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Front. Immunol. | doi: 10.3389/fimmu.2018.00898

Induction of cytotoxic T-lymphocyte responses upon subcutaneous administration of a subunit vaccine adjuvanted with an emulsion containing the TLR3 ligand poly(I:C)

  • 1Department of Infectious Disease Immunology, State Serum Institute (SSI), Denmark
  • 2Department of Pharmacy, Faculty of Health Sciences, University of Copenhagen, Denmark

There is an unmet medical need for new subunit vaccines that induce cytotoxic T-lymphocyte (CTL) responses to prevent infection with a number of pathogens. However, stimulation of CTL responses via clinically acceptable subcutaneous (s.c.) and intramuscular (i.m.) injection is challenging. Recently, we designed a liposomal adjuvant (CAF09) composed of the cationic lipid dimethyldioctadecylammonium (DDA) bromide, a synthetic monomycoloyl glycerol analogue and polyinosinic:polycytidylic acid, which induce strong CTL responses to peptide and protein antigens after intraperitoneal administration. In contrast, CAF09 does not stimulate CTL responses upon s.c. or i.m. injection because the vaccine forms a depot that remains at the injection site. Hence, we engineered a series of nanoemulsions (CAF24a-c) based on the active components of CAF09. The oil phase consisted of biodegradable squalane, and the surface charge was varied systematically by replacing DDA with zwitterionic distearoylphosphoethanolamine. We hypothesized that the nanoemulsions drain to the lymph nodes to a larger extent than CAF09, upon s.c. co-administration with the model antigen chicken egg ovalbumin (OVA). This results in an increased dose fraction that reaches the draining lymph nodes and subsequently activates cross-presenting dendritic cells (DCs), which can prime CTL responses. Indeed, the nanoemulsions induced antigen-specific CD8+ T-cell responses, which were significantly higher than those stimulated by OVA adjuvanted with CAF09. We explain this by the observed rapid localization of CAF24a in the draining lymph nodes and the subsequent association with conventional DCs, which promotes induction of CTL responses. Uptake of CAF24a was not specific for DCs, because CAF24a was also detected in association with B cells and macrophages. No measurable dose fraction of CAF09 was detected in the draining lymph nodes within the study period, and CAF09 formed a depot at the site of injection. Importantly, s.c. vaccination with OVA adjuvanted with CAF24a induced significant levels of specific lysis of antigen-pulsed splenocytes were induced after, which was not observed for OVA adjuvanted with CAF09. Thus, CAF24a is a promising adjuvant for induction of CTL responses upon s.c. and i.m. immunization, and it offers interesting perspectives for the design of vaccines against pathogens for which CTL responses are required to prevent infection.

Keywords: subunit vaccine, adjuvant, Nanoemulsion, cytotoxic T-lymphocytes, formulation, Poly(I:C)

Received: 14 Feb 2018; Accepted: 11 Apr 2018.

Edited by:

José Mordoh, Leloir Institute Foundation (FIL), Argentina

Reviewed by:

Paola Massari, Tufts University School of Medicine, United States
Arun Kumar, Linköping University, Sweden  

Copyright: © 2018 Schmidt, Pedersen, Neustrup, Korsholm, Rades, Andersen, Foged and Christensen. 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 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. Dennis Christensen, State Serum Institute (SSI), Department of Infectious Disease Immunology, Copenhagen, Denmark, Den@ssi.dk