Researchers at the University of Pittsburgh and Case Western Reserve University have found that SARS-CoV-2 nanobodies, or microscopic molecules that counter COVID-19 in animals, are useful in treating COVID-19 variants, including the delta variant.

The analysis looked at molecules at almost an atomic level in animals. The findings could serve as a guide for the development of future vaccines and treatments that may work against a wide variety of coronaviruses and their variants.

Last year, a team lead by senior author Yi Shi, Ph.D., assistant professor of cell biology at Pitt, was able to extract SARS-CoV-2 antibody fragments, called “nanobodies,” from llamas. The nanobodies could be made inhalable as a COVID-19 treatment and preventative.

“Back then, we didn't know exactly how the nanobodies inhibited the virus,” Dr. Shi said. “We knew they strongly inhibited the virus, but didn't know the mechanism.”

Since then, preclinical studies have verified that the nanobodies can prevent and treat severe COVID-19 in hamsters, and further, that inhalation treatment, or breathing in the nanobodies in mist form, reduced virus particles in the animals' respiratory tracts by a million-fold.

“Nanobodies are extremely stable, which makes them useful for therapeutics. They're also very small compared to human antibodies,” Shi said. “We developed technologies to enable discovery of many thousands of nanobodies that bind very strongly to SARS-CoV-2 spikes.”

The study identified three main ways that the nanobodies can combat the COVID-19 virus, and divided them into three “classes.”Class I nanobodies block the part of the cell that COVID-19 spike proteins would usually get stuck to, keeping the virus from getting into cells.Class II sticks to a region on the spike protein that has persisted through several different variants and mutations of coronaviruses. This makes it effective against a number of coronaviruses, including future COVID-19 variants.Class III sticks onto a specific region of the spike protein that bigger human antibodies can't reach, stopping the protein from folding to access a human cell.All three classes work to get in the way of the COVID-19 virus.

Shi's lab isn't the only group researching nanobodies—other researchers across the globe are studying the same topic. But Shi says his lab is the first to a number of goalposts.“We are, so far, the first group that demonstrated the preclinical efficacy to use [nanobodies] for inhalation therapy — we showed for the first time these can be inhaled by animal models, drastically reduce the virus, and protect the animals,” he said. “I think we're also the first group to classify many different neutralizing nanobodies. Classifications based on nanobody structure are novel.”Shi's lab is mostly involved in technology development, and is very interested in pushing forward this nanobody technology. They're encouraged by other COVID-19 researchers and their stories, and believe that later on, this technology could be used to treat other diseases beyond COVID-19.“For COVID development, we are pushing very hard to try and quickly finish these evaluation of these nanobodies for preclinical trials beyond hamsters,” he said. “We're planning to use a primate model, like an African green monkey, which is closer to humans, so we could see the efficacy of treating the animals before we could move this technology to clinical trials. We're working with the university to locate resources to help us with this, and to really help other people as well.”