Table 1.

Properties of RBD-based vaccine immunogens compared to full-length S-protein immunogens.

Properties	RBD	S-protein	Comments
Structure	3°	4°	Tertiary structure recognized by conformational nAb
Neutralizing antibody titer	High	High	>90% Target RBD but Spike protein offers anti-NTD and anti-S2 nAb
RBD epitopes	Yes	Yes	RBD epitopes appear to undergo convergent evolution and cross-protect against CoV-2 variants and other sarbecoviruses.
NTD epitopes	No	Yes	NTD is showing deletions, insertions, and divergent substitutions
Neutralizing : binding antibody ratio	High	Medium	Induction of nAb that contribute to efficacy (CoP) favors an immune-focused strategy
CD4+ epitopes	Medium	High	RBD-specific immunity can be augmented by multimeric display (virus-like particles) and adjuvants
CD8+ epitopes	Low	Low	Subunit approaches (S-protein and RBD) appear to be devoid of CD8+ T-cell responses. S-protein offers better coverage for cell-mediated immunity (CMI).
B-cell memory	High	High	RBD-specific memory B cells show evidence of somatic hypermutation, which increases breadth of neutralization
Antibody persistence	Yes	Yes	Demonstrated >6 months (e.g., SK bioscience RBD-np and Pfizer-BioNTech S-protein vaccines)
NHP efficacy	High	High	Proof-of-concept demonstrated against upper and lower respiratory tract infection and disease
Clinical efficacy	Yes	Yes	15 S-protein-based vaccines have reported ≥50% efficacy, with variations depending on the dominant viral variant. News reports of >90% for two Cuban RBD-based vaccines.
Supply volume	High	Medium	COVAX has negotiated favorable access terms for RBD vaccine candidates
Cost	Low	Medium	COGs low as produced by developing country vaccine manufacturers