Omicron's dominance amidst immune escape sparks debate: should it be classified as a separate serotype?

A recent study published in hLife reported distinct serotypes for severe acute respiratory syndrome (SARS)-related coronaviruses (CoVs).

Study: Distinctive serotypes of SARS-related coronaviruses defined by convalescent sera from unvaccinated individuals. Image Credit: Imilian/Shutterstock.com

Background

In the past two decades, two major CoV outbreaks due to SARS-CoV-1 and middle-east respiratory syndrome (MERS)-CoV caused epidemics in humans before the coronavirus disease 2019 (COVID-19) pandemic, leading to significant economic and human losses and public health disruptions.

SARS-CoV-2 has extensively evolved through recombination and mutations in its spike protein, emerging as new variants with increased immune evasion and transmissibility.

SARS-CoV-2 Omicron, harboring over 30 mutations, was first detected in South Africa in November 2021, and many sub-variants have since emerged at an unprecedented pace. The Omicron sub-variants continue to show convergent evolution, acquiring new mutations in the spike's receptor-binding domain (RBD), leading to escape from neutralizing antibodies (nAbs).

Moreover, breakthrough infections by the Omicron variant have significantly reduced nAb epitope diversity. Overall, this presents significant challenges to the efficacy of existing immunity and future vaccine development. Further, SARS-CoV-2 Omicron sub-variants might functionally represent a distinct serotype, given their extent of immune evasion.

The study and findings

In the present study, researchers serotyped SARS-related CoVs. Prior attempts to define SARS-CoV-2 antigenic cartography relied on sera from vaccinated individuals or animals. Instead, the team used sera from non-vaccinated individuals after recovering from infection by ancestral SARS-CoV-2, Beta, Delta, Omicron (BA.1, BA.2, or BA.5), or SARS-CoV-1.

Eighty serum samples were obtained from non-vaccinated convalescent individuals. Sera from ancestral SARS-CoV-2-infected subjects did not neutralize SARS-CoV-1 and SARS-CoV-2 Omicron BA.1, BA.2, or BA.5. Serum samples from Beta variant-infected individuals neutralized SARS-CoV-2 Delta and, to some extent, BA.1 and BA.2, especially those with high titers.

Sera from Delta variant-infected individuals did not neutralize SARS-CoV-1, SARS-CoV-2 Beta, and Omicron sub-variants. Likewise, samples from SARS-CoV-1-infected individuals showed high neutralizing titers against SARS-CoV-1 but did not cross-neutralize SARS-CoV-2.

Sera from those infected with SARS-CoV-2 Omicron sub-variants had generally much lower nAb titers than others and failed to neutralize SARS-CoV-1, ancestral SARS-CoV-2, Beta, and Delta.

Moreover, limited cross-neutralization was observed between Omicron sub-variants. Samples from BA.5-infected subjects showed low cross-neutralization against BA.2 and did not neutralize SARS-CoV-1, ancestral SARS-CoV-2, and BA.1. The team generated an antigenic map based on neutralizing titers.

The map indicated that SARS-CoV-2 Omicron subvariants were antigenically distinct from ancestral SARS-CoV-2 and SARS-CoV-1.

Given the antigenic similarities among ancestral SARS-CoV-2, Alpha, Beta, and Delta variants, these were considered in the same serotype. The lack of cross-neutralization between SARS-CoV-1, ancestral SARS-CoV-2, and Omicron sub-variants corroborated classifying Omicron (sub-variants) as a distinct serotype.

Finally, the team used sera from individuals vaccinated with Pfizer's BNT162b2 vaccine to explore further the antigenic distance and the relationship of variants, including the more recent ones. Vaccinees induced high nAb titers against ancestral SARS-CoV-2.

Although the third dose increased titers against the ancestral strain and improved cross-neutralization against Omicron sub-variants, neutralization was limited against Omicron BQ.1.1 and XBB.

Notably, the capability of BQ.1.1 and XBB to evade nAbs exceeded that of SARS-CoV-1 despite both sub-variants being phylogenetically closer to ancestral SARS-CoV-2. Data indicated that BQ.1.1 and XBB were more distinct than SARS-CoV-1 relative to ancestral SARS-CoV-2.

With the third vaccine dose, there was a lower antigenic distance between Omicron BA.1 or BA.2 and ancestral SARS-CoV-2. However, SARS-CoV-1 clustered with Omicron BA.2.75.2 and BA.4.6 and was more antigenically closer to XBB than to ancestral SARS-CoV-2.

Conclusions

In sum, antigenic maps based on vaccinated sera revealed antigenic differences between SARS-CoV-2 and circulating Omicron sub-variants, suggesting that pre-existing immunity is inadequate to prevent infections.

Antigenic cartography based on vaccinated sera with hyper-immunity against ancestral SARS-CoV-2 was not meaningful for serotyping. Moreover, it indicated that Omicron BQ.1.1 and XBB evolved to the extent that they are antigenically closer to SARS-CoV-1 than to ancestral SARS-CoV-2.

The findings suggest the importance of convalescent sera from vaccine-naïve individuals since vaccinated sera are likely to yield masked profiles.

Nevertheless, the study had a few limitations, such as the small sample size of the BA.5 cohort and the lack of samples for those infected by post-BA.5 sub-variants. Altogether, the results support assigning distinct serotypes to SARS-CoV-1, ancestral SARS-CoV-2, and Omicron sub-variants.

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.