Since SARS-CoV-2 is here to stay, it is important to assess how our understanding of this virus has changed post-pandemic. Dr. Jamie Guenthoer, a staff scientist in the Overbaugh lab at Fred Hutchinson Cancer Center, provided her insight in this area. “SARS-CoV-2 demonstrated a remarkable ability for viral evolution, especially in the receptor binding domain of the S1 subunit of the spike entry protein, which led to considerable evasion from vaccine-induced antibody responses and antibody-based therapies.” These insights have contributed to changes in the SARS-CoV-2 research landscape as well. Dr. Guenthoer is now working to find vaccine targets beyond the S1 subunit that are conserved—less susceptible to change over time—and that accordingly retain sensitivity to vaccine-induced immunity. In their work, recently published in PLoS Pathogens, Dr. Guenthoer and colleagues identified seven potential vaccine target regions also in the spike entry protein, but this time in the S2 subunit that is highly conserved across coronaviruses including SARS-CoV-2.
The spike protein decorates the exterior of coronavirus particles and enables a virus particle to bind to and infect a cell. Vaccines developed during the SARS-CoV-2 pandemic elicited an antibody-mediated immune response to neutralize or activate cell killing pathways to protect an individual from severe disease. However, as variants of SARS-CoV-2 expanded in the population, immunity to new variants waned driven largely by changes in the S1 subunit of the spike protein. “In our study, we focused on antibodies that targeted more conserved regions of the spike protein, specifically the S2 subunit,” shared Dr. Guenthoer. “Not only have these regions remained largely unchanged in SARS-CoV-2 variants, but they show a high degree of homology across other circulating human coronaviruses as well. We discovered that the epitopes [small regions of a protein] in S2 were more diverse than previously appreciated, and understanding the breadth of these epitopes could inform protection strategies across coronaviruses.”
The researchers went straight to the source—human blood samples—to find antibodies that target regions of the S2 subunit of the spike protein. These samples came from two individuals who recently recovered from SARS-CoV-2 infection. Monoclonal antibodies were generated based on sequences from isolated spike-specific memory B-cells. Several methods were used to determine antibody binding affinity to the S2 subunit. The 40 tested antibodies bound to SARS-CoV-2 spike trimers, the cluster of three spike proteins as found on the virus particle exterior, and/or S2 subunit proteins. Epitopes recognized by the antibodies were also mapped through multiple methods and the researchers estimated seven distinct regions in the S2 subunit that can be recognized by antibodies, some of which included previously described antigenic regions—portions of a protein known to trigger an immune response. “Furthermore, we demonstrated that many of the S2 antibodies, while not neutralizing, were able to mediate antibody-dependent cellular cytotoxicity (ADCC), which has been shown to be an important component of antibody-based in vivo protection in model systems and appears to be more durable than neutralization,” stated Dr. Guenthoer. ADCC is important for elimination of host cells already infected by the virus. Continued study of these seven regions on the S2 subunit of spike and their respective targeting antibodies will help in the design of new vaccine strategies that elicit broadly protective immune responses against SARS-CoV-2 variants.
As SARS-CoV-2 continues to evolve, so do the strategies to combat this virus and related diseases. “One of the ongoing questions is how best to elicit vaccine-induced immune responses to these more conserved regions of SARS-CoV-2 spike protein,” commented Dr. Guenthoer. “Hybrid immunity from a combination of vaccination and infection enriches the S2-targeting response, but eliciting a similar response from a vaccine-only approach is still in development.” Efforts to optimize this vaccine approach will not only be beneficial for SARS-CoV-2 variants but may also provide protective benefits to other coronaviruses since the S2 subunit is broadly conserved across this virus family.
The spotlighted research was funded by the National Institutes of Health and the Howard Hughes Medical Institute.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Dr. Frederick Matsen contributed to this work.
Guenthoer J, Garrett ME, Lilly M, Depierreux DM, Ruiz F, Chi M, Stoddard CI, Chohan V, Yaffe ZA, Sung K, Ralph D, Chu HY, Matsen FA 4th, Overbaugh J. 2024. The S2 subunit of spike encodes diverse targets for functional antibody responses to SARS-CoV-2. PLoS Pathog. 20(8):e1012383.
Science spotlight writer Annabel Olson is a postdoctoral research fellow in the Nabet lab at Fred Hutchinson Cancer Center. Her research focuses on studying the mechanisms that drive cancer development for both genetic and virus-associated cancers. A key tool in her research is the use of targeted protein degradation to dissect dysregulated signaling pathways in cancer and to double as a relevant pre-clinical therapeutic platform.
For the Media