A clinician will use harmless ultrasound to guide a needle into the lymph nodes of healthy volunteers of different ages, sampling the cells that orchestrate the immune response to a flu vaccine. This matters because vaccines work by training the immune system to remember an infection, but the key training ground—the lymph node—has been largely ignored in human studies. Blood is easy to sample; lymph nodes are not. Without knowing what happens inside the nodes, scientists cannot explain why older people often respond poorly to vaccines, requiring higher doses or extra boosters. The research directly compares T cell behaviour in blood and lymph nodes before and after vaccination, and across age groups, to pinpoint exactly where the ageing immune system falters. If successful, this work will provide a practical, repeatable method for studying human lymph node responses without radiation. That could transform how vaccines are designed for older populations and for rapidly mutating viruses like flu, HIV, and SARS-CoV-2. More immediately, it will generate a detailed molecular picture—cell by cell, RNA by RNA—of how T cells help B cells make antibodies, and why that process slows with age. The project is fundamentally about understanding a basic biological process, but that understanding is a prerequisite for rational vaccine improvement.
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Vaccines protect by training the immune system to retain memory of an infection. This is made up of different kinds of cells which can retain information, like bits in a computer software system. This is called immune memory. It is this feature which allows us to be protected after vaccination if we encounter an infection. We do not fully understand the processes involved. One very important type of T cell interacts with B cells to help them make antibodies. These interactions happen in specialised tissues called lymph nodes. These are small kidney-shaped organs found together in clusters in certain areas such as the underarm. It is here that T cells and B cells meet the vaccine or parts of the vaccine and as a result, the cells respond, change and multiply. In older people, we know that the processes of immune priming, maintaining immune memory and recalling it may all happen differently, perhaps more slowly, but we don't know precisely why. One possibility is that T cells respond differently in older people. Vaccines for older people often need a high dose or an extra activating component. Although lymph nodes are important, they have not been well studied in humans. This is because taking a lymph node sample requires different skills from taking blood and these have not previously been invested in. A clinician who is skilled in ultrasound-guided needle biopsy, is needed. This means that we are missing key information in understanding how vaccines work, and how we might design them better in different circumstances; for older people for example, or to tackle highly complex infections that rapidly change such as HIV, flu and SARS-CoV-2. This Fellowship aims to change that. Not just for the duration of this project but for the future of vaccine science. Firstly, I will develop bedside imaging to determine which lymph nodes are responding to the vaccine and which are not. At present this is sometimes possible with greyscale ultrasound but the results are not always reliable, or with PET/CT but this involves a dose of radiation. I believe we can do this more frequently and in more people using harmless ultrasound. Volunteers will be vaccinated with a vaccine against influenza and attend for an imaging appointment on multiple days before and after vaccination. Each time they attend they will have a scan to see the size and blood flow in the lymph nodes near to the site of vaccination. This will determine the best site and best day on which to take a sample using these types of vaccines. Secondly, I will use the ultrasound to guide a fine needle aspiration (USFNA) biopsy to take a sample of the lymph node before and after vaccination with influenza vaccine. I will also ask volunteers to give a sample of the blood at the same time. Samples from lymph nodes on the same side and opposite (control) side can be taken. The cells will be stained and measured using a machine called a flow cytometer so that I can determine which are T cells, what type of T cells, what they are responding to and whether they are growing in number (in cell cycle). I will compare this in the blood and in the lymph node. Thirdly, I will measure how individual T cells are responding to vaccination by testing the ribonucleic acid (RNA) that they are producing. This will indicate in detail how different types of T cells respond to the vaccine. To understand how age might affect the immune response, I will ask people of different ages to participate. My vision is to generate a picture of how T cells respond to vaccines in lymph nodes, and to demonstrate how, and why, this changes with age. This will provide new insight for the future of vaccine design.
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