Protection against reinfection with Mycobacterium tuberculosis extends across heterologous Mtb lineages

Immunological memory elicited either through previous or ongoing M. tuberculosis (Mtb) infection provides a critical mechanism by which hosts protect against re-infection and disease progression upon Mtb re-exposure. Conversely, the global circulation of—and uneven competition between—distinct Mtb strains suggest certain bacterial clades are able to better spread across communities, potentially by evading memory responses gained by prior infection with genomically different strains. To address this question, we conducted a heterologous reinfection study in cynomolgus macaques involving primary infection by a Lineage 4 Erdman Mtb strain and subsequent re-infection by a Lineage 2 strain (L2-HT), which belongs to a clade that has been epidemiologically shown to be successfully spreading over the last decade in Lima, Peru cohort. Here, through microbiologic, PET-CT and sequencing of Mtb genomic barcodes, we show that reinfected animals developed fewer lung lesions and controlled both pulmonary and disseminated forms of disease better than naïve animals that have had no prior exposure to Mtb. Thus, protection against reinfection is not limited by Mtb lineage, providing optimism that vaccines can be effective across populations and geographic locations.