Powerful new antibody neutralizes all known variants of COVID
Future vaccine development could be inspired by the findings.
Therapeutic antibodies that were effective at the start of the pandemic lost their effectiveness as SARS-CoV-2 has changed and mutated, and newer variants, especially Omicron, have learned to bypass the antibodies our systems produce in response to vaccinations. We may be able to better guard against possible variations thanks to a new broadly neutralizing antibody created at Boston Children’s Hospital. In testing, it neutralized all known SARS-CoV-2 variants of concern, including all Omicron variants.
“We hope this humanized antibody will prove as effective in neutralizing SARS-CoV-2 in patients as it has proven in preclinical evaluations so far,” says Frederick Alt, Ph.D., of the Program in Cellular and Molecular Medicine at Boston Children’s Hospital, who co-directed the research.
In a study published in Sciences Immunology, Alt and Sai Luo, Ph.D., used a modified version of a humanized mouse model that his lab had previously used to search for broadly neutralizing antibodies against HIV, another virus that often mutates. Since mice do indeed have a built-in human immune system, the model closely resembles how the trial-and-error process our immune system uses to create increasingly effective antibodies.
The researchers initially introduced two human gene segments into the mice, causing their B cells to create a large repertoire of humanized antibodies in a short time. They then exposed the mice to the original Wuhan-Hu-1 strain of the virus’ SARS-CoV-2 spike protein, which is the main protein targeted by our current antibodies and vaccines. The modified mice evolved nine lineages, or “families,” of humanized antibodies that bound to the spike in response.
Working with a team from Duke University led by Dr. Barton Haynes, Alt and Luo then assessed the effectiveness of these antibodies. Antibodies from three of the nine lineages were effective in neutralizing the original Wuhan-Hu-1 virus. The SP1-77 antibody and other members of its lineage, in particular, have demonstrated extremely broad activity, neutralizing Alpha, Beta, Gamma, Delta and all previous and current Omicron strains.
A new approach to virus neutralization
What made the SP1-77 antibody so broadly neutralizing? Structural studies by a collaborative team led by Bing Chen, Ph.D. and Jun Zhang, Ph.D. at Boston Children’s Hospital and the Haynes Group at Duke, have shown that SP1-77 works differently than current antibodies (either therapeutic antibodies, i.e. those we make in response to current vaccines).
Many existing antibodies work by attaching to the receptor binding domain (RBD) of the tip in certain regions, preventing SARS-CoV-2 from binding to ACE2 receptors on our cells, which is the first step in infection. . The SP1-77 antibody also binds to the RBD, but in a completely different way that does not prevent the virus from binding to ACE2 receptors.
Using a novel live-cell imaging platform described in a preprint, collaborators Alex Kreutzberger, Ph.D. and Tomas Kirchhausen, Ph.D., from 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 last necessary step that opens the door to infection.
These characteristics may inform the design of new SARS-CoV-2 vaccines. “SP1-77 binds to the spike protein at a site that so far has not been mutated in any SARS-CoV-2 variant, largely neutralizing current variants by a novel mechanism,” says Kirchhausen.
Reference: “An antibody from a single human VH rearrangement mouse neutralizes all SARS-CoV-2 variants via BA.5 by inhibiting membrane fusion” by Sai Luo, Jun Zhang, Alex JB Kreutzberger, Amanda Eaton, Robert J. Edwards, Changbin Jing, Hai-Qiang Dai, Gregory D. Sempowski, Kenneth Cronin, Robert Parks, Adam Yongxin Ye, Katayoun Mansouri, Maggie Barr, Novalia Pishesha, Aimee Chapdelaine Williams, Lucas Vieira Francisco, Anand Saminathan, Hanqin Peng, Himanshu Batra, Lorenza Bellusci, Surender Khurana, S. Munir Alam, David C. Montefiori, Kevin O. Saunders, Ming Tian, Hidde Ploegh, Tom Kirchhausen, Bing Chen, Barton F. Haynes, and Frederick W. Alt, August 11 2022, Sciences Immunology.
The study was funded by the Howard Hughes Medical Institute, Bill & Melinda Gates Foundation, NIH NIAID Consortia for HIV/AIDS Vaccine Development, Massachusetts Consortium on Pathogen Readiness, Emergent Ventures, Food and Drug Administration, NIH Maximizing Investigators’ Research Award, NIH Grant AI163019, Danish Technical University and SANA, IONIS, and a Harvard Virology Program NIH Training Fellowship.
Alt and Ming Tian, Ph.D., of Boston Children’s are the authors of a patent application describing the mouse model. Luo, Haynes and Alt are the authors of patent applications describing the antibodies.