Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient: a source of immune escape variants

ABSTRACT

The recent emergence of SARS-CoV-2 variants showing increased transmissibility and immune escape is a matter of global concern. Their origin remains unclear, but intra-host virus evolution during persistent infections could be a contributing factor. Here, we studied the long-term SARS-CoV-2 infection in an immunosuppressed organ transplant recipient. Frequent respiratory specimens were tested for variant viral genomes by RT-qPCR, next-generation sequencing (NGS), and virus isolation. Late in infection, several virus variants emerged which escaped neutralization by COVID-19 convalescent and vaccine-induced antisera and had acquired genome mutations similar to those found in variants of concern first identified in UK, South Africa, and Brazil. Importantly, infection of susceptible hACE2-transgenic mice with one of the patients escape variants elicited protective immunity against re-infection with either the parental virus, the escape variant or the South African variant of concern, demonstrating broad immune control. Upon lowering immunosuppressive treatment, the patient generated spike-specific neutralizing antibodies and resolved the infection. Our results indicate that immunocompromised patients are an alarming source of potentially harmful SARS-CoV-2 variants and open up new avenues for the updating of COVID-19 vaccines.