Beyond polyclonal antibody responses: dissecting susceptibility to newly emerging SARS-CoV-2 variants

The COVID-19 pandemic continues to have a huge impact on global health. The SARS-CoV-2 encoded surface glycoprotein, Spike, is the primary target for neutralizing antibodies elicited during natural infection and is also the antigen used in most COVID-19 vaccines. Vaccines based on the ancestral Spike are highly successful at reducing hospitalization and death. One of the greatest challenges to the current pandemic has been the emergence of SARS-CoV-2 viral variants which encode mutations in the Spike protein. Although there were initial concerns that this could lead to reduced vaccine efficacy, encouragingly, vaccine booster programmes have proven successful at continuing to prevent hospitalizations and death caused by infection with current circulating variants of concern (VOC), including omicron.

As population immunity increases through vaccination and/or SARS-CoV-2 breakthrough infection, antibodies will mount increasing pressure on the virus to generate mutations in Spike and these mutations have the potential to evade vaccine-elicited antibody responses. Although my lab and others have identified the binding sites (epitopes) for neutralizing antibodies on the Spike surface the contribution these epitopes make to the serum neutralizing activity and how this changes upon repeated SARS-CoV-2 exposure has not been studied. A detailed understanding of the contribution these epitopes make to serum neutralization activity, and how different histories of SARS-CoV-2 exposure can impact on this, will be vital for understanding continued Spike evolution and provide insights into our susceptibility to newly emerging viral variants.

Extensive research on the neutralizing antibody response to SARS-CoV-2 infection and vaccination has been conducted on immune sera and whilst this provides information on the overall breadth of the polyclonal response to SARS-CoV-2, it does not provide information on the epitopes targeted by the antibodies present. In this project we will study the antibody response in individuals receiving the COVID-19 vaccine as well as those who experience a breakthrough infection with a VOC at the monoclonal antibody level. This proposal will address three basic and translational biomedical questions:

1) How does an individual's SARS-CoV-2 exposure history influence the specificity of their neutralizing antibody response and their subsequent susceptibility to newly emerging variants?

2) How does repeated immunization with vaccines that encode the ancestral Spike generate a neutralizing antibody response that can provide broad protection against VOCs?

3) Will second generation COVID-19 vaccines based on VOCs generate a superior neutralizing antibody response?

By addressing these questions, we will gain insights into the population susceptibility to newly emerging SARS-CoV-2 variants and inform on selection of Spike variants to be used as second generation COVID-19 vaccines.

SARS-CoV-2 Spike is the target for neutralizing antibodies elicited during infection and is the antigen encoded by COVID-19 vaccines. One of the greatest challenges in the current pandemic has been the emergence of SARS-CoV-2 viral variants which encode mutations in the Spike protein. As population immunity increases through repeated vaccination and/or SARS-CoV-2 breakthrough infection, antibody-mediated immune escape will play an increasing role in driving Spike evolution and in the emergence of viral variants. It is therefore vital to understand how immunity derived from previous exposure(s) to SARS-CoV-2 antigens (both vaccination and/or infection) shapes the B cell response through immune imprinting. Furthermore, although neutralizing epitopes present on Spike have been identified through isolation of monoclonal antibodies from convalescent individuals, their differential contribution towards the neutralization activity in convalescent or vaccine sera, and how epitope immunodominance is influenced by SARS-CoV-2 exposure history remains to be determined. This proposal will move beyond studying the breadth of polyclonal antibody responses to study the dynamics of epitope immunodominance following different SARS-CoV-2 exposure histories and determine how the neutralizing antibody response evolves under repeated exposure to ancestral SARS-CoV-2 (through vaccination) and SARS-CoV-2 viral variants (through breakthrough infection) at the monoclonal antibody level. Overall, a more detailed understanding of immune imprinting and evolving epitope immunodominance in the context of repeated SARS-CoV-2 antigen exposure will provide important insights into population susceptibility to newly emerging viral variants and will directly inform on Spike antigen selection for second generation COVID-19 vaccine development.