Pan-vaccine antigen strategy confers protection against cross-clade SARS-CoV-2 variants, including vaccine-resistant Omicron variants

In a recent article published in Science Translational Medicine, researchers developed a novel pan-vaccine antigen (S_pan)-based subunit vaccine against coronavirus disease 2019 (COVID-19). Using a mouse model, they also demonstrated that this vaccine formulation conferred protection against multiple clades of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Background

Currently used messenger ribonucleic acid (mRNA) technology-based and some other COVID-19 vaccines have proven immensely successful in combating the disease. However, since the evolutionary trajectory of SARS-CoV-2 has remained highly diversified and unpredictable, there is an urgent need for updated vaccines that could fight newer variants displaying rapid antigenic drift in their spike (S) sequences.

It is noteworthy that the SARS-CoV-2 S had over 7,000 amino acid (AA) mutations, including insertions, substitutions, and deletions. For instance, mutations in the 484 position of E484 AA critically diminished the neutralization response against antibodies by over 10-fold, leading to increased immune evasion capability.

About the study

In the present study, researchers analyzed 2,675 S protein sequences from five SARS-CoV-2 strains that emerged before the Delta variant, obtained from the National Center for Biotechnology Information (NCBI) database, to design S_pan, which harbored AA residues that were consistent across multiple SARS-CoV-2 strains.

Furthermore, they systemically screened the infectivity of 54 pseudotyped SARS-CoV-2 strains to examine each one’s mutations. This exercise covered wild-type (WT) strain, eight variants, and 45 single mutations and helped the researchers analyze the evolutionary path taken by the SARS-CoV-2 S protein.

The researchers vaccinated keratin 18 (K18)–hACE2 mice with subunit vaccines formulated using Span antigen and an adjuvant. The test animals received 25 μg per dose of antigen at an interval of 14 days. The team collected mouse serum samples 14 days post-second vaccination.

Study findings

Sera from S_pan-vaccinated mice exhibited a broader spectrum of neutralizing activities against all 10 variants evaluated in the study but markedly higher activity in six of 10 variants. It had better neutralization activity against multiple immune-evading mutations (e.g., E484K, del69-70, N501Y).

Thus, S_pan also elicited an effective neutralization response against the Omicron subvariants, with geometric mean titers ranging between 180 and 2333. Surprisingly, it could combat Delta, Beta, and Omicron VOCs because the researchers designed it using SARS-CoV-2 S sequences collated before their emergence. These findings indicate that S_pan might have potential immunogenicity against the future antigenic drift of SARS-CoV-2.

Regarding SARS-CoV-2 S protein evolution, the researchers noted that it evolved in three distinct evolutionary directions. These evolutionary trajectories either increased their infectivity and lowered immune resistance or vice -a versa. Nevertheless, they resulted in heterogeneous antigenicity of S.

A universal SARS-CoV-2 vaccine, thus, needs to consider all the heterogeneous mutations within the same antigen to be effective against multiple SARS-CoV-2 variants. It further implies that averaging or superimposing mutations does not work. Instead, all phylogenetic calculations must also account for experimental evidence of an antigen’s evolutionary trajectory to yield a universal S sequence, including the most frequent mutations.

Accordingly, the researchers noted that S_pan improved immune protection against uncovered mutations, such as E484Q. It further favors the generalizability of the S_pan antigen. Regarding the effect of mutations on SARS-CoV-2 infectivity, the researchers found that the mutations nested in the N-terminal domain (NTD) and receptor-binding domain (RBD) of S had the most distinguished effect. Conversely, mutations nested outside these domains had minimal effect on viral infectivity.

Unassumingly, the S982A mutation nested in the heptad repeat 1 (HR1) domain of the S2 subunit increased viral infectivity. Perhaps the highly conserved nature of the HR1 domain and its critical role in the SARS-CoV-2 membrane fusion process makes it a good target for SARS-CoV-2 therapeutic interventions. Moreover, the S982A mutation decreased SARS-CoV-2’s sensitivity to neutralization by group IV monoclonal antibodies. Thus, the researchers identified a novel mutation that, if re-surfaces frequently, must be considered while designing COVID-19 therapies.

Conclusions

Overall, high-frequency mutations in the S_pan vaccine helped it confer adequate protection against the highly infectious Delta variant. It also elicited a broad humoral immune response against heterogeneous variants, such as Beta.

To conclude, the study data emphasize the need for further development of S_pan as a vaccine antigen. Redesigning the S_pan and optimizing current vaccination strategies could help combat SARS-CoV-2 antigenic drift. Furthermore, it could make way for universal vaccines offering broad protection against existing and future SARS-CoV-2 variants, including vaccine-resistant Omicton-like variants.