title: Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis.
abstract: Heterologous prime-boosting has emerged as a powerful vaccination approach against tuberculosis. However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell responses in BCG-primed mice and investigated its BCG-booster potential. The Apa-specific T-cell response peaked 32-52 weeks after parenteral or mucosal BCG-priming but waned significantly by 78 weeks. A subunit-Apa-boost during the contraction-phase of BCG-response had a greater effect on the magnitude and functional quality of specific cellular and humoral responses compared to a boost at the peak of BCG-response. The cellular response increased following mucosal BCG-prime-Apa-subunit-boost strategy compared to Apa-subunit-prime-BCG-boost approach. However, parenteral BCG-prime-Apa-subunit-boost by a homologous route was the most effective strategy in-terms of enhancing specific T-cell responses during waning in the lung and spleen. Two Apa-boosters markedly improved waning BCG-immunity and significantly reduced Mycobacterium tuberculosis burdens post-challenge. Our results highlight the challenges of optimization of prime-boost regimens in mice where BCG drives persistent immune-activation and suggest that boosting with a heterologous vaccine may be ideal once the specific persisting effector responses are contracted. Our results have important implications for design of prime-boost regimens against tuberculosis in humans.
authors.affiliation: Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Subhadra
authors.initials: S
authors.lastname: Nandakumar
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kannanganat
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Dobos
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Lucas
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Spencer
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
authors.forename: Rama Rao
authors.initials: RR
authors.lastname: Amara
authors.affiliation: Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Bonnie B
authors.initials: BB
authors.lastname: Plikaytis
authors.affiliation: Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Posey
authors.affiliation: Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Suraj B
authors.initials: SB
authors.lastname: Sable
mesh_terms: D018829:Adhesins, Bacterial / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001500:BCG Vaccine / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007109:Immunity / Q000187:drug effects; D018928:Immunity, Mucosal / Q000187:drug effects; D007117:Immunization, Secondary; D007074:Immunoglobulin G / Q000097:blood; D007700:Kinetics; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology; D022223:Vaccines, Subunit / Q000276:immunology*
chemical_list: D018829:Adhesins, Bacterial; D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D016207:Cytokines; D007074:Immunoglobulin G; D022223:Vaccines, Subunit