Candida auris is an urgent antimicrobial resistance threat due to its global emergence, high mortality, and persistent transmissions. Nearly half of C. auris clinical and surveillance cases in the United States are from the New York and New Jersey Metropolitan area.

Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been reported in immune-compromised individuals and people undergoing immune-modulatory treatments. Although intrahost evolution has been documented, direct evidence of subsequent transmission and continued stepwise adaptation is lacking. Here we describe sequential persistent SARS-CoV-2 infections in three individuals that led to the emergence, forward transmission, and continued evolution of a new Omicron sublineage, BA.1.23, over an eight-month period. The initially transmitted BA.1.23 variant encoded seven additional amino acid substitutions within the spike protein (E96D, R346T, L455W, K458M, A484V, H681R, A688V), and displayed substantial resistance to neutralization by sera from boosted and/or Omicron BA.1-infected study participants. Subsequent continued BA.1.23 replication resulted in additional substitutions in the spike protein (S254F, N448S, F456L, M458K, F981L, S982L) as well as in five other virus proteins. Our findings demonstrate not only that the Omicron BA.1 lineage can diverge further from its already exceptionally mutated genome but also that patients with persistent infections can transmit these viral variants. Thus, there is, an urgent need to implement strategies to prevent prolonged SARS-CoV-2 replication and to limit the spread of newly emerging, neutralization-resistant variants in vulnerable patients.

Persistent SARS-CoV-2 infections have been reported in immune-compromised individuals and people undergoing immune-modulatory treatments. It has been speculated that the emergence of antigenically diverse SARS-CoV-2 variants such as the Omicron variant may be the result of intra-host viral evolution driven by suboptimal immune responses, which must be followed by forward transmission. However, while intrahost evolution has been documented, to our knowledge no direct evidence of subsequent forward transmission is available to date. Here we describe the emergence of an Omicron BA.1 sub-lineage with 8 additional amino acid substitutions within the spike (E96D, L167T, R346T, L455W, K458M, A484V, H681R, A688V) in an immune-compromised host along with evidence of 5 forward transmission cases. Our findings show that the Omicron BA.1 lineage can further diverge from its exceptionally mutated genome during prolonged SARS-CoV-2 infection; highlighting an urgent need to employ therapeutic strategies to limit duration of infection and spread in vulnerable patients.

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