Researchers have identified another potential target for neutralizing antibodies on the SARS-CoV-2 Spike protein that is masked by metabolites in the blood. As a result of this masking, the target may be inaccessible to antibodies, because they must compete with metabolite molecules to bind to the otherwise open region, the study authors speculate. This competitive binding activity may represent another method of immune evasion by the SARS-CoV-2 virus. Although further validation work is needed, the findings suggest that strategies to unmask this region - thus making it more visible and accessible to antibodies - may help lead to new vaccine designs. To date, the majority of neutralizing antibodies characterized in COVID-19 patients are those that bind the receptor binding domain of the SARS-CoV-2 Spike protein, while much less is known about the structure of - and antibody interactions with - the Spike's N-terminal domain (NTD). Using cryo-electron microscopy and X-ray crystallography, Annachiara Rosa and colleagues mapped a deep cleft of the N-terminal domain, showing that a specific pocket in the cleft binds the blood metabolite biliverdin with high affinity. This activity leads to stabilization of the NTD structure and "hides" the Spike protein site from binding and neutralization by a subset of human anti-Spike protein antibodies. Successful binding of antibodies to this Spike region requires conformational changes in the NTD that are inhibited by biliverdin binding. Addition of excess biliverdin to sera isolated from SARS-CoV-2-infected and convalescent individuals reduced the reactivity of the immune sera by as much as 50%. The results highlight the importance of this small pocket in the NTD for the stimulation of antibody immunity against SARS-CoV-2.