Spike protein

The surface glycoprotein on SARS-CoV-2 that binds the ACE2 receptor to enter human cells. The "S" in the virus's name. Target antigen for most COVID-19 vaccines and a focus of research into post-acute syndromes.

Edited by M. Callahan · Last reviewed 2026-05-10

How researchers study it

The spike protein (S protein) is one of four structural proteins of SARS-CoV-2 and the largest target on the viral surface. Structural biologists at NIH used cryo-electron microscopy in early 2020 to publish its 3.5-angstrom structure (Wrapp et al., Science, 2020), which revealed the receptor-binding domain (RBD) that contacts the human ACE2 enzyme.

Researchers describe spike as having two subunits: S1, which carries the RBD and handles receptor binding, and S2, which drives membrane fusion. A cleavage site between the two — the furin cleavage site — is one of the structural features that distinguishes SARS-CoV-2 from earlier sarbecoviruses and has been studied extensively (Hoffmann et al., Nature, 2020).

In post-acute research, the question being asked is whether spike protein — or fragments of it — can persist in tissue after acute infection clears, and whether such persistence might contribute to ongoing inflammation. The NIH's RECOVER initiative is the largest U.S. effort cataloguing post-acute findings. Persistence studies have detected spike protein or RNA in monocytes, gut tissue, and other reservoirs months after acute illness in some patients (Patterson et al., 2022, PubMed 35262865), but the field is still working out what those findings mean clinically.

The spike protein is also the antigen most COVID-19 vaccines train the immune system against — whether via mRNA (Pfizer-BioNTech, Moderna), adenoviral vector (Janssen, AstraZeneca), or protein-subunit (Novavax) platforms.

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