigenic sin
Solution Approach 1:
The patent segments the antibody isolation process by selecting B cells from flavivirus-naïve individuals who have only been exposed to Zika virus, rather than from individuals with prior flavivirus exposure. This segmentation allows isolation of antibodies with high Zika-specificity while maintaining cross-neutralizing capability, resolving the contradiction between specificity and cross-reactivity
Solution Approach 2:
The patent uses a unique B cell sorting strategy with whole Zika virus as an intermediary to isolate B cells that naturally produce cross-neutralizing antibodies. The whole virus acts as a mediator to select B cells with the desired dual properties of Zika-specificity and broad flavivirus neutralization capability
2Reliability
If vaccine development focuses on eliciting high titer neutralizing antibodies, then protective immunity is enhanced, but the impact of pre-existing DENV immunity on vaccine response is not addressed
Solution Approach 1:
The patent performs preliminary characterization of antibody responses in flavivirus-naïve individuals before vaccine development. By understanding the baseline immune response in the absence of pre-existing flavivirus immunity, the patent establishes a reference framework for designing vaccines that will be effective in both naïve and DENV-experienced populations
Solution Approach 2:
The patent changes the parameter of subject selection from DENV-experienced individuals to flavivirus-naïve individuals for antibody isolation and characterization. This parameter change allows establishment of baseline immune response data that can guide vaccine development for broader population applicability, including those with pre-existing DENV immunity
3Reliability
If monoclonal antibodies target conventional epitopes on E glycoprotein, then neutralizing activity is achieved, but novel cross-protomer epitopes and mechanisms are not identified
Solution Approach 1:
The patent extends the epitope search to a new dimension by identifying cross-protomer epitopes that span multiple E glycoprotein protomers. This dimensional extension from single-protomer to multi-protomer epitopes reveals novel antibody binding sites and mechanisms of neutralization that were previously unrecognized
Solution Approach 2:
Instead of starting with known epitopes and finding antibodies, the patent inverts the approach by using unique B cell sorting with whole virus to directly isolate antibodies binding to novel epitopes. This inversion of the traditional approach allows discovery of unexpected epitope types including cross-protomer and quaternary structures
Data Source
AI summary
The invention described herein provides antibodies to Zika virus. The novel polypeptides are useful alone or as portions of larger molecules, such as antibodies or antibody fragments, that can be used to treat or prevent infection of Zika virus.