Vaccination clearly decreases coronavirus disease 2019 (COVID-19) mortality; however, they also impose selection pressure on the virus, which promotes the evolution of immune escape variants. For example, despite the high vaccination level in especially Western countries, the Omicron variant caused millions of breakthrough infections, suggesting that the highly mutated spike protein in the Omicron variant can escape antibody immunity much more efficiently than the other variants of concern (VOCs). In this study, we investigated the resistance/susceptibility of T helper cell responses that are necessary for generating efficient long-lasting antibody immunity, in several VOCs. By predicting T helper cell epitopes on the spike protein for most common HLA-DRB1 alleles worldwide, we found that although most of high frequency HLA-DRB1 alleles have several potential T helper cell epitopes, few alleles like HLA-DRB1 13:01 and 11:01 are not predicted to have any significant T helper cell responses after vaccination. Using these predictions, a population based on realistic human leukocyte antigen-II (HLA-II) frequencies were simulated to visualize the T helper cell immunity on the population level. While a small fraction of this population had alarmingly little predicted CD4 T cell epitopes, the majority had several epitopes that should be enough to generate efficient B cell responses. Moreover, we show that VOC spike mutations hardly affect T helper epitopes and mainly occur in other residues of the spike protein. These results suggest that lack of long-lasting antibody responses is not likely due to loss of T helper cell epitopes in new VOCs.

疫苗接种明显降低了 2019 年冠状病毒病 (COVID-19) 死亡率；然而，它们也对病毒施加了选择压力，从而促进了免疫逃逸变体的进化。例如，尽管西方国家的疫苗接种水平很高，但 Omicron 变体还是造成了数百万例突破性感染，这表明 Omicron 变体中高度突变的刺突蛋白可以比其他受关注变体 (VOC) 更有效地逃避抗体免疫。在这项研究中，我们研究了几种 VOC 中产生有效持久抗体免疫所必需的 T 辅助细胞反应的耐药性/敏感性。通过预测全球最常见 HLA-DRB1 等位基因的刺突蛋白上的 T 辅助细胞表位，我们发现虽然大多数高频 HLA-DRB1 等位基因具有多个潜在的 T 辅助细胞表位，但很少有像 HLA-DRB1 13:01 和 11 这样的等位基因:01 预计接种疫苗后不会产生任何显着的 T 辅助细胞反应。利用这些预测，模拟了基于真实人类白细胞抗原 II (HLA-II) 频率的群体，以可视化群体水平上的 T 辅助细胞免疫。虽然该群体中的一小部分预测的 CD4 T 细胞表位少得惊人，但大多数人都有几个足以产生有效 B 细胞反应的表位。此外，我们发现VOC刺突突变几乎不影响T辅助表位，并且主要发生在刺突蛋白的其他残基中。这些结果表明，缺乏持久的抗体反应不太可能是由于新 VOC 中 T 辅助细胞表位的丢失。