Development of variant-proof severe acute respiratory syndrome coronavirus 2, pan-sarbecovirus, and pan-β-coronavirus vaccines

Abstract

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with high transmission rates and striking immune evasion have posed a serious challenge to the application of current first-generation SARS-CoV-2 vaccines. Other sarbecoviruses, such as SARS-CoV and SARS-related coronaviruses (SARSr-CoVs), have the potential to cause outbreaks in the future. These facts call for the development of variant-proof SARS-CoV-2, pan-sarbecovirus or pan-β-CoV vaccines. Several novel vaccine platforms have been used to develop vaccines with broad-spectrum neutralizing antibody responses and protective immunity to combat the current SARS-CoV-2 and its variants, other sarbecoviruses, as well as other β-CoVs, in the future. In this review, we discussed the major target antigens and protective efficacy of current SARS-CoV-2 vaccines and summarized recent advances in broad-spectrum vaccines against sarbecoviruses and β-CoVs.

Keywords: COVID-19; RBD; SARS-CoV-2; pan-sarbecovirus; pan-β-coronavirus; vaccines.

Figure 1

Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Sequence diagram and structure diagram of S protein. S protein contains S1 and S2 subunits. The left (three RBDs, down S trimer) and the right (one RBD, up S trimer) were shown as surface in Cryo‐EM resolved structures (modified from 6ZGE and 6ZGG). CTD, C terminal domain; HR, heptad repeat; NTD, N terminal domain; RBD, receptor binding domain.

Figure 2

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) RBD‐specific binding footprints of neutralizing antibodies. RBD (RBM) top face, inner face and outer face were shown in the left with teal RBM. Sequence conservation was calculated by the ConSurf Database. RBD‐specific binding interface footprints of four classifications of neutralizing antibody regions were colored in teal in the right. For each class of antibody binding region (RBD1‐4), the footprints of two representative antibodies on the RBD are shown. RBD, receptor binding domain; RBM, receptor binding motif.

Figure 3

Currently utilized severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine types. Six types of currently used vaccines against the COVID‐19 pandemic. Illustration created by the authors using BioRender (http://www.biorender.com).

Figure 4

Potent efficacy of pan‐sarbecovirus vaccine CF501/RBD‐Fc. CF501 is a small‐molecule STING agonist. severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) receptor binding domain (RBD)‐Fc adjuvanted with CF501 elicited potent and durable neutralizing antibody and T cell responses, broad neutralizing activity against sarbecoviruses, and durable protective immunity in mice, rabbits, and nonhuman primates.

Figure 5

Strategies of protein nanoparticle vaccines and antigen chimera vaccines for broad‐spectrum neutralization. (A) Three representative types of selfassembled nanoparticles for antigen delivery. Spy‐tagged antigen was conjugated with a Spycather003‐mi3, forming nanoparticles. I53‐50A and I53‐50B could assemble into virus‐like particle (VLP) nanoparticles after mixing. Helicobacter pylori‐derived ferritin conjugated with antigens could form 24‐mer or 60‐mer nanoparticles. (B) Four types of genetically fused S chimera trimer were shown above, and S protein was generally divided into 3 parts, N terminal domain (NTD), receptor binding domain (RBD), and others (CTD and S2). For each part, one type of coronavirus was filled in with specific colors. Yellow stands for SARS‐CoV, teal for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), gray for HKU3‐1 and green for RsSHC014. Chimera 1 contained SARS‐CoV (RBD)—HKU3‐1 (NTD)—SARS‐CoV‐2 (Others); chimera 2 contained SARS‐CoV‐2 (RBD)—SARS‐CoV (NTD)—SARS‐CoV (Others); chimera 3 contained SARS‐CoV (RBD)—SARS‐CoV‐2 (NTD)—SARS‐CoV‐2 (Others) and chimera 4 contained RsSHC014 (RBD)—SARS‐CoV‐2 (NTD)—SARS‐CoV‐2 (Others).

Figure 6

Corresponding differences in immunization reactions between inhalation and intramuscular route. Intramuscular immunization induces antigen‐directed innate and adaptive responses and activates T and B cell responses. IgG⁺ plasma cells are generated, differentiated and maturated to create anti‐antigen neutralization antibodies. Apart from these immunological responses, inhalation immunization also induces tissue‐resident T cells and IgA⁺ B cells for circulating mucosal IgA antibodies.