Spike protein diversity enables SARS-CoV-2 to evade full neutralization, paving the way for viral persistence!

Medical News: Scientists Discover How SARS-CoV-2 Spike Variations Help It Evade Complete Neutralization
A team of researchers from the CSIR-Institute of Microbial Technology, the Indian Institute of Science Bangalore, Mynvax Pvt. Ltd, BRIC-Translational Health Science & Technology Institute, CSIR-Institute of Genomics and Integrative Biology, and Amsterdam UMC, University of Amsterdam have made a significant discovery about why some SARS-CoV-2 viruses remain resistant to even the most potent antibodies. Their study reveals that variations in the structure and glycosylation (sugar coating) of the virus’s spike protein contribute to incomplete neutralization - a phenomenon where antibodies fail to fully block the virus, leaving behind a small but persistent fraction of infectious particles.


Spike protein diversity enables SARS-CoV-2 to evade full neutralization, paving the way for viral persistence!

This Medical News report explains the key findings of this study and how they contribute to our understanding of COVID-19’s ability to persist despite the immune system’s defenses. The findings could have profound implications for vaccine design and monoclonal antibody treatments.
 
Understanding the Challenge of Incomplete Neutralization
Antibodies are our body’s primary defense against viruses. When a virus like SARS-CoV-2 enters the body, antibodies target its spike protein to prevent it from attaching to and infecting human cells. Most research on COVID-19 has focused on two key aspects of neutralizing antibodies: their potency (how strong they are) and their breadth (how many viral variants they can neutralize). However, one critical aspect that has been overlooked is completeness - how well the antibodies can fully neutralize a viral population.
 
In standard laboratory tests, several monoclonal antibodies, including S309 (Sotrovimab), have shown incomplete neutralization of SARS-CoV-2. This means that even at high concentrations, these antibodies leave behind a small number of virus particles that continue to be infectious. This residual virus, referred to as the persistent fraction (PF), is a major concern because it allows SARS-CoV-2 to continue infecting human cells, potentially leading to prolonged infections and even new viral mutations.
 
Why Do Some Virus Particles Escape Neutralization?
The study found that the persistent fraction of virus particles has unique characteristics that make them resistant to neutralization. These include:
 
-Increased furin cleavage: The spike protein is made up of two subunits, S1 and S2, which are separated by an enzyme called furin. The researchers found that the virus particles in the persistent fraction had higher levels of furin cleavage, which made them more resistant to antibodies.
 
-Closed spike protein conformation: Most neutralizing antibodies work by targeting the Receptor Binding Domain (RBD) in its open state. However, the study showed tha t the persistent fraction of virus particles keeps its spike protein in a closed conformation, making it harder for antibodies to attach.
 
-Different glycosylation patterns: The spike protein is covered in sugar molecules, known as glycans, which influence its structure and immune evasion capabilities. The researchers found that persistent virus particles had a higher level of mannosidic glycans, which made them more resistant to certain antibodies but more sensitive to mannose-binding lectins - proteins that recognize specific sugar structures.
 
Experimental Evidence Confirms Virus Escape Mechanism
To confirm their findings, the researchers conducted virus depletion experiments. In these experiments, they removed the virus particles that were susceptible to neutralizing antibodies and analyzed the ones that remained.
 
When they removed the virus particles targeted by S309 (Sotrovimab), the remaining virus population was highly resistant to the same antibody and even to other antibodies targeting the RBD.
 
The persistent fraction viruses were still capable of infecting human cells, even when exposed to high concentrations of neutralizing antibodies.
 
The same trends were observed with real SARS-CoV-2 virus samples, confirming that the findings were not limited to laboratory-generated pseudoviruses.

The study also found that variants like Delta and Omicron had a larger persistent fraction than earlier strains, explaining why these variants were more resistant to vaccines and monoclonal antibody treatments.
 
The Real-World Implications of This Study
The discovery of persistent fraction viruses has major implications for COVID-19 treatments, vaccines, and future pandemic preparedness.
 
-Why Some People Get Reinfected: Even if someone has high levels of neutralizing antibodies, persistent fraction viruses can still cause breakthrough infections. This explains why some fully vaccinated or previously infected individuals still contract COVID-19.
 
-How the Virus Adapts Over Time: The presence of a persistent fraction allows SARS-CoV-2 to continue infecting cells even in the presence of strong immune responses. This means the virus gets more opportunities to evolve, leading to new variants that are even more resistant to antibodies.
 
-Improving COVID-19 Treatments: The study suggests that future monoclonal antibody treatments should not only focus on potency but also on completeness of neutralization. This could lead to the development of better therapeutic antibodies that leave behind fewer virus particles.
 
-Vaccine Design Needs to Evolve: Current vaccines are based on generating antibodies that target the RBD in its open conformation. However, this study suggests that vaccines should also consider targeting closed spike conformations to ensure complete neutralization.
 
Conclusion
This groundbreaking study highlights the hidden weaknesses in our current approach to COVID-19 immunity. While potent neutralizing antibodies can significantly reduce the virus, some SARS-CoV-2 particles still escape due to variations in spike conformation, glycosylation, and furin cleavage. These persistent virus particles not only enable reinfections and breakthrough cases but also contribute to the ongoing evolution of the virus.
 
Going forward, researchers, vaccine developers, and public health officials must consider completeness of neutralization when designing future treatments and vaccines. By addressing the persistent fraction of SARS-CoV-2, we can take a more effective step towards eliminating COVID-19 rather than just suppressing it.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.researchsquare.com/article/rs-6134096/v1
 
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