
La impronta inmunitaria, apodada “pecado antigénico original” por Thomas Francis Jr., ocurre cuando los linfocitos B de memoria producidos en respuesta a una infección viral inicial dominan las respuestas posteriores a virus relacionados, produciendo anticuerpos dirigidos a la exposición original.
La memoria inmunitaria a largo plazo tiene muchas ventajas, pero la impronta inmunitaria puede ser perjudicial si interfiere con la respuesta inmunitaria a infecciones posteriores.
La siguiente colección de más de 100 artículos revisados por pares sugiere que las “vacunas” contra la COVID-19 dejaron una impronta en el sistema inmunológico de los receptores a través de la exposición a la proteína de pico de “tipo salvaje” de la cepa original de Wuhan, lo que moldeó su respuesta a variantes posteriores de formas potencialmente dañinas.
La impronta inmunológica perjudicó las respuestas a las nuevas variantes al sesgar la producción de anticuerpos de las células B hacia la proteína pico o spike “ancestral” a expensas de nuevos anticuerpos específicamente diseñados para la proteína pico fuertemente mutada de las variantes.
Además, al imprimir un solo antígeno (la proteína de pico o spike) en el sistema inmunológico de los receptores, las “vacunas” les impidieron formar anticuerpos contra otras partes del virus menos propensas a las mutaciones, como las proteínas de la nucleocápside del virus (Ahmed MIM et al., Delgado JF et al., Paula NM et al., Smith CP et al., Yao D et al).
Otros hallazgos apuntan a una “impronta inmunológica profunda” o “amortiguación inmunológica híbrida”, en la que la “vacunación” combinada con la infección altera la respuesta inmunológica posterior de manera impredecible
Otros hallazgos apuntan a una “impronta inmunológica profunda” o “amortiguación inmunológica híbrida”, en la que la “vacunación” combinada con la infección altera la respuesta inmunológica posterior de manera impredecible
- Addetia A et al., «Neutralization, efector function and immune imprinting of Omicron variants,»
Nature 2023, 621: 592-601. doi: https://doi.org/10.1038/s41586-023-06487-6
• «Omicron breakthrough infections of Wu-vaccinated subjects primarily recall cross-reactive MBCs specific for epitopes shared by multiple SARS-CoV-2 variants rather than priming naive B cells that recognize Omicron RBD-specific epitopes. We observed an unexpectedly small number of MBCs specific for Omicron RBDs (and not cross-reacting with the Wu RBD) even after two exposures to Omicron S antigens, including after Wu/BA.5 or Wu/BA.1 bivalent mRNA vaccination.» - Aguilar-Bretones M et al., «Impact of antigenic evolution and original antigenic sin on SARS-CoV-2
immunity,» J Clin Invest. 2023, 133, 1: e162192. doi: 10.1172/JCI162192
• «… vaccinated individuals infected with the Alpha or Delta variant have a relatively decreased response to variant-specific epitopes compared with unvaccinated individuals, which is indicative of OAS… In addition, more traits of immune imprinting have recently been identified in hybrid-immune individuals who were infected with Wuhan-1 strain before vaccination, in whom enhancement of VOC cross-reactive antibody titers and T cells by Omicron infection was nullified, a phenomenon termed hybrid immune damping.» - Ahmed MIM et al., «Enhanced Spike-specific, but attenuated Nucleocapsid-specific T cell responses upon SARS-CoV-2 breakthrough versus non-breakthrough infections,» Front. Immunol. 2022, 13 (Sec. Vaccines and Molecular Therapeutics). doi: https://doi.org/10.3389/fimmu.2022.1026473 • «Subjects with vaccine breakthrough infection had significantly higher CD4 and CD8 T cell responses targeting the vaccine-encoded Spike during the first and third/fourth week after PCR diagnosis compared to non-vaccinated controls, respectively. In contrast, CD4 T cells targeting the non-vaccine encoded Nucleocapsid antigen were of significantly lower magnitude in BTI as compared to non-BTI. Hence, previous vaccination was linked to enhanced T cell responses targeting the vaccine-encoded Spike antigen, while responses against the non-vaccine encoded Nucleocapsid antigen were significantly attenuated.»
- Alsoussi WB et al., «SARS-CoV-2 Omicron boosting induces de novo B cell response in humans,»
Nature 2023, 617, 7961: 592-598. doi: https://doi.org/10.1038/s41586-023-06025-4
• «mRNA-1273 and mRNA-1273.213 both elicited robust germinal centre responses and maturation of the MBC and BMPC responses, but we did not isolate any antibodies specifically targeting S proteins from the variant strains encoded by the mRNA-1273.213 vaccine that did not cross-react to the original WA1/2020 S protein. Thus, the B cell response after boosting with the mRNA-1273.213 vaccine was imprinted by the primary vaccination series with mRNA-1273, which encodes the ancestral S protein.» - Altmann DM et al., «COVID-19 vaccination: The road ahead,» Science 2022, 375, 6586: 1127-1132.
doi: 10.1126/science.abn1755
• «In terms of immune imprinting (‘original antigenic sin’), the data show that di3erent repertoires emerge, with associated implications for variable quality and quantity of neutralization of current or future VOC. For example, our comparative analysis of di3erential VOC neutralization patterns in vaccinees shows the development of imprinted di3erences between those who had a prior infection with either the ancestral or Alpha virus. Faced with these diverse scenarios, the question is whether to keep developing boosters carrying prototypic Wuhan Hu-1 spike sequence or focus on being reactive to regionally predominant VOCs. The iteration of this that pools VOC sequences into multivalent vaccines has appeal, although the immune imprinting data argue the potential for unforeseen, diferential response patterns dependent on prior history and subsequent SARS-CoV-2 exposure. There is a danger that, even with ‘plug and play’ platforms and rapid pipelines, this entails a future of playing catchup against oncoming VOCs for diminishing and unpredictable returns in protective immunity.» - Amano M et al., «Restoration of Neutralization Activity Against Omicron BA.2 and BA.5 in Older
Adults and Individuals With Risk Factors Following the Fourth Dose of Severe Acute Respiratory
Syndrome Coronavirus 2 BNT162b2 Vaccine,» J. Infect. Dis. 2023, 227, 1: 161-163. doi:
https://doi.org/10.1093/infdis/jiac393
• «The present data, that a fourth vaccine dose restores protection but does not further enhance the humoral response, may be related to ‘original antigenic sin,’ wherein high-afinity memory B cells inhibit the recruitment of naive B cells against subsequent antigenic stimuli, in particular, against new stimuli. Thus, it is likely that despite the fourth dose, breakthrough infections continue to occur.» - Arunachalam PS et al. «Systems vaccinology of the BNT162b2 mRNA vaccine in humans,» Nature
2021, 596: 410-416. doi: https://doi.org/10.1038/s41586-021-03791-x
• «BNT162b2 vaccination also induced a neutralizing antibody response against the B.1.351 variant of concern, albeit at a tenfold-lower magnitude than against the wild-type WA1/2020 (WA1) strain.» - Atari N et al., «Omicron BA.2.75 variant is eficiently neutralised following BA.1 and BA.5
breakthrough infection in vaccinated individuals, Israel, June to September 2022,» Eurosurveillance
2022, 27, 44: 2200785. doi: https://doi.org/10.2807/1560-7917.ES.2022.27.44.2200785
• «The neutralisation eficiency in HCW who were infected with BA.1/BA.5 and had previously been vaccinated with three doses of Comirnaty vaccine was significantly higher for all of Omicron variants (unpaired T-test, p value > 0.0008) than in vaccinated but SARS-CoV-2-naïve HCW.» - Aydillo T et al., «Immunological imprinting of the antibody response in COVID-19 patients,» Nat.
Commun. 2021, 12: 3781. doi: https://doi.org/10.1038/s41467-021-23977-1
• «Our findings thus provide evidence of immunological imprinting by previous seasonal coronavirus infections that can potentially modulate the antibody profile to SARS-CoV-2 infection… A similar scenario to our studies in infected people could be proposed for the vaccines, with some diferences due to the nature of the stimulus itself. Back-boost of cross- reactive antibody responses might lead to less protective antibodies directed against non- neutralizing conserved epitopes between the S antigen of the vaccine and the S proteins of seasonal human betacoronaviruses.» - Baerends EAM et al., «Omicron Variant-Specific Serological Imprinting Following BA.1 or BA.4/5
Bivalent Vaccination and Previous SARS-CoV-2 Infection: A Cohort Study,» Clin. Infect. Dis. 2023,
77, 11: 1511-1520. doi: https://doi.org/10.1093/cid/ciad402
• «Vaccination and previous infection leave a clear serological imprint that is focused on the variant-specific antigen.» - Bayarri-Olmos R et al., «Unraveling the impact of SARS-CoV-2 mutations on immunity: insights from innate immune recognition to antibody and T cell responses,» Front Immunol. 2024, 15 (Sec. Viral Immunology). doi: https://doi.org/10.3389/fimmu.2024.1412873
• «Of note, we observed no significant diference in T cell reactivity against the Delta and Omicron spike MP in those with an Omicron infection, nor in T cell reactivity against the Omicron spike in the diferent donor groups, suggesting that immune imprinting from vaccination may had dampened the induction of Omicron-specific T cells after infection… Taken together, these findings suggest that deployment of Omicron-based vaccines, or other highly divergent SARS- CoV-2 strains, in immune-naïve individuals may induce poorly cross-reactive antibody responses, while Omicron boosters in vaccinees may be of limited use due to the imprinted responses from the ancestral strain-based vaccines.» - Belik M et al., «Long-term COVID-19 vaccine- and Omicron infection-induced humoral and cell-
mediated immunity,» Front. Immunol. 2024, 15 (Sec. Viral Immunology). doi:
https://doi.org/10.3389/fimmu.2024.1494432
• «Interestingly, the bivalent vaccine induced equally high neutralizing antibodies against D614G as the monovalent vaccine, and repeated vaccinations with the original Wuhan-type monovalent vaccine or booster vaccination with a bivalent BA.1 or BA.4/5 vaccine did not broaden the specificity of neutralizing antibodies against XBB.1.5. These results indicate that the vaccines elicit antibody responses based on immune imprinting and the repeated Omicron exposure does not override ancestral SARS-CoV-2 immune imprinting.» - Blankson JN, «Bivalent COVID-19 Vaccines: Can the Original Antigenic Sin Be Forgiven?» J. Infect.
Dis. 2023, 11, 1: 1221-1223. doi: https://doi.org/10.1093/infdis/jiad073
• «… the lack of a more potent response to BA.5 following bivalent vaccination in some cases may reflect the fact that we are looking at a primary immune response. If that is the case, then there is a chance that subsequent exposure to BA.5 spike protein, either by vaccination or natural infection, will lead to an improved response. Unfortunately, by the time 2 bivalent booster shots are given to a significant part of the population—an unlikely prospect given the limited uptake of the bivalent vaccine and the vaccine weariness of the US population—the variant in question will probably no longer be the dominant variant in circulation.» - Boynton JR and DM Altmann, «Imprinted hybrid immunity against XBB reinfection,» Lancet Infect
Dis. 2023, 23, 7: 764-765. doi: 10.1016/S1473-3099(23)00138-X
• «If we now appreciate that even hybrid immunity to SARS-CoV-2 infection is (di3erentially, depending on previous immune experience) poorly durable and annual debates on booster strategy are required, how should we move forward? The dataset from Singapore reminds us that suggesting the booster strategy will simply involve tweaking vaccines annually, as for influenza, seriously underestimates the complexity of the current challenge. The long-term strategy will require considerable efort towards the development of both next-generation vaccines (targeting neutralising epitopes that are truly conserved and disadvantageous for viral mutations) and vaccine platforms that provide durable, local protection in the nasal mucosa, thereby blocking viral transmission.» - Brown E and HT Essigmann, «Original Antigenic Sin: the Downside of Immunological Memory and
Implications for COVID-19,» mSphere 2021, 6, 2. doi: https://doi.org/10.1128/msphere.00056-21
• «The impact of OAS on the elicitation of protective immunity should not be ignored in vaccine development. Selection of a vaccine candidate or candidates that are too similar to antigens already ‘seen’ by the population at large could result in three distinct outcomes: (i) a «back- boost» or enhanced protective immunity resulting from a second round of GCRs in response to shared antigens between primary and secondary exposures, (ii) boosting of a nonprotective antibody response, or (iii) in the context of a multicomponent vaccine formulation, the masking of a protective response against some vaccine components if other antigens in the formulation have been previously «seen» by the population as observed with Gardasil 9.» - Cao Y et al., «BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection,» Nature 2022, 608, 593-602. doi: https://doi.org/10.1038/s41586-022-04980-y
• «Of note, BA.2.12.1 and BA.4/BA.5 display increased evasion of neutralizing antibodies compared with BA.2 against plasma from triple-vaccinated individuals or from individuals who developed a BA.1 infection after vaccination… BA.1 infection after vaccination predominantly recalls humoral immune memory directed against ancestral… SARS-CoV-2 spike protein.» - Cao Y et al., «Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution,» Nature 2023, 614: 521–529. doi: https://doi.org/10.1038/s41586-022-05644-7 • «In this work, we showed that due to immune imprinting, our humoral immune repertoire is not efectively diversified by infection with new Omicron variants. The immune pressure on the RBD becomes increasingly concentrated and promotes convergent evolution, explaining the observed sudden acceleration of SARS-CoV-2 RBD evolution and the convergence pattern. Although this study only examines inactivated vaccines, immune imprinting is also observed in those receiving mRNA vaccines.»
- Carreño JM et al., «Bivalent COVID-19 booster vaccines and the absence of BA.5-specific
antibodies,» Lancet Microbe 2023, 4, 8: E569. doi: 10.1016/S2666-5247(23)00118-0
• «Pre-booster and post-booster RBD antibody avidity was lower against BA.5 RBD than wild-type RBD, which prompted us to look for BA.5 specific antibodies. Wild-type RBD depleted serum samples had undetectable reactivity to wild-type RBD—as expected—and to BA.5 RBD, suggesting that a single exposure to BA.5 antigens by the administration of bivalent vaccine boosters does not elicit robust concentrations of BA.5 specific serum antibodies.» - Chalkias S et al., «A Bivalent Omicron-Containing Booster Vaccine against Covid-19,» N Eng J Med
2022, 387: 1279-1291. doi: 10.1056/NEJMoa2208343
• «In the primary analysis set of participants without evidence of previous SARS-CoV-2 infection, the observed geometric mean titers of neutralizing antibodies against ancestral SARS-CoV-2 (D614G) were 5977.3 (95% confidence interval [CI], 5321.9 to 6713.3) and 5649.3 (95% CI, 5056.8 to 6311.2) and against omicron were 2372.4 (95% CI, 2070.6 to 2718.2) and 1473.5 (95% CI, 1270.8 to 1708.4) 28 days after the mRNA-1273.214 and mRNA-1273 boosters, respectively.» - Chemaitelly H et al., «2332. COVID-19 Primary Series and Booster Vaccination and Potential for
Immune Imprinting,» Open Forum Infect. Dis. 2023, 10 (Issue Supplement_2): ofad500.1954. doi:
https://doi.org/10.1093/ofid/ofad500.1954
• «History of primary-series vaccination enhanced immune protection against omicron reinfection, but history of booster vaccination compromised protection against omicron reinfection.» - Chemaitelly H et al., «Long-term COVID-19 booster efectiveness by infection history and clinical
vulnerability and immune imprinting: a retrospective population-based cohort study,» Lancet Infect
Dis. 2023, 23, 7: 816-827. doi: 10.1016/S1473-3099(23)00058-0
• «Protection against omicron infection waned after the booster, and eventually suggested a possibility for negative immune imprinting.» - Chen JJ et al., «Neutralization against XBB.1 and XBB.1.5 after omicron subvariants breakthrough
infection or reinfection,» Lancet Reg Health West Pac. 2023, 33: 100759.
doi: 10.1016/j.lanwpc.2023.100759
• «In all six groups, neutralization titers were lower against all omicron subvariants than against the D614G strain; the level of neutralizing antibodies was lowest against the XBB.1, followed by XBB.1.5… In addition, significantly enhanced neutralizing activity against all omicron subvariants was observed after BA.5.2 reinfection.» - Chen SY et al., «The Efectiveness of Bivalent COVID-19 Vaccination: A Preliminary Report,» Life
2023, 13, 10: 2094. doi: https://doi.org/10.3390/life13102094
• «Therefore, the human immune system elicits more robust immunity against the initial strain following a booster with an MV or BV. This ‘first love phenomenon’ may explain why the induced immunogenicity against BA.5 is not promising in people who receive a BA.5-containing booster. Our study also demonstrates much higher levels of immunogenicity against ancestral strains than new additional variant strains across enrolled studies.» - Cho A et al., «Anti-SARS-CoV-2 receptor-binding domain antibody evolution after mRNA
vaccination,» Nature 2021, 600: 517-522. doi: https://doi.org/10.1038/s41586-021-04060-7
• «Between prime and boost, memory B cells produce antibodies that evolve increased neutralizing activity, but there is no further increase in potency or breadth thereafter. Instead, memory B cells that emerge five months after vaccination of naive individuals express antibodies that are similar to those that dominate the initial response.» - Collier ARY et al. «Immunogenicity of BA.5 Bivalent mRNA Vaccine Boosters,» N Engl J Med 2023,
388, 6: 565-567. doi: 10.1056/NEJMc2213948
• «Our data indicate that both monovalent and bivalent mRNA boosters markedly increased antibody responses but did not substantially augment T-cell responses. Neutralizing antibody titers against the ancestral strain of SARS-CoV-2 were higher than titers against BA.5 after both monovalent and bivalent boosting… Our findings suggest that immune imprinting by previous antigenic exposure may pose a greater challenge than is currently appreciated for inducing robust immunity against SARS-CoV-2 variants.» - Corbett KS et al., «Protection against SARS-CoV-2 Beta variant in mRNA-1273 vaccine–boosted
nonhuman primates,» Science 2021, 374, 6573: 1343-1353. doi: 10.1126/science.abl8912
• «The relative frequency of B cells specific for WA-1, β, or both did not change after boost with either the homologous or heterologous mRNA, suggesting that priming with mRNA-1273 imprinted the B cell repertoire.» - Cui T et al., «Dynamic immune landscape in vaccinated-BA.5-XBB.1.9.1 reinfections revealed a 5-
month protection-duration against XBB infection and a shift in immune imprinting,» eBioMedicine
2024, 99: 104903. doi: 10.1016/j.ebiom.2023.104903
• «… XBB.1.9.1 reinfection results in immune imprinting shifting from WT antigen induced by previous vaccination to the new XBB.1.9.1 antigen.» - da Silva ES et al., «Vaccine- and Breakthrough Infection-Elicited Pre-Omicron Immunity More
Efectively Neutralizes Omicron BA.1, BA.2, BA.4 and BA.5 Than Pre-Omicron Infection Alone,» Curr
Issues Mol Biol. 2023, 45, 2: 1741-1761. doi: 10.3390/cimb45020112
• «… immune imprinting by first generation vaccines may restrict, but not abolish, cross- neutralization.» - Davis-Gardner ME et al., «Neutralization against BA.2.75.2, BQ.1.1, and XBB from mRNA Bivalent
Booster,» N Engl J Med 2022, 388, 2: 183-185. doi: 10.1056/NEJMc2214293
• «The results in both of these cohorts correspond with neutralization titers against BA.1 and BA.5 that were 5 to 9 times as low as that against WA1/2020 and neutralization titers against BA.2.75.2, BQ.1.1, and XBB that were 23 to 63 times as low as that against WA1/2020.» - Degryse J et al., «Antigenic Imprinting Dominates Humoral Responses to New Variants of SARS-
CoV-2 in a Hamster Model of COVID-19,» Microorganisms 2024, 12, 12: 2591.
doi: https://doi.org/10.3390/microorganisms12122591
• «Our results show that both Comirnaty® XBB.1.5 and YF-S0* induce robust, however, poorly cross-reactive, neutralizing antibody (nAb) responses. In either case, total antibody and nAb levels increased following infection. Intriguingly, the specificity of these boosted nAbs did not match the respective challenge virus, but was skewed towards the primary antigen used for immunization, suggesting a marked impact of antigenic imprinting, confirmed by antigenic cartography… our findings strongly suggest that antigenic imprinting by previous encounter (in this case, by vaccination) dominates the subsequent humoral response to new SARS-CoV-2 variants.» - Delgado JF et al., «SARS-CoV-2 Spike Protein Vaccine-Induced Immune Imprinting Reduces
Nucleocapsid Protein Antibody Response in SARS-CoV-2 Infection,» J. Immunol. Res. 2022. doi:
https://doi.org/10.1155/2022/8287087
• «SARS-CoV-2 primary infection in vaccinated healthcare workers (HCWs) produced significantly lower titers of anti-N antibodies than that in nonvaccinated HCWs: 5.7 (IQR 2.3-15.2) versus 12.2 (IQR 4.2-32.0), respectively (p = 0.005). Therefore, spike protein vaccine-induced immune imprinting (original antigenic sin) reduces N protein antibody response.» - Dowell AC et al., «Immunological imprinting of humoral immunity to SARS-CoV-2 in children,» Nat.
Commun. 2023, 14: 3845. doi: https://doi.org/10.1038/s41467-023-39575-2
• «Prior pre-Omicron SARS-CoV-2 virus infection or vaccination primes for robust antibody responses following Omicron infection but these remain primarily focussed against ancestral variants.» - Edara VV et al., «mRNA-1273 and BNT162b2 mRNA vaccines have reduced neutralizing activity
against the SARS-CoV-2 omicron variant,» Cell Rep Med. 2022, 3, 2: 100529.
doi: 10.1016/j.xcrm.2022.100529
• «Six months after the initial two-vaccine doses, sera from naive vaccinated subjects show no neutralizing activity against omicron. In contrast, COVID-19-recovered individuals 6 months after receiving the primary series of vaccinations show a 22-fold reduction, with the majority of the subjects retaining neutralizing antibody responses.» - Einhauser S et al., «Longitudinal efects of SARS-CoV-2 breakthrough infection on imprinting of
neutralizing antibody responses,» eBioMedicine 2024, 110: 105438. doi:
10.1016/j.ebiom.2024.105438
• «Notably, the longitudinal analysis reveals an initial augmentation of the vaccine-primed nAb response upon infection, followed by a progressive expansion of neutralization capacity towards the infecting SARS-CoV-2 variant. Long-term observation reveals a subsequent contraction and inclination towards dominant wild-type (WT) immunity post-breakthrough infection.» - Erice A et al., «Long-Term Analyses of SARS-CoV-2 Humoral and T Cell Responses and
Breakthrough SARS-CoV-2 Infections after Two Doses of BNT162b2 Followed by mRNA-1273 and
Bivalent Omicron-Adapted BNT162b2 Vaccines: A Prospective Study over 2 Years in Non-
Immunocompromised Individuals,» Vaccines 2023, 11, 12: 1835.
doi: https://doi.org/10.3390/vaccines11121835
• «In healthy adults who received two doses of BNT162b2 followed by a booster of mRNA-273 and the bivalent Omicron-adapted BNT162b2 over a 26-month period, the evolution of anti-RBD antibodies suggests modulation of the immune response through immune imprinting.» - Faraone JN and SL Liu, «Immune imprinting as a barrier to efective COVID-19 vaccines,» Cell Rep
Med. 2023, 4, 11: 101291. doi: 10.1016/j.xcrm.2023.101291
• «Imprinting from three doses of monovalent vaccine can be alleviated by BA.5 or BQ-lineage breakthrough infection but not by a bivalent booster.» - Faraone JN et al., «Immune evasion and membrane fusion of SARS-CoV-2 XBB subvariants EG.5.1
and XBB.2.3,» Emerg Microbes Infect 2023, 12, 2: 2270069. doi:
https://doi.org/10.1080/22221751.2023.2270069
• «Bivalent vaccination-induced antibodies neutralized ancestral D614G eficiently, but to a much less extent, two new EG.5.1 and XBB.2.3 variants. In fact, the enhanced neutralization escape of EG.5.1 appeared to be driven by its key defining mutation XBB.1.5-F456L.» - Fujita S et al., «Impact of Imprinted Immunity Induced by mRNA Vaccination in an Experimental
Animal Model,» J Infect Dis. 2023, 228, 8: 1060-1065. doi: https://doi.org/10.1093/infdis/jiad230
• «The concept of ‘imprinted immunity’ suggests that individuals vaccinated with ancestral virus- based vaccines may not develop efective immunity against newly emerging Omicron subvariants, such as BQ.1.1 and XBB.1. In this study, we investigated this possibility using hamsters. Although natural infection induced efective antiviral immunity, breakthrough infections in hamsters with BQ.1.1 and XBB.1 Omicron subvariants after receiving the 3-dose mRNA-lipid nanoparticle vaccine resulted in only faintly induced humoral immunity, supporting the possibility of imprinted immunity.» - Gagne M et al., «mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits similar B cell
expansion, neutralizing responses, and protection from Omicron,» Cell 2022, 185, 9: P1556-
1571.E18. doi: 10.1016/j.cell.2022.03.038
• «The observation that boosting with either mRNA-1273 or mRNA-Omicron resulted in the expansion of a similarly high frequency of cross-reactive B cells likely stems from the recall of prior immune memory after a related antigenic encounter. This principle has been termed original antigenic sin, imprinting, and back boosting… As we have now shown in two di3erent NHP studies, boosting animals with either mRNA-Beta or mRNA-Omicron has not yet been shown to provide any significant advantage over mRNA-1273 in recalling high titer neutralizing antibodies across all variants tested in the short term and protecting from virus replication after challenge. These considerations may apply to the large numbers of individuals with prior immunity from vaccination or infection with current and previous variants.» - Gao B et al., «Repeated vaccination of inactivated SARS-CoV-2 vaccine dampens neutralizing
antibodies against Omicron variants in breakthrough infection,» Cell Res. 2023, 33: 258-261. doi:
https://doi.org/10.1038/s41422-023-00781-8
• «Strikingly, we found that although nAb titers against SARS-CoV-2 were comparable between the 2-dose and the 3-dose groups of patients with BA.2 breakthrough infection, nAb titers against the Omicron BA.2, BA.4 and BA.5 variants were significantly lower in the 3-dose group. Our data suggest that repeated vaccination with inactivated virus vaccine back-boosts previous memory and dampens the immune response to a new antigenically related but distinct viral strain. Such vaccination-induced immune imprint could reflect the ‘original antigenic sin’ doctrine…» - Garcia-Beltran WF et al., «Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity,» Cell 2021, 184, 9: P2372-2383.E9. doi: 10.1016/j.cell.2021.03.013
• «Strikingly, neutralization of all three South African B.1.351 strains was substantially decreased for both two-dose vaccines (v1: 34.5-fold for BNT162b2 and 27.7-fold for mRNA-1273; v2: 41.2- fold for BNT162b2 and 20.8-fold for mRNA-1273; v3: 42.4-fold for BNT162b2 and 19.2-fold for mRNA-1273; p < 0.0001 for all comparisons). These strains contain the same three RBD mutations as P.1 except for an asparagine versus threonine substitution at K417 (K417N) and several additional mutations in non-RBD regions… Notably, 36.7% (11/30) recipients of two-dose BNT162b2 and 42.9% (15/35) recipients of two-dose mRNA-1273 vaccines did not have detectable neutralization of at least one of the B.1.351 variants.» - Germanio CD et al., «Spike and nucleocapsid antibody dynamics following SARS-CoV-2 infection
and vaccination: Implications for sourcing COVID-19 convalescent plasma from routinely collected
blood donations,» Transfusion 2024, 64, 11: 2063-2074. doi: https://doi.org/10.1111/trf.18017
• «In our study, seroreactivity for variant-specific bAb (MSD) and nAb (RVPN) assays to omicron variant S proteins was lower than the other variants in all the donor groups, including among VI cases during the omicron wave. Since all these donors were vaccinated during 2020–2021 when Moderna, Pfizer-BioNTech, or Janssen monovalent vaccines based on the ancestral virus S RNA/protein were administered, this phenomenon may be a result of ‘immune imprinting’. Studies have shown that the first encounter with SARS-CoV-2 S protein, by either vaccination or infection, establishes immunologic memory to the corresponding S antigenic determinants, which impacts capacity for responses to SARS-CoV-2 variant S antigens during subsequent infections.» - Gong X et al., «Repeated Omicron infection dampens immune imprinting from previous vaccination and induces broad neutralizing antibodies against Omicron sub-variants,» J. Infect. 2024, 89, 2:
- doi: 10.1016/j.jinf.2024.106208 • «Neutralizing potency against the corresponding infected variant is significantly hampered along with the doses of vaccination during first infection… Breakthrough infection with BA.1 predominantly recalls humoral immune memory against the WT SARS-CoV-2 spike protein and elicited non-neutralizing antibodies, and repeated vaccination of inactivated SARS-CoV-2 vaccine dampens neutralizing antibodies against Omicron variants in breakthrough infection.»
- Gruell H et al., «mRNA booster immunization elicits potent neutralizing serum activity against the
SARS-CoV-2 Omicron variant,» Nat. Med. 2022, 28: 477-480. doi: https://doi.org/10.1038/s41591-
021-01676-0
• «We report a near-complete lack of neutralizing activity against Omicron in polyclonal sera from individuals vaccinated with two doses of the BNT162b2 COVID-19 vaccine and from convalescent individuals, as well as resistance to di3erent monoclonal antibodies in clinical use. However, mRNA booster immunizations in vaccinated and convalescent individuals resulted in a significant increase of serum neutralizing activity against Omicron.» - Haralambieva IH et al., «Restricted Omicron-specific cross-variant memory B-cell immunity after a
3rd dose/booster of monovalent Wuhan-Hu-1-containing COVID-19 mRNA vaccine,» Vaccine 2024,
42, 4: 912-917. doi: https://doi.org/10.1016/j.vaccine.2024.01.032
• «… we observed significantly lower frequencies of MBCs reactive to the receptor-binding domain/RBD, the N-terminal domain/NTD, and the S1 of Omicron/BA.1, compared to Wuhan and Delta, even after a 3rd vaccine dose/booster. Our study is a proof of concept that MBC cross-reactivity to variants with greater sequence divergence from the vaccine strain may be overestimated and suggests that these variants may exhibit immune escape with reduced recognition by circulating pre-existing MBCs upon infection.» - Hofman M et al., «efect of hybrid immunity and bivalent booster vaccination on omicron sublineage neutralization,» Lancet Infect Dis. 2023, 23, 1: 25-28. doi: 10.1016/S1473- 3099(22)00792-7
• «Collectively, our results show that the emerging omicron sublineages BQ.1.1 and particularly BA.2.75.2 eficiently evade neutralisation independent of the immunisation history. Although monovalent and bivalent vaccine boosters both induce high neutralising activity and increase neutralisation breadth, BA.2.75.2-specific and BQ.1.1-specific neutralisation activity remained relatively low. This finding is in keeping with the concept of immune imprinting by initial immunisation with vaccines targeting the ancestral SARS-CoV-2 B.1 lineage. Furthermore, the observation that neutralisation of BA.2.75.2pp and BQ.1.1pp was most eficient in the cohort that had a breakthrough infection during the BA.1 and BA.2 wave and later received a bivalent booster vaccination, but was still less eficient than neutralisation of B.1pp, implies that a3inity maturation of antibodies and two-time stimulation with di3erent omicron antigens might still not be su3icient to overcome immune imprinting.» - Hofman M et al., «Profound neutralization evasion and augmented host cell entry are hallmarks of the fast-spreading SARS-CoV-2 lineage XBB.1.5,» Cel Mol Immunol 2023, 20, 419-422. doi:
https://doi.org/10.1038/s41423-023-00988-0
• «Finally, we investigated the neutralization sensitivity of XBB.1.5pp to antibodies induced by vaccination with or without breakthrough infection (BTI). For this, we utilized plasma from triple- vaccinated individuals that experienced a BTI during the BA.5 wave in Germany, and plasma from quadruple-vaccinated individuals that received a monovalent or bivalent mRNA-vaccine booster as fourth vaccination. All tested plasma showed high neutralizing activity against B.1pp, while neutralizing activity against BA.4-5pp and BQ.1.1pp was moderately (BA.4-5pp: 2.3–7.2-fold reduced compared to B.1pp) or strongly (BQ.1.1pp: 6.4–19.9-fold reduced compared to B.1pp) reduced, as expected. In line with published results, neutralizing activity against XBB.1pp was even further reduced compared to BA.4-5pp and BQ.1.1pp (XBB.1pp: 22.5–38.2-fold reduced compared to B.1pp), and neutralizing activity against XBB.1.5pp was comparable to that of XBB.1pp (XBB.1pp: 23.7–35.9-fold reduced compared to B.1pp).» - Hornsby H et al., «Omicron infection following vaccination enhances a broad spectrum of immune
responses dependent on infection history,» Nat. Commun. 2023, 14: 56. doi:
https://doi.org/10.1038/s41467-023-40592-4
• «These ‘previously-infected’ individuals have higher spike-specific serum antibody and T-cell responses after each vaccine dose compared to infection-naive vaccinees. Hybrid immunity generated by post-vaccination infections may be quantitatively and qualitatively di3erent from responses seen in individuals who experienced SARS-CoV-2 infection before receiving a vaccination course. This may be due to di3erences in the priming SARS-CoV-2 exposure or lower antigenic exposure during the attenuated disease course of omicron viruses; although it is di3icult to tease apart the contributions of viral phenotype change from those of pre-existing immunity.» - Jia T et al., «Expanded immune imprinting and neutralization spectrum by hybrid immunization
following breakthrough infections with SARS-CoV-2 variants after three-dose vaccination,» J. Infect.
2024, 89, 6: 106362. doi: https://doi.org/10.1016/j.jinf.2024.106362
• «Following Omicron breakthrough infections, the levels of nAbs against WT and pre-Omicron VOCs were higher due to immune imprinting established by WT-based vaccination, in comparison to nAbs against Omicron variants.» - Johnston TS et al., «Immunological imprinting shapes the specificity of human antibody responses
against SARS-CoV-2 variants,» Immunity 2024, 57, 4: P912-925.E4. doi:
10.1016/j.immuni.2024.02.017
• «We determined the specificity and functionality of antibody and B cell responses following exposure to BA.5 and XBB variants in individuals who received ancestral SARS-CoV-2 mRNA vaccines. BA.5 exposures elicited antibody responses that targeted epitopes conserved between the BA.5 and ancestral spike. XBB exposures also elicited antibody responses that primarily targeted epitopes conserved between the XBB.1.5 and ancestral spike.» - Ju B et al., «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,» Nat. Commun. 2022, 13: 7120.
https://doi.org/10.1038/s41467-022-34400-8
• «Compared with the neutralizing antibody titers against BA.2, marked reductions are observed against BA.2.75 in both 2-dose and 3-dose vaccine groups. In addition, although BA.2 breakthrough infections induce a certain cross-neutralization capacity against later Omicron subvariants, the original antigenic sin phenomenon largely limits the improvement of variant- specific antibody response. These findings suggest that BA.2 breakthrough infections seem unable to provide su3icient antibody protection against later subvariants such as BA.2.75 in the current immunization background with wild-type vaccines.» - Ju B et al., «Striking antibody evasion of SARS-CoV-2 Omicron sub-lineages BQ.1.1, XBB.1 and
CH.1.1,» Natl. Sci. Rev. 2023, 10, 8: nwad148. doi: https://doi.org/10.1093/nsr/nwad148
• «Overall, due to the original antigenic sin (or so-called immune imprinting) of the initial WT vaccination, these plasma samples from BA.4 or BA.5 breakthrough infected individuals acquired weaker neutralization against subsequent Omicron sub-lineages, such as BQ.1.1, XBB.1 and CH.1.1.» - Kaku CI et al., «Evolution of antibody immunity following Omicron BA.1 breakthrough infection,»
Nat. Commun. 2023, 14: 2751. doi: https://doi.org/10.1038/s41467-023-38345-4
• «While the acute B cell response following BA.1 breakthrough infection was dominated by vaccine-induced cross-reactive clones that exhibited preferential WT binding and neutralization, antibodies isolated from the same donors 5 to 6 months post-infection accumulated additional somatic mutations and displayed enhanced BA.1 recognition at the expense of WT binding… De novo BA.1-specific B cell responses only comprised a small fraction of the total RBD-directed response at both time points studied.» - Kaku CI et al., «Recall of preexisting cross-reactive B cell memory after Omicron BA.1 breakthrough
infection,» Sci. Immunol. 2022, 7, 73. doi: 10.1126/sciimmunol.abq3511
• «BA.1 breakthrough infection donors exhibited similar (within twofold) serum IgG binding titers to BA.1 and WT S and RBD. In contrast, uninfected/mRNA-vaccinated donors displayed a two- to fourfold and four- to ninefold reduced serum IgG binding to full-length BA.1 S and BA.1 RBD, respectively, relative to WT.» - Kaplonek P et al., «Hybrid immunity expands the functional humoral footprint of both mRNA and
vector-based SARS-CoV-2 vaccines,» Cell Rep Med. 2023, 4, 5: 101048. doi:
10.1016/j.xcrm.2023.101048
• «However, hybrid immunity shows a unique augmentation of S2-domain-specific functional immunity that was poorly induced for the vaccination only. These data highlight the importance of natural infection in breaking the immunodominance away from the evolutionarily unstable S1 domain and potentially a3ording enhanced cross-variant protection by targeting the more highly conserved S2 domain of SARS-CoV-2.» - Kim W, «Germinal Center Response to mRNA Vaccination and Impact of Immunological Imprinting
on Subsequent Vaccination,» Immune Netw. 2024, 24, 4: e28.
doi: https://doi.org/10.4110/in.2024.24.e28
• «The immunological imprinting induced by ancestral spike-based vaccination was also reflected in serological responses, which are outcomes of B cell responses to subsequent exposures. Individuals who have received two doses of primary vaccination and encountered omicron infection still exhibit low levels of omicron-specific Ab responses.» - King SM et al., «First Impressions Matter: Immune Imprinting and Antibody Cross-Reactivity in
Influenza and SARS-CoV-2,» Pathogens 2023, 12, 2: 169. doi:
https://doi.org/10.3390/pathogens12020169
• «This issue may already be playing out with the SARS-CoV-2 bivalent vaccines produced by Pfizer-BNT and Moderna. The first bivalent boosters contained mRNA designed to elicit immunity against the original WA1/2020 SARS-CoV-2 strain, present in the previous monovalent boosters, as well as the then newly emergent BA.1 strain. The results of these were disappointing, with only modest increases in anti-BA.1 neutralizing antibodies. As BA.1 was no longer circulating in the United States, the United States Food and Drug Administration approved new bivalent boosters directed against the now dominant circulating variants BA.4 and BA.5. Results emerging from very recent studies suggest limited boosts in antibody levels with modest protection against target strains, with minimal increases in BA.4 and BA.5 protection from the WA1/2020 and BA.1 boosters. These results are thought to be due to immune imprinting from multiple rounds of the prior WU1/2020 monovalent vaccine series.» - Kurhade C et al., «Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1 and XBB.1 by
parental mRNA vaccine or a BA.5 bivalent booster,» Nat. Med. 2023, 29: 344-347, doi:
https://doi.org/10.1038/s41591-022-02162-x
• «The results showed that a BA.5 bivalent booster elicited a high neutralizing titer against BA.4/5 measured at 14–32 days after boost; however, the BA.5 bivalent booster did not produce robust neutralization against the newly emerged BA.2.75.2, BQ.1.1 or XBB.1. Previous infection substantially enhanced the magnitude and breadth of BA.5 bivalent booster-elicited neutralization.» - Lasrado N et al., «Waning immunity and IgG4 responses following bivalent mRNA boosting,» Sci.
Adv. 2024, 10, 8. doi: 10.1126/sciadv.adj9945
• «Here, we show limited durability of neutralizing antibody (NAb) responses against XBB variants and isotype switching to immunoglobulin G4 (IgG4) responses following bivalent mRNA boosting. Bivalent mRNA boosting elicited modest XBB.1-, XBB.1.5-, and XBB.1.16-specific NAbs that waned rapidly within 3 months. In contrast, bivalent mRNA boosting induced more robust and sustained NAbs against the ancestral WA1/2020 strain, suggesting immune imprinting.» - Lee WS et al., «Durable reprogramming of neutralizing antibody responses following Omicron
breakthrough infection,» Sci. Adv. 2023, 9, 29. doi: DOI: 10.1126/sciadv.adg5301
• «We show that only cross-reactive memory B cells were expanded by breakthrough infection, and the resulting antibody response was dominated by antibodies cross-reactive with ancestral spike, indicating that limited de novo responses were generated against neo-epitopes within BA.1 or BA.2 spike. In line with recent studies, our results are suggestive of immune imprinting, with no evident increase in BA.1 or BA.2 monospecific B cells even up to 4 to 7 months after infection… While the isolation of receptor binding domain (RBD)–specific monoclonal antibodies (mAbs) specific for the BA.1 RBD that do not cross-react with ancestral RBD has been reported, these comprised only a small fraction (median, 4%) of the response to RBD, confirming that neo- epitopes are poorly recognized during breakthrough infection. Immune imprinting is not constrained to breakthrough infections, as monovalent Omicron BA.1 or bivalent Beta/Delta mRNA vaccines also predominantly boost preexisting cross-reactive responses.» - Liang CY et al., «Imprinting of serum neutralizing antibodies by Wuhan-1 mRNA vaccines,» Nature
2024, 630: 950-960. doi: https://doi.org/10.1038/s41586-024-07539-1
• «Because serum neutralizing responses against Omicron strains and other sabercoronaviruses were abrogated after pre-clearing with Wuhan-1 spike protein, antibodies induced by XBB.1.5 boosting in humans focus on conserved epitopes targeted by the antecedent mRNA-1273 primary series.» - Liu S et al., «Sera from breakthrough infections with SARS-CoV-2 BA.5 or BF.7 showed lower
neutralization activity against XBB.1.5 and CH.1.1,» Emerg Microb Infect 2023, 12, 2: 2225638. doi:
https://doi.org/10.1080/22221751.2023.2225638
• «The level of neutralizing antibody against the wild strain is the highest which may be attributed to the imprinted original immune responses against the prototype vaccine strain. » 63. Madhi SA et al., «eficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant,» N Engl J Med 2021, 384, 20: 1885-1898. doi: 10.1056/NEJMoa2102214
• «Six of 13 vaccine recipients (46%) without evidence of previous SARS-CoV-2 infection showed no neutralization activity against an RBD triple-mutant pseudovirus (containing K417N, E484K, and N501Y variants), and 11 of the 13 (85%) had no neutralization activity against B.1.351 pseudovirus. Geometric mean titers dropped from 297 against the original virus to 85 against the RBD-only mutant and 74 against the B.1.351 variant.» - Maltseva M et al., «Immune imprinting: The persisting influence of the first antigenic encounter with
rapidly evolving viruses,» Hum Vaccin Immunother 2024, 20, 1: 2384192. doi:
https://doi.org/10.1080/21645515.2024.2384192
• «Breakthrough infections with the Alpha or Delta variants resulted in a greater increase in antibody titers against the ancestral strain compared to the VOC strain in individuals vaccinated with three doses of ancestral mRNA-LNP, highlighting the efects of immune imprinting… eforts to enhance vaccine eficacy by updating vaccines have led to improved VOC neutralization. However, individuals previously vaccinated with the ancestral mRNA vaccines showed dominant recall antibody responses following monovalent Beta or Delta boosters, or bivalent ancestral and Beta/Delta boosters… Omicron breakthrough infections pre-dominantly promoted recall responses, leading to reduced neutralization of Omicron variants.» - Marcotte H et al., «Limited cross-variant neutralization after primary Omicron infection:
consideration for a variant-containing booster,» Signal Transduct Target Ther 2022, 7: 294. doi:
https://doi.org/10.1038/s41392-022-01146-0
• «The plasma of individuals receiving three doses of mRNA vaccines or a combination of inactivated and mRNA vaccines were shown to neutralize BA.1 but with titers 32-fold lower compared to the wild-type strain. Furthermore, two recent studies showed that sera from individuals who received three doses of vaccines (Pfizer, AstraZeneca, or CoronaVac) and from vaccinated individuals with BA.1 breakthrough infection have a reduced ability to neutralize BA.4, BA.5, and BA.2.12.1 compared with BA.1 and BA.2 due to RBD mutations involving L452R and F486V (BA.4/5) and L452Q (BA.2.12.1). They found that BA.1 Omicron breakthrough infections mainly reactivate WT-induced memory B cells, reducing the diversity of antibodies, and possibly facilitating the emergence of new mutants.» - Marzi R et al., «Maturation of SARS-CoV-2 Spike-specific memory B cells drives resilience to viral
escape,» iScience 2023, 26, 1: 105726. doi: 10.1016/j.isci.2022.105726
• «Whereas MBCs of infected individuals targeted both prefusion and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion- stabilized S in mRNA vaccines.» - Medits I et al., «Di3erent Neutralization Profiles After Primary SARS-CoV-2 Omicron BA.1 and BA.2
Infections,» Front. Immunol. 2022, 13 (Sec. Vaccines and Molecular Therapeutics). doi:
https://doi.org/10.3389/fimmu.2022.946318
• «Serum neutralization of Omicron BA.1 and BA.2 variants was detectable after three-dose mRNA vaccinations, but with reduced titers. Vaccination-breakthrough infections with either Omicron BA.1 or BA.2, however, generated equal cross-neutralizing antibody levels against all SARS-CoV-2 variants tested.» - Milne G et al., «Does infection with or vaccination against SARS-CoV-2 lead to lasting immunity?»
Lancet Respir Med 2021, 9, 12: 1450-1466. doi: 10.1016/S2213-2600(21)00407-0
• «Upon natural infection, the T-cell-mediated response appears to be targeted across a larger variety of epitopes than the humoral response, and hence might be more durable to genetic changes in key immunogenic viral epitopes. Nonetheless, the neutralising antibody response also comprises a key aspect of protection against reinfection… Compared with the immune response to natural infection, vaccination elicits a response of greater magnitude and higher specificity, largely focused on the RBD. Increasing evidence of reduced neutralisation and vaccine efectiveness against emerging variants, alongside emerging data on breakthrough infections, suggests that vaccines will need to be updated in the short-to-medium term.» - Moreno A et al., «Divergence of variant antibodies following SARS-CoV-2 booster vaccines in
myeloma and impact of hybrid immunity,» npj Vaccines 2024, 9: 201. doi:
https://doi.org/10.1038/s41541-024-00999-6
• «It has been suggested that immune imprinting provided by prior infection or SARS-CoV-2 vaccination negatively impacts vaccine immunogenicity of booster immunizations. Consistent with this, we observed preferential boosting of nAb against the ancestral WA1 strain following booster immunization.» - Mueksche F et al., «Increased memory B cell potency and breadth after a SARS-CoV-2 mRNA
boost,» Nature 2022, 607: 128-134. doi: https://doi.org/10.1038/s41586-022-04778-y
• «Consistent with prior reports, the third vaccine dose significantly boosted geometric mean NT50 values by 16-fold, 12-fold and 37-fold for the Beta, Delta and Omicron BA.1 variants, respectively. The level of activity against the Beta and Delta variants was not significantly di3erent from that against Wuhan-Hu-1, whereas the activity against Omicron BA.1 was 16-fold lower than that against Wuhan-Hu-1 (P = 0.58, P = 0.24 and P = 0.0013, respectively)… given the correlation between neutralizing antibody levels and protection from Wuhan-Hu-1 infection, the reduced activity against Omicron BA.1 in recipients of a third dose of vaccine probably explains why vaccinated individuals remained particularly susceptible to infection by this variant.» - Muik A et al., «Immunity against conserved epitopes dominates after two consecutive exposures to
SARS-CoV-2 Omicron BA.1,» Cell Rep. 2024, 43, 8: 114567. doi: 10.1016/j.celrep.2024.114567
• «Upon exposure to the highly altered Omicron spike glycoprotein, pre-immunized individuals predominantly mount recall responses of Wuhan-Hu-1 (wild-type)-imprinted memory B (BMEM) cells mostly targeting conserved non-neutralizing epitopes, leading to diminished Omicron neutralization. We investigated the impact of imprinting in individuals double/triple vaccinated with a wild-type-strain-based mRNA vaccine who, thereafter, had two consecutive exposures to Omicron BA.1 spike (breakthrough infection followed by BA.1-adapted vaccine). We found that depletion of conserved epitope-recognizing antibodies using a wild-type spike bait results in strongly diminished BA.1 neutralization. Furthermore, spike-specific BMEM cells recognizing conserved epitopes are much more prevalent than BA.1-specific BMEM cells. Our observations suggest that imprinted BMEM cell recall responses limit the induction of strain-specific responses even after two consecutive BA.1 spike exposures. Vaccine adaptation strategies need to consider that prior SARS-CoV-2 infections and vaccinations may cause persistent immune imprinting.» - Muik A et al., «Progressive loss of conserved spike protein neutralizing antibody sites in Omicron
sublineages is balanced by preserved T cell immunity,» Cell Rep. 2023, 42, 8: 112888.
doi: 10.1016/j.celrep.2023.112888
• «We report that Omicron BA.4/BA.5 breakthrough infection of individuals immunized with SARS- CoV-2 wild-type-strain-based mRNA vaccines results in a boost of Omicron BA.4.6, BF.7, BQ.1.1, and BA.2.75 neutralization but does not eficiently boost BA.2.75.2, XBB, or XBB.1.5 neutralization. In silico analyses showed that the Omicron spike glycoprotein lost most neutralizing B cell epitopes, especially in sublineages BA.2.75.2, XBB, and XBB.1.5.» - Mykytyn AZ et al., «Antigenic mapping of emerging SARS-CoV-2 omicron variants BM.1.1.1, BQ.1.1,
and XBB.1,» Lancet Microbe 2023, 4, 5: E294-295. doi: 10.1016/S2666-5247(22)00384-6
• «Our data reveal substantial cross-neutralisation of BA.5 antiserum samples against BQ.1.1 but little cross-neutralisation against XBB.1 and BM.1.1.1. Despite the antigenic similarities between BA.5 and BQ.1.1, thus far there is little evidence for increased neutralisation of BQ.1.1 by BA.5 bivalent vaccines, potentially due to immunological imprinting.» - Norton NJ et al., «Characteristics of Vaccine- and Infection-Induced Systemic IgA Anti-SARS-CoV-2
Spike Responses,» Vaccines 2023, 11, 9: 1462. doi: https://doi.org/10.3390/vaccines11091462
• «As with circulating IgG responses, vaccination with an ancestral SARS-CoV-2 S antigen imposed immunological imprinting on IgA responses with preferred recognition of ancestral SARS-CoV-2 S protein over Omicron SARS-CoV-2 S protein persisting following Omicron breakthrough infection.» - Paciello I et al., «Antigenic sin and multiple breakthrough infections drive converging evolution of
COVID-19 neutralizing responses,» Cell Rep. 2024, 43, 9: 114645.
doi: 10.1016/j.celrep.2024.114645
• «In line with recent studies, our data revealed that while the initial antibody response was di3erent in vaccinated or infected people, breakthrough infections by a distantly related virus such as Omicron induced the expansion of previously unseen germ lines and, most important, rescued the B cell primed by the original antigenic sin.» - Pape KA et al., «High-a3inity memory B cells induced by SARS-CoV-2 infection produce more
plasmablasts and atypical memory B cells than those primed by mRNA vaccines,» Cell Rep. 2021,
37, 2: 109823. doi: 10.1016/j.celrep.2021.109823
• «However, infection-induced primary MBCs have better antigen-binding capacity and generate more plasmablasts and secondary MBCs of the classical and atypical subsets than do vaccine- induced primary MBCs. Our results suggest that infection-induced primary MBCs have undergone more a3inity maturation than vaccine-induced primary MBCs and produce more robust secondary responses.» - Park YJ et al., «Imprinted antibody responses against SARS-CoV-2 Omicron sublineages,» Science
2022, 387, 6620: 619-627. doi: 10.1126/science.adc9127
• «Park et al. found that either a vaccination booster or a breakthrough infection elicits neutralization activity against the Omicron variants, but only a breakthrough infection induces an antibody response in the nasal mucosa, which might give better protection against transmission.» - Paula NM et al., «Symptomatology and IgG Levels before and after SARS-CoV-2 Omicron
Breakthrough Infections in Vaccinated Individuals,» Vaccines 2024, 12, 10: 1149.
doi: https://doi.org/10.3390/vaccines12101149
• «The anti-N and anti-S IgG titers followed the expected pattern, with anti-S titers raised after a vaccination event, whereas both anti-S and anti-N levels increased after an infection event… [P]reexisting anti-S IgG levels correlate poorly with symptomatology during infections caused by Omicron variants. There was also no correlation between the COVID-19 symptoms and anti-S IgG titers after the infections. Quite surprisingly, COVID-19 symptoms correlated with anti-N IgG levels detected after the infection (Spearman r −0.55, p = 0.03). Thus, individuals with lower anti-N IgG levels after infection were the ones who experienced the most intense COVID-19 symptoms. This observation suggests that human anti-N IgG antibodies may play an important role in resolution of the disease.» - Pepkowitz SH et al., «Prior vaccination has changed the composition of the COVID-19 convalescent
plasma inventory,» Transfusion 2022, 62, 10: 2153-2154. doi: https://doi.org/10.1111/trf.17089
• «The lower IgG anti-nucleocapsid antibody, lower IgM anti-spike antibody, and higher IgG anti- RBD antibody present in post-breakthrough COVID-19 CCP are likely due to extensive a3inity maturation and a decreased presence of IgM memory-cells post-vaccination and to a component of ‘original antigenic sin’ in which the immune system is focused on producing those anti-spike antibodies previously developed in response to prior vaccination, while relatively ignoring additional newly presented viral immunogens.» - Pérez-Alós L et al., «Previous immunity shapes immune responses to SARS-CoV-2 booster
vaccination and Omicron breakthrough infection risk,» Nat. Commun. 2023, 14: 5624. doi:
https://doi.org/10.1038/s41467-023-41342-2
• «Our study shows that both humoral and cellular responses following vaccination were generally higher after SARS-CoV-2 infection compared to infection-naive. Notably, viral exposure before vaccination was crucial to achieving a robust IgA response. Individuals with lower IgG, IgA, and neutralizing antibody responses postvaccination had a significantly higher risk of reinfection and future Omicron infections.» - Petras M and IV Lesna, «SARS-CoV-2 vaccination in the context of original antigenic sin,» Hum
Vaccin Immunother. 2022, 18, 1: 1949953. doi: https://doi.org/10.1080/21645515.2021.1949953
• «Given the above, it is most appropriate – when scheduling booster vaccination or even re- vaccination – to carefully monitor the seroresponse of those vaccinated since a reduced immune response to new SARS-CoV-2 variants at the expense of an enhanced response to original variants could in fact result in inadequate protection of those vaccinated against the current virus variants. Hence, the extremely high levels of specific anti-SARS-CoV-2 antibodies achieved by vaccination, which – as indicated by the most recent data – tend to persist for months post-vaccination, should serve as a warning sign. In addition, it is not yet obvious if the robust vaccination-induced response of T cells can compensate for original antigenic sin to a3ord a su3icient level of protection against the new SARS-CoV-2 variants.» - Piubelli C et al., «Subjects who developed SARS-CoV-2 specific IgM after vaccination show a longer
humoral immunity and a lower frequency of infection,» eBioMedicine 2023, 89: 104471.
doi: 10.1016/j.ebiom.2023.104471
• «Taken together these data, including ours, draw attention on the so-called ‘original immunological sin’, whereby an immune response conditioned by prior immunity against other hCoVs could result in a non-specific SARS-CoV-2 humoral immunity after vaccination, impairing the immune protection.» - Powers JP et al., «Divergent pathogenetic outcomes in BALB/c mice following Omicron subvariant
infection,» Virus Res. 2024, 341: 199319. doi: https://doi.org/10.1016/j.virusres.2024.199319
• «Using a live-virus nLuc neutralization assays and sera from mice vaccinated with an alum adjuvanted Wuhan S2P protein vaccine, we observed a significance decrease in neutralizing antibody titer against the three Omicron nLuc viruses as compared to SARS-CoV-2 D614G. Antibodies retained the most activity against BQ.1.1 nLuc, reflecting the reduced numbers of amino acid changes as compared with XBB.1 and XBB.1.5. Further reductions were observed with XBB.1 and XBB.1.5 with only 3 and 2 serum samples neutralizing above the limit of detection, respectively.» - Pušnik J et al., «efect of XBB.1.5-adapted booster vaccination on the imprinting of SARS-CoV-2 immunity,» npj Vaccines 2024, 9: 231. doi: https://doi.org/10.1038/s41541-024-01023-7
• «Taken together our data support the previously observed imprinting by the original wild-type- based SARS-CoV-2 vaccines but also suggest that vaccination with XBB.1.5-adapted vaccine might help to withdraw antigenic imprinting in some individuals.» - Pušnik J et al., «Vaccination impairs de novo immune response to omicron breakthrough infection, a precondition for the original antigenic sin,» Nat. Commun. 2024, 15: 3102. doi:
https://doi.org/10.1038/s41467-024-47451-w
• «Our data demonstrate a robust humoral response in thrice-vaccinated individuals following omicron breakthrough which is a recall of vaccine-induced memory. The humoral and memory B cell responses against the altered regions of the omicron surface proteins are impaired.» - Qu P et al., «Enhanced neutralization resistance of SARS-CoV-2 Omicron subvariants BQ.1, BQ.1.1,
BA.4.6, BF.7, and BA.2.75.2,» Cell Host Microb. 2023, 31, 1: P9-17.ef. doi:
10.1016/j.chom.2022.11.012
• «We also found that BA.4/5-wave patient sera exhibited weaker neutralization of BA.4/5 than of BA.2, which could be related to prior exposure to SARS-CoV-2 variant antigen biasing patient neutralizing antibody response to BA.4/5 infection.» - Quandt J et al., «Omicron BA.1 breakthrough infection drives cross-variant neutralization and
memory B cell formation against conserved epitopes,» Sci. Immunol. 2022, 7, 75. doi:
10.1126/sciimmunol.abq2427
• «We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2, and previous SARS-CoV-2 VOCs but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding memory B (BMEM) cells against epitopes shared broadly among variants, rather than inducing BA.1-specific B cells… our data also suggest that the immunity in the early stage of Omicron BA.1 infection in vaccinated individuals is based on recognition of conserved epitopes and is narrowly focused on a small number of neutralizing sites that are not altered in Omicron BA.1 and BA.2. Such a narrow immune response bears a high risk that those few epitopes may be lost by acquisition of further alterations in the course of the ongoing evolution of Omicron and may result in immune escape, as is being experienced with sublineages BA.2.12.1, BA.4, and BA.5.» - Regev-Yochay G et al., «eficacy of a Fourth Dose of Covid-19 mRNA Vaccine against Omicron,» N
Eng J Med 2022, 386, 14: 1377-1380. doi: 10.1056/NEJMc2202542
• «Furthermore, we observed low vaccine eficacy against infections in health care workers, as well as relatively high viral loads suggesting that those who were infected were infectious. Thus, a fourth vaccination of healthy young health care workers may have only marginal benefits.» - Reynolds CJ et al., «Heterologous infection and vaccination shapes immunity against SARS-CoV-2
variants,» Science 2021, 375, 6577: 183-192. doi: 10.1126/science.abm0811
• «Vaccine responses after infection were found to be less efective if the infection involved heterologous spike from a variant virus. Unfortunately, the N501Y spike mutation, found in many variants, seems to induce the regulatory T cell transcription factor FOXP3, indicating that the virus could subvert efective T cell function. Changes to antibody binding between variants also means that serology data using the Wuhan Hu-1 S1 receptor-binding domain sequence may not be a reliable measure of protection.» - Reynolds CJ et al., «Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2
exposure,» Science 2022, 377, 6603. doi: 10.1126/science.abq1841
• «…imprinted patterns such as the specific combination of vaccination with infection during the first ancestral Wuhan Hu-1 wave followed by the B.1.1.529 (Omicron) wave require an additional term: ‘hybrid immune damping’… Notably, although B1.1.529 (Omicron) infection in triple- vaccinated previously uninfected individuals could indeed boost antibody, T cell, and MBC responses against other VOCs, responses to Omicron itself were reduced. This relatively poor immunogenicity against itself may help to explain why frequent B.1.1.529 (Omicron) reinfections with short time intervals between infections are proving a novel feature in this wave. It also concurs with observations that mRNA vaccination carrying the B.1.1.529 (Omicron) spike sequence (Omicron third-dose after ancestral sequence prime and boost) o3ers no protective advantage.» - Reynolds CJ et al., «Prior SARS-CoV-2 infection rescues B and T cell responses to variants after first
vaccine dose,» Science 2021, 372, 6549: 1418-1423. doi: 10.1126/science.abh1282
• «Genotyping indicated that a genetic component underlies heterogeneity in immune responses to vaccine and to natural infection. After vaccination, naïve individuals developed antibody responses similar to those seen in naturally infected persons, but T cell responses were more limited and sometimes absent.» - Rodda LB et al., «Imprinted SARS-CoV-2-specific memory lymphocytes define hybrid immunity,»
Cell 2022, 185, 9: P1588-1601.E14. doi: 10.1016/j.cell.2022.03.018
• «SARS-CoV-2 infection prior to vaccination elicits a robust CD4+ T Th1/IFN-ɣ response. Infection- induced Th1/IFN-ɣ signature is not reproduced by three vaccinations.» - Röltgen K et al., «Immune imprinting, breadth of variant recognition, and germinal center response
in human SARS-CoV-2 infection and vaccination,» Cell 2022, 185, 6: P1025-1040.E14. doi:
10.1016/j.cell.2022.01.018
• «Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens.» - Rössler A et al., «Neutralization Profile after Recovery from SARS-CoV-2 Omicron Infection,» N Engl J
Med 2022, 386, 18: 1764-1766. doi: 10.1056/NEJMc2201607
• «We found that neutralizing antibody titers against all the variants were high among vaccinated persons after omicron BA.1 breakthrough infection and among vaccinated or unvaccinated persons who had had previous infection with the wild-type, alpha, or delta variant before infection with the omicron BA.1 variant. Mean neutralizing antibody titers against the omicron BA.1 variant were lower than those against the other variants among previously vaccinated persons but were similar to those against the other variants among unvaccinated persons who had had infection with the wild-type, alpha, or delta variant before infection with the omicron BA.1 variant.» - Selva KJ et al., «Preexisting immunity restricts mucosal antibody recognition of SARS-CoV-2 and Fc
profiles during breakthrough infections,» JCI Insight 2023, 8, 18: e172470. doi:
10.1172/jci.insight.172470
• «IgG and FcγR engagement, but not IgA, responses to breakthrough COVID-19 variants were dampened and narrowed by increased preexisting vaccine-induced immunity against the ancestral strain.» - Servellita V et al., «Neutralizing immunity in vaccine breakthrough infections from the SARS-CoV-2 Omicron and Delta variants,» Cell 2022, 185, 9: P1539-1548.E5. doi: 10.1016/j.cell.2022.03.019
• «Among immunocompetent, unboosted patients, Delta breakthrough infections induced 10.8- fold higher titers against WT compared with Omicron (p = 0.037)… Following either Delta or Omicron breakthrough infection, limited variant-specific cross-neutralizing immunity was observed. These results suggest that Omicron breakthrough infections are less immunogenic than Delta, thus providing reduced protection against reinfection or infection from future variants.» - Shen X et al., «SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral spike vaccines,» Cell Host Microbe 2021, 29, 4: P529-539.E3. doi: 10.1016/j.chom.2021.03.00
• «The B.1.1.7 variant was neutralized by all vaccine sera, although with modestly diminished susceptibility compared to the D614G variant. A modest decrease in neutralization susceptibility was also seen with convalescent sera, although not to the same extent seen with vaccine sera.» - Shrestha NK et al., «Efectiveness of the 2023–2024 Formulation of the COVID-19 Messenger RNA
Vaccine,» Clin. Infect. Dis. 2024, 79, 2: 405-411. doi: https://doi.org/10.1093/cid/ciae132
• «Risk of COVID-19 was lower among those previously infected with an XBB or more recent lineage and increased with the number of vaccine doses previously received.» - Smith CP et al., «The Trajectory of Antibody Responses One Year Following SARS-CoV-2 Infection
among Indigenous Individuals in the Southwest United States,» Viruses 2024, 16, 10: 1573.
doi: https://doi.org/10.3390/v16101573
• «The peak antibody concentrations and resulting time to seroreversion were the highest for those with a prior history of vaccination and infection and the lowest for those with a prior history of vaccination but not infection. This is consistent with prior findings showing a blunted anti-N response to infection in people who have been vaccinated and a faster time to seroreversion for anti-N compared to anti-S antibodies, likely resulting from vaccine-induced immune imprinting against the S protein, leading to decreased dissemination of the virus and partial inhibition of the immune response to the N protein.» - Sokol A et al., «SARS-CoV-2 Omicron BA.1 breakthrough infection drives late remodeling of the
memory B cell repertoire in vaccinated individuals,» Immunity 2023, 56, 9: P2137-2151.E7.
doi: 10.1016/j.immuni.2023.07.007
• «Here, we show that this imprinting was not limited to the early extrafollicular response but persisted over time, with very few BA.1-restricted naive B cell clones recruited in de novo GCs. High-a3inity serum antibodies elicited during the primary response have recently been demonstrated to reduce the recruitment of naive B cells to GCs during secondary responses.» - Solforosi L et al., «Booster with Ad26.COV2.S or Omicron-adapted vaccine enhanced immunity and
eficacy against SARS-CoV-2 Omicron in macaques,» Nat. Commun. 2023, 14, 1944. doi:
https://doi.org/10.1038/s41467-023-37715-2
• «Based on the observation that the booster immunization mostly recalled cross-reactive S WA1/2020 and S Omicron BA.1 B cells, we speculate that de novo induction of neutralizing antibodies targeting key new epitopes in Omicron S is impaired in boosted animals, at least shortly after vaccination, likely mediated by an imprinting efect of the primary Ad26.COV2.S vaccination.» - Stamatos L et al., «mRNA vaccination boosts cross-variant neutralizing antibodies elicited by
SARS-CoV-2 infection,» Science 2021, 372, 6549: 1413-1418. doi: DOI: 10.1126/science.abg9175
• «Vaccination elevated postinfection serum-neutralizing capacity approximately 1000-fold against Wuhan-Hu-1 and other strains, and serum neutralization against the variant B.1.351 was enhanced. Although responses were relatively muted against the variant, they still showed characteristic memory responses.» - Stankov MV et al., «Humoral and cellular immune responses following BNT162b2 XBB.1.5 vaccination,» Lancet Infect Dis. 2024, 24, 1: E1-E3. doi: 10.1016/S1473-3099(23)00690-4
• «… these data suggest cross-reactive MBC dominance even after multiple exposures to omicron spikes and underscore persistent immune imprinting.» - Szekely J et al., «Breakthrough SARS-CoV-2 Omicron Variant in Individuals Primed with Heterologous Vaccines Enhances Inhibition Performance of Neutralizing Antibody to BA.2 Parental Lineage,» Vaccines 2023, 11, 7: 1230. doi: https://doi.org/10.3390/vaccines11071230 • «Negative results for neutralizing antibody against both Omicron variants were observed in persons with antibody levels to wild-type ranging from 12.78–4679.94 BAU/mL. This observation indicates that the level of IgG antibody to wild-type does not correlate with the presence of efective neutralizing antibodies to Omicron variants.»
- Tan CW et al., «Comparative neutralisation profile of SARS-CoV-2 omicron subvariants BA.2.75 and
BA.5,» Lancet Microbe 2022, 3, 13: E898. doi: 10.1016/S2666-5247(22)00220-8
• «Despite an overall improvement in neutralising antibody titres following mRNA booster vaccination or an omicron breakthrough infection, there was a significant loss of neutralising antibody potency against omicron subvariants compared with ancestral SARS-CoV-2, with BA.5 being the most efective subvariant at escaping neutralising antibodies. Relative to geometric mean pVNT50s against BA.2, titres against BA.2.75 were 1·1 to 1·4 times lower and those against BA.5 were 2·2 to 3·8 times lower in individuals who had received three doses of mRNA vaccine or recovered from an omicron breakthrough infection.» - Tan CW et al., «Distinctive serotypes of SARS-related coronaviruses defined by convalescent sera
from unvaccinated individuals,» hLife 2023, 1, 1: 26-34. doi:
https://doi.org/10.1016/j.hlife.2023.07.002
• «Unlike viruses such as measles and polioviruses that have little to no change in their sensitivity to vaccine-induced immunity for decades, the high structure plasticity of the coronavirus spike protein and the vast diversity of animal coronaviruses make the complete eradication an impossible task with current vaccines. Antigenic maps of vaccinated sera showed a greater extent of antigenic di3erences between the circulating Omicron variants and SARS-CoV-2, implying that pre-existing SARS-CoV-2 immunity is insu3icient to prevent current and future infections. In addition, because of the original antigenic sin, breakthrough infections do not increase NAb epitope diversity but instead further promote the RBD to evolve convergently.» - Tarke A et al., «SARS-CoV-2 breakthrough infections enhance T cell response magnitude, breadth,
and epitope repertoire,» Cell Rep Med. 2024, 5, 6: 101583. doi: 10.1016/j.xcrm.2024.101583
• «In conclusion, BMem responses after a variant BTI showed considerable imprinting by the ancestral sequence in the vaccines, consistent with other reports.» - Tavasolian F et al., «HLA, Immune Response, and Susceptibility to COVID-19,» Front. Immunol.
2021, 11 (Sec. Viral Immunology). doi: https://doi.org/10.3389/fimmu.2020.601886
• «Thus, an inadequate immune response to the mutated virus due to the OAS may generate a significant number of sub-neutralizing cross-reactive antibodies that enhance inflammation and may paradoxically promote virus entry into host cells. The intracellular presence of the pathogen activates a pyroptosis mechanism with the subsequent release of danger-associated molecular patterns (DAMPs) to trigger additional inflammatory cells, which in response release a great number of cytokines; which may be the basis of the ‘cytokine storm’ identified in severe cases of COVID-19.» - Tian S et al., «Neutralization against emerging Omicron subvariants after SARS-CoV-2 reinfection,»
J. Infect. 2023, 87, 6: 598-601. doi: 10.1016/j.jinf.2023.09.013
• «XBB subvariants escape the immunity induced by primary infection or reinfection. SARS-CoV-2 reinfection can alleviate WT-vaccination-induced immune imprinting. G339H, G446S, N460K, and F486S/P mutations are essential for immune escape.» 110. Torresi J and MA Edeling, «Immune imprinting of SARS-CoV-2 responses: changing first immune impressions,» mSphere 2024. doi: https://doi.org/10.1128/msphere.00758-23 • «Although infection with viral variants produces variant-specific antibody responses, prior vaccination with WuH-1 S containing COVID-19 mRNA vaccines has been shown to imprint antibody responses toward the ancestral virus rather than to variant antigens. So prior mRNA vaccination with a WuH-1 vaccine followed by Alpha or Delta infection results in stronger antibody response toward WuH-1 virus and decreased antibody responses to viral variant epitopes compared to unvaccinated individuals infected with these variant viruses. In contrast, individuals infected with Alpha or Delta variants and with no history of vaccination develop antibodies with stronger binding to Alpha or Delta variant receptor binding domain (RBDs) compared to WuH-1 RBD.» - Tortorici MA et al., «Persistent immune imprinting occurs after vaccination with the COVID-19
XBB.1.5 mRNA booster in humans,» Immunity 2024, 57, 4: P904-911.E4. doi:
10.1016/j.immuni.2024.02.016
• «Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron breakthrough infections and bivalent COVID-19 vaccination primarily recall cross-reactive memory B cells induced by prior Wuhan-Hu-1 spike mRNA vaccination rather than priming Omicron-specific naive B cells… The finding that administration of an XBB.1.5 S booster elicited higher plasma neutralizing activity against Wuhan-Hu-1/D614G S VSV (vaccine mismatched) relative to XBB.1.5 S VSV (vaccine matched) at both time points examined is a serological indication of immune imprinting… These data suggest that XBB.1.5 S vaccination boosts cross-reactive plasma antibody titers previously elicited by Wuhan-Hu-1 S exposure, which are also binding to and neutralizing XBB.1.5 and other variants instead of inducing de novo antibody responses against XBB.1.5 S.» - Tseng HF et al., «efectiveness of mRNA-1273 vaccination against SARS-CoV-2 omicron subvariants
BA.1, BA.2, BA.2.12.1, BA.4, and BA.5,» Nat. Commun. 2023, 14, 189. doi:
https://doi.org/10.1038/s41467-023-35815-7
• «Similarly, four-dose VE against infection with BA.2, BA.2.12.1, BA.4, and BA.5 was moderate, and was only approximately 35% against BA.5. The four-dose VE against these subvariants was short-lived, disappearing beyond 90 days after the fourth dose… Taken together, these findings appear to be consistent with those of a recent study that found that the primary benefit of booster vaccines is augmentation of neutralizing antibodies without a strong efect on cellular immunity beyond that already induced by the primary vaccination series.» - Uraki R et al., «Humoral immune evasion of the omicron subvariants BQ.1.1 and XBB,» Lancet Infect Dis. 2023, 23, 1: 30-32. doi: 10.1016/S1473-3099(22)00816-7
• «The FRNT50 geometric mean titres against BQ.1.1 and XBB were 21·1-fold and 21·6-fold lower, respectively, than those against the ancestral strain (SARS-CoV-2/UT-NC002- 1T/Human/2020/Tokyo). In addition, the geometric mean titres against BQ.1.1 and XBB were 1·7- fold and 2·6-fold lower, respectively, than those against BA.5 and BA.2. Similar results were obtained with samples from individuals who received four doses of mRNA vaccine; the FRNT50 geometric mean titres against BQ.1.1 and XBB were 43·3-fold and 51·6-fold lower, respectively, than those against the ancestral strain, and were 3·7-fold and 6·2-fold lower than those against BA.5 and BA.2, respectively. In contrast, most of the samples from vaccinees with BA.2 breakthrough infection neutralised BQ.1.1 and XBB; however, the FRNT50 geometric mean titres against BQ.1.1 and XBB were 35·2-fold and 61·7-fold lower, respectively, than those against the ancestral strain, and were 4·9-fold and 15·1-fold lower than those against BA.5 and BA.2, respectively.» - Voss WN et al., «Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination,» Cell Rep Med. 2024, 5, 8: 101668. doi: 10.1016/j.xcrm.2024.101668
• «Infection primarily triggers S2/N-terminal domain (NTD)-reactive antibodies, whereas vaccination mainly induces anti-receptor-binding domain (RBD) antibodies. This imprint persists after secondary exposures wherein >60% of ensuing hybrid immunity derives from the original IgG pool.» - Walls AC et al., «SARS-CoV-2 breakthrough infections elicit potent, broad, and durable neutralizing
antibody responses,» Cell 2022, 185, 5: P872-880.E3. doi: 10.1016/j.cell.2022.01.011
• «Here, we demonstrate that breakthrough infections induce serum-binding and -neutralizing antibody responses that are markedly more potent, durable, and resilient to spike mutations observed in variants than those in subjects who received only 2 doses of vaccine.» - Wang K et al., «Memory B cell repertoire from triple vaccinees against diverse SARS-CoV-2
variants,» Nature 2022, 603: 919-925. doi: https://doi.org/10.1038/s41586-022-04466-x
• «Here we examined whether sera from individuals who received two or three doses of inactivated SARS-CoV-2 vaccine could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2 out of 60) and 95% (57 out of 60) for individuals who had received 2 and 3 doses of vaccine, respectively. For recipients of three vaccine doses, the geometric mean neutralization antibody titre for Omicron was 16.5-fold lower than for the ancestral virus (254).» - Wang M et al., «Original Antigenic Sin on Antibody Response in SARS-CoV-2 Infection,» Infect. Dis.
Immun. 2024, 4, 3: 132-137. doi: 10.1097/ID9.0000000000000125
• «OAS is a barrier to the generation of variant-specific antibodies against the current vaccines against rapidly evolving SARS-CoV-2. New vaccine strategies that promote nAb responses to mutated RBD epitopes and avoid boosting imprinted B cell immune responses are required in the future.» - Wang Q et al., «Deep immunological imprinting due to the ancestral spike in the current bivalent
COVID-19 vaccine,» Cell Rep Med. 2023, 4, 11: 101258. doi: 10.1016/j.xcrm.2023.101258
• «Monovalent and BA.5 bivalent mRNA vaccine boosters induced similar antibody responses. BA.5 breakthrough infections yielded higher neutralizing activity than vaccine boosters. The ancestral spike in BA.5 bivalent vaccines caused deep immunological imprinting. Bivalent boosters did not yield superior antibody responses due to immune imprinting.» - Wang Z et al., «Ancestral SARS-CoV-2 immune imprinting persists on RBD but not NTD after
sequential Omicron infections,» iScience, 2025, 28, 1: 111557. doi: 10.1016/j.isci.2024.111557
• «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 robustly induced, immune imprinting is not countered by successive Omicron challenges.» - Weber T et al., «Enhanced SARS-CoV-2 humoral immunity following breakthrough infection builds upon the preexisting memory B cell pool,» Sci. Immunol. 2023, 8, 89. doi: 10.1126/sciimmunol.adk5845
• «However, the SARS-CoV-2–specific memory B cell pool was significantly expanded only in individuals with a breakthrough infection after third dose. This was due to selection of pre- existing Omicron-neutralizing memory B cells that potently neutralized a broad range of variants that arose after initial vaccination. These findings demonstrate that SARS-CoV-2 immunity is imprinted during early antigen exposure and adapts to new variants.»
- Wei D et al., «Sequential reinfection with Omicron variants elicits broader neutralizing antibody profiles in booster vaccinees and reduces the duration of viral shedding,» J Med Virol 2023, 95, 10:
e29151. doi: https://doi.org/10.1002/jmv.29151
• «Sequential reinfection with Omicron variants elicits broader and high-titer variant-specific neutralizing antibody profiles against Omicron variants. It could also dampen the hyperactivation of WT-specific neutralization induced by previous WT-based vaccination.» - Wheatley AK et al., «Immune imprinting and SARS-CoV-2 vaccine design,» Trend Immunol. 2021,
42, 11: 956-959. doi: 10.1016/j.it.2021.09.001
• «We hypothesize that updated vaccines against SARS-CoV-2 variants might primarily boost ‘imprinted’ immune responses to conserved regions of the Spike protein to the detriment of new neutralizing responses to antigenically altered sites within new variants.» - Yamamoto S et al., «Omicron BA.1 neutralizing antibody response following Delta breakthrough
infection compared with booster vaccination of BNT162b2,» BMC Infect. Dis. 2023, 23, 282. doi:
https://doi.org/10.1186/s12879-023-08272-2
• «Breakthrough infection cases showed marked increases in NAb titers against Wild-type (4.1- fold) and Delta (5.5-fold), and 64% had detectable NAb against Omicron BA.1 at follow-up, although the NAb against Omicron after breakthrough infection was 6.7- and 5.2-fold lower than Wild-type and Delta, respectively. The increase was apparent only in symptomatic cases and as high as in the third vaccine recipients… Given the much lower NAb against Omicron BA.1, infection prevention measures must be continued irrespective of vaccine and infection history while the immune evasive variants are circulating.» - Yang Y et al., «Comparative neutralization profiles of naive and breakthrough infections with Delta,
Omicron BA.1 and BA.2 variants of SARS-CoV-2,» Signal Transduct Target Ther 2022, 7: 316. doi:
https://doi.org/10.1038/s41392-022-01166-w
• «Our results for the naive and breakthrough infections with Delta and BA.1 variants showed that limited cross-neutralizing responses were induced, especially for the currently dominant BA.4/5 variant. This is consistent with previous findings that vaccination with BA.1 specific mRNA vaccine alone or infection with BA.1 provided poor cross-protection, and that BA.4/5 variant could significantly escape the immune response induced by BA.1 breakthrough infection. These observations might result from that BA.1 breakthrough infection predominantly recalls humoral immune memory against the WT SARS-CoV-2 spike protein…» - Yao D et al., «Antibody Responses in SARS-CoV-2-Exposed and/or Vaccinated Individuals Target
Conserved Epitopes from Multiple CoV-2 Antigens,» Int. J. Mol. Sci. 2024, 25, 18: 9814.
doi: https://doi.org/10.3390/ijms25189814
• «The majority of the current vaccine eforts against SARS-CoV-2 are limited by targeting the S- protein; however, it is important to consider N and M proteins as potential targets that will allow us to establish cross-reactive responses. Our results demonstrate that mRNA-vaccinated, AstraZeneca-vaccinated, and unvaccinated donors generate N- and M-specific IgG antibody titers. However, within the vaccinated groups, those with known COVID-19 infections showed significantly higher N-specific IgG titer.» - Yisimayi A et al. «Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting,»
Nature 2024, 625: 148-156. doi: https://doi.org/10.1038/s41586-023-06753-7
• «… immune imprinting induced by vaccination based on the ancestral (hereafter referred to as WT) strain would compromise the antibody response to Omicron-based boosters… in humans, repeated Omicron infections could alleviate WT vaccination-induced immune imprinting and generate broad neutralization responses in both plasma and nasal mucosa.» 127. Zelm MCV, «Immune memory to SARS-CoV-2 Omicron BA.1 breakthrough infections: To change the vaccine or not?» Sci. Immunol. 2022, 7, 74. doi: 10.1126/sciimmunol.abq5901 • «Analysis of memory B cell responses to Spike antigen after Omicron BA.1 breakthrough infections suggests that ‘original antigenic sin’ is in play.» - Zhang L et al., «Neutralisation sensitivity of SARS-CoV-2 lineages EG.5.1 and XBB.2.3,» Lancet Infect
Dis. 2023, 23, 10: e391 – e392. doi: 10.1016/S1473-3099(23)00547-9
• «Finally, we investigated neutralisation by plasma from quadruple vaccinated people collected 2 months (cohort one) or 4–8 (cohort two) months after vaccination, or from people who were vaccinated three to four times with breakthrough infection (cohort three). Particles bearing XBB S proteins were generally less well neutralised as compared with B.1pp (15–194-fold reduction). No major di3erences were observed between neutralisation of XBB.1.5pp, XBB.1.16pp, and XBB.2.3pp. However, it is noteworthy that EG.5.1pp evaded neutralisation by plasma collected for cohorts one and three with higher eficiency than XBB.2.3pp, XBB.1.5pp, and XBB.1.16pp… we obtained evidence that EG.5.1 evades neutralising antibodies with increased eficiency, at least in the context of the immune background of the plasma donors analysed.» - Zhou Z et al., «Immune Imprinting and Implications for COVID-19,» Vaccines 2023, 11, 4: 875.
doi: https://doi.org/10.3390/vaccines11040875
• «It is plausible that imprinted memory B cells induced by the original mRNA vaccine dominate the response to the booster vaccine. Thus, based on the small-scale preclinical study, at least in the short term, boosting with Omicron-mRNA vaccine has not yet presented big advantage over the original mRNA vaccine regarding the induction of protective NAbs against variant as well as control of viral replication after challenge, and immune imprinting seemingly involved in damping the B cell response to variant epitopes.» - Zhu A et al., «Antigenic characterization of SARS-CoV-2 Omicron subvariants XBB.1.5, BQ.1, BQ.1.1,
BF.7 and BA.2.75.2,» Signal Transduct Target Ther 2023 8: 125. doi: https://doi.org/10.1038/s41392-
023-01391-x
• «Similar trends were observed for both vaccine- and infection-induced plasma, regardless of the vaccination status, enhanced neutralization resistance of SARS-CoV-2 Omicron subvariants BF.7, BQ.1, BQ.1.1, BA.2.75.2, XBB and XBB.1.5 was observed when compared with their parent BA.2 and BA.4/5. Multiple vaccination strategies… failed to elicit high neutralizing antibody titer against the newly emerged Omicron subvariant and the rank of neutralization evasion is in the order of BA.2/BA.5 < BF.7 < BQ.1 < BQ.1.1 < BA.2.75.2 < XBB/XBB.1.5, especially XBB/XBB.1.5 which shows superior antibody escaping capability. Consistent to our results, antibody evasion to new subvariants BA.2.75.2, BQ.1.1, XBB.1.5, CH.1.1, and CA.3.1 have been reported in parental mRNA vaccine or BA.5-bivalent booster…» - Zuo F et al., «Heterologous inactivated virus/mRNA vaccination response to BF.7, BQ.1.1, and XBB.1,» Lancet Reg Health West Pac. 2023, 33: 100762. doi: 10.1016/j.lanwpc.2023.100762
• «Due to humoral immune imprinting, a phenomenon in which initial exposure to the original strain of SARS-CoV-2, by infection or vaccination, limits a person’s future immune response against variants, the bivalent vaccine booster and hybrid immunity may not provide su3icient protection against emerging Omicron subvariants.»
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