Aotearoa New Zealand’s COVID-19 elimination response placed the nation in a unique position where much of the population had not encountered the virus prior to vaccination. To study the immune response to vaccination in the naïve Aotearoa population, peripheral blood mononuclear cells (PBMCs) were isolated prior to vaccination, 28 days after second vaccination, and 12 months after third vaccination. These PBMCs will be analysed using high-dimensional full spectrum flow cytometry utilising three panels targeting different aspects of vaccine immune responses. The first panel assesses antigen specific B cells, the next evaluates the cytokine response of T cells, and the third looks at the expression of surface activation markers of T cells. These panels have undergone a lengthy optimisation process with several challenges requiring panel and/or protocol iterations such as fluorophore reassignments, addition of sequential staining, and improving cell processing procedures. Optimisation of these areas has improved marker resolution through reduction of spillover spreading error and increased brightness of staining, and improved the viability of cells being taken through the in vitro stimulation and subsequent staining process. Through undertaking the full optimisation process for the three panels, the quality of the data obtained from this unique cohort will be suitable to be analysed with unbiased high-dimensional analysis algorithms and will provide the best possible insight to the vaccine immune response in Aotearoa.