Dual-Role SARS-CoV-2 Antibody Discovered, Both Assisting and Blocking Virus Depending on Variant

Study results published in PLOS Pathogens are the first to identify an antibody of SARS-CoV-2, the virus that causes COVID-19, that can both assist pre-Omicron variants of the virus to infect cells while preventing cells from the Omicron variant from doing the same.^1,2

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This discovery pushes back against previously understood research that has shown how antibodies can either block the virus, have no effect on viral infection, or assist the virus in infecting cells in rare cases. Antibody drugs do work to block infections, but the results of the trial challenge the current understanding of their function.²

Investigators from the University of Minnesota made the discovery using nanobodies—single-domain antibodies from camelid animals—as probes to identify a unique epitope on the SARS-CoV-2 spike protein that had opposing functions across different variants of the virus. The team has been developing these nanobodies, which are ideal tools for studying how the spike protein on the viral cell works.^1,2

“The battle between viral infection and treatment development is like an arms race. Our findings highlight how complex it can be to develop treatments as viruses evolve,” Fang Li, co-director of the Midwest AViDD Center and a professor and endowed chair at the Medical School, said in a news release. However, he noted that this effect was only observed in lab-grown cells, with no evidence observed in humans.¹

Research began to center around Nanosota-5, after they found that the epitope at a wide concentration range significantly enhanced SARS-CoV-2 pseudovirus entry. It was selected for further observation because it was the most effective at enhancing viral entry among the non-receptor binding domain (RBD)-targeting nanobodies.¹

The infection efficiency of live SARS-CoV-2 in the presence or absence of Nanosota-5 was examined. It was found that, at all nanobody concentrations, there was significantly enhanced viral infection at the high virus titer, with even greater prominence in the low virus titer. Remarkably, the same Nanosota-5 epitope effectively neutralized the pseudovirus entry of Omicron subvariants, with these results confirmed through a cell-cell fusion assay.¹

Nanosota-5 was observed to increase the binding affinity between the prototypic spike protein and ACE2, while at the same time decreasing the binding affinity between XBB.1.5. spike and ACE2. According to the investigators, the results suggest that Nanosota-5 promotes more RBDs to stand up in prototypic spike as it has the opposite effect on the Omicron spike.¹

Though these results were confirmed in vitro, it was emphasized, as Li said in the news release, that it remains unclear whether the antibody-dependent enhancement (ADE) caused by Nanosota-5 epitope can occur in vivo. This will have to be investigated in future studies; however, this current research offers novel perspectives on how non-RBD epitopes can heighten the ability of prototypic SARS-CoV-2 to enter cells.¹

“This discovery challenges the traditional categorization of epitopes, underscores the complex evolution of SARS-CoV-2 spike, and offers new insights into antiviral antibody therapies,” the investigators discussed.¹

Specifically, antiviral antibody therapies could become more targeted based on the results of this trial. In the future, antiviral therapies for infectious diseases such as the virus caused by SARS-CoV-2 could potentially utilize epitopes that can both increase and decrease cell proliferation depending on the variant.¹

Overall, “the discovery highlights the complexity of viral evolution,” and future approaches to antibody therapies “need to consider the versatile nature of epitopes on viral glycoproteins,” the study authors concluded.¹

REFERENCES

1. Ye G, Bu F, Pan R, et al. Dual-role epitope on SARS-CoV-2 spike enhances and neutralizes viral entry across different variants. PLOS Pathogens. 2024. doi:10.1371/journal.ppat.1012493

2. University of Minnesota Medical School. University of Minnesota scientists discover dual roles of antibodies in COVID-19 infections. EurekAlert! News Release. Released September 10, 2024. Accessed October 8, 2024. https://www.eurekalert.org/news-releases/1057473