[4][5] The distinctive appearance of these spikes when visualized using negative stain transmission electron microscopy, "recalling the solar corona",[6] gives the virus family its main name.

[9] Most COVID-19 vaccine development efforts in response to the COVID-19 pandemic aim to activate the immune system against the spike protein.

[7] The S1 region of the spike glycoprotein is responsible for interacting with receptor molecules on the surface of the host cell in the first step of viral entry.

The CTD of these viruses can be further divided into two subdomains, known as the core and the extended loop or receptor-binding motif (RBM), where most of the residues that directly contact the target receptor are located.

[5] Comparisons of spike proteins from multiple coronaviruses suggest that divergence in the RBM region can account for differences in target receptors, even when the core of the S1 CTD is structurally very similar.

[5][7][8] The S2 region contains the fusion peptide, a stretch of mostly hydrophobic amino acids whose function is to enter and destabilize the host cell membrane.

[5][8] The S2 region is also considered to include the transmembrane helix and C-terminal tail located in the interior of the virion.

[8] The interaction of the receptor-binding domain in the S1 region with its target receptor on the cell surface initiates the process of viral entry.

[7][9][27] Human serum albumin binds to the S1 region, competing with ACE2 and therefore restricting viral entry into cells.

[7] The specific proteases responsible for this cleavage depends on the virus, cell type, and local environment.

[5][7] Receptor binding and proteolytic cleavage (sometimes known as "priming") are required, but additional triggers for this conformational change vary depending on the coronavirus and local environment.

[44] Antibodies to the SARS-CoV and SARS-CoV-2 spike proteins have been identified that target epitopes on the receptor-binding domain[9][44][46] or interfere with the process of conformational change.

[44][47][48] More recently antibodies targeting the S2 subunit of the spike protein have been reported with broad neutralization activities against variants.

[10][11][12] Building on techniques previously used in vaccine research aimed at respiratory syncytial virus and SARS-CoV, many SARS-CoV-2 vaccine development efforts have used constructs that include mutations to stabilize the spike protein's pre-fusion conformation, facilitating development of antibodies against epitopes exposed in this conformation.

[50][51] According to a study published in January 2023, markedly elevated levels of full-length spike protein unbound by antibodies were found in people who developed postvaccine myocarditis (vs. controls that remained healthy).

[52][non-primary source needed] Monoclonal antibodies that target the receptor-binding domain of the spike protein have been developed as COVID-19 treatments.

As of July 8, 2021, three monoclonal antibody products had received Emergency Use Authorization in the United States:[55] bamlanivimab/etesevimab,[56][57] casirivimab/imdevimab,[58] and sotrovimab.

[55] Throughout the COVID-19 pandemic, the genome of SARS-CoV-2 viruses was sequenced many times, resulting in identification of thousands of distinct variants.

In a World Health Organization analysis from July 2020, the spike (S) gene was the second most frequently mutated in the genome, after ORF1ab (which encodes most of the virus' nonstructural proteins).

[61] Analyses of SARS-CoV-2 genomes suggests that some sites in the spike protein sequence, particularly in the receptor-binding domain, are of evolutionary importance[62] and are undergoing positive selection.

[47][63] Spike protein mutations raise concern because they may affect infectivity or transmissibility, or facilitate immune escape.

[47] The mutation D614G has arisen independently in multiple viral lineages and become dominant among sequenced genomes;[64][65] it may have advantages in infectivity and transmissibility[47] possibly due to increasing the density of spikes on the viral surface,[66] increasing the proportion of binding-competent conformations or improving stability,[67] but it does not affect vaccines.

[73] The mutation P681R alters the furin cleavage site, and has been responsible for increased infectivity, transmission and global impact of the SARS-CoV-2 Delta variant.

[80][81] During the COVID-19 pandemic, anti-vaccination misinformation about COVID-19 circulated on social media platforms related to the spike protein's role in COVID-19 vaccines.

[7] The surface-exposed position of the CTD, vulnerable to the host immune system, may place this region under high selective pressure.