In vitro model for the assessment of human immune responses to subunit RSV vaccines

PLoS One. 2020 Mar 19;15(3):e0229660. doi: 10.1371/journal.pone.0229660. eCollection 2020.

Abstract

Respiratory syncytial virus (RSV) is the single most important cause of serious lower respiratory tract disease in infants and young children worldwide and a high priority for vaccine development. Despite over 50 years of research, however, no vaccine is yet available. One block to vaccine development is an incomplete understanding of the aberrant memory response to the formalin-inactivated RSV vaccine (FI-RSV) given to children in the 1960s. This vaccine caused enhanced respiratory disease (ERD) with later natural RSV infection. Concern that any non-live virus vaccine may also cause ERD has blocked development of subunit vaccines for young children. A number of animal FI-RSV studies suggest various immune mechanisms behind ERD. However, other than limited data from the original FI-RSV trial, there is no information on the human ERD-associated responses. An in vitro model with human blood specimens may shed light on the immune memory responses likely responsible for ERD. Memory T cell responses to an antigen are guided by the innate responses, particularly dendritic cells that present an antigen in conjunction with co-stimulatory molecules and cytokine signaling. Our in vitro model involves human monocyte derived dendritic cells (moDC) and allogenic T cell cultures to assess innate responses that direct T cell responses. Using this model, we evaluated human responses to live RSV, FI-RSV, and subunit RSV G vaccines (G-containing virus-like particles, G-VLP). Similar to findings in animal studies, FI-RSV induced prominent Th2/Th17-biased responses with deficient type-1 responses compared to live virus. Responses to G-VLPs were similar to live virus, i.e. biased towards a Th1 and not a Th2/Th17. Also mutating CX3C motif in G gave a more pronounced moDC responses associated with type-1 T cell responses. This in vitro model identifies human immune responses likely associated with ERD and provides another pre-clinical tool to assess the safety of RSV vaccines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • Antigens, Viral / immunology
  • Child, Preschool
  • Dendritic Cells / immunology
  • Dendritic Cells / virology
  • Humans
  • Immunity, Innate
  • Immunologic Memory
  • In Vitro Techniques
  • Infant
  • Models, Immunological
  • Respiratory Syncytial Virus Infections / etiology
  • Respiratory Syncytial Virus Infections / immunology
  • Respiratory Syncytial Virus Infections / prevention & control
  • Respiratory Syncytial Virus Vaccines / adverse effects*
  • Respiratory Syncytial Virus Vaccines / immunology*
  • Respiratory Syncytial Virus, Human / immunology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / virology
  • Vaccines, Subunit / adverse effects
  • Vaccines, Subunit / immunology

Substances

  • Antigens, Viral
  • Respiratory Syncytial Virus Vaccines
  • Vaccines, Subunit

Grants and funding

TC, TVH, and LJA received funding through the NIH 2U19AI095227 (https://grants.nih.gov/grants/guide/rfa-files/RFA-AI-16-065.html). The Emory Pediatric/Winship Flow Cytometry Core provided support for flow cytometry services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.