Heteromultimeric sarbecovirus receptor binding domain immunogens primarily generate variant-specific neutralizing antibodies.
Heteromultimeric sarbecovirus receptor binding domain immunogens primarily generate variant-specific neutralizing antibodies.
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DOI：
10.1073/pnas.2317367120
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发表时间：
2023-12-19
影响因子：
11.1
通讯作者：
Bieniasz, Paul D.
中科院分区：
文献类型：
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作者：
Zang, Trinity;Kuffour, Edmund Osei;Baharani, Viren A.;Canis, Marie;Schmidt, Fabian;Da Silva, Justin;Lercher, Alexander;Chaudhary, Pooja;Hoffmann, Hans- Heinrich;Gazumyan, Anna;Miranda, Ileana C.;MacDonald, Margaret R.;Rice, Charles M.;Nussenzweig, Michel C.;Hatziioannou, Theodora;Bieniasz, Paul D.
含有来自相关病毒的变体蛋白的多聚体疫苗预期产生更广泛的中和抗体应答。在单个异源多聚体免疫原颗粒或多肽中组合变体可以优先刺激识别多种病毒变体并随后产生交叉反应性抗体的B细胞。我们表明，交叉反应的B细胞和抗体确实可以引发使用免疫原建立从两个不同的SARS样冠状病毒受体结合域。然而，由此类免疫原产生的大多数具有病毒中和活性的抗体仅识别与两种免疫原成分之一相对应的病毒。这可能是因为序列变异集中在中和抗体识别的区域;因此，交叉反应性B细胞主要识别多种病毒变体中保守的序列，并主要产生缺乏中和活性的抗体。疫苗接种可能是减少或预防未来Sarbecovirus大流行和减少未来SARS-CoV-2变异感染和疾病流行的战略的关键组成部分。一种“泛肉瘤病毒”疫苗，提供最大可能的人类疾病的缓解，应引起中和抗体与最大可能的广度。通过将多个不同的受体结合结构域（RBD）抗原紧密接近地定位在单个免疫原上，假定交叉反应性B细胞受体可能被选择性地接合。因此，异源多聚体疫苗可以引发中和广泛病毒种类的个体抗体。在这里，我们使用模型系统来研究多聚体肉瘤病毒RBD免疫原扩增交叉反应性B细胞并引发广泛反应性抗体的能力。同源多聚体RBD免疫原产生的血清中和抗体滴度高于等同的单体免疫原，而异源多聚体RBD免疫原产生的中和抗体识别每个RBD组分。此外，与同二聚体相比，RBD异二聚体引发了更大比例的交叉反应性生发中心B细胞和交叉反应性RBD结合抗体。然而，当使用一种RBD组分耗尽来自RBD异源二聚体免疫小鼠的血清抗体时，去除了针对同源病毒假型的中和活性，但是针对对应于另一种RBD组分的假型的中和活性不受影响。总的来说，简单地将不同的RBD组合在单一免疫原中会产生大量单独的RBD特异性中和血清抗体，这些抗体大多不能中和与免疫原组分不同的病毒。
Multimeric vaccines containing variant proteins from related viruses are expected to generate broader neutralizing antibody responses. Combining variants in a single heteromultimeric immunogen particle or polypeptide may preferentially stimulate B cells that recognize multiple viral variants and subsequently produce cross-reactive antibodies. We show that cross-reactive B cells and antibodies can indeed be elicited using immunogens built from two distinct SARS-like coronaviruses receptor binding domains. However, most antibodies with virus neutralizing activity generated by such immunogens recognize viruses corresponding to only one of the two immunogen components. This is likely because sequence variation is concentrated in areas recognized by neutralizing antibodies; thus, the cross-reactive B cells mostly recognize sequences conserved in multiple viral variants and primarily generate antibodies lacking neutralizing activity. Vaccination will likely be a key component of strategies to curtail or prevent future sarbecovirus pandemics and to reduce the prevalence of infection and disease by future SARS-CoV-2 variants. A “pan-sarbecovirus” vaccine, that provides maximum possible mitigation of human disease, should elicit neutralizing antibodies with maximum possible breadth. By positioning multiple different receptor binding domain (RBD) antigens in close proximity on a single immunogen, it is postulated that cross-reactive B cell receptors might be selectively engaged. Heteromultimeric vaccines could therefore elicit individual antibodies that neutralize a broad range of viral species. Here, we use model systems to investigate the ability of multimeric sarbecovirus RBD immunogens to expand cross-reactive B cells and elicit broadly reactive antibodies. Homomultimeric RBD immunogens generated higher serum neutralizing antibody titers than the equivalent monomeric immunogens, while heteromultimeric RBD immunogens generated neutralizing antibodies recognizing each RBD component. Moreover, RBD heterodimers elicited a greater fraction of cross-reactive germinal center B cells and cross-reactive RBD binding antibodies than did homodimers. However, when serum antibodies from RBD heterodimer-immunized mice were depleted using one RBD component, neutralization activity against the homologous viral pseudotype was removed, but neutralization activity against pseudotypes corresponding to the other RBD component was unaffected. Overall, simply combining divergent RBDs in a single immunogen generates largely separate sets of individual RBD-specific neutralizing serum antibodies that are mostly incapable of neutralizing viruses that diverge from the immunogen components.
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影响因子：
56.9
作者：
Prunas, Ottavia;Warren, Joshua L.;Crawford, Forrest W.;Gazit, Sivan;Patalon, Tal;Weinberger, Daniel M.;Pitzer, Virginia E.
通讯作者：
Pitzer, Virginia E.
影响因子：
64.8
作者：
Gaebler C;Wang Z;Lorenzi JCC;Muecksch F;Finkin S;Tokuyama M;Cho A;Jankovic M;Schaefer-Babajew D;Oliveira TY;Cipolla M;Viant C;Barnes CO;Bram Y;Breton G;Hägglöf T;Mendoza P;Hurley A;Turroja M;Gordon K;Millard KG;Ramos V;Schmidt F;Weisblum Y;Jha D;Tankelevich M;Martinez-Delgado G;Yee J;Patel R;Dizon J;Unson-O'Brien C;Shimeliovich I;Robbiani DF;Zhao Z;Gazumyan A;Schwartz RE;Hatziioannou T;Bjorkman PJ;Mehandru S;Bieniasz PD;Caskey M;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
32.4
作者：
Muecksch F;Weisblum Y;Barnes CO;Schmidt F;Schaefer-Babajew D;Wang Z;C Lorenzi JC;Flyak AI;DeLaitsch AT;Huey-Tubman KE;Hou S;Schiffer CA;Gaebler C;Da Silva J;Poston D;Finkin S;Cho A;Cipolla M;Oliveira TY;Millard KG;Ramos V;Gazumyan A;Rutkowska M;Caskey M;Nussenzweig MC;Bjorkman PJ;Hatziioannou T;Bieniasz PD
通讯作者：
Bieniasz PD
DOI：
10.1126/science.abq3773
发表时间：
2022-08-12
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
通讯作者：
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影响因子：
64.8
作者：
通讯作者：
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