Pfister Heiko, Uhlig Carsten, Mayer Zsuzsanna, Polatoglou Eleni, Randeu Hannah, Burglechner-Praun Silke, Berchtold Tabea, Sernetz Susanne, Heitzer Felicitas, Strötges-Achatz Andrea, Deml Ludwig, Sander Michaela, Holdenrieder Stefan
Munich Biomarker Research Center, Institute of Laboratory Medicine, TUM University Hospital German Heart Center, Lazarettstr. 36, 80636 Munich, Germany.
Occupational Medicine Service, TUM University Hospital German Heart Center, Lazarettstr. 36, 80636 Munich, Germany.
Vaccines (Basel). 2025 Aug 15;13(8):867. doi: 10.3390/vaccines13080867.
: Systematic studies providing differentiated insight into the contribution of immunity directed against conserved and non-conserved epitopes of SARS-CoV-2 Spike on long-term protection are rare and insufficiently guide future pan-variant vaccine research. The present observational cohort study aimed to evaluate the correlation of neutralizing antibody levels and cellular immunity against the Spike protein with symptomatic Omicron breakthrough infection. : Neutralizing antibody levels against multiple (sub)variants were analyzed 6 months following the second wild-type mRNA vaccination and 6 months after booster in 107 subjects using a multiplex surrogate virus neutralization assay. To assess cellular immunity, cytokine mRNA expression levels were determined after peptide pool stimulation in whole blood samples of a study subgroup. : Neutralizing antibody titers were found to serve as a reasonably reliable correlate of protection prior to booster immunization. However, the predictive power of neutralizing antibody titers was diminished after boosting. This loss appears to be due to a critical remodeling of the antibody repertoire-a process that was dose-dependent on pre-boost humoral immunity. Vaccination against Omicron infection was most effective when a balanced immune response to both conserved and non-conserved epitopes of the viral Spike protein was induced. While neutralizing antibodies against receptor-binding domain epitopes affected by mutations were specifically associated with protection from symptomatic variant infection, cellular immunity was most effective when targeting conserved Spike epitopes. : Optimal long-term protection against Omicron infection requires balanced immunity to both conserved and non-conserved epitopes of the viral Spike protein. The limited availability of cross-neutralizing antibodies targeting non-conserved epitopes and their inherently lower efficacy renders them a limiting factor as humoral immunity wanes over time. Future pan-SARS-CoV-2 variant vaccines that primarily target conserved epitopes may therefore provide less effective long-term protection against symptomatic variant infection than vaccines targeting a broader epitope spectrum including both conserved and non-conserved epitopes.
：关于针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白保守和非保守表位的免疫对长期保护作用的差异洞察的系统性研究很少，且不足以指导未来的泛变体疫苗研究。本观察性队列研究旨在评估针对刺突蛋白的中和抗体水平和细胞免疫与有症状的奥密克戎突破性感染之间的相关性。 ：在107名受试者中，使用多重替代病毒中和试验分析了第二次野生型mRNA疫苗接种后6个月以及加强免疫后6个月针对多种（亚）变体的中和抗体水平。为了评估细胞免疫，在研究亚组的全血样本中进行肽池刺激后测定细胞因子mRNA表达水平。 ：发现中和抗体滴度在加强免疫前可作为保护的合理可靠指标。然而，加强免疫后中和抗体滴度的预测能力减弱。这种下降似乎是由于抗体库的关键重塑——这一过程在剂量上依赖于加强免疫前的体液免疫。当对病毒刺突蛋白的保守和非保守表位诱导出平衡的免疫反应时，针对奥密克戎感染的疫苗接种最为有效。虽然针对受突变影响的受体结合域表位的中和抗体与预防有症状的变体感染特异性相关，但当靶向保守的刺突表位时，细胞免疫最为有效。 ：针对奥密克戎感染的最佳长期保护需要对病毒刺突蛋白的保守和非保守表位都有平衡的免疫。随着时间的推移，体液免疫减弱，靶向非保守表位的交叉中和抗体可用性有限且其内在效力较低，这使其成为一个限制因素。因此，主要靶向保守表位的未来泛SARS-CoV-2变体疫苗可能比靶向包括保守和非保守表位在内的更广泛表位谱的疫苗提供的针对有症状变体感染的长期保护效果更差。
