The SARS-CoV-2 spike receptor-binding domain has evolved decreased inherent antigenicity in humans

In a new study led by Catherine Jacob-Dolan, we show SARS-CoV-2's spike RBD has evolved reduced inherent antigenicity as quantified by decreased recognition by naive human B cells.

It's been clear for some time now that SARS-CoV-2 evolves to escape the antibodies elicited by prior infection and vaccination. In this study, we asked a different question: Has it also evolved to reduce its recognition by naive human B cells?

To answer this question, we measured the percentage of naive human B cells (from pre-2019 human samples) that bound to the spike RBD from the early Wuhan-Hu-1 variant or several later variants. We found a roughly 3-fold decrease in binding of naive human B cells to later variants. In contrast, there was no decrease in binding to naive mice B cells, indicating a specific loss of recognition by the human naive antibody repertoire.

Our interpretation: early viral variant RBDs are strongly targeted by “public” human germline antibodies, putting pressure on virus to change those epitopes. As the epitopes evolve, sometimes they become less recognized by human germline repertoire, decreasing inherent antigenicity.

However, the decrease in inherent antigenicity is modest (~3-fold), and plenty of naïve human B cells still bind newer variant RBDs. We lack data to assess how much ~3-fold drop in inherent antigenicity affects human neutralizing antibody response. This is an interesting area for future work.

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