Ancestral SARS-CoV-2 immune imprinting persists on RBD but not NTD after sequential Omicron infections

Area of Science:

• Immunology
• Virology
• Vaccinology

Background:

• Immune imprinting, a phenomenon where initial immune exposures shape subsequent responses, is critical in understanding SARS-CoV-2 variant immunity.
• The impact of Omicron variant infections on pre-existing immunity, particularly immune imprinting from ancestral strains, remains incompletely understood.

Purpose of the Study:

• To analyze B cell responses following sequential Omicron infections in both vaccinated and unvaccinated individuals.
• To investigate whether Omicron exposures can overcome ancestral SARS-CoV-2 immune imprinting.
• To characterize the impact of immune imprinting on antibody responses targeting different SARS-CoV-2 spike protein domains.

Main Methods:

• Analysis of plasma neutralizing antibody titers against ancestral SARS-CoV-2 and variants.
• Comparison of binding specificities, neutralizing capacities, and targeting epitopes of monoclonal antibodies.
• Assessment of B cell responses in vaccinated and unvaccinated individuals with sequential Omicron infections.

Main Results:

• Immune imprinting is not consistently induced by inactivated or recombinant protein vaccines but, once established, is not countered by successive Omicron challenges.
• Immune imprinting primarily shapes antibody responses to the receptor-binding domain (RBD), impeding Omicron-specific neutralizing antibodies while facilitating broadly neutralizing antibodies.
• Antibody responses targeting the N-terminal domain (NTD) were less affected by immune imprinting.

Conclusions:

• Sequential Omicron infections do not overcome established immune imprinting.
• Immune imprinting influences the development of neutralizing antibodies, with distinct effects on RBD-targeting versus NTD-targeting antibodies.
• Vaccine strategies could leverage or neglect immune imprinting: NTD-based vaccines might induce variant-specific antibodies, while RBD-containing vaccines could induce broadly neutralizing antibodies.