Evolution of SARS-CoV-2 in long-term persistent infections is hypothesised to be a major source of variants of concern (VOC). However, the linkage of intra-host variants into haplotypes that reflect viral subpopulations has been limited by commonly used genomic sequencing techniques. We developed a sequencing and bioinformatic workflow for identifying full-length spike haplotypes and analysed their diversification over the course of persistent infections in individuals with inherited or acquired immunodeficiencies. Mutations frequently emerged in positions found in VOCs that confer escape from neutralising antibodies, while phylogenetic analyses showed that specific amino acid positions primarily undergo positive selection. In a single chronic infection lasting more than 500 days from the first wave of the pandemic, we detailed the evolution of spike as it gradually acquired mechanisms to evade both autologous and heterologous neutralising antibodies, redolent of Omicron variants. This