Scientific rationale for developing potent RBD-based vaccines targeting COVID-19

Abstract

Vaccination of the global population against COVID-19 is a great scientific, logistical, and moral challenge. Despite the rapid development and authorization of several full-length Spike (S) protein vaccines, the global demand outweighs the current supply and there is a need for safe, potent, high-volume, affordable vaccines that can fill this gap, especially in low- and middle-income countries. Whether SARS-CoV-2 S-protein receptor-binding domain (RBD)-based vaccines could fill this gap has been debated, especially with regards to its suitability to protect against emerging viral variants of concern. Given a predominance for elicitation of neutralizing antibodies (nAbs) that target RBD following natural infection or vaccination, a key biomarker of protection, there is merit for selection of RBD as a sole vaccine immunogen. With its high-yielding production and manufacturing potential, RBD-based vaccines offer an abundance of temperature-stable doses at an affordable cost. In addition, as the RBD preferentially focuses the immune response to potent and recently recognized cross-protective determinants, this domain may be central to the development of future pan-sarbecovirus vaccines. In this study, we review the data supporting the non-inferiority of RBD as a vaccine immunogen compared to full-length S-protein vaccines with respect to humoral and cellular immune responses against both the prototype pandemic SARS-CoV-2 isolate and emerging variants of concern.

Fig. 1. Structure of the SARS-CoV-2 S-protein in the trimeric prefusion conformation.

The structure of the S-protein trimer was modeled based on PDB 7LXY. The three protomers (A, B, and C) are colored in cyan, yellow, and lilac, respectively. Structural components indicated include the NTD, the RBD, the N terminus, and the S2 domain.

Fig. 2. Overview of SARS-CoV-2 RBD cross-neutralizing antigenic sites.

Center panel: composite model of the SARS-CoV-2 S-protein trimer (gray) with four distinct monoclonal antibodies (S2E12 in purple, S2X259 in red, S2H97 in green, and S309 in blue) bound to one RBD in the open conformation. Top and bottom, left and right panels: magnified model of RBD (gray) with the ACE2-binding site outlined in black and the respective mAb cognate epitopes indicated by color. In dark blue is a surface representation of the glycan at position N343, which is conserved across the sarbecovirus subgenus. Top left: antigenic site Ia (purple) is targeted by the S2E12 mAb, which neutralizes the VOC and clade 1b, SARS-CoV-2-related, sarbecoviruses. Bottom left: antigenic site IIa (red) is targeted by the S2X259 mAb, which inhibits ACE2 binding, neutralizes the VOC and clades 1a&b SARS-CoV-2-related sarbecoviruses, and binds to clades 2/3 sarbecoviruses. Bottom right: antigenic site IV (blue) is targeted by the S309 mAb, which neutralizes the VOC and clades 1a&b SARS-CoV-2-related sarbecoviruses^,. Top right: antigenic site V (green) is targeted by S2H97, which neutralizes the VOC and clades 1a&b SARS-CoV-2-related sarbecoviruses, and binds to clades 2/3 sarbecoviruses.