Determining the immunological basis for weakened SARS-CoV-2 vaccination outcomes

这项研究的目的是了解新冠肺炎疫苗接种后的反应有多有效，以及它们持续多长时间。具体地说，我们将在免疫系统受损的人中进行调查，因为早期报告显示，他们对新冠肺炎疫苗的反应非常差。如果这些人患有新冠肺炎，他们往往也是患严重疾病的最大风险者，因此我们的工作将为未来如何保护这些弱势群体的建议/政策提供信息。除了个人利益之外，重要的是要理解为什么有些人对控制病毒在人群中传播的疫苗反应效果较差。这是因为，弱的疫苗反应意味着它们可能更有可能感染和传播病毒，从而使其保持在循环中，并可能导致出现更多的变种。我们将通过观察不同免疫功能的个体来实现两个目标：健康志愿者、艾滋病毒携带者(主要是T细胞缺乏症患者)和B细胞恶性肿瘤患者(他们主要接受了大幅减少B细胞数量的治疗)。首先，我们将评估他们血液中的疫苗反应，并对其有效性进行排名。然后，我们将把它与他们的免疫细胞(特别是B、T和NK细胞)表现如何的数据联系起来，以了解疫苗反应不佳的人的免疫学特征。其次，我们将试图了解一些人的疫苗反应是否对变异病毒的应对能力较差。我们将通过观察他们制造抗体的B细胞的多样性和弹性来实现这一点，并通过检查T和NK细胞如何对病毒做出反应并合作帮助B细胞制造抗体来实现这一点。我们的发现将根据个人免疫系统受损的严重程度，而不是仅仅基于他们的临床诊断，为有关各种强化疫苗的最佳频率以及是否需要全程疫苗接种或单次强化接种的政策提供参考。

The goal of this study is to understand how effective post COVID-19 vaccine responses are and how long they last. Specifically, we will investigate this in people with compromised immune systems because early reports suggest they make very poor responses to COVID-19 vaccines. These people are often also the most at risk of severe disease if they develop COVID-19 so our work will inform future recommendations/policy on how to protect these vulnerable people. Beyond individual benefit, it is important to understand why some people make less effective vaccine responses to control the spread of the virus in the population. This is because, weak vaccine responses mean they may be more likely to catch and transmit the virus thus keeping it in circulation and potentially leading to emergence of additional variants. We will complete two aims by looking at individuals across a spectrum of immune function: healthy volunteers, people living with HIV (who have predominantly T cell deficiencies) and people with B cell malignancies (who have mainly had treatment that drastically reduces their B cell numbers). Firstly we will evaluate the vaccine responses in their blood and rank their effectiveness. We will then link this to data on how well their immune cells (B, T and NK cells in particular) are performing to understand what the immunological profile is of someone who makes a poor vaccine response. Secondly, we will attempt to understand whether some people's vaccine responses are less able to cope with variant viruses. We will do this by looking at diversity and resilience within their B cells, which make antibodies, and by examine how the T and NK cells respond to virus and cooperate to help B cells make antibody. Our findings will inform policy regarding the best frequency of variant boosters and whether a full course of vaccination or single boost is needed based on how severely a person's immune system has been compromised not based solely on their clinical diagnosis.