Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis

• Type of Material: Article
• Authors: Subhadra Nandakumar, Centers for Disease Control and Prevention; Sunil Kannanganat, Emory University; Karen M. Dobos, Colorado State University; Megan Lucas, Colorado State University; John S. Spencer, Colorado State University; Rama Amara, Emory University; Bonnie B. Plikaytis, Centers for Disease Control and Prevention; James E. Posey, Centers for Disease Control and Prevention; Suraj B. Sable, Centers for Disease Control and Prevention
• Language: English
• Date: 2016-05-13
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2016, Macmillan Publishers Limited.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/srep25837
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 6
• Start Page: 25837
• End Page: 25837
• Grant/Funding Information: This work was supported by the Georgia Research Alliance collaboration grant (SBS, RRA, JEP and TM Shinnick), NIH/NIAID contract HHSN266200400091c (KD) and Centers for Disease Control and Prevention intramural funds.
• Keywords: EFFICACY; Science & Technology; GLYCOPROTEIN; TH1; IFN-GAMMA; INFECTION; Multidisciplinary Sciences; CD8(+) T-CELLS; Tuberculosis; Protein vaccines; MUCOSAL; MICE; BOVIS BCG; STRATEGY
• Research Categories: Health Sciences, Immunology; Health Sciences, Pharmacology

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.