Are Your COVID-19 Antibodies Actually Neutralizing Antibodies? That is the Real Question.

The mere presence of antibodies (Abs) does not tell the entire story of how the body’s immune system deploys multiple mechanisms to fend off an infectious pathogen, nor does Ab presence imply efficacy. How and how well an invading microbe or a virus–such as SARS-CoV-2 that causes COVID-19–is kept from completing its mission to enter a healthy cell and replicate, is dependent upon whether the host’s antibody arsenal can bind to and block (neutralize) cellular entry by the offending pathogen. The level of affinity, or antibody binding strength, plays an important role in ascertaining the rate at which an infection is terminated.

Antibody Binding 101

Antibodies, also known as immunoglobulins (Ig), are Y-shaped glycoprotein molecules produced by B lymphocytes (specialized white blood cells) for the purpose of seeking out, identifying, intercepting, and if possible, stopping foreign pathogens, like SARS-CoV-2, in their tracks.

The key to the immune response is preventing specialized proteins (antigens), found on the surface of pathogens, from specifically sticking to and unlocking the doorways (receptors) on the host cell surface, thereby gaining illegal entry. All the action takes place at the tips (paratopes) of the Y-shaped antibody, which act as decoy receptors that stick to the tips (epitopes) of the antigen and thereby shield host cells from attack.

We all have millions of different paratopes that have been taught to recognize and bind to the millions of different pathogens that invade the body.

All neutralizing antibodies are binding, but not all binding antibodies are neutralizing.

Non-Neutralizing Antibodies Can Only Bind and Tag

Non-neutralizing antibodies and lower-affinity antibodies have paratopes that are close, but not perfect epitope fits. They are able to bind specifically to the pathogen, but are unable to interfere with its infectivity. Cells are left potentially vulnerable.

Even if these antibodies are not capable of subduing the pathogen on their own, they can flag the intruder and signal for reinforcement from other host defense cells, such as phagocytes, that can engulf and destroy the pathogen.

The Y shape of antibodies gives them the capacity to bind to two separate pathogens at once. Repeating this binding process with a legion of antibodies forms sticky clusters of pathogens that become more visible to consuming phagocytes.

Only Neutralizing Antibodies Can Block the Dock

Neutralizing antibodies (NAbs) need no backup; their binding affinity to critical epitopes is specific and strong enough to neutralize the pathogen directly, prohibiting a breach of the healthy cell membrane, and quickly terminating the infection on their own.

In the case of SARS-CoV-2, the virus’s spike glycoprotein receptor binding domain (RBD) interlocks perfectly with host ACE2 protein receptors, its main entry point into upper respiratory cells. Before the coronavirus can reach the ACE2 receptors, virus-neutralizing antibodies attack with paratope ends that are an even more perfect fit than the ACE2 receptors themselves. Covered in neutralizing antibodies, the virus is rendered powerless. The antibody’s neutralizing efficacy is correlated to the precision of the bond between its paratope and the virus’s RBD protein. According to a study conducted at Sheba Medical Center in Israel, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers (a measure of binding strength) during the peri-infection period. This is why people are less likely to become infected by COVID-19 if they have higher levels of tightly-binding neutralizing antibodies.

Only 30 US Labs Have Practical Tests for Neutralizing Antibodies

The Sheba hospital analysis is further evidence that a person’s neutralizing antibody count predicts whether that person will become infected with COVID-19.

Standard COVID-19 antibody, or serology, tests simply look for the presence of antibodies in blood samples, indicating whether a person has had a previous infection or vaccination. These first line tests, like the standard rapid assay and ELISA (Enzyme-Linked ImmunoSorbent Assay) for total antibody detection, do not measure neutralizing ability or binding strength (affinity).

Neutralizing affinity against SARS-CoV-2 can be tested in the blood of patients by performing virus neutralization tests (VNT) or pseudovirus-based virus neutralization tests (pVNT); however, these methodologies have serious drawbacks, which prevent scaling for more general use. Both types of cell-based neutralizing assays must be conducted in highly-restricted containment facilities because they require handling live virus. In addition, both take 2 to 4 days to complete, during which time, an infection has critical time to develop.

The new cPass SARS-CoV-2 Neutralization Antibody Detection assay panel* does detect circulating neutralizing antibodies against SARS-CoV-2, within only 1 to 2 hours in a less restrictive environment, and without needing to work with live virus. This assay panel is the only such test with FDA Emergency Use Authorization. cPass would be instrumental in vaccine and therapeutic development, contact tracing, as well as in tracking how long protective immunity lasts in response to natural infections and/or vaccines.

Currently, the cPass SARS-CoV-2 Neutralization Antibody Detection assay panel has only been licensed to 30 laboratories in the United States. Provista Diagnostics, outside of Atlanta, is proud to be one of these laboratories.

This test has not been FDA cleared or approved. This test has been authorized by FDA under an EUA for use by authorized laboratories. This test has been authorized only for the presence of total neutralizing antibodies against SARS-CoV-2, not for any other viruses or pathogens. This test is only authorized for the duration of the declaration that circumstances exist justifying the authorization of emergency use of in vitro diagnostics for detection and/or diagnosis of COVID-19 under Section 564(b)(1) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner.

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