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Breaking down the complexities of COVID-19 Antibodies

COVID-19: Antibodies – What are they?

We’ve all become very familiar with the antigen/lateral flow and PCR tests that are used to determine whether you have COVID-19. However, these tests just measure the presence of the virus (SARS-CoV-2) in the body and do not provide any insights on prior infection and possible immunity. This is where antibody testing comes in.

To understand antibody detection, we first need to understand the components of the virus that may be recognized by the immune system. Like all coronaviruses, and in fact most other viruses, SARS-CoV-2 has four main structural proteins: the spike (S), nucleocapsid (N), membrane (M) and envelope (E) proteins.

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S versus N proteins

The S protein is located on the surface of the virus and is responsible for entry of the virus into host cells. We’ve all seen the images of the virus with the spikes on the surface! Because of its location, this protein is easily detected by the immune system and is highly immunogenic, meaning it provokes a strong immune response including the production of specific antibodies.

The N protein is located within the viron and forms a closed capsule that contains the genetic material of the virus. It’s also thought to function in suppressing the host antiviral immune response, but that’s a story for another day. During a viral infection, the N protein is abundantly produced and is also highly immunogenic.

Because both the S and N proteins are highly immunogenic, detecting the presence of antibodies specific for these proteins is a good way of determining whether a person has been infected by that virus. M and E proteins are not particularly immunogenic and don’t induce good antibody responses.

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Issues with antibody detection

A key issue in antibody detection is protein homology… in this case, how similar are the S and N proteins from SARS-CoV-2 to those from other coronaviruses? The reason this is important is because of cross-reactivity, whereby an antibody that is specific for a protein from one virus can potentially recognize the same protein from a related virus if that protein is very similar in structure (high homology), thereby giving you a false positive.

The S protein has low protein homologies to other coronaviruses. However, the N protein from SARS-CoV-2 is more similar to the N protein from other coronaviruses and therefore there is a higher risk of cross-reactivity with N protein-specific antibodies.

A second issue is that not all antibodies are made equally — there are binding antibodies and neutralizing antibodies. Binding antibodies bind to the pathogen and alert the immune system to its presence, whereas neutralizing antibodies can block a pathogen from infecting the body. When considering immunity to a pathogen, it’s the presence of neutralizing antibodies that is important.

A recent study1 has shown that a higher proportion of antibodies recognizing the S protein (specifically the receptor-binding domain (RBD)) had neutralizing capacity compared with N protein-specific antibodies (86% to 74%). Furthermore, 3% of the blood samples from healthy individuals that were COVID-19-negative (healthy controls) contained antibodies that recognized the N protein whereas just 1% of the control samples were positive for RBD-specific antibodies. This may be due to prior exposure to SARS-CoV-2 or to cross-reactivity.

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Implications

So, what does this tell us about detecting antibodies as a possible measure of COVID-19 immunity? First, the detection of antibodies specific for the S protein gives a better measurement of the possible presence of neutralizing antibodies to SARS-CoV-2. Second, caution is needed with the use of tests that only measure antibodies specific for the N protein, as there is a greater risk of cross-reactivity.

There is one final complicating factor: all current COVID vaccines are based on the S protein and therefore S protein-based antibody detection cannot differentiate between vaccine-induced and infection-induced immune responses. However, by combining S protein- and N protein-specific antibody detection, you can determine whether the immune response was induced by a natural infection or by a vaccine. Also, a combined test would give a high degree of confidence that you are assessing antibodies against just SARS-CoV-2.

1McAndrews, K. M. et al. Heterogeneous antibodies against SARS-CoV-2 spike receptor-binding domain and nucleocapsid with implications for COVID-19 immunity. JCI Insight 5, e142386 (2020). Article

Immunogenicity
The ability of a substance that can induce an immune response

Protein Homology
The similarity in protein sequence that reflects a common ancestry.

Cross-Reactivity
Occurs when an antibody specific for one antigen binds to another, different antigen