Genome sequences of BCG Pasteur ATCC 35734 and its derivative, the vaccine candidate BCGΔBCG1419c

Giuseppe D'Auria; Yordan Hodzhev; Michel de Jesús Aceves-Sánchez; Andrés Moya; Stefan Panaiotov; Mario Alberto Flores-Valdez

doi:10.1186/s12864-023-09169-9

Genome sequences of BCG Pasteur ATCC 35734 and its derivative, the vaccine candidate BCGΔBCG1419c

BMC Genomics. 2023 Feb 10;24(1):69. doi: 10.1186/s12864-023-09169-9.

Authors

Giuseppe D'Auria^#^{1

2}, Yordan Hodzhev^#³, Michel de Jesús Aceves-Sánchez⁴, Andrés Moya^{5

2

6}, Stefan Panaiotov⁷, Mario Alberto Flores-Valdez⁸

Affiliations

¹ Sequencing and Bioinformatics Service, Foundation for the Promotion of Health and Biomedical Research of Valencia Region, FISABIO, Valencia, Spain.
² CIBER in Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.
³ National Center of Infectious and Parasitic Diseases, 1504, Sofia, Bulgaria.
⁴ Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y diseño del Estado de Jalisco, A.C., Av. Normalistas 800, Col. Colinas de la Normal, 44270, Guadalajara, Jalisco, Mexico.
⁵ Area of Genomics and Health, Foundation for the Promotion of Sanitary and Biomedical Research of Valencia Region (FISABIO-Public Health), Valencia, Spain.
⁶ Instituto de Biologia Integrativa de Sistemas, Universitat de València y Consejo Superior de Investigaciones Científicas, Valencia, Spain.
⁷ National Center of Infectious and Parasitic Diseases, 1504, Sofia, Bulgaria. spanaiotov@ncipd.org.
⁸ Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y diseño del Estado de Jalisco, A.C., Av. Normalistas 800, Col. Colinas de la Normal, 44270, Guadalajara, Jalisco, Mexico. floresv@ciatej.mx.

^# Contributed equally.

Abstract

Background: Bacillus Calmette-Guérin (BCG) remains the only vaccine to prevent tuberculosis (TB) during childhood, with relatively low to no efficacy against pulmonary TB in adolescents and adults. BCG consists of close to 15 different substrains, where genetic variations among them might contribute to the variable protective efficacy afforded against pulmonary TB. We have shown that the vaccine candidate, BCGΔBCG1419c, which is based on BCG Pasteur, improved protection against chronic TB in murine models, as well as against pulmonary and extrapulmonary TB in guinea pigs. Here, to confirm deletion of the BCG1419c gene and to detect possible genetic variations occurring as a consequence of the spontaneous mutations that may arise during in vitro culture of mycobacteria, the genomes of BCG Pasteur ATCC 35734 and its isogenic derivative, BCGΔBCG1419c, were sequenced and subjected to a comparative analysis between them and against BCG Pasteur 1173P2.

Results: The complete catalog of variants in genes relative to the reference genome BCG Pasteur 1173P2 (GenBank NC008769) showed that the parental strain BCG Pasteur ATCC 35734, from which the mutant BCGΔBCG1419c originated, showed five synonymous mutations, three missense mutations, and five codon insertions, whereas the BCGΔBCG1419c mutant reported the same changes. When BCG Pasteur ATCC 35734 and BCGΔBCG1419c were compared, we confirmed that the latter was devoid of the BCG1419c gene, with only one unanticipated SNP at position 2, 828, 791 which we consider has no role in vaccine properties reported thus far.

Conclusion: We provide evidence that the mutagenesis performed to remove BCG1419c from BCG Pasteur ATCC 35734 solely deleted this gene, and that compared with the reference strain BCG Pasteur 1173P2, few changes were present confirming that they are BCG Pasteur strains, and that changes in immunogenicity or efficacy observed thus far in BCGΔBCG1419c are most likely derived solely from the elimination of the BCG1419c gene.

Keywords: BCG; BCGΔBCG1419c; Genomic analysis; Pasteur; Vaccine.

MeSH terms

Animals
BCG Vaccine / genetics
Genome
Guinea Pigs
Mice
Mycobacterium bovis* / genetics
Tuberculosis* / microbiology
Tuberculosis, Pulmonary*

Substances

BCG Vaccine