This is the case report of an 84-year-old man affected by COVID-19 between the two shots of vaccinal procedure, with negative exitus. We analysed nasopharyngeal samples of viral RNA collected during the disease and nasopharyngeal and lung samples collected post-mortem by RT-LAMP PCR and Next Generation Sequencing (NGS). NGS results were analysed with different bioinformatic tools to define virus lineages and the related SNPs. Both the lung and nasopharyngeal samples tested positive for SARS-CoV-2 on RT-LAMP. The bioinformatic analysis identified two viral RNAs from the nasal swabs as belonging to the B.1.1.7 lineage, whereas the RNA collected from the lung was shown to belong to the B.1.533 lineage. This genetic observation suggested that the SARS-CoV-2 virus tends to change under selective pressure. The high mutation rate of ORFa1b, containing a replicase gene, was a biological image of a complex viral survival system.