Amassing antibodies

Having colleagues close to one of the earliest outbreaks of COVID-19 gave Linqi Zhang’s team at the Gates-Tsinghua Research Center for Global Health and Infectious Diseases, at Tsinghua University, early access to antibodies from the blood of recovering patients.

Zhang’s team were able to rapidly identify hundreds of antibodies for SARS-CoV-2 using lymphocytes gathered by their collaborators at Tsinghua Shenzhen International Graduate School. Shenzhen, in southern China, has close ties to the Hubei province, where the initial outbreak began, and the city had a small number of early cases.

“Once you have a convalescent patient’s B lymphocytes, you throw in viral proteins as bait,” explains Zhang. “Those B lymphocytes that have antibodies on their surface capture the proteins. Then we use flow cytometry to collect these B lymphocytes one by one. Using single cell sequencing technology, we can obtain antibody gene profiles within weeks, instead of going through a whole antibody library procedure that could take months or years.”

In a paper published in Nature in May 2020, his team described isolating and characterizing 206 receptor-binding domain-specific monoclonal antibodies. The researchers then used high-throughput analysis of viral protein binding and neutralizing activity to identify the two most effective antibodies.

Xiao Liu, who works closely with Zhang through the Tsinghua Shenzhen International Graduate School, does antibody receptor repertoire analysis using adaptive immune receptor repertoire sequencing and creates databases for therapeutic antibody discovery. He is establishing a platform to help understand antigen-specific lymphocyte responses, as well as the responses of innate immunity.

The sophistication of this sequencing method, which uses genomic analysis to reveal key adaptive immune receptor characteristics, has expanded with advances in high-throughput analysis and computing, says Liu. “The technology helps us to better understand the adaptive responses of an individual or population’s B and T lymphocytes to vaccines and virus exposure,” he explains.

“From a clinical translation perspective, we could possibly one-day use adaptive immune receptor repertoire sequencing data to diagnose, monitor and predict the prognosis of COVID-19,” says Liu.

Meanwhile, the antibodies identified by Zhang’s team and others on his databases mayfind uses against evolving variants. A July 2021 paper published by Zhang’s team in Immunity demonstrated thatdue to mutations in their N terminal domain and receptor-binding domains, variants of SARS-CoV-2 coming out of South Africa, Brazil, the United Kingdom, and India were somewhat resistant to the monoclonal antibodies used in current vaccines.

Each of the two antibodies identified by Zhang’s team recognized different portions of the virus protein. These differences may prove vital in providing vaccines with wider coverage as the virus mutates, says Zhang.