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Front. Immunol. | doi: 10.3389/fimmu.2018.02634

Microphysiologic human tissue constructs reproduce autologous age-specific BCG and HBV primary immunization in vitro

 Guzman Sanchez-Schmitz1, 2, 3*,  Chad R. Stevens1, Ian A. Bettencourt1,  Peter J. Flynn1,  Klaus Schmitz-Abe2, 3, 4, 5,  Gil Metser1,  David E. Hamm6, Kristoffer J. Jensen7, 8, 9,  Christine S. Benn7, 9 and  Ofer Levy1, 2, 3, 5*
  • 1Division of Infectious Diseases, Boston Children's Hospital, United States
  • 2Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, United States
  • 3Harvard Medical School, Harvard University, United States
  • 4Newborn Department, Boston Children's Hospital, United States
  • 5Broad Institute of Harvard and MIT, United States
  • 6Adaptive Biotechnologies (United States), United States
  • 7Bandim Health Project, Guinea-Bissau
  • 8Department of Biotechnology and Biomedicine, Technical University of Denmark, Denmark
  • 9Research center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Denmark

Current vaccine development disregards human immune ontogeny, relying on animal models to select vaccine candidates targeting human infants, who are at greatest risk of infection worldwide and receive the largest number of vaccines. To help accelerate and de-risk development of early-life effective immunization, we engineered a human age-specific microphysiologic vascular-interstitia interphase, suitable for pre-clinical modeling of distinctive age-targeted immunity in vitro. Our Tissue Constructs (TCs) allow for autonomous extravasation of monocytes that undergo fast self-directed differentiation into migratory Dendritic Cells (DCs) in response to adjuvants and vaccines such as Bacille Calmette-Guérin (BCG) or Hepatitis B virus Vaccine (HBV). TCs contain a confluent human endothelium grown atop a tri-dimensional human extracellular matrix substrate, employ human age-specific monocytes and autologous non heat-treated plasma, and avoid the use of xenogenic materials and exogenous cytokines. Self-developed DCs from vaccine-pulsed TCs were able to induce single-antigen recall proliferation and cytokine responses from autologous naïve and memory CD4+ T lymphocytes, matching current vaccine immune-status of study participants. Overall, our microphysiologic culture method reproduced same age- and antigen-specific recall responses to BCG and HBV immunization, as those observed after a birth immunization of human cohorts in vivo, offering for the first time a new approach to early pre-clinical selection of effective age-targeted vaccine candidates.

Keywords: Microphysiology, Newborn, Immunization, Tissue-construct, autologous, BCG - Bacille Calmette-Guérin vaccine, HBV - Hepatitis B Virus vaccine, human, Ontogeny, Dendritic Cells, Antigen preparation, naive

Received: 22 Aug 2018; Accepted: 25 Oct 2018.

Edited by:

Urszula Krzych, Walter Reed Army Institute of Research, United States

Reviewed by:

Juraj Ivanyi, King's College London, United Kingdom
YING ZHENG, University of Washington, United States  

Copyright: © 2018 Sanchez-Schmitz, Stevens, Bettencourt, Flynn, Schmitz-Abe, Metser, Hamm, Jensen, Benn and Levy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
PhD. Guzman Sanchez-Schmitz, Division of Infectious Diseases, Boston Children's Hospital, Boston, United States, Guzman.Sanchez-Schmitz@childrens.harvard.edu
MD, PhD. Ofer Levy, Division of Infectious Diseases, Boston Children's Hospital, Boston, United States, ofer.levy@childrens.harvard.edu