The virus that causes COVID-19 now is not the same as the one that infected patients for the first time in December 2019 (Coronaviridae Study Group of the International Committee on Taxonomy of 2020). Many current strains are resistant to some antibody-based therapies developed in response to the original virus. As the epidemic progresses, new variations will emerge, exacerbating the resistance problem.
Researchers at Washington University School of Medicine in St. Louis discovered an antibody that is highly protective against various viral variations at low dosages. Furthermore, the antibody binds to a region of the virus that changes little between variations, indicating that resistance is unlikely to develop at this site.
The results, published online in the journal Immunity (VanBlargan et al., 2021), might pave the way for developing novel antibody-based therapeutics that are less likely to lose efficacy when the virus mutates.
“Current antibodies may work against some but not all variations,” stated senior author and Herbert S. Gasser Professor of Medicine Michael S. Diamond, MD, Ph.D. “The virus will most likely develop through time and space. Having widely neutralizing, effective antibodies that function alone and may be combined to form novel combinations is likely to prevent resistance.”
SARS-CoV-2, the virus that causes COVID-19, attaches to and invades the respiratory tract’s cells through a spike protein. Antibodies blocking the virus from adhering to cells kill it and keep it from causing sickness. Many variations have gained mutations in their spike genes, allowing them to avoid certain antibodies created against the original strain, reducing the efficacy of antibody-based therapies.
To develop neutralizing antibodies that work against a wide variety of variations, the researchers first immunized mice with the receptor-binding domain of the spike protein. The researchers next isolated antibody-producing cells and isolated 43 antibodies that target the receptor-binding region.
The 43 antibodies were tested by determining how well they inhibited the original version of SARS-CoV-2 from infecting cells in a dish. Nine of the most strong neutralizing antibodies were then tested in mice to determine if they might prevent sickness in animals infected with the original SARS-CoV-2. Multiple antibodies, with varying degrees of potency, passed both tests.
The researchers chose the two most efficient antibodies to prevent illness in mice and tested them against a panel of viral variations. The panel included viruses with spike proteins representing all four worry variations (alpha, beta, gamma, and delta), two of interest variants (kappa and iota), and other nameless variants being monitored as possible hazards. SARS2-38 antibody easily neutralized all variations.
Furthermore, a humanized form of SARS2-38 protected mice from sickness induced by two variations: kappa and a virus harboring the beta variant’s spike protein. The beta version is generally resistant to antibodies; therefore, its failure to withstand SARS2-38 is especially noteworthy, according to the researchers.
Further research discovered the specific place on the spike protein targeted by the antibody, as well as two mutations at that location that may, in theory, prevent the antibody from operating. However, in the actual world, these mutations are extremely rare. The researchers examined approximately 800,000 SARS-CoV-2 sequences and discovered escape mutations in just 0.04% of them.
“This antibody is both highly neutralizing (meaning it works effectively at low doses) and broadly neutralizing (meaning it works against all variations),” said Diamond, who also teaches pathology and immunology.
“That’s a rare and very desired antibody combination. It also attaches to a distinct region of the spike protein that is not targeted by other antibodies in development. That is excellent for combo treatment. We may consider combining one antibody with another that attaches someplace else to produce a combined treatment that the virus would find tough to fight.”