Researchers at Washington University School of Medicine in St. Louis have identified an antibody that is highly protective at low doses against a wide range of viral variants reported in a press release. Moreover, the antibody attaches to a part of the virus that differs little across the variants, meaning that it is unlikely for resistance to arise at this spot. The findings, available online in the journal Immunity, could be a step toward developing new antibody-based therapies that are less likely to lose their potency as the virus mutates.
“Current antibodies may work against some but not all variants,” said senior author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine. “The virus will likely continue to evolve over time and space. Having broadly neutralizing, effective antibodies that work individually and can be paired to make new combinations will likely prevent resistance.”
SARS-CoV-2, the virus that causes COVID-19, uses a protein called spike to attach to and invade cells in the body’s respiratory tract. Antibodies that prevent spike from attaching to cells neutralize the virus and prevent disease. Many variants have acquired mutations in their spike genes that allow them to evade some antibodies generated against the original strain, undermining the effectiveness of antibody-based therapeutics.
To find neutralizing antibodies that work against a wide range of variants, the researchers began by immunizing mice with a key part of the spike protein known as the receptor-binding domain. Then, they extracted antibody-producing cells and obtained 43 antibodies from them that recognize the receptor-binding domain. Along with Diamond, the research team included co-first authors Laura VanBlargan, PhD, a staff scientist; Lucas J. Adams, an MD/PhD student; and Zhuoming Liu, PhD, a staff scientist; as well as co-author Daved Fremont, PhD, a professor of pathology & immunology, of biochemistry & molecular biophysics and of molecular microbiology.
The researchers screened the 43 antibodies by measuring how well they prevented the original variant of SARS-CoV-2 from infecting cells in a dish. Nine of the most potent neutralizing antibodies were then tested in mice to see whether they could protect animals infected with the original SARS-CoV-2 from disease. Multiple antibodies passed both tests, with varying degrees of potency.
Further experiments pinpointed the precise spot on the spike protein recognized by the antibody, and identified two mutations at that spot that could, in principle, prevent the antibody from working. These mutations are vanishingly rare in the real world, however. The researchers searched a database of nearly 800,000 SARS-CoV-2 sequences and found escape mutations in only 0.04% of them.