Study finds pan-sarbecovirus nanobodies can enhance development of super-immunity

With the emergence of severe acute respiratory coronavirus 2 (SARS-CoV-2) and its mutated variants of concern, scientists are looking ahead to prevent the spread of respiratory viruses altogether. A new study published in the bioRxiv* preprint server found that applying pan-sarbecovirus nanobodies shows a strong affinity toward all sarbecovirus clades and neutralized SARS-CoV-2 receptor binding domains. The result is a “super-immunity” against sarbecoviruses, including the Omicron variant.

Study: Super-immunity by broadly protective nanobodies to sarbecoviruses. Image Credit: Juan Gaertner/ShutterstockStudy: Super-immunity by broadly protective nanobodies to sarbecoviruses. Image Credit: Juan Gaertner/Shutterstock

The researchers note that preventing future viral outbreaks will require proactive methods that use a combination of protective and cost-effective technologies. They suggest the small size and multiple routes of administration in nanobodies are an appealing complement to vaccines, small molecule drugs, and monoclonal antibody treatments.

The study

A llama was given a recombinant vaccine containing the SARS-CoV-2 receptor binding domain-Fc fusion protein. Blood samples were collected two months after the initial dose and three booster shots. The llama was then given another four boosters in two months before collecting another set of blood samples.

Blood samples after booster immunization showed antibodies with high affinity towards the receptor-binding domain of SARS-CoV-2 compared to the initial immunization blood samples. In addition, strong neutralization potency was observed against the original SARS-CoV-2 strain along with the Alpha and Lambda variants.

Booster shots increased the neutralizing power to Beta, Delta, and severe acute respiratory coronavirus (SARS-CoV). To the researchers’ surprise, the vaccine boosters showed increasing binding affinity to receptor binding domains and broad neutralization potency against a spectrum of sarbecoviruses.

The researchers next investigated the use of broad-spectrum pan-sarbecovirus nanobodies to help with inhibiting sarbecoviruses. They found 100 nanobodies showed a strong affinity towards the SARS-CoV-2 receptor binding domain, which also showed cross-reactivity with other sarbecoviruses. For instance, 42% of nanobodies were bound to four different sarbecoviruses and neutralized SARS-CoV-2 at a low dose below 500 nanomolar.

Nanobodies are composed of multiple clusters and have a wide range of physiochemical properties, including isoelectric point and hydropathy. The three largest nanobody clusters had neutralizers bound to at least three sarbecoviruses.

The binding affinity of seventeen nanobodies was tested against the receptor-binding domain of five SARS-CoV-2 variants — including Omicron — and 18 other sarbecoviruses. All nanobodies showed strong binding towards the variants. Sixteen of the 17 nanobodies bound to four sarbecoviruses and seven showed broad activity towards all sarbecoviruses studied. These nanobodies are also highly specific to sarbecoviruses and showed no cross-reactivity with high concentrations of a human whole protein extract.

Group A Nb 2-67 showed exceptional potency against SARS-CoV-2 and its variants.

Nanobodies showed high durability and stability as they withstood aerosolization without compromising their activity.

The researchers found five distinct epitope classes on the SARS-CoV-2 receptor binding domain through epitope clustering. Nanobodies did not overlap with mutations observed in Alpha, Beta, Delta, Lambda, Gamma, and Omicron, and nanobodies covered over 85% of receptor-binding domain residues.

Further, nanobodies appeared to lock in a 3-up conformation. Despite different epitopes, the small nanobodies allow three copies to bind to the spike trimer simultaneously.

Throughout the study, the researchers observed an overrepresentation of a certain class of nanobodies known as Class II. Those collected after the first immunization show high diversity, but the Class II nanobodies collected after booster shots converged more. These nanobodies share a conserved hydrophobic core epitope with the region stabilized through a disulfide bond.

Class IIB nanobodies makeup two large clusters and have the best breadth and potency against sarbecoviruses. Nanobodies form hydrophobic interactions with strong binding to conserved charged residues through electrostatic interactions.

Class III nanobodies destabilize the spike protein, and their structure involves targeting a rare non-RBS epitope with a slight overlap with Nb17. Nb17 was collected after the initial blood sample and was effective against variants. Beyond Nb17, other class III nanobodies work through a recognition motif shifting towards a smaller and conserved epitope.

Class IV nanobodies operate via distinct scaffold orientations and sequence-specific bonding networks. They share a highly conserved and cryptic epitope accessible only in the receptor-binding domain up conformation.

Class V nanobodies target the receptor-binding domain through a conserved epitope buried in the spike protein and in a region that partially overlaps with the binding motif of class IV nanobodies.

Continuous immunization produced antibodies targeting various conserved sites on the receptor-binding domain. Applying ultrahigh-affinity nanobodies also showed neutralization potencies.

Pan-sarbecovirus nanobodies could neutralize the virus by sterically interfering with the binding of the receptor-binding domain and the glycan N322 of human ACE2.

Compared to previous nanobodies, pan-sarbecovirus nanobodies target small, flat, or convex regions.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Jocelyn Solis-Moreira

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.

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