For centuries, humans have depended on llamas for transportation, wool and food. Now, thanks to key findings about their immune systems, these animals may become critical in the fight against COVID-19.
In a study published July 13 in Nature Structural & Molecular Biology, researchers from the University of Oxford the Rosalind Franklin Institute in England announced the creation of two nanobodies that could block the novel coronavirus from entering human cells.
Llamas, camels and alpacas produce nanobodies, which are cousins of the antibody that are smaller, more stable and easier to produce, according to a statement from the University of Reading. Like human antibodies, nanobodies found in llamas can detect and attach to certain proteins, like the ones that cover the SARS-CoV-2 virus. Antibodies from humans and other animals bind to these spike proteins, blocking them from entering the cell. Because they are smaller, however, nanobodies can bind to little pockets in the protein that larger antibodies might miss. Additionally, nanobodies can maintain their shape in extreme environments, such as the acid-filled stomach, where human antibodies are less stable.
“These [nanobodies] can block—do block quite potently—the interaction between the virus and the human cell,” Ray Owens, a professor of molecular biology at the University of Oxford and one of the study’s senior authors, tells Grace Huckins of Wired. “They basically neutralize the virus.”
Prior studies show that llamas can naturally create nanobodies to protect against a variety of intruding pathogens, including those that cause cancer. But waiting for the animals to produce new nanobodies can take months. Instead, Owens and his team introduced the spike protein to a collection of different, pre-existing sequences to identify one that could bind to the protein.
Initially, the llama nanobodies didn’t attach tightly enough to the virus to keep it from entering cells. The team mutated the portion of the nanobody that connects with the spike protein until latches more snuggly onto the virus. They eventually identified two nanobodies which, when introduced in large quantities to SARS-CoV-2, successfully prevented the virus from entering human cells.
Modifying old nanobodies provides only a short-term solution. Scientists are still working on projects in which llama’s produce their own nanobodies from scratch. “Using immunization, the natural immune system, to mature high affinity interactions obviously gives you the best binders,” Owens tells Wired.
Currently, infected individuals can receive antibodies via plasma infusions from the blood of recovered COVID-19 patients during a process called passive immunization. These recovered patients create antibodies that can be used to protect others without an existing immune response. According to the American Society of Hematology, health care providers have used this method for nearly 100 years to fight various pathogens. Though there is evidence that this is somewhat successful for treating COVID-19, the infusion is often paired with other therapies, so its individual efficacy remains unclear. Additionally, the process of finding and matching plasma donors with recipients can be onerous.
By contrast, llama nanobodies can be created in the lab at a large scale and stockpiled. Rather than relying on fresh plasma donations, medical providers can easily store and distribute these nanobodies, James Naismith, lead researcher for the study, tells Carol Hills of Public Radio International.
Nanobodies’ small size gives the added benefit of being easier to introduce into the body. Unlike larger antibodies, they do not necessarily need to be injected, and can travel more easily through body tissue. “Potentially, they could be inhaled directly into the lung, where the respiratory infections are occurring,” Jason McLellan, a molecular bioscientist at the University of Texas tells Wired. McLellan and his team reported the discovery of a different llama nanobody in Cell in May.
The most effective transmission method is yet to be determined. Current passive immunization methods usually only require one shot, but Naismith says there may need to be multiple doses or alternative ways of introducing the nanobodies.
“Llamas are closely related to humans, but they are different. So we don't know whether your immune system will actually form an immune response to the llama nanobodies,” he tells PRI.
At the University of Reading, scientists introduced Fifi the llama to harmless virus proteins. Preliminary screenings show that Fifi has already produced different antibodies from those identified in the lab. The team is hopeful that these and additional antibodies from her immune system can be used to treat a variety of COVID-19 mutations.
“One of the next steps is to start trying to identify antibodies and nanobodies that can broadly bind and neutralize diverse coronaviruses,” McLleland says. “In the event there's another coronavirus outbreak in the future, we might then already have the antibody immediately, from day one, that could work and neutralize the virus.”