An Overview on Neutralizing Antibodies

Srabani Roy Chowdhury, MAKAUT, West Bengal

Neutralizing antibodies are antibodies from the adaptive humoral immune system that neutralize a pathogen before entering our cells. And, they provide sterilizing immunity to our bodies by neutralizing the pathogen before infection.

Production of these antibodies in our body happens naturally by our immune system. They are in charge of protecting our body cells from disease-causing pathogens. Neutralizing antibodies are triggered as a part of our immune response whenever our body gets infected or vaccinated against any infection. They bind to the antigen present on the surface of a pathogen. After neutralization, the pathogen is breaking down by the white blood cells and excreted out.

These antibodies are highly pathogen-specific. But, due to high genetic variability, some pathogens can change their surface conformation. When this happens, neutralizing antibodies that were highly specific to their old conformation fails to recognize the pathogens. Broadly such antibodies are a special type of neutralizing antibody. These are capable of binding and neutralizing different strains of a pathogen. These antibodies are found for Influenza, Dengue, and Hepatitis. Neutralizing antibodies can be detected by plaque reduction (a comparative study of pathogen plaque counts), micro-neutralization, and colorimetric assays.

Mechanism

Neutralizing antibodies play an important role in defense against viral infections. They do so by blocking the entry of a pathogen so that they cannot enter and replicate inside our cells. These antibodies bind to the pathogen in a way that hinders the interaction between the pathogen and a receptor. These work by determining the mode of infection of a pathogen. They are able to cause conformational changes in the pathogen to restrict them from entering our cells. Prevention of toxin production in certain bacterial infections is also one of their properties. They interfere with the biological activity of the pathogen. They can restrict the molecules needed by the pathogen for entering the cells. However, these are not much effective against extracellular bacteria since they cannot prevent bacterial replication.

Antibody-Dependent Cellular Cytotoxicity or ADCC counteracts viral infection by killing the virus-producing cell with the help of effector cells. The antibodies involved are neutralizing, but only in the absence of the effector cells.

Neutralizing antibodies and Binding antibodies

Not all antibodies that bind to pathogens are neutralizing. Binding antibodies are antibodies that only bind to a pathogen . These antibodies do not interfere with the activity of the pathogen. They help in marking the pathogen for the immune system to notice and target it easily. They interfere and restrict the activities of the pathogen itself.

Virus Inactivity by Neutralizing Antibodies

Virus neutralization refers to the act of reducing viral activity. The antibodies are able to attach themselves to the viral proteins successfully hindering viral replication and transcription. An antibody can also bind to a budding virion. In that case, it acts late in the viral replication cycle. It blocks the release of newly formed viruses from the infected cell surface. For instance, antibodies on the surface of the influenza virus act in this manner.

Generally, neutralization is carried out in the absence of a complementary component. But, complement-mediated enhancement of neutralization is also often useful because the complementary factors can reduce viral activity by binding directly to the cell surface instead of virions. The mechanism of neutralization starts with blocking the earliest step in the viral replicative cycle. For a heat-resistant virus with no lipid membrane, the neutralizing antibodies bind to the capsid protein. But for a heat-sensitive virus with an existing lipid membrane, the neutralizing antibodies restrict its attachment with the receptor.

Viral entry and attachment to the targeted cell are blocked by neutralization

In the above figure, V1, V2, and V3 represent virus particles (yellow spheres). A neutralizing antibody (dark grey triangle) is bound to the receptor-binding protein (blue cylinder) of V1 and prevents attachment to the receptor on the cell surface (orange cylinder). V2 has already attached itself to the receptor on the cell surface with the help of its receptor-binding protein.

The neutralizing antibody binds to an exposed epitope and prevents other steps of the replication cycle. V3 is about to be bind to the cell surface, but the neutralizing antibodies would not let it bind. V4 is in the cytoplasm in a complex with neutralizing antibodies and will be sent for proteasomal degradation. V5 represents a naked virion. It binds itself to a receptor on the cell surface and injects the genetic material into the cytoplasm. V6 is present inside the endosome (green circle), unable to fuse with the cell because of the neutralizing antibodies attached to it.

Antibody-Dependent Enhancement

Antibody-dependent enhancement is when In certain situations, due to improper neutralization of the neutralizing antibodies, pathogens can evade the effects of the antibodies. Hence, it can easily enter and replicate inside host cells. It can happen due to-

1. Regular mutation where the antibodies are unable to recognize a pathogen.
2. Neutralizing antibodies binding to the macrophage.
3. Antibodies binding to a different serotype of the virus.
4. Binding to the Fc-region of antibody receptors.

Therapeutic Applications

1. Passive Immunization- It refers to immunizing a person who is not infected yet with antibodies from another individual who has recovered from the respective infection. Neutralizing antibodies also play a vital role in COVID-19 treatment. Neutralizing antibodies make conformational changes in the Spike protein of the SARS-COV-2 virus and block its entry. Due to those conformational changes, the virus cannot bind to the ACE2 receptor.
2. Active Immunization- Vaccination is active immunization. Vaccines contain an active specimen of a pathogen that initiates an immune response in our body. The immune system produces neutralizing antibodies in return and helps our body to identify that pathogen later.
3. Neutralizing antibodies can help cure Multiple Sclerosis (MS).
4. The recombinant protein drugs used for this treatment are mostly targeted by neutralizing antibodies.

Conclusion

The medical industry uses neutralizing antibodies to create vaccines. An antibody does not require any special feature to be neutralizing. Its capacity to ligate functional entry-mediating viral proteins on the virion surface is enough. Once a primary infection gets cured, these antibodies work as immunity markers against reinfection.

Also read: Cervical cancer screening task: ASCCP

References:

1. Klasse, P. J. (2014). Neutralization of virus infectivity by antibodies: Old problems in new perspectives. Advances in Biology, 2014, e157895. https://doi.org/10.1155/2014/157895
2. Khoury, D. S., Cromer, D., Reynaldi, A., Schlub, T. E., Wheatley, A. K., Juno, J. A., Subbarao, K., Kent, S. J., Triccas, J. A., & Davenport, M. P. (2021). Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nature Medicine, 1–7. https://doi.org/10.1038/s41591-021-01377-8
3. Functional and protective role of neutralizing antibodies (Nabs) against viral infections. (2019). Recent Developments in Applied Microbiology and Biochemistry, 83–93. https://doi.org/10.1016/B978-0-12-816328-3.00007-6

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