The SARS-CoV-2 Spike Protein and Neutralizing Antibody

Targeting the right antibody can have a major impact on understanding patient immune response

Why use a SARS-CoV-2 antibody assay that targets the receptor-binding domain (RBD) of the S1 spike protein? Here are 3 reasons:

  1. Cross-reactivity: Evidence showed an assay using the S1 RBD target did not cross-react with 4 common coronaviruses.
  2. S1 RBD antibodies have shown strong correlation to neutralization while evidence for neutralizing antibodies to the Nucleocapsid (N) protein is sparse.
  3. Potential vaccine response: The spike protein and particularly the RBD are the most common target of vaccine designs.
With hundreds of SARS-CoV-2 antibody tests on the market,1 healthcare providers (HCP) need to be confident that they can use results to provide actionable information to manage patient health. Assay design is proving to be a strong factor in how valuable different testing solutions are in helping HCP’s protect individual patients and communities.

Humans produce antibodies against the spike protein and S1 RBD, as well as other proteins, but the key question to answer is “are they neutralizing antibodies?” Multiple studies indicate a primary role for neutralizing antibodies that target the spike protein of SARS-CoV-2, with antibodies to S1 RBD estimated to comprise ~90% of neutralizing activity.2-5

Our SARS-CoV-2 antibody assays* target the S1 RBD to detect and measure the level of neutralizing antibodies to SARS-CoV-2 in the blood. This enables clinicians to assess and track the level of an individual's immune response over time.

A correlation study using a viral neutralizing test demonstrated a strong relationship between the Atellica® IM SARS-CoV-2 IgG*§ and SARS-CoV-2 Total* assays Index results and neutralizing antibody titers. This enables clinicians to assess and track patients’ neutralizing antibody levels. In the future this strong correlation is critical for potential convalescent donor identification as well as potentially assessing vaccine efficacy and tracking post-vaccination antibody levels.

The S1 RBD is the most common target of vaccine designs, with the goal of producing protective antibody. The RBD is what recognizes and binds the human ACE2 receptor. Without successful binding, the virus cannot replicate or cause infection, so it is a critical focus for immunity. Assessment of vaccine efficacy for those that focus/include the S1 RBD may include identifying seroconversion of that antibody to identify patients with appropriate antibody response. 

Data indicate the likelihood of cross-reactivity is impacted by the choice of target in SARS-CoV-2 assays and may be more likely in assays that target both S1 and S2 or the N protein versus assays targeting just S1 or S1 RBD, like the Siemens Healthineers assays.6

  • S1 RBD is highly specific for SARS-CoV-2 vs. other coronaviruses. Internal testing and an external study using the S1 RBD target showed that these assays did not cross react with the 4 very common coronaviruses.6,7
  • Evidence indicates that assays that target the N antigen may have cross reactivity with other coronaviruses, increasing the chances of false positive results and lower specificity.8

Humans produce antibodies against both the nucleocapsid and spike protein, as well as other proteins.

But key questions to answer are “Are they neutralizing antibodies?” and “Can they protect you from reinfection?” A common part of the immune response is for humans to neutralize or block the binding of the virus to the ACE2 receptor. If an antibody interferes with binding, you may have some level of protection. Different antibodies will target different proteins in the viral structure.

Spike (S1 and S2) Protein:

  • The S1 protein is the head of the spike protein and contains a receptor-binding domain (RBD). The S1 RBD is instrumental for allowing the SARS-CoV-2 virus to reproduce by attaching to and infecting host cells.9
  • The S2 protein is the stalk of the spike protein and allows the SARS-CoV-2 virus to remain fused to host cells.9

Nucleocapsid (N) Protein:

The N protein is located inside of the capsid (the viral protein shell), along with RNA of SARS-CoV-2. This protein functions in the dispersal of genetic material during viral reproduction. The SARS-CoV-2 N protein is highly similar in structure to that of the SARS coronavirus (SARS-CoV).10