Modified Vaccinia Virus Ankara Preferentially Targets Antigen Presenting Cells In Vitro, Ex Vivo and In Vivo

Arwen F Altenburg,Geert Van Amerongen,Rudi W Hendriks,Bobby W S Li,Ron A M Fouchier,Guus F Rimmelzwaan,Rory D De Vries,Asisa Volz,Gerd Sutter,Rik L De Swart,Carolien E Van De Sandt,Ronan J Macloughlin

doi:10.1038/s41598-017-08719-y

Abstract

Modified Vaccinia virus Ankara (MVA) is a promising vaccine vector with an excellent safety profile. However, despite extensive pre-clinical and clinical testing, surprisingly little is known about the cellular tropism of MVA, especially in relevant animal species. Here, we performed in vitro, ex vivo and in vivo experiments with recombinant MVA expressing green fluorescent protein (rMVA-GFP). In both human peripheral blood mononuclear cells and mouse lung explants, rMVA-GFP predominantly infected antigen presenting cells. Subsequent in vivo experiments performed in mice, ferrets and non-human primates indicated that preferential targeting of dendritic cells and alveolar macrophages was observed after respiratory administration, although subtle differences were observed between the respective animal species. Following intramuscular injection, rMVA-GFP was detected in interdigitating cells between myocytes, but also in myocytes themselves. These data are important in advancing our understanding of the basis for the immunogenicity of MVA-based vaccines and aid rational vaccine design and delivery strategies.

Highlights

Despite frequent testing in clinical trials, the cellular tropism of Modified Vaccinia virus Ankara (MVA), in relevant animal models, has been studied only to a limited extent
A mouse study with rMVA-green fluorescent protein (GFP) demonstrated predominant infection of CD11c+ dendritic cells (DC) in the spleen at 9 hour post- administration (HPA), in this study rMVA-GFP was administered intravenously[19], which is not a standard immunization route. These studies focused on tissue tropism in mice, but the nature and phenotype of cells targeted by MVA in vivo in this and other, more relevant, animal models after administration via routes commonly used for vaccination, remain largely unknown
RMVA-GFP was detected in both interdigitating cells in between myocytes and myocytes themselves after IM injection, whereas direct administration of rMVA-GFP to the respiratory tract led to preferential targeting of alveolar macrophages (AM) in mice and DC in non-human primates, respectively

Summary

Introduction

Despite frequent testing in clinical trials, the cellular tropism of MVA, in relevant animal models, has been studied only to a limited extent. Previous in vitro studies with human peripheral blood mononuclear cells (PBMC), performed to determine the cellular tropism of VACV, showed that recombinant VACV expressing green fluorescent protein (GFP) preferentially infected professional antigen-presenting cells (APC)[9, 16, 17]. A mouse study with rMVA-GFP demonstrated predominant infection of CD11c+ dendritic cells (DC) in the spleen at 9 hour post- administration (HPA), in this study rMVA-GFP was administered intravenously[19], which is not a standard immunization route These studies focused on tissue tropism in mice, but the nature and phenotype of cells targeted by MVA in vivo in this and other, more relevant, animal models after administration via routes commonly used for vaccination, remain largely unknown. Since GFP+ cells were subsequently detected in the LN draining the site of administration, we concluded that rMVA-GFP-infected cells migrated to secondary lymphoid tissues and that direct targeting of professional APC is involved in the shaping of the immune response

Methods

Results

Conclusion