We thank Drs. Alexander and Caldera for their stimulating and compelling editorial that excellently contextualised our study evaluating the immunogenicity of original and variant-adapted COVID-19 mRNA vaccines in patients with inflammatory bowel disease (IBD) and healthy controls [1, 2].

To date, the STAR SIGN study has evaluated immunity against wild-type SARS-CoV-2 and the omicron BA.1, BA5, BQ.1.1, XBB.1.5 and the JN.1 variants in a cohort of healthy individuals and patients with IBD (Figure 1) [1, 3-5]. Three doses of original mRNA vaccines induced robust neutralisation against wild-type SARS-CoV-2, but the tested omicron lineages displayed an increasing level of resistance against vaccine-induced neutralising.

Vaccine adaptation is an effective strategy to boost variant-specific immunity [6]. However, the currently recommended vaccines targeting the JN.1 and KP.2 variants are already the third generation of variant-adapted COVID-19 vaccines. Throughout the last years, variant-adapted vaccines were unable to prevent COVID-19 surges with millions of infections worldwide. The rise of the JN.1 variant shortly after the start of XBB.1.5 vaccine roll-out has shown that immunity elicited by variant-adapted vaccines—while efficient against the targeted variant—is not immune to being evaded. In our current study, vaccines encoding the spike protein of the XBB.1.5 variant failed to induce JN.1 neutralisation in 44% of patients with IBD, highlighting the need to develop strategies to induce escape-resistant immune responses. This might be achieved by enhancing the breadth of systemic antibodies to enhance their cross-reactivity with emerging SARS-CoV-2 variants. Previous immunisations with original vaccines may impair the immunogenicity of XBB.1.5-adapted COVID-19 mRNA vaccines via immune imprinting, which might partially explain the success of the JN.1 variant [7]. However, repeated vaccination with adapted COVID-19 vaccines may override original vaccine-mediated immune imprinting and drive the expansion of antibodies that cross-neutralise emerging SARS-CoV-2 variants [7, 8]. These studies highlight an additional benefit of frequent booster immunisation with adapted vaccines for patients with IBD.

As the authors pointed out in the editorial, the conservative COVID-19 vaccination guidelines in many European countries have resulted in vaccine hesitancy. Many believe that frequent COVID-19 infections with circulating variants are an adequate and safe strategy to boost immunity against circulating variants which is a deceitful notion. The continuing threat of post-acute sequelae of COVID-19 that increases with every SARS-CoV-2 infection mandates the maintenance of high immunoprotection. Ours and other studies have demonstrated that this requires frequent COVID-19 vaccination in patients with IBD, especially in those treated with anti-TNF agents [1, 3, 4, 9, 10]. It is the responsibility of gastroenterologists to emphasise the critical advantages of vaccines regarding both safety and efficacy to their patients and convince them to keep up to date with variant-adapted COVID-19 vaccines.

我们感谢 Alexander 和 Caldera 博士的刺激性和引人注目的社论，这些社论很好地为我们的研究提供了背景，评估了原始和变体适应的 COVID-19 mRNA 疫苗在炎症性肠病 （IBD） 患者和健康对照中的免疫原性 [1， 2]。

迄今为止，STAR SIGN 研究已经评估了健康个体和 IBD 患者队列中对野生型 SARS-CoV-2 和奥密克戎 BA.1、BA5、BQ.1.1、XBB.1.5 和 JN.1 变体的免疫力（图 1）[1， 3-5]。三剂原始 mRNA 疫苗诱导了对野生型 SARS-CoV-2 的强效中和，但测试的 omicron 谱系对疫苗诱导的中和表现出越来越强的抵抗力。

疫苗适应是增强变异特异性免疫的有效策略 [6]。然而，目前推荐的针对 JN.1 和 KP.2 变体的疫苗已经是第三代适应变体的 COVID-19 疫苗。在过去几年中，适应变体的疫苗无法防止 COVID-19 激增，全球有数百万人感染。XBB.1.5 疫苗推出后不久 JN.1 变体的兴起表明，变体适应疫苗引发的免疫力虽然对目标变体有效，但不能避免被逃避。在我们目前的研究中，编码 XBB.1.5 变体刺突蛋白的疫苗未能在 44% 的 IBD 患者中诱导 JN.1 中和，这凸显了制定诱导逃逸抗性免疫反应的策略的必要性。这可以通过增加全身抗体的广度来增强它们与新出现的 SARS-CoV-2 变体的交叉反应性来实现。先前使用原始疫苗进行的免疫接种可能会通过免疫印记损害 XBB.1.5 适应的 COVID-19 mRNA 疫苗的免疫原性，这可能部分解释了 JN.1 变体的成功 [7]。然而，重复接种适应的 COVID-19 疫苗可能会覆盖原始疫苗介导的免疫印记，并推动交叉中和新出现的 SARS-CoV-2 变体的抗体的扩增 [7， 8]。这些研究强调了 IBD 患者使用适应性疫苗频繁加强免疫的额外好处。

正如作者在社论中指出的那样，许多欧洲国家保守的 COVID-19 疫苗接种指南导致了疫苗犹豫。许多人认为，频繁感染传播变种的 COVID-19 是增强对传播变种的免疫力的适当且安全的策略，这是一个欺骗性的概念。COVID-19 急性后遗症的持续威胁随着每次 SARS-CoV-2 感染而增加，因此需要维持高度免疫保护。我们的研究和其他研究表明，这需要 IBD 患者频繁接种 COVID-19 疫苗，尤其是接受抗 TNF 药物治疗的患者 [1， 3， 4， 9， 10]。胃肠病学家有责任向患者强调疫苗在安全性和有效性方面的关键优势，并说服他们及时接种适应变种的 COVID-19 疫苗。