Study: Adaptation-proof SARS-CoV-2 vaccine design. Image Credit: creativeneko/Shutterstock

Important methodology for targeting conserved SARS-CoV-2 epitopes and an immunity-focused approach in the design of pan-sarbeco and universal CoV vaccines

The ongoing coronavirus disease 2019 (COVID-19), the causative agent of which is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has massively affected the global economy and healthcare system. Although scientists have rapidly developed effective vaccines against COVID-19, their effectiveness has declined due to the emergence of new variants of SARS-CoV-2 that can evade immune responses generated by vaccination or infection. natural. Thus, there is a need for novel, high-efficiency, stable, cost-effective, and safe vaccines for global use.

Study: Adaptation-proof SARS-CoV-2 vaccine design. Image Credit: creativeneko/Shutterstock

Background

Previous studies have reported that SARS-CoV-2 is an RNA virus belonging to the family Coronaviridae of the genus Betacoronavirus. The surface spike protein of this virus binds to the hosts receptor, namely angiotensin converting enzyme 2 (ACE2), and thus establishes the infection.

The SARS-CoV-2 spike protein is a homotrimer that contains two domains, namely the N-terminal S1 domain and the C-terminal S2 domain. The S1 domain binds to the host’s ACE2 through its receptor binding domain (RBD), while the S2 domain mediates cell membrane fusion between the virus and the host cell. Scientists have targeted RBD to develop vaccines and treatments against COVID-19 (monoclonal antibodies). However, several studies have indicated that RBD is prone to mutation, which leads to rapid evolution of the virus.

Although available COVID-19 vaccines have reduced the death rate and serious infections, which require hospitalization, the accumulation of mutations in the RBD has reduced the effectiveness of available vaccines and therapies. Several variants of SARS-CoV-2 have emerged and are categorized into variants of concern (VOC) and variants of interest (VOI). VOCs are highly transmissible and virulent and can evade immune responses induced by COVID-19 vaccination and natural infection.

Because vaccines target conserved structural regions of the spike protein, they can combat the adaptive abilities of SARS-CoV-2. Available COVID-19 vaccines are based on various platforms which include mRNA and adenoviral vectors. Scientists said scaffolding and epitope grafting are high-precision approaches for designing immunogens used for vaccine and therapy development

A new study

The researchers believe that creating an immunogen based on the conserved epitope would produce widespread immunity. An effective SARS-CoV-2 immunogen that targets conserved regions of the SARS-CoV-2 virus would effectively reduce the emergence of variants resistant to neutralization or those that can evade immune responses. These types of immunogens would be effective against other coronavirus as well.

A new study published on the bioRxiv* The preprint server focused on the design of immunogens associated with the conserved region of the SARS-CoV-2 spike protein. In this study, researchers used structure-guided scaffolding and epitope grafting methods. In a previous study by the same research team, a computational protocol for designing epitope scaffolds was described, which was also used in this study.

In the current study, scientists designed a SARS-CoV-2 immunogen using three unique and conserved epitope regions of the S2 domain to develop structural mimics of the epitopes. These small protein mimics or epitope scaffolds have been used as immunogens for a specific immune response.

Main conclusions

The current method of structure-guided antigen design offers speed and precision for vaccine development. The combination of epitope grafting and the scaffolding method has made it possible to create vaccines that are said to be highly effective against viruses and their variants. In this study, scientists reported designing potential immunogens by targeting conserved regions of the SARS-CoV-2 spike protein.

The scientists designed immunogens with atomic-level detail, which mimic the conformation of the non-RBD conserved epitopes of the spike protein. A previous study focused on creating an immunogen using the grafting method, which targeted the moderately conserved region of RBD. The developed immunogen could effectively induce structure-specific antibodies against SARS-CoV-2.

In this study, researchers reported that biophysical and structural characterization data of epitope scaffolds were consistent with computational design data. An immunization experiment using a mouse model revealed that the newly designed epitope-grafted immunogen induced a targeted immune response.

Importantly, the scientists reported that the ED2 and ED5 epitope scaffolds exhibited a specific and high immune response per graft compared to other immunogenic designs. Among these two, ED2 grafted with two different epitopes induced higher immune response. This finding implies that the inclusion of multiple epitopes in a single immunogenic design or the incorporation of an epitope-scaffold mixture could induce an enhanced immune response.

The researchers observed that the epitope scaffolds showed limited neutralizing capacity in sera. However, when ED2 was tested against serum samples from human COVID-19 patients, positive binding was observed. Scientists performed various analyses, such as X-ray crystallography, small-angle X-ray scattering and modeling (SAX), circular dichroism spectroscopy (CD), and enzyme immunoassay (ELISA) in this study. . These analyzes revealed that the synthesized immunogen was stabilized and possessed a conformation mimicking the native epitope of the epitope scaffolds.

Despite the conformational stabilization, the reason for the limited neutralizing activity of the immunogen is unclear; however, binding to human patient sera indicates that the neutralizing activity is species specific.

Conclusion

One limitation of the study is that only linear epitopes were included in the design of SARS-CoV-2 immunogens. In the future, conformational epitopes could be optimized while designing immunogens to elicit enhanced immune responses. The results of the current study support the utility of epitope scaffolds in vaccine development.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

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