Migration and tuberculosis transmission in Hamburg, Germany: insights from 25 years of molecular epidemiology

Tuberculosis (TB) epidemiology in low-incidence settings is increasingly influenced by the importation of Mycobacterium tuberculosis complex (Mtbc) strains from high-incidence regions. Globally, more virulent "generalist" lineages such as Lineage 2 (L2) and Lineage 4 (L4) contrast with geographically restricted "specialist" lineages (L1, L3, L5-L9), reflecting differences in transmissibility and adaptation. The introduction of strains of diverse lineages can alter local transmission dynamics and drug susceptibility patterns, underscoring the need for high-resolution genomic surveillance.

We performed whole genome sequencing (WGS) on 3,131 Mtbc strains collected from patients with TB in Hamburg, Germany, over 25 years (1997-2021). We analysed population structure and transmission dynamics in relation to patients' self-reported geographical origins.

Strains from major Mtbc lineages L1-L6 and M. bovis were detected, with L4 strains being most prevalent (74.6%, n = 2,337). Lineage distribution shifted over time: L4 strains decreased from 83.5% in the first five years to 63.0% in the last five years, while L3 strains increased from 4.8% to 18.1%. These changes correlated with an increasing number of foreign-born patients rather than enhanced transmission of strains of specific lineages. L4 strains accounted for most clusters (81%, 218/269). In-depth analyses revealed heterogeneity in transmission potential among L4 sublineages, underscoring the importance of sublineage-level resolution. Strains of sublineages L4.1.2.1, L4.8, and L4.3 were detected in patients born in over 15 regions each, with >57% of cases from Europe, supporting their representation as globally successful generalist lineages.

Migration substantially increased the genetic diversity of the Mtbc population in Hamburg but did not fundamentally alter local transmission dynamics. Transmission remained lineage-specific and was predominantly driven by established L4 strains, suggesting that successful transmission is mediated by locally adapted sublineages. Predominant L4.1.2.1 and L4.8 sublineages occurred in individuals from a wide range of countries, supporting the generalist-specialist hypothesis at the sublineage level. These findings highlight the interplay between pathogen characteristics and host demographics in shaping transmission and the value of integrating genomic, demographic, and epidemiological data to distinguish imported cases from sustained local transmission in low-incidence settings.