COVID-19 News: Chinese Scientists Classify SAR-CoV-2 Variants And Sub-Lineages Into Five Distinct Serotypes Based On RBD Antigenicities

COVID-19 News: The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought the world to a standstill, resulting in nearly 7 million deaths worldwide over the past three years. In response to this global health crisis, researchers and scientists have raced against time to develop a wide array of vaccines and therapeutic antibodies. However, the relentless evolution of SARS-CoV-2 has given rise to numerous variants, some of which exhibit increased immune escape, rendering existing vaccines and treatments less effective.


 
This has led to the intriguing possibility that SARS-CoV-2 has evolved into multiple serotypes. To shed light on this phenomenon, Chinese scientists from Shanxi Agricultural University, the Chinese Academy of Sciences, Yunnan University, Peking University, and the University of Macau embarked on a mission to classify SARS-CoV-2 variants into distinct serotypes based on the antigenic properties of their receptor-binding domain (RBD) in the viral spike (S) protein. Their findings, which are based on a comprehensive evaluation of 23 representative SARS-CoV-2 variants, including pre-Omicron variants and Omicron sub-variants, have resulted in the classification of these variants into five serotypes. This groundbreaking research covered in this COVID-19 News report could serve as a foundation for the rapid classification of emerging SARS-CoV-2 variants and inform the development of more effective vaccines and neutralizing antibodies against COVID-19.
 
The Ongoing Battle Against COVID-19
The battle against COVID-19 has been one of the most significant global public health challenges in recent history. In a race against time, researchers worldwide have developed a wide range of vaccines, including inactivated vaccines, mRNA vaccines, DNA vaccines, protein subunit vaccines, and adenoviral vector vaccines. In addition to vaccines, monoclonal antibodies (mAbs) have been developed for clinical therapeutic use. These efforts have led to large-scale vaccination campaigns in many countries, offering protection against COVID-19.
 
Despite these remarkable achievements, the pandemic has been characterized by waves of breakthrough infections, even in the presence of vaccination campaigns. These breakthrough infections can be attributed to various factors, including the waning of antibodies and the continuous evolution of the SARS-CoV-2 virus, resulting in the emergence of new variants. Some of these variants, classified as Variants of Concern (VOCs) or Variants of Interest (VOIs) by the World Health Organization (WHO), possess the ability to evade the immunity conferred by earlier infection or vaccination. The receptor-binding domain (RBD) in the spike (S) protein of SARS-CoV-2 is a key player in determining the virus's ability to enter human host cells, as it directly interacts with the human angiotensin-converting enzyme 2 (ACE2) receptor. Consequently, the RBD is the most antigenic region, eliciting the production of neutralizing antibodies.
 
During previous coronavirus outbreaks, such as the 2003 SARS epidemic, the antigenicity and immunogenicity of the RBD in the spike protein were well-documented. This research led to the development of RBD-targeted vaccines a nd neutralizing antibodies, providing a foundation for combating SARS-CoV-2. Notably, SARS-CoV-2 variants with more mutations in the RBD have exhibited increased immune evasion capabilities while maintaining high transmissibility.
 
The Emergence of SARS-CoV-2 Variants
Throughout the COVID-19 pandemic, several VOCs have arisen, distinguished by their ability to evade the immune system. Examples include the Beta and Gamma VOCs, characterized by specific mutations at the K417, E484, and N501 sites in the RBD. These mutations led to the initial wave of breakthrough infections and immune evasion, rendering some mAbs ineffective.
 
Towards the end of 2021, the world witnessed the mysterious emergence of the Omicron variants (BA.1/BA.2/BA.3). These variants carried an unprecedented number of mutations in the RBD, resulting in reduced efficacy of most previously approved vaccines and mAbs. They caused a significant wave of breakthrough infections, even in regions with strong vaccination campaigns.
 
As Omicron continued to evolve, it gave rise to numerous sub-variants with enhanced immune evasion capabilities. For example, antibodies produced in response to BA.1 infection were ineffective against BA.2.12.1, BA.4, or BA.5, and the XBB sub-variant completely evaded all approved mAbs. This lack of cross-neutralization among SARS-CoV-2 variants, especially the Omicron sub-variants, raised the question of whether SARS-CoV-2 had developed multiple serotypes.
 
Understanding Serotypes in Viral Classification
The concept of serotypes in viral classification is not new and has been instrumental in understanding and combatting various viruses. For instance, more than 100 serotypes of adenoviruses have been defined, with 49 of them infecting humans. These serotypes exhibit distinctive antigenic properties, and their classification is based on their lack of cross-reaction in neutralization assays.

Similarly, coronaviruses have also shown serotype divergence. Seven feline coronavirus (FCoV) isolates were classified into two serotypes based on their antigenic properties. The establishment of serotypes has served as the foundation for developing broad-spectrum vaccines, antibodies, and rapid evaluation of the antigenicity of newly emerged variants.
 
Classifying SARS-CoV-2 Variants into Serotypes
The classification of SARS-CoV-2 variants into serotypes has been a topic of interest in the scientific community. While several reports have analyzed the antigenic landscape of some SARS-CoV-2 variants, the comprehensive classification of serotypes has remained elusive due to the need for a wide dataset of representative variants.
 
In this context, Chinese scientists embarked on a mission to classify SARS-CoV-2 variants into serotypes. To achieve this, they selected 23 representative variants, including prototype (PT), pre-Omicron VOCs, pre-Omicron VOIs, and Omicron sub-variants, and constructed mRNA vaccines containing the RBDs derived from these variants. These vaccines were administered to mice to simulate the infection of each specific variant.
 
The researchers then evaluated the ability of the antisera produced by these mice to cross-neutralize the pseudotyped viruses (PVs) of the 23 SARS-CoV-2 variants. This extensive data allowed for the classification of these variants into five serotypes based on the similarities in their RBD antigenicities.
 
The Five Distinct Serotypes
The serotype classification revealed five distinct serotypes:

-Serotype-I: Encompassing all pre-Omicron variants, this serotype includes two subtypes. Notably, Beta, Theta, Gamma, Zeta, Mu, and Kappa variants within serotype-Ib exhibited cross-neutralization with six pre-BA.5 sub-variants, suggesting potential protection against BA.1. However, it's important to note that the initial wave of BA.1 breakthrough infections did not seem to be prevented by serotype-Ib variants, possibly due to antibody waning. The presence of the E484K/Q mutation in RBD among serotype-Ib variants may contribute to their additional immunogenicity.
 
-Serotype-II: Comprising the BA.1 and BA.1.1 sub-variants, this serotype exhibited cross-neutralization with only BA.1 and BA.1.1.
 
-Serotype-III: Consisting of BA.3, BA.2, BA.2.12.1, and BA.2.75 sub-variants, serotype-III displayed specific cross-reaction with the pre-BA.5 sub-variants, but not the pre-Omicron variants.
 
-Serotype-IV: Including BA.5, BF.7, BQ.1, and BQ.1.1 sub-variants, serotype-IV showed cross-neutralization primarily against post-BA.5 sub-variants and weaker cross-neutralization with pre-BA.5 sub-variants. These variants exhibited little cross-neutralization with serotype-I and serotype-II variants.
 
-Serotype-V: Comprising XBB and XBB.1.5 sub-variants, serotype-V exhibited effective immune responses against the currently circulating XBB derivatives.
 
Implications and Future Research
The classification of SARS-CoV-2 variants into serotypes based on RBD antigenicities holds significant implications for the development of broad-spectrum COVID-19 vaccines. This research suggests that including reference members from serotype-Ib, IV, and V could lead to broader protection against all SARS-CoV-2 variants. However, further research is needed to validate these suggestions and develop effective vaccines based on XBB and its derivatives.
 
Additionally, the classification of serotypes can facilitate the rapid determination of the serotype of newly emerged SARS-CoV-2 variants. This can aid in timely risk assessment, predict potential immune escape, and guide the selection of appropriate vaccines.
 
While this research represents a significant step towards understanding the antigenic properties of SARS-CoV-2 variants, it is essential to acknowledge that the antigenicity of the virus can be influenced by factors beyond the RBD and the spike protein. Nevertheless, the classification of serotypes provides valuable insights into the complex world of COVID-19 variants and offers a path forward for more effective prevention and control measures.
 
In conclusion, the classification of SARS-CoV-2 variants into five serotypes based on RBD antigenicities represents a crucial milestone in our ongoing battle against the pandemic. This classification not only enhances our understanding of SARS-CoV-2 antigenicity but also provides valuable guidance for the development of vaccines and neutralizing antibodies, ensuring that we are better prepared to combat the ever-evolving threat of COVID-19.
 
The study findings were published in the peer reviewed journal: Science Bulletin.
https://www.sciencedirect.com/science/article/pii/S2095927323006837
 
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