Immunogenicity of DNA Vaccines Encoding Simian Immunodeficiency Virus Antigen Targeted to Dendritic Cells in Rhesus Macaques

Matthias Tenbusch,Katharina Töpfer,Ralf Ignatius,Godwin Nchinda,Christine Trumpfheller,Ralf Wagner,Andres M Salazar,Paul Racz,Christiane Stahl-Hennig,Klara Tenner-Racz,Ulrike Sauermann,Klaus Überla,Drew Hannaman

doi:10.1371/journal.pone.0039038

Abstract

BackgroundTargeting antigens encoded by DNA vaccines to dendritic cells (DCs) in the presence of adjuvants enhances their immunogenicity and efficacy in mice.Methodology/Principal FindingsTo explore the immunogenicity of this approach in non-human primates, we generated a single chain antibody to the antigen uptake receptor DEC-205 expressed on rhesus macaque DCs. DNA vaccines encoding this single chain antibody fused to the SIV capsid protein were delivered to six monkeys each by either intramuscular electroporation or conventional intramuscular injection co-injected or not with poly ICLC, a stabilized poly I: C analogue, as adjuvant. Antibodies to capsid were induced by the DC-targeting and non-targeting control DNA delivered by electroporation while conventional DNA immunization at a 10-fold higher dose of DNA failed to induce detectable humoral immune responses. Substantial cellular immune responses were also observed after DNA electroporation of both DNAs, but stronger responses were induced by the non-targeting vaccine. Conventional immunization with the DC-targeting DNA at a 10-fold higher dose did not give rise to substantial cellular immune responses, neither when co-injected with poly ICLC.Conclusions/SignificanceThe study confirms the potent immunogenicity of DNA vaccines delivered by electroporation. Targeting the DNA via a single chain antibody to DEC-205 expressed by DCs, however, does not improve the immunogenicity of the antigens in non-human primates.

Highlights

DNA immunization is a promising vaccine platform with potential applications in prevention and treatment of infectious diseases and cancer
Co-injection of DEC-205-targeted protein antigens with poly I: C or its analogue, poly ICLC that is stabilized against serum nucleases, which both bind to the innate pattern recognition receptors, Toll-like receptor 3 (TLR3) and melanoma differentiation-associated gene-5 (MDA5) [2,3], leads to increased antigen-specific T cell and B cell responses in mice [4,5,6] and non-human primates [7,8,9]
Our study aimed at improving the immunogenicity of DNA vaccines in primates by targeting the encoded antigen to an antigen-uptake receptor expressed by myeloid dendritic cells (DCs), DEC-205 [22]

Summary

Introduction

DNA immunization is a promising vaccine platform with potential applications in prevention and treatment of infectious diseases and cancer. One approach to improve the immunogenicity and efficacy of DNA vaccines is the targeting of the encoded antigen to molecules expressed by dendritic cells (DCs) such as DEC-205 (CD205) (Fig. 1). Lymph node sections from macaques not previously exposed to HIV or SIV antigen were incubated with 3G9 coupled to the HIV-p41 Gag fragment (3G9-p41) This mAb consists of human IgG1 constant domains and a truncated HIV p55 protein, and subsequent incubation with antibodies against these antigens revealed binding of 3G9-p41 to large cells with abundant cytoplasm, which were located in the T-cell region as indicated by the presence of high endothelial venules (Fig. 2 A and B). Targeting antigens encoded by DNA vaccines to dendritic cells (DCs) in the presence of adjuvants enhances their immunogenicity and efficacy in mice

Methods

Results

Conclusion