REINVIGORATE: Repeated Enhanced INfluenza Vaccines In Geriatrics of a Randomised trial for Antibody and T cell Effects - Valkenburg REINVIGORATE NIH Project summary Older adults experience the greatest burden of respiratory virus infections, especially influenza viruses. Older adults are recommended for annual influenza vaccination due the high morbidity in this age group, yet underperformance of standard inactivated vaccines has led to the recommendation of enhanced vaccines, which include high dose, HA only or adjuvanted formulations to improve immunogenicity. However, there is still no consensus on preferred formulation in older adults despite their recommendation, and up to 80% of older adults fail to seroconvert after vaccination. Age impacts the ability to prime new immune responses to antigenic drift variants of influenza viruses, due to reduced immune functions and competition of existing responses for subtle changes in new vaccine strains, which is compounded by annual vaccination. Here, in this study we plan to leverage our completed 4-year randomised control trial in older adults of standard versus enhanced influenza vaccines, to determine the combination and longitudinal repeated effect of vaccination on the antibody and cellular response. Our initial studies have found adjuvanted vaccines increase total T follicular helper cells increasing the magnitude, avidity, and cross-reactivity of the antibody response. Therefore, we plan to use mutational profiling of influenza viruses grown in the presence of vaccine serum across different conditions to assess the antigenic focussing and mutational pressure generated. The quality of antibody responses will be assessed in multiplex approaches. Whilst cytokine producing T cell responses are minimally boosted by inactivated vaccines, we found a year 1 advantage of adjuvanted vaccines for CD8+ T cells which was diminished by year 4 of the study. High dimensional flow cytometry, antigen specific probes for T and B cells, and in vitro stimulation will be used to characterise the phenotype and function of innate and adaptive cellular responses, including repertoire shaped by repeat vaccination. Innate, T and B cell responses will be assessed at the molecular level by repertoire analysis, and transcriptional activity by 10X scRNAseq, with a focus on participants that fail to seroconvert by standard HAI antibodies as their T cell responses come to the fore. Ultimately, this study will provide rationale for vaccine use in older adults and universal vaccine development for broadly cross-reactive immunity. 1
