Leveraged Vaccination Strategy by Fudan University's Jiang/Shu Team Breaks Original Antigenic Sin Barrier to Enhance Broad Neutralizing Antibody Responses Against SARS-CoV-2 Omicron Subvariants

"Original Antigenic Sin" (Original Antigenic Sin, OAS), also known as“Immune Imprinting”（Immune Imprinting), isThomas FrancisIn1960Proposed for the first time in (On the doctrine of original antigenic sin. Proc Am Phil Soc. 1960;104:572–578). ItsThe classic meaning is:When the body againWhen encountering a new pathogen (such as the latest prevalent variant strain of the influenza virus) that is antigenically similar but distinct from the initially exposed pathogen (such as the wild strain of the influenza virus), the immune response still prioritizes the antigens of the initially exposed pathogen, while the response to the new strain's antigens is significantly weaker.

Now,Coronavirus (SARS-CoV-2) Omicron VariantContinuous Evolution: Immune Escape Intensifies. Although multiple responses to the new epidemic have been developed,Variant StrainBooster vaccine (such asBA.5/Original Strain BivalentmRNABooster vaccine ) approved for marketing or emergency use, but pre-existingOASStill makes the body“Stubborn”Significantly reduced the ability to recall antibodies against the original strain, substantially weakening the response to newly prevalentVariant StrainThe ability to combat. How to respondOASEffect, becoming a common challenge in the development of the next generation of vaccines.

2025Year7Month7Day, Shanghai Institute of Major Infectious Diseases and Biosecurity/Jiang Shibo from the School of Basic Medical Sciences, Fudan University/Land route team collaborates with Abogen Biosciences inMedComm （IF: 10.7, CAS1Area) Published an article titled“Leveraged Vaccination to Alleviate Original Antigenic Sin for Enhancing Broad-Neutralizing Antibody Response against SARS-CoV-2 Omicron Subvariants”Research paper.

The study used the coronavirus as a model, targeting pre-infection or vaccination with the original strain of the coronavirus or its vaccine-induced“Original Antigenic Sin”Effect, proposed an innovative“Leverage Vaccination”Strategy, namely“Long Lever + Lever Arm”(Leverage: Selection of antigens from the original strain (WT-RBD) Longer-distance variant antigens (XBB-RBD) as a booster vaccine antigen; Lever arm: Through two XBB-RBDVaccine Booster Immunization, Amplified“Leverage”Effect)(Figure1)。 

Figure1：“Leverage Vaccination”Schematic Diagram of Strategy

The study usedTargetingOriginal Strain Antigen(WT-RBD), Antigen of Early Variants(BA.2-RBD)And the antigen of late-stage mutant strains(XBB-RBD) ThemRNAVaccine. First useWT–RBD mRNAVaccines for priming, followed by separate use ofWT–RBD (WT–WTGroup)、BA.2–RBD (WT–BA.2Group)Or XBB–RBD (WT–XBBGroup) mRNAVaccines for booster immunization. Subsequently, an antigenic map was constructed based on neutralizing activity to visualize antigenic distances. The results showed that the original strain and the late流行 strain...OmicronVariant StrainEG.5.1、BA2.86、JN.1The antigenic distance between (4.38~4.95) and the original strain with the late predominant epidemicOmicronVariant StrainXBBThe antigenic distance between (4.56) Similar, but much greater thanWTCompared with the earlier prevalentOmicronVariant strainBA.2The antigen distance (1.79) (Figure2）。

Figure2: CoronavirusWTAntigenic Distance Between Strains and Their Variants and Subvariants

WT-WTImmune Mouse Serum AgainstXBB、EG.5.1、BA2.86、JN.1The neutralizing effect was significantly lower than that ofWTAndBA.2The neutralizing effect, butWT-XBBImmune mouse serum against theseOmicronNeutralization of mutant strains has improved, whileWT-XBB-XBBImmune mouse serum against theseOmicronNeutralization of mutant strains significantly increased (Fig.3), demonstrating that this leveraged vaccination strategy can effectively attenuate by using a "longer lever" (i.e., greater antigenic distance) and "greater pressure" (i.e., two booster immunizations).OASEffect, improved response to new epidemicsOmicronBroad-spectrum neutralizing antibody responses against variant sub-lineages. Meanwhile, to evaluate the long-term effects of leveraged vaccination strategies, the study also assessed antigen-specific bone marrow-resident plasma cells among different groups (BMPCs) level, and it was found that the antigen-specific response in the leveraged vaccination strategy group BMPCs The quantity was significantly higher. These findings suggest that the leveraged vaccination strategy can effectively activate long-lasting humoral immunity while weakening OAS Impact (Fig.3）。

Figure3: The use of the "leverage vaccination" strategy can significantly reduceOASEffect, enhancing the response to new epidemicsOmicronBroad-spectrum neutralizing antibody response to variants

In summary,The study'sCore research findings include:1) Antigen distance is a key lever:Mouse immunization experiments showed that, compared with the use of antigens at a closer distance,BA.2-RBD mRNACompared to vaccines used as booster shots, the use of antigens is further away.XBB-RBD mRNAVaccines for booster immunization (especially two boosters) can significantly reduceOASEffect, and induce a potent, broad-spectrum neutralizing antibody response against multiple Omicron subvariants.2）Visual Antigen Distance:By constructing neutralization activity maps, the study quantified the antigenic distances between different strains. The results showed that the original strain(WT) AndXBBThe antigenic distance between is much greater thanWTAndBA.2The distance between. UseXBB-RBDBooster shots can effectively induce immunity against most circulating strainsOmicronNeutralizing Antibodies Against Subvariants Prove Selection“Longer Leverage”(Greater antigen distance) can attenuateOASAnd enhance broad-spectrum neutralizing activity.3）Increase“Force”Enhancement Effect:To verify whether it is possible to achieve the goal by increasing the number of vaccinations (simulated“Increase the force on the lever”) To further enhance the effect, research on the initial vaccinationWTAfterwards, implement twiceXBB-RBDStrengthening Immunity (WT–XBB–XBBGroup). The results showed that the two boosts weakenedOASSignificantly superior in effects and enhancement of broad-spectrum neutralizing antibody responses compared to a single booster.4）Induce Persistent Immunity:Evaluation of Antigen-Specific Bone Marrow-Resident Plasma Cells (BMPCs) Horizontal discovery,“Leveraged Vaccination "Strategy Group (especially twiceXBBStrengthening Group)BMPCsSignificantly higher numbers indicate that this strategy can not only effectively weakenOASresponse, and can also induce a long-lasting humoral immune response. Therefore, this study provides important new ideas for vaccine development and immunization strategies to address rapidly mutating viruses in the future.

Shanghai Institute of Major Infectious Diseases and Biosecurity/Prof. Shibo Jiang and Researcher Lu Lu from the School of Basic Medical Sciences, Fudan University, and Dr. Bo Ying from Abogen Biosciences are the corresponding authors of this article. Ph.D. candidate Guangxu Zhang, Dr. Qian Wang, and Ph.D. candidate Yuanzhou Wang from Fudan University, and Dr. Kai Ji from Abogen Biosciences are the co-first authors of this article.

Original link:

https://onlinelibrary.wiley.com/doi/10.1002/mco2.70273

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