Evolving SARS-CoV-2 Vaccines: From Current Solutions to Broad-Spectrum Protection

Abstract

The continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the emergence of variants of concern (VOCs) underscore the critical role of vaccination in pandemic control. These mutations not only enhance viral infectivity but also facilitate immune evasion and diminish vaccine efficacy, necessitating ongoing surveillance and vaccine adaptation. Current SARS-CoV-2 vaccines, including inactivated, live-attenuated, viral vector, protein subunit, virus-like particle, and nucleic acid vaccines, face challenges due to the immune evasion strategies of emerging variants. Moreover, other sarbecoviruses, such as SARS-CoV-1 and SARS-related coronaviruses (SARSr-CoVs) pose a potential risk for future outbreaks. Thus, developing vaccines capable of countering emerging SARS-CoV-2 variants and providing broad protection against multiple sarbecoviruses is imperative. Several innovative vaccine platforms are being investigated to elicit broad-spectrum neutralizing antibody responses, offering protection against both current SARS-CoV-2 variants and other sarbecoviruses. This review presents an updated overview of the key target antigens and therapeutic strategies employed in current SARS-CoV-2 vaccines. Additionally, we summarize ongoing approaches for the development of vaccines targeting infectious sarbecoviruses.

Keywords: broadly neutralizing antibodies; coronavirus; immune evasion; sarbecovirus; vaccines.

Figure 1

Structural organization of SARS-CoV-2 and progressive accumulation of key spike mutations in variants. (A) SARS-CoV-2 consists of four primary structural proteins: spike (S), nucleocapsid (N), membrane (M), and envelope (E). The S protein is subdivided into several functional domains, each indicated by a distinct color. Key regions include the S1 and S2 subunits, N-terminal domain (NTD), receptor-binding domain (RBD), S1/S2 and S2′ protease cleavage sites, fusion peptide (FP), heptad repeats (HR1 and HR2), central helix (CH), connector domain (CD), stem helix (SH), and the transmembrane (TM) domain. The schematic also illustrates the viral entry process into host cells. (B) Overall structure of the SARS-CoV-2 S trimer complex, highlighting major domains (PDB ID: 7DDN). (C) Progressive accumulation of representative S mutations in SARS-CoV-2 variants compared to the ancestral strain. Mutations are represented by color-coded bars: colored bars indicate presence, while white bars indicate absence. Asterisks mark key amino acid residues associated with immune escape, as identified in recent studies.

Figure 2

Overview of SARS-CoV-2 vaccine platforms and their associated immunogenic characteristics. This figure summarizes the major types of SARS-CoV-2 vaccines under development or in clinical use, categorized by platform: inactivated virus, protein subunit, viral vector-based (replicating and non-replicating), nucleic acid-based (mRNA and DNA), and virus-like particle (VLP) vaccines. Each vaccine type is depicted alongside its mechanism of action and characteristic immune responses, including humoral and cellular immunity profiles, as well as potential advantages and limitations.

Figure 3

Potential strategies to optimize COVID-19 vaccines. This figure outlines multiple strategies aimed at enhancing the efficacy, breadth, and durability of COVID-19 vaccines. These approaches include antigen design optimization (e.g., inclusion of conserved regions such as the S2 domain or mosaic RBDs), use of adjuvants to boost immune responses, heterologous prime-boost regimens, and alternative delivery platforms such as intranasal or mucosal vaccines to induce local immunity. In addition, incorporating pan-sarbecovirus targets and updating immunogens to match emerging variants are highlighted as key directions for next-generation vaccine development.