Ashley Luu

 Introduction COVID-19 is highly contagious and is known to cause significant mortality in populations with pre-existing conditions. Current vaccines available in the United States notably create immunity by stimulating antibody response to the spike protein of SARS-CoV-2^1,2. Since the virus is highly transmissible and continues to undergo mutations in the gene encoding spike, it’s important to examine the relationship between viral variation and immunogenicity. In this study, we ask: what viral characteristics should be considered in studying the effects of viral variants and vaccination efficacy? Methods: Blood samples from vaccinated individuals were examined via ELISA to determine antibody binding to canonical virus and selected variants¹. Using cryo-electron microscopy, SARS-CoV-2 was visualized and its physical binding sites were visualized to understand the antibodies and virus specificity. Researchers used a megapool (MP) approach to test large numbers of T cell target epitopes. Blood samples were compared from clinically recovered COVID-19 patients and control donors². Lastly, researchers used phylogenetics, population genetics, and structural bioinformatic analyses to determine the diversity of mutations in SAR-CoV-2³. Results: High levels of IgM and IgG antibodies to the SARS-CoV-2 spike protein, generally including receptor-binding-domain, were found in vaccinated individuals and found to have neutralizing activity to canonical. This activity was statistically significantly reduced in the E484K-, N501Y-, and K417N/E484K/N501-mutant spike protein¹. Highly antigenic targets included spike protein, nsp6, ORF3a, and nucleocapsid proteins. Additionally, significant CD4+ responses were identified against nsp3, nsp4, ORF3s, ORF7a, nsp12, and ORF8 proteins². One of the dominant mutations (at the time of publication) D614G, is NOT highly reactive with vaccine or infection derived antibodies, suggesting that its interaction with antibodies is not highly affected and might lead to viral escape from existing immunity³. Finally, steric hindrance is a major contributor to preventing viral entry into cells; antibody P2B-2F6 binds to ACE2 receptors, competing with the viral spike protein and can be used as a probe to interrogate relationship between structure and neutralization⁴. Conclusion Neutralizing antibodies and its physical blockade of viral entry is an important factor when thinking about changes in the virus. Currently, some mutations do not necessarily affect antibody response due to its site; however, this should be considered when studying future variants. Acknowledging that future mutations could affect the spike protein’s physical structure and current vaccines’ efficacy, other spike variants or additional viral proteins should be considered in the evolution of vaccine design.

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