Rapid and recent evolution of fetA phase variability among hyperinvasive MenW:cc11 disease isolates

Neisseria meningitidis serogroup W (MenW) clonal complex 11 isolates are a major worldwide cause of invasive meningococcal disease. This lineage has exhibited significant plasticity with multiple evolutionary events occurring during international and national spread. Phase variation is a major mechanism for the modulation of surface antigen expression including for FetA, a major immunogenic meningococcal antigen. Alterations in switching rates occur due to changes in the repeat numbers of phase-variable genes. Analysis of 1521 MenW:cc11 carriage and disease isolates detected evidence of ongoing evolution within the UK. The rebound in MenW:cc11 disease in the post-coronavirus disease 2019(COVID-19) pandemic era was associated with isolates belonging to four sub-clusters (SC). One of these SCs was associated with isolates circulating at low levels for more than 50 years, whilst another contained novel variants. Evolution of the fetA promoter and repeat region was detected with increases in the tract length from 6C to 8C or longer becoming highly prevalent from 2015 onwards. Acquisition of phase-variable tracts of 8C or longer was correlated with other alterations in the fetA promoter and genic region. The predominant repeat number for this promoter-located repeat tract was 11C, which is associated with intermediate expression. The potential for heightened phase variation of FetA mirrors earlier evolution of increases in repeat numbers of two other surface proteins, PorA and Opa, in this lineage. Ongoing evolution of phase variation may be aiding maintenance of significant levels of the transmission of this hypervirulent lineage and persistent associations with invasive disease despite widespread vaccine usage.