Improving the Long Term Immune Response to the Flu Vaccine (IRFLUVA)

Flu is a major threat to public health with most deaths in older people. In Wales, from 2016-2021 there were 3738 flu outbreaks in care homes and 116,307 flu deaths in the UK. 21.8% of all GP consultations in Wales were flu-related (1,2). Vaccines are less effective in older people, especially flu vaccines (3). This is because in older people, long-lasting antibody levels and immune cell responses to the flu vaccine are hard to achieve, only 52% make and keep a good  immune response to the flu vaccine and many of those who do not are at high risk of serious  illness, resulting in hospitalisation or death (4). The immune system is less efficient in older people, immune cells are less long-lived and immune responses to vaccines wane faster (5). In younger people, the process of autophagy 'hoovers up' parts of immune cells that are damaged or not working as they should. It degrades damaged parts of cells and recycles them, making way for better functioning cells and a rejuvenated immune system. Autophagy is reduced in older people. Key cells of the immune system are called T and B cells. B cells make antibodies and T cells are 'killer' cells that destroy cells infected with the flu virus (8). Our experiments on cells, pre-clinical models and human studies, found a way of increasing levels of autophagy in immune cells with Spermidine  (SPD) an oral food supplement and rejuvenate T and B cells. We hypothesize, based on this data, that SPD can improve the response to flu vaccines in older people by increasing autophagy in immune cells. We will examine the safety of SPD in older people when given with the flu vaccine; determine the effects of SPD on the immune response to the flu vaccine and measure antibody levels made by B cells and proteins by T cells as part of the immune response. We will measure the length and strength of the immune response over 37 weeks in a pilot study of 80 participants aged over 65 years. It will be a double blind, randomised controlled study where we give 40 people SPD and 40 a placebo with a flu vaccine. It will take place at a Clinical Research Centre (CRC) which has experience in running studies in Cwm Taf Morgannwg University Health Board (CTMUHB).

Participants will attend the centre for 4 visits over 37 weeks. At the 1st visit they will donate a venous blood sample, receive a flu vaccine and placebo/SPD supplements and take them daily by mouth at home for 13 weeks. They will attend the CRC at weeks 2, 13 and 37 to have a clinical review and donate a venous blood sample. Blood samples will be anonymised and processed to measure organ function and immune responses. Support will be available from researchers at the CRC. Our team will do the routine immune response readouts at Cardiff University and specialised assays will be performed in collaboration with a centre of vaccine excellence at University of Oxford. At the end of the study we will unblind the study and analyse results, share it with the public, participants, health boards, Public Health Wales and scientists. We designed this study with 2 PPI co-applicants and PPI events. We have adopted feedback into the study design and plans for dissemination of results. We formed a Project Advisory Group (PAG) and will appoint a study steering committee (SSC) for the duration of the study, for which we have identified an eminent chair, to include a methodologist, statistician, Research Ethics Committee member and 2 PPI members, with at least one from outside Wales.