Antigenic sin of wild-type SARS-CoV-2 vaccine shapes poor cross-neutralization of BA.4/5/2.75 subvariants in BA.2 breakthrough infections

Ju, Bin; Fan, Qing; Wang, Miao; Liao, Xuejiao; Guo, Huimin; Wang, Haiyan; Ge, Xiangyang; Liu, Lei; Zhang, Zheng

doi:10.1038/s41467-022-34400-8

Cited by 39 publications

(36 citation statements)

References 30 publications

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“…As we recently reported minimal to no neutralizing antibodies against the Omicron variant in subjects with vaccine-induced or hybrid immunity at the beginning of the surge in COVID-19 cases in December 2021 [16] and none of participants had received a booster dose of vaccine, our data suggests that enhanced neutralizing antibody titers observed in this study in the cohort of individuals (Fig 6E) is due to natural exposure to SARS-CoV-2 Omicron variants. The highest titers of neutralizing antibodies elicited against the Delta variant in breakthrough infections of Omicron lineages further confirms the hypothesis of original antigenic sin proposed by others which may explain the lowest level of neutralizing antibody titers observed against BA.2.75 [44]. We were able to collect a six-month follow-up sample from nine of the participants who were infected with one of the Omicron variants prior to Feb 2022 (…”

Section: Plos Pathogenssupporting

confidence: 85%

BA.1, BA.2 and BA.2.75 variants show comparable replication kinetics, reduced impact on epithelial barrier and elicit cross-neutralizing antibodies

et al. 2023

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The Omicron variant of SARS-CoV-2 is capable of infecting unvaccinated, vaccinated and previously-infected individuals due to its ability to evade neutralization by antibodies. With multiple sub-lineages of Omicron emerging in the last 12 months, there is inadequate information on the quantitative antibody response generated upon natural infection with Omicron variant and whether these antibodies offer cross-protection against other sub-lineages of Omicron variant. In this study, we characterized the growth kinetics of Kappa, Delta and Omicron variants of SARS-CoV-2 in Calu-3 cells. Relatively higher amounts infectious virus titers, cytopathic effect and disruption of epithelial barrier functions was observed with Delta variant whereas infection with Omicron sub-lineages led to a more robust induction of interferon pathway, lower level of virus replication and mild effect on epithelial barrier. The replication kinetics of BA.1, BA.2 and BA.2.75 sub-lineages of the Omicron variant were comparable in cell culture and natural infection in a subset of individuals led to a significant increase in binding and neutralizing antibodies to the Delta variant and all the three sub-lineages of Omicron but the level of neutralizing antibodies were lowest against the BA.2.75 variant. Finally, we show that Cu2+, Zn2+ and Fe2+ salts inhibited in vitro RdRp activity but only Cu2+ and Fe2+ inhibited both the Delta and Omicron variants in cell culture. Thus, our results suggest that high levels of interferons induced upon infection with Omicron variant may counter virus replication and spread. Waning neutralizing antibody titers rendered subjects susceptible to infection by Omicron variants and natural Omicron infection elicits neutralizing antibodies that can cross-react with other sub-lineages of Omicron and other variants of concern.

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Section: Plos Pathogenssupporting

confidence: 85%

BA.1, BA.2 and BA.2.75 variants show comparable replication kinetics, reduced impact on epithelial barrier and elicit cross-neutralizing antibodies

et al. 2023

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“…Accordingly, such vaccines could, in fact, boost responses to conserved epitopes rather than induce responses to the new variants. It is uncertain if a broad immunity conferred by a bivalent vaccine containing Wuhan and Omicron strains will prove to be the best choice ( 35 ) especially considering the antigenic sin phenomenon that may impair specific responses to Omicron ( 36 ). Maybe the next steps will be to develop specific vaccines based on novel dominant and/or subdominant variants without boosting the index strain, as shown by promising results in pre-clinical assays ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Immunodominant antibody responses directed to SARS-CoV-2 hotspot mutation sites and risk of immune escape

et al. 2023

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IntroductionConsidering the likely need for the development of novel effective vaccines adapted to emerging relevant CoV-2 variants, the increasing knowledge of epitope recognition profile among convalescents and afterwards vaccinated with identification of immunodominant regions may provide important information.MethodsWe used an RBD peptide microarray to identify IgG and IgA binding regions in serum of 71 COVID-19 convalescents and 18 vaccinated individuals. ResultsWe found a set of immunodominant RBD antibody epitopes, each recognized by more than 30% of the tested cohort, that differ among the two different groups and are within conserved regions among betacoronavirus. Of those, only one peptide, P44 (S415-429), recognized by 68% of convalescents, presented IgG and IgA antibody reactivity that positively correlated with nAb titers, suggesting that this is a relevant RBD region and a potential target of IgG/IgA neutralizing activity.DiscussionThis peptide is localized within the area of contact with ACE-2 and harbors the mutation hotspot site K417 present in gamma (K417T), beta (K417N), and omicron (K417N) variants of concern. The epitope profile of vaccinated individuals differed from convalescents, with a more diverse repertoire of immunodominant peptides, recognized by more than 30% of the cohort. Noteworthy, immunodominant regions of recognition by vaccinated coincide with mutation sites at Omicron BA.1, an important variant emerging after massive vaccination. Together, our data show that immune pressure induced by dominant antibody responses may favor hotspot mutation sites and the selection of variants capable of evading humoral response.

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“…Previous infection usually negatively impacts the response to a subsequent infection with pathogens sharing cross-reactive antigens. The initial immune background places restrictions on the antibody response induced by a subsequent SARS-CoV-2 variant [ 40 , 41 , 42 ], but it seems to show limited impact on recalling CD8 + T-cell responses [ 43 ]. The spike mutation of Omicron BA.1 induced two new MHC-I-restricted epitopes in BALB/c mice and one new MHC-I-restricted epitope in C57BL/6 mice.…”

Section: Discussionmentioning

confidence: 99%

Effects of SARS-CoV-2 Omicron BA.1 Spike Mutations on T-Cell Epitopes in Mice

Wang¹,

Wang²,

Zhao³

et al. 2023

Viruses

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T-cell immunity plays an important role in the control of SARS-CoV-2 and has a great cross-protective effect on the variants. The Omicron BA.1 variant contains more than 30 mutations in the spike and severely evades humoral immunity. To understand how Omicron BA.1 spike mutations affect cellular immunity, the T-cell epitopes of SARS-CoV-2 wild-type and Omicron BA.1 spike in BALB/c (H-2d) and C57BL/6 mice (H-2b) were mapped through IFNγ ELISpot and intracellular cytokine staining assays. The epitopes were identified and verified in splenocytes from mice vaccinated with the adenovirus type 5 vector encoding the homologous spike, and the positive peptides involved in spike mutations were tested against wide-type and Omicron BA.1 vaccines. A total of eleven T-cell epitopes of wild-type and Omicron BA.1 spike were identified in BALB/c mice, and nine were identified in C57BL/6 mice, only two of which were CD4+ T-cell epitopes and most of which were CD8+ T-cell epitopes. The A67V and Del 69-70 mutations in Omicron BA.1 spike abolished one epitope in wild-type spike, and the T478K, E484A, Q493R, G496S and H655Y mutations resulted in three new epitopes in Omicron BA.1 spike, while the Y505H mutation did not affect the epitope. These data describe the difference of T-cell epitopes in SARS-CoV-2 wild-type and Omicron BA.1 spike in H-2b and H-2d mice, providing a better understanding of the effects of Omicron BA.1 spike mutations on cellular immunity.

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Antigenic sin of wild-type SARS-CoV-2 vaccine shapes poor cross-neutralization of BA.4/5/2.75 subvariants in BA.2 breakthrough infections

Cited by 39 publications

References 30 publications

BA.1, BA.2 and BA.2.75 variants show comparable replication kinetics, reduced impact on epithelial barrier and elicit cross-neutralizing antibodies

BA.1, BA.2 and BA.2.75 variants show comparable replication kinetics, reduced impact on epithelial barrier and elicit cross-neutralizing antibodies

Immunodominant antibody responses directed to SARS-CoV-2 hotspot mutation sites and risk of immune escape

Effects of SARS-CoV-2 Omicron BA.1 Spike Mutations on T-Cell Epitopes in Mice

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