The study by Watanabe et al. investigates the site-specific glycan analysis of the SARS-CoV-2 spike protein, a key target in vaccine development. The authors used a mass spectrometric approach to map the glycan structures on a recombinant SARS-CoV-2 S immunogen, revealing the glycan-processing states across the trimeric viral spike. They found that the SARS-CoV-2 S glycans differ from typical host glycan processing, with two sites (N234 and N709) predominantly displaying oligomannose-type glycan structures. The analysis also showed that 8 out of 22 sites contain substantial populations of oligomannose-type glycans, highlighting divergent processing compared to host glycoproteins. The study mapped the glycosylation status onto the three-dimensional structure of the prefusion SARS-CoV-2 S protein, showing how N-linked glycans occlude distinct regions, including receptor binding sites. The findings suggest that the SARS-CoV-2 S protein is less densely glycosylated than other viral glycoproteins, which may facilitate the elicitation of neutralizing antibodies. The detailed glycan analysis provides a benchmark for comparing immunogen integrity and monitoring manufacturing processes for clinical use.The study by Watanabe et al. investigates the site-specific glycan analysis of the SARS-CoV-2 spike protein, a key target in vaccine development. The authors used a mass spectrometric approach to map the glycan structures on a recombinant SARS-CoV-2 S immunogen, revealing the glycan-processing states across the trimeric viral spike. They found that the SARS-CoV-2 S glycans differ from typical host glycan processing, with two sites (N234 and N709) predominantly displaying oligomannose-type glycan structures. The analysis also showed that 8 out of 22 sites contain substantial populations of oligomannose-type glycans, highlighting divergent processing compared to host glycoproteins. The study mapped the glycosylation status onto the three-dimensional structure of the prefusion SARS-CoV-2 S protein, showing how N-linked glycans occlude distinct regions, including receptor binding sites. The findings suggest that the SARS-CoV-2 S protein is less densely glycosylated than other viral glycoproteins, which may facilitate the elicitation of neutralizing antibodies. The detailed glycan analysis provides a benchmark for comparing immunogen integrity and monitoring manufacturing processes for clinical use.