Humoral correlates of protection against Mycobacterium tuberculosis following intravenous BCG vaccination in rhesus macaques
Edward B. Irvine,
Patricia A. Darrah,
Shu Wang,
Chuangqi Wang,
Ryan P. McNamara,
Mario Roederer,
Robert A. Seder,
Douglas A. Lauffenburger,
JoAnne L. Flynn,
Sarah M. Fortune,
Galit Alter
Affiliations
Edward B. Irvine
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Patricia A. Darrah
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD 20892, USA
Shu Wang
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Chuangqi Wang
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Ryan P. McNamara
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
Mario Roederer
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD 20892, USA
Robert A. Seder
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD 20892, USA
Douglas A. Lauffenburger
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
JoAnne L. Flynn
Department of Microbiology and Molecular Genetics and Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Sarah M. Fortune
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Corresponding author
Galit Alter
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Corresponding author
Summary: Altering Bacille Calmette-Guérin (BCG) immunization from low-dose intradermal (i.d.) to high-dose intravenous (i.v.) vaccination provides a high level of protection against Mycobacterium tuberculosis (Mtb). In addition to strong T cell immunity, i.v. BCG drives robust humoral immune responses that track with bacterial control. However, given the near-complete protection afforded by high-dose i.v. BCG immunization, a precise correlate of protection was difficult to define. Here we leveraged plasma and bronchoalveolar lavage fluid (BAL) from a cohort of rhesus macaques that received decreasing doses of i.v. BCG and aimed to define correlates of immunity following Mtb challenge. We show an i.v. BCG dose-dependent induction of mycobacterial-specific humoral immune responses. Antibody responses at peak immunogenicity predicted bacterial control post-challenge. Multivariate analyses revealed antibody-mediated complement and natural killer (NK) cell-activating humoral networks as key signatures of protective immunity. This work extends our understanding of humoral biomarkers and potential mechanisms of i.v. BCG-mediated protection against Mtb.
