BCG-Prime and boost with Esx-5 secretion system deletion mutant leads to better protection against clinical strains of Mycobacterium tuberculosis

• DOI: 10.1016/j.vaccine.2020.08.004
• Publication Date: 2020-09-23T07:50:29Z
• Authors: Sangeeta Tiwari; Taru S. Dutt; Bing Chen; Mei Chen; John Kim; Annie Zhi Dai; Regy Lukose; Crystal Shanley; Amy Fox; Burton R. Karger; Steven A. Porcelli; John Chan; Brendan K. Podell; Andres Obregon-Henao; Ian M. Orme; William R. Jacobs; Marcela Henao-Tamayo
• Keywords: Heterologous; BCG vaccine; Tuberculosis vaccines

Although vaccination with BCG prevents disseminated forms of childhood tuberculosis (TB), it does not protect against pulmonary infection or Mycobacterium tuberculosis (Mtb) transmission. In this study, we generated a complete deletion mutant of the Mtb Esx-5 type VII secretion system (Mtb Δesx-5). Mtb Δesx-5 was highly attenuated and safe in immunocompromised mice. When tested as a vaccine candidate to boost BCG-primed immunity, Mtb Δesx-5 improved protection against highly virulent Mtb strains in the murine and guinea pig models of TB. Enhanced protection provided by heterologous BCG-prime plus Mtb Δesx-5 boost regimen was associated with increased pulmonary influx of central memory T cells (TCM), follicular helper T cells (TFH) and activated monocytes. Conversely, lower numbers of T cells expressing exhaustion markers were observed in vaccinated animals. Our results suggest that boosting BCG-primed immunity with Mtb Δesx-5 is a potential approach to improve protective immunity against Mtb. Further insight into the mechanism of action of this novel prime-boost approach is warranted.