Imprinting of serum neutralizing antibodies by Wuhan-1 mRNA vaccines

Liang, Chieh-Yu; Raju, Saravanan; Liu, Zhuoming; Li, Yuhao; Asthagiri Arunkumar, Guha; Case, James Brett; Scheaffer, Suzanne M.; Zost, Seth J.; Acreman, Cory M.; Gagne, Matthew; Andrew, Shayne F.; Carvalho dos Anjos, Deborah Carolina; Foulds, Kathryn E.; McLellan, Jason S.; Crowe, James E.; Douek, Daniel C.; Whelan, Sean P. J.; Elbashir, Sayda M.; Edwards, Darin K.; Diamond, Michael S.

doi:10.1038/s41586-024-07539-1

Cited by 10 publications

(7 citation statements)

References 53 publications

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“…This is validated by mAb analyses, in alignment with our earlier discovery that repeated Omicron infections may mitigate the imprinting of inactivated vaccines based on the ancestral strain 22 . Nevertheless, recent research involving individuals who underwent Omicron reinfection after receiving mRNA vaccines based on the ancestral strain revealed pronounced immune imprinting; as a result, Omicron-specific MBCs were scarcely detectable even after two exposures to Omicron [27][28][29] .…”

Section: Jn1-induced Memory B Cell Repertoirementioning

confidence: 99%

“…Recent research has highlighted an exceptionally strong immune imprinting in individuals vaccinated with mRNA vaccines, as they fail to mount an Omicron-specific antibody response even following multiple Omicron exposures [27][28][29] . However, this phenomenon cannot be observed in individual who received inactivated vaccines, or in mRNA-vaccinated mice 27 . Upon the comprehensive characterization of Omicron-specific antibodies, we surprisingly discovered that all Omicron-specific neutralizing epitopes on RBD compete with the A1 mAbs, which are well-known for the convergent usage of IGHV3-53/3-66 germline (Fig.…”

Section: Clash Of Class 1 and Omi-specific Nabsmentioning

confidence: 99%

Section: Jn1-induced Memory B Cell Repertoirementioning

confidence: 99%

“…This aligns with our earlier discovery that repeated Omicron infections may mitigate the imprinting of inactivated vaccines based on the ancestral strain 15 . Nevertheless, recent research involving individuals who underwent Omicron reinfection after receiving mRNA vaccines based on the ancestral strain revealed pronounced immune imprinting; as a result, Omicron-specific MBCs were scarcely detectable even after two exposures to Omicron [16][17][18] . Additionally, we aim to dissect the specific molecular constituents responsible for the broad-spectrum neutralization observed in the pAbs elicited by infections with the JN.1 lineage to understand how prior vaccination or infection with BA.5 facilitates the development of cross-lineage NAbs following infections with XBB/JN.1.Importantly, analyzing the MBC repertoire also help predict the response to future exposures.Consequently, it is imperative and compelling to deconvolute the roles of antibodies that exhibit diverse cross-reactivities and target multiple epitopes, particularly on the virus RBD, the most immunogenic domain targeted by NAbs.Therefore, we employed fluorescence-activated cell sorting (FACS) to isolate RBD-specific CD20 + CD27 + IgM − IgD − B cells using fluorescence activated cell sorting (FACS) from the peripheral blood mononuclear cells (PBMCs) of the human donors previously mentioned.…”

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confidence: 99%

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Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1

Jian,

Wang,

Yisimayi

et al. 2024

Preprint

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The ongoing evolution of SARS-CoV-2 continues to challenge the global immune barrier established by infections and vaccine boosters. Recently, the emergence and dominance of the JN.1 lineage over XBB variants have prompted a reevaluation of current vaccine strategies. Despite the demonstrated effectiveness of XBB-based vaccines against JN.1, concerns persist regarding the durability of neutralizing antibody (NAb) responses against evolving JN.1 subvariants. In this study, we compared the humoral immunogenicity of XBB and JN.1 lineage infections in human subjects with diverse immune histories to understand the antigenic and immunogenic distinctions between these variants. Similar to observations in naive mice, priming with XBB and JN.1 in humans without prior SARS-CoV-2 exposure results in distinct NAb responses, exhibiting minimal cross-reactivity. Importantly, breakthrough infections (BTI) with the JN.1 lineage induce 5.9-fold higher neutralization titers against JN.1 compared to those induced by XBB BTI. We also observed notable immune evasion of recently emerged JN.1 sublineages, including JN.1+R346T+F456L, with KP.3 showing the most pronounced decrease in neutralization titers by both XBB and JN.1 BTI sera. These results underscore the challenge posed by the continuously evolving SARS-CoV-2 JN.1 and support the consideration of switching the focus of future SARS-CoV-2 vaccine updates to the JN.1 lineage.

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Section: Jn1-induced Memory B Cell Repertoirementioning

confidence: 99%

Section: Clash Of Class 1 and Omi-specific Nabsmentioning

confidence: 99%

Section: Jn1-induced Memory B Cell Repertoirementioning

confidence: 99%

mentioning

confidence: 99%

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Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1

Jian,

Wang,

Yisimayi

et al. 2024

Preprint

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“…To examine whether repeated Omicron infections could induce de novo antibody responses from naïve B cells in the presence of immune imprinting, we move on to investigate the origins of neutralizing mAbs from each group. In published literatures, it is generally assumed that cross-reactive antibodies derive from memory B cells induced by WT whereas omicron-specific antibodies originate from naïve B cells activated by Omicron (22)(23)(24)(25). However, these assumptions remain to be confirmed by experiments to exclude possibilities that memory B cells induced by WT may lose cross-reactivity and Omicron-specific naïve B cells may develop cross-reactivity during affinity maturation.…”

Section: Repeated Omicron Infections Induce De Novo Omicron-specific ...mentioning

confidence: 99%

Ancestral SARS-CoV-2 immune imprinting persists on RBD but not NTD after sequential Omicron infections

Wang,

Li,

et al. 2024

Preprint

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SummaryWhether Omicron exposures could overcome ancestral SARS-CoV-2 immune imprinting remains controversial. Here we analyzed B cell responses evoked by sequential Omicron infections in vaccinated and unvaccinated individuals. Plasma neutralizing antibody titers against ancestral SARS-CoV-2 and variants indicate that immune imprinting is not consistently induced by inactivated or recombinant protein vaccines. However, once induced, immune imprinting is not countered by successive Omicron challenges. We compared binding specificities, neutralizing capacities, developing origins and targeting epitopes of monoclonal antibodies from individuals with or without immune imprinting. Although receptor-binding domain (RBD) and N- terminal domain (NTD) of spike are both primary targets for neutralizing antibodies, immune imprinting only shapes antibody responses to RBD by impeding the production of Omicron-specific neutralizing antibodies while facilitating the development of broadly neutralizing antibodies. We propose that immune imprinting can be either neglected by NTD-based vaccines to induce variant-specific antibodies or leveraged by RBD-containing vaccines to induce broadly neutralizing antibodies.HighlightsImmune imprinting is not consistently induced by vaccinationRepeated Omicron infections could not counter immune imprintingImmune imprinting shapes antibody responses to RBD but not NTDImmune imprinting leads to broadly neutralizing antibodies

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