The SARS-CoV-2 variants that keep appearing are still manageable with currently available COVID-19 vaccines. Still. One day, “still” could become “no longer.” One way to deal with this grim possibility is to deploy new vaccines. Another way is to target SARS-CoV-2 variants with neutralizing antibodies.

The latter option is being explored by many researchers. They’re on the lookout for SARS-CoV-2 structures that would provide reliable binding sites for antibodies—reliable as in highly conserved. Alas, conserved structures can be hard to access, especially with large, clumsy antibodies. So, might smaller, nimbler antibodies become available?

They could. According to a study from a multi-institutional team of scientists, SARS-CoV-2 variants can be neutralized by VHH antibodies, or nanobodies. The scientists isolated nanobodies from llamas and “nanomice” that they had engineered to produce VHHs cloned from alpacas, dromedaries, and camels. Next, the scientists identified several nanobodies that were especially adept at adept at recognizing highly conserved features of the receptor-binding domain (RBD), the part of the notorious spike protein on SARS-CoV-2 that allows the virus to break into host cells. Finally, the scientists engineered multivalent versions of the best nanobodies, and succeeded in enhancing the antibodies’ neutralizing powers.

Details about this work recently appeared in Nature, in an article titled, “Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants.” This article, which describes how the scientists identified two sets of highly neutralizing nanobodies, was prepared by scientists from various NIH agencies, Ohio State University, Rockefeller University, Columbia University, and the Frederick National Laboratory for Cancer Research.

“Group 1 circumvents antigenic drift by recognizing an RBD region that is highly conserved in coronaviruses but rarely targeted by human antibodies,” the article’s authors wrote. “Group 2 is almost exclusively focused to the RBD-ACE2 interface and fails to neutralize variants carrying E484K or N501Y substitutions. Notably however, group 2 nanobodies retain full neutralization activity against variants when expressed as homotrimers, rivaling the most potent antibodies produced to date against SARS-CoV-2.”

Nanobodies in each group used different mechanisms to bypass mutations and disable the virus’s ability to bind to ACE2, a host cell receptor. It is by binding ACE2 that the virus is able to enter the host cell.

“That RBD-ACE2 interface is on the top of the RBD—that region is the primary target for the protective human antibodies, generated by vaccination or previous infection, to block the viral entry,” said Kai Xu, assistant professor of veterinary biosciences at the Ohio State University and a co-lead author of the research. “But it is also a region frequently mutated in the variants.”

In the current study, three emerging variants—Alpha, Beta, and Gamma—were neutralized by the nanobodies that the scientists generated.

“We found that [one group of nanobodies] can recognize a conserved region of the RBD, a hidden location that is too narrow for human antibodies to reach,” Xu noted. And attaching at this location, even though it is some distance away from where RBD connects to ACE2, still accomplishes what is intended—blocking SARS-CoV-2 from entering a host cell.

The other group of nanobodies, attracted to the RBD-ACE2 interface, while in their original form could not neutralize certain variants. However, when the researchers engineered this group to be homotrimers—three copies linked in tandem—the nanobodies achieved potent neutralization of the virus. Altering the structure of the nanobodies that attached to the conserved region of RBD in the same way enhanced their effectiveness as well.

The findings suggest nanobodies could be help prevent COVID-19 mortality when vaccines are compromised. “Our plan,” Xu noted, “is to further isolate antibodies specifically against emerging variants for therapeutic development, and to find a better solution for vaccines by learning from those antibodies.”