How could we forget the SARS-CoV-2 pandemic, right? It’s now part of our history, a story to pass on to the next generation.
There are hundreds of related SARS-CoV strains known to infect different non-human species. Coronaviruses are considered a zoonotic subgenus of Sarbecoviruses. They are accumulating a notorious history of jumping from animals to humans and are a continuing threat to public health.
Sarbecoviruses gain entry into host cells by binding to the ACE2 receptor via the receptor-binding domain (RBD) of their spike protein. Once infected, our immune system recognizes the RBD and generates antibodies that bind to sequences -epitopes- within the RBD preventing viral entry and preventing infection. The problem, though, the RBD is highly adaptable and can mutate to escape these antibodies, diminishing the effectiveness of antibody-based therapies.
“Antibodies against SARS-CoV-2 have played an important role in mitigating the length of disease and disease severity” said Dr. Feli Ruiz, a postdoctoral fellow in the lab of Dr. Julie Overbaugh, a professor in the Human Biology Division at Fred Hutch.
“The antigenic evolution of SARS-CoV-2 has diminished the efficacy of antibody-based therapies and the elicited antibody response. Given that SARS-CoV-2 continues to evolve and there are numerous diverse SARS-like coronavirus strains (sarbecoviruses) circulating in animal reservoirs with human spillover potential, it is important to study antibodies that are robust in the face of evolution,” Ruiz added.
In a recent study led by Dr. Ruiz, the team characterized cross-reactive antibodies capable of recognizing SARS-CoV-1, SARS-CoV-2, and other sarbecoviruses. “Isolating and characterizing monoclonal antibodies (mAbs) allows us to identify conserved regions across not just SARS-CoV-2 variants but also sarbecoviruses from animal reservoirs. This could inform the development of broad-spectrum antibody therapies for pandemic preparedness,” Ruiz explained. Their findings were published in PLOS Pathogens.
The research team analyzed antibodies from an individual who had a Delta variant breakthrough infection. Several of these antibodies showed cross-reactivity against diverse sarbecoviruses, including SARS-CoV-1 and SARS-CoV-2. “We thoroughly examined the functional properties of these cross-reactive antibodies,” Dr. Ruiz explained. In addition to identifying new antibodies, the team also included previously FDA-approved therapeutic antibodies targeting SARS-CoV-2 variants in their analysis. The study found that some of the newly identified antibodies could potently neutralize specific sarbecoviruses, while others displayed moderate neutralization but a broader range of activity. Further analysis revealed that the newly identified antibodies target conserved epitopes in the RBD of the spike protein across sarbecoviruses including SARS-CoV-2 variants. In contrast, the previously authorized therapeutic antibodies bind to a different RBD epitope that is not conserved across these viruses. The ability of the new antibodies to target conserved regions within the RBD makes them promising candidates for the development of a broad-spectrum antibody cocktail.
“These antibodies were isolated from an individual with multiple exposures to early variants of SARS-CoV-2 through vaccination (Wuhan-Hu-1 or the parental strain of SARS-CoV-2) and infection (Delta variant, a variant of SARS-CoV-2 that emerged back in 2021),” Ruiz explained. Since then, “a number of heavily mutated variants of SARS-CoV-2 have arisen, namely the Omicron variants.” Moving forward, the team is trying to understand “how the antibody response changes after multiple diverse exposures to SARS-CoV-2 to inform how to elicit broadly neutralizing antibodies by vaccination,” Ruiz concluded.
The spotlighted research was supported by grants from the National Institute of Health.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Dr. Frederick A. Matsen contributed to this work.
Ruiz F, Foreman WB, Lilly M, Baharani VA, Depierreux DM, Chohan V, Taylor AL, Guenthoer J, Ralph D, Matsen Iv FA, Chu HY, Bieniasz PD, Côté M, Starr TN, Overbaugh J. 2024. Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses. PLoS Pathog. 20(10):e1012650.
Joss Landazuri is a PhD candidate at the University of Washington in the Microbiology program working at the intersection of biomedical science, public policy, and science diplomacy. As a Latina scientist, communicator, and policy advocate, she is passionate about leveraging her academic training, personal background, and cultural heritage to engage underserved communities in both science and the policymaking process.
For the Media