Designing VOC-targeted vaccines is likely necessary to overcome immune evasion from current vaccines and neutralizing antibodies. We conclude that individual spike mutations influence viral infectivity and vaccine immunogenicity. In addition, T-cell responses were unlikely affected by mutations tested in the spike. All immunogens tested, however, showed low neutralization against circulating B.1.1.529. B.1.351 elicited adequate broad cross-NAbs against both B.1.351 and B.1.617.2. S982A, L18F, and Del 242–244 hindered the induction of cross-NAbs, whereas Del 69–70, Del144, R246I, and K417N showed the opposite effects. All sera showed reduced cross-neutralization activity against B.1.351, B.1.617.2 (Delta) and B.1.1.529 (Omicron BA.1). S982A weakened the generation of binding antibodies. In the B.1.351 lineage, L18F and Del 242–244 in the NTD, K417N in the RBD and A701V in S2 also increased viral entry. In the B.1.1.7 lineage, Del69–70 and Del 144 in NTD, A570D and P681H in SD1 and S982A and D1118H in S2 significantly increased viral entry, whereas T716I resulted in a decrease. Cellular and humoral immune responses were then compared to determine the impact of individual mutations on immunogenicity. BALB/c mice were immunized with 2-dose DNA vaccines encoding B.1.1.7, B.1.351, B.1.1.529 and their single mutations. The entry efficiency of individual spike mutations was determined in vitro using pseudotyped viruses. How naturally occurring spike mutations affect the infectivity and antigenicity of VOCs remains to be investigated. Mutations in SARS-CoV-2 variants of concern (VOCs) have enhanced transmissibility and immune evasion with respect to current vaccines and neutralizing antibodies (NAbs).
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