As SARS-CoV-2 has evolved and mutated, therapeutic antibodies that worked early in the pandemic have become less effective, and newer variants, especially Omicron, have developed ways to evade the antibodies we make in response to vaccines. A new, broadly neutralizing antibody developed at Boston Children's Hospital could potentially improve our ability to defend against future variants. In tests, it neutralized all currently known SARS-CoV-2 variants of concern, including all Omicron variants.
"We hope that this humanized antibody will prove to be as effective at neutralizing SARS-CoV-2 in patients as it has proven to be thus far in preclinical evaluations," says Frederick Alt, PhD, of the Program in Cellular and Molecular Medicine at Boston Children's Hospital, who co-led the research.
As described in Science Immunology on August 11, Alt and Sai Luo, PhD, in his lab turned to a modified version of a humanized mouse model that the lab has used to search for broadly neutralizing antibodies to HIV, another virus that frequently mutates. The mice essentially have built-in human immune systems, and the model mimics the trial-and-error process our immune system uses to create increasingly effective antibodies.
The researchers first inserted two human gene segments into the mice, pushing their B cells to rapidly produce a diverse repertoire of humanized antibodies. They then exposed the mice to the SARS-CoV-2 spike protein, the main protein targeted by our antibodies and current vaccines, from the original Wuhan-Hu-1 strain of the virus. In response, the modified mice produced nine lineages or "families" of humanized antibodies that bound to the spike.
Alt and Luo then vetted these antibodies for efficacy in collaboration with the group of Barton Haynes, MD at Duke University. Antibodies in three of the nine lineages were potent neutralizers of the original Wuhan-Hu-1 virus. In particular, the SP1-77 antibody and other members of its lineage showed very broad activity, neutralizing Alpha, Beta, Gamma, Delta, and all previous and current Omicron strains.
A novel approach to virus neutralization
What made the SP1-77 antibody so broadly neutralizing? Structural studies by a collaborating team led by Bing Chen, PhD and Jun Zhang, PhD at Boston Children's Hospital and the Haynes group at Duke, showed that SP1-77 works differently from current antibodies (either therapeutic antibodies or those we make in response to current vaccines).
Many of the existing antibodies function by binding to the spike's receptor-binding domain (RBD) in specific locations that prevent SARS-CoV-2 from binding to our cells' ACE2 receptors, the first step in initiating infection. The SP1-77 antibody also binds to the RBD, but in a totally different manner that does not block the virus from binding to ACE2 receptors.
Using a novel live-cell imaging platform described in a preprint, collaborators Alex Kreutzberger, PhD and Tomas Kirchhausen, PhD, of Boston Children's Hospital showed that SP1-77 prevents the virus from fusing its outer membrane with the membrane of the target cell. This thwarts the final necessary step that throws the door open to infection.
These features may inform design of new SARS-CoV-2 vaccines. "SP1-77 binds the spike protein at a site that so far has not been mutated in any SARS-CoV-2 variant, broadly neutralizing current variants by a novel mechanism," says Kirchhausen.
Luo, Zhang, and Kreutzberger were co-first authors on the paper. Kirchhausen, Chen, Haynes, Luo, and Alt were co-corresponding authors. The work was supported by the Howard Hughes Medical Institute, the Bill & Melinda Gates Foundation (INV-021989), the NIH NIAID Consortia for HIV/AIDS Vaccine Development (UM1-AI144371, P01 AI158571), the Massachusetts Consortium on Pathogen Readiness, Emergent Ventures, the Food and Drug Administration (OCET 2021-1565, GCBER005), the NIH Maximizing Investigators' Research Award (GM130386), NIH Grant AI163019, he Danish Technical University and SANA, IONIS, and a Harvard Virology Program NIH training grant (T32 AI07245).
Alt and Ming Tian, PhD, at Boston Children's are authors on a patent application describing the mouse model (US 16/973,125)., and Luo, Haynes, and Alt are authors on patent applications describing the antibodies (63/256,384 and 63/305,424).
About Boston Children's Hospital
Boston Children's Hospital is ranked the #1 children's hospital in the nation by U.S. News & World Report and is a pediatric teaching affiliate of Harvard Medical School. Home to the world's largest research enterprise based at a pediatric medical center, its discoveries have benefited both children and adults since 1869. Today, 3,000 researchers and scientific staff, including 11 members of the National Academy of Sciences, 25 members of the National Academy of Medicine and 10 Howard Hughes Medical Investigators comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's is now a 485-bed comprehensive center for pediatric and adolescent health care. For more, visit our Answers
