3D print of a spike protein of SARS-CoV-2 in front of a 3D print of a SARS-CoV-2 virus particle. The spike protein (foreground) enables the virus to enter and infect human cells. On the virus model, the virus surface (blue) is covered with spike proteins (red) that enable the virus to enter and infect human cells. Credit: NIH
Last week, California researchers showed how they were applying their COVID-19 wastewater research to the current monkeypox outbreak. This week, researchers in Boston leveraged a humanized mouse model previously used to search for HIV antibodies in the ever-ongoing fight against SARS-CoV-2.
Using the mouse model, the team from Boston Children’s Hospital discovered an antibody that neutralizes all 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,” said Frederick Alt, a geneticist at Boston Children’s Hospital, who co-led the research.
Alt and his colleague Sai Luo first inserted two human gene segments into the mice, pushing their B cells to rapidly produce a diverse range of humanized antibodies. They then exposed the mice to the SARS-CoV-2 spike protein from the original strain of the virus. In response, the modified mice produced nine lineages of humanized antibodies that bound to the spike.
Working with scientists at Duke University, the team discovered that antibodies in three of the nine lineages were potent neutralizers of the original virus strain. But one, in particular, stood out. 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.
What makes SP1-77 novel and unique is where it binds to the spike protein. Most of the existing antibodies—either therapeutic or those made in response to vaccines—bind to the spike’s receptor-binding domain (RBD) in specific locations that prevent SARS-CoV-2 from binding to cells’ ACE2 receptors, the first step in initiating infection.
And while SP1-77 also binds to the RBD, it does so in a manner that does not block the virus from binding to ACE2 receptors. Rather, the researchers discovered, 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.
Like HIV, SARS-CoV-2 is a rapidly evolving RNA virus, enabling it to circumvent initial vaccines and even boosters. In particular, omicron-variants, which contain a high number of mutations in their spike proteins, have demonstrated a great amount of resistance to most prior SARS-CoV-2-neutralizing antibodies and those induced by vaccinations. For instance, in India, Omicron sub-variant BA.2.75 is causing an infection surge.
That’s what makes SP1-77 such an interesting and positive discovery.
“SP1-77 binds the spike protein at a site that so far has not been mutated in any SARS-CoV-2 variant,” said Tomas Kirchhausen, senior investigator at Boston Children's Hospital.
Next, the researchers plan to test SP1-77 in vivo. If the antibody continues to exhibit broad neutralization activity against SARS-CoV-2 variants in vivo, the team says SP1-77 would have potential as a therapeutic against current and evolving VOCs.
“Also, SP1-77 might be useful in a cocktail with other neutralizing antibodies, such as LY-CoV1404, that potently neutralizes all tested VOCs through an ACE2-blocking mechanism,” the researchers explain in their paper, published in Science Immunology.
Ultimately, the scientists agree the non-traditional neutralization mechanism of SP1-77 could inspire the design of new SARS-CoV-2 vaccines.