Llama antibodies open door to future coronavirus protection

A Belgian research team has discovered a novel class of small antibodies that are strongly protective against a wide range of SARS coronaviruses, including SARS-CoV-1 and numerous early and recent SARS-CoV-2 variants. Their findings, published in the journal Nature Communications, offer a promising route to developing broad-spectrum antiviral treatments that could remain effective against future viral variants.

SARS-CoV-2, the virus behind COVID-19, continues to be a potential threat as it evolves into newer variants that are resistant to currently approved antibody therapies. Resistance largely emerges because antibodies typically target virus regions, such as the receptor binding domain of the spike protein, that also frequently mutate, enabling escape from antibody recognition.

To address this, a research team led by Professor Xavier Saelens and Dr Bert Schepens at the VIB-UGent Center for Medical Biotechnology explored a different strategy by focusing on one of the more stable subunits of the spike protein. The so-called S2 subunit is critical for the virus’s ability to fuse with host cells, a process essential for infection, and it is more conserved across different coronaviruses. The team worked together with researchers from the VIB-VUB Center for Structural Biology, the VIB-UGent Center for Inflammation Research and VIB NANOBODY VHH Core (under the umbrella of VIB Technologies).

The team turned to llamas, which generate so-called single-domain antibodies (also known as VHHs or nanobodies) that are much smaller than the antibodies generated by most animals, including humans. The researchers identified several antibodies that strongly neutralise a broad panel of SARS coronaviruses in a llama named Winter, who had been injected with stabilised spike proteins from SARS-CoV-1 and MERS-CoV viruses back in 2016.

What makes the antibodies in question particularly promising is their mode of action: they act like a molecular clamp. They latch onto the poorly exposed, highly conserved region (a coiled coil of three alpha helices) at the base of the virus’s spike protein. In doing so, they lock the spike protein in its original shape, physically preventing it from unfolding into the form the virus needs to infect cells.

The antibodies showed strong protection against infection in lab animals, even at low doses. When the researchers attempted to force the virus to evolve resistance, the virus struggled, producing only rare escape variants that were much less infectious. This points to a powerful, hard-to-evade treatment option.

“This region is so crucial to the virus that it can’t easily mutate without weakening the virus itself,” said Schepens, who was senior author on the study. “That gives us a rare advantage: a target that’s both essential and stable across variants.”

The team’s discovery thus marks an advancement in the quest for durable and broadly effective antiviral therapies, offering hope for treatments that can keep pace with viral evolution.

“The combination of high potency, broad activity against numerous viral variants, and a high barrier to resistance is incredibly promising,” Saelens said. “This work provides a strong foundation for developing next-generation antibodies that could be vital in combating not only current but also future coronavirus threats.”

Image caption: Winter the llama lives on a farm in the Belgian countryside that is operated by VIB. Image credit: Tim Coppens.