Structure-based Immunogen Design
Creative Biolabs is one of the few CROs in the world with full-service capabilities for vaccine development. The development of vaccines is a systematic project, and it is particularly necessary to carry out thorough investigation and design in the early stage. Our experts have rich practical experience in vaccine development, which enables them to comprehensively consider when designing vaccines to ensure vaccine safety and effectiveness, and avoid unnecessary detours and losses.
Background
As the most successful invention of modern medicine, vaccines have greatly reduced the burden of infectious diseases, and they are playing an increasingly important role in combating non-infectious diseases. The traditional vaccine strategy is to attenuate or inactivate pathogens, but for HIV-1, RSV, Zika virus, and other pathogens, such strategies often fail to stimulate the production of protective neutralizing antibodies. Many pathogens have evolved multiple strategies to evade the host's neutralizing immune response, and it is currently widely believed that non-neutralizing antibodies can facilitate the virus to enter host cells and cause antibody-dependent disease enhancement (ADE) effects.
Strategies for Structure-based Immunogen Design
The key to the next generation vaccine, the so-called precision vaccine, is to recognize the neutralizing epitope of the pathogen and place it under the effective recognition and presentation of the immune system to enhance the production of epitope-specific antibodies. This puts forward requirements for encoding structural information of epitopes that can be recognized by broad and effective neutralizing antibodies in vaccine immunogens. Generally speaking, silencing non-neutralizing epitopes, germline targeting, stabilizing immunogen conformation and epitope scaffolding are four conventional structure-based immunogen design methods.
- Silencing Non-Neutralizing Epitopes
Removing or masking those non-neutralizing epitopes is the most direct method to shift antibody responses to conserved subdominant epitopes. At present, there are two main approaches to achieve this. One is to remove the epitopes targeted by non-neutralizing antibodies in the immunogen. The other is to reduce the accessibility of non-neutralizing epitopes through the introduction of glycan caps, etc. The first of these has been used in the development of universal influenza vaccines.
- Stabilizing Antigenic Conformation
Viral surface proteins that mediate the entry of viruses into host cells for replication are often in a metastable pre-fusion state on the surface of virions, and when they are fused to the host cell membrane, structural rearrangements occur to a stable post-fusion conformation. Studies have found that RSV neutralizing antibodies are mostly directed against pre-fusion RSVF. Therefore, using the pre-fusion virus protein as the vaccine antigen may be an important strategy to exert the effectiveness of the vaccine, and the problem that needs to be solved is how to maintain the conformational stability of such proteins.
Table.1 Strategies for stabilizing antigenic conformation of viral fusion proteins
Strategies | Example |
Cavity filling mutations | RSVF, HIV env |
Disulfides | RSVF, HIV env |
Fusion of trimerization domains | T4 fibritin foldon |
Introducing DT crosslinks | Stem domain of HA in Influenza virus |
Substitution by prolines | RSVF, HIV gp41 |
Structural deletions | RSVF DS2, HIV Env SOSIP.664, HIV Env gp140 |
- Germline Targeting
Studies found that typical broadly neutralizing antibodies (bnAbs) against HIV-1 carry a mass number of somatic hypermutations, so researchers have begun to use germline targeting to stimulate well-defined antibody lineages. By engaging non-mutated precursors of bnAbs, drives them to mutate towards bnAbs. Creative Biolabs’ experts use computer design and in vitro evolution to achieve this strategy.
- Epitope Scaffolding
With the exact conformation of the epitope recognized by the neutralizing antibody known, this structural information can be used to design heterologous proteins that mimic the epitope structure and are structurally compatible with the antigen-binding pattern. Use computer design to graft the epitope onto the scaffold protein, and the correct simulation of the epitope was confirmed through biochemical and structural characterization. It was subsequently discovered that this epitope-scaffold can induce an antibody response similar to the parent antibody.
Creative Biolabs' advanced technologies and rich experience in the vaccine field not only guarantee its high-quality scientific research service capabilities, but also allow us to further improve our technologies in the process of serving customers, which makes us more and more equipped to provide higher-level services. We have a comprehensive vaccine design team that can help you formulate a suitable development strategy early in the vaccine development process, greatly improving your research and development efficiency and saving your vaccine development costs.
All of our products can only be used for research purposes. These vaccine ingredients CANNOT be used directly on humans or animals.