Viruses Like SARS-CoV-2 Exploit Built-In Antibody Bias: A Threat Lurking in Our Immune Systems

COVID-19 News: Picture this: a massive crowd of people shouting in unison, “WE ARE ALL INDIVIDUALS!” Suddenly, a lone voice from the crowd sheepishly mutters, “I’m not.” This famous scene from the Monty Python comedy troupe brings to light the concept of immunodominant public antibody responses, an immune system phenomenon that could make us vulnerable to viral reinfections.


Pic Credit: Steven McDowell-Science Photo Library

Public antibody responses refer to the situation where different individuals produce the same antibodies targeting the same epitopes (regions on viral proteins recognized by antibodies). This phenomenon seems to be our immune system's attempt at efficiency. However, it could leave us exposed to potential threats. When antibodies repeatedly target the same epitopes, even if they are not protective, it could provide viruses such as SARS-CoV-2 an opportunity to evade our immune response. By mutating only a few target residues, a virus can dodge the antibodies shared by many people.
 
A new study led by researchers from Brigham and Women’s Hospital, Boston-USA provides a better understanding of this phenomenon.
 
The study findings suggests that the generation of antibodies is far from random, largely due to germline-encoded amino acid–binding (GRAB) motifs. These motifs predispose antibodies to recognize particular structures, influencing epitope selection and composition.
 
According to corresponding author Dr Stephen J. Elledge, PhD, a professor at the Division of Genetics, Department of Medicine, Brigham and Women's Hospital, this study may help explain patterns observed during the COVID-19 pandemic, particularly concerning reinfections.
 
The study findings could significantly impact immune predictions and strategies. Before this study, there was no clear evidence that people’s immune systems didn’t target sites on a viral protein at random. Isolated examples had been observed of recurrent antibody responses across individuals, but the extent and underlying mechanisms remained unclear.
 
Dr Elledge and his team used a tool called VirScan, developed in 2015 by the Elledge lab. VirScan detects thousands of viral epitopes and provides a snapshot of a person’s immunological history using a single drop of blood. In this study, the researchers used VirScan to analyze 569 blood samples from participants in the United States, Peru, and France. The study team discovered that recognizing public epitopes was a general feature of the human antibody response.
 
Systematic analysis of antibody-antigen structures identified 18 human and 21 partially overlapping mouse GRAB motifs within heavy and light V gene segments, which proved critical for public epitope recognition. GRAB motifs correspond to antibody regions that are particularly good at identifying one specific amino acid. They help explain why human antibodies repeatedly bind the same spots, focusing on regions where these amino acids are available for binding.
 
With just a few mutations, a virus can avoid detection by these shared antibodies and reinfect previously immune populations. As reported in recent ws/articles/coronavirus">COVID-19 News coverages, this is exactly what the newer emerging Omicron and recombinant SARS-CoV-2 sub-lineages are currently doing.
 
Lead author Dr Ellen L. Shrock, PhD, of the Elledge lab at the Department of Genetics, Harvard Medical School, explained that the immune system's underlying architecture causes individuals worldwide to create virtually identical antibodies. This gives viruses a small number of targets to evade for reinfection and further expansion and evolution. Interestingly, the study also found that nonhuman species produce antibodies that recognize different public epitopes from those that humans recognize.
 
While it is more likely for a person to produce antibodies against a public epitope, some people do produce rarer antibodies, which may more effectively protect them from reinfection. This discovery could have significant implications for treatments developed against COVID-19, such as monoclonal antibodies, as well as for vaccine design.
 
Dr Elledge emphasized the importance of considering the potential of unique antibodies, stating that they could be "a lot harder to evade" by viruses. This insight is crucial as researchers continue to design better therapies and vaccines to combat viral infections.
 
Understanding the role of GRAB motifs in shaping our immune response opens up new avenues for exploration. This knowledge could guide the development of more tailored and effective vaccines that target a broader range of epitopes or leverage rarer antibodies. By doing so, we might create vaccines that offer broader protection and prevent viral reinfections.
 
Moreover, the study's findings could also help researchers identify the most effective monoclonal antibody treatments. These treatments utilize lab-made antibodies designed to target specific viral proteins, neutralizing the virus and preventing it from infecting cells. By studying the GRAB motifs and the immune system's predispositions, scientists may be able to develop monoclonal antibodies that target less common, harder-to-evade epitopes, offering a more robust defense against viral infections.
 
Another exciting implication of this research is the potential to predict an individual's susceptibility to reinfection by examining their antibody repertoire. This could lead to personalized medicine approaches, where healthcare providers tailor treatments and preventive measures to an individual's unique immune response. For instance, those with a higher risk of reinfection could receive more targeted therapies or booster vaccinations to enhance their protection.
 
In conclusion, the discovery of GRAB motifs and their role in the immunodominant public antibody response opens up a world of possibilities in the battle against viral infections. This groundbreaking study may lead to more effective vaccines, monoclonal antibody treatments, and personalized medicine strategies, ultimately changing the way we think about and approach immune system responses.
 
As we continue to face new and emerging viral threats, it is essential to understand the intricacies of our immune systems and the vulnerabilities that may exist within them. Armed with this knowledge, we can work towards a future where we are better equipped to prevent and treat viral infections, ensuring the health and wellbeing of people worldwide.
 
The study, titled “Germline-encoded amino acid–binding motifs drive immunodominant public antibody responses,” was published in the peer reviewed journal: Science.
https://www.science.org/doi/10.1126/science.adc9498
 
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