Comparison of intradermal and intramuscular delivery followed by in vivo electroporation of SIV Env DNA in macaques

Abstract

A panel of SIVmac251 transmitted Env sequences were tested for expression, function and immunogenicity in mice and macaques. The immunogenicity of a DNA vaccine cocktail expressing SIVmac239 and three transmitted SIVmac251 Env sequences was evaluated upon intradermal or intramuscular injection followed by in vivo electroporation in macaques using sequential vaccination of gp160, gp120 and gp140 expressing DNAs. Both intradermal and intramuscular vaccination regimens using the gp160 expression plasmids induced robust humoral immune responses, which further improved using the gp120 expressing DNAs. The responses showed durability of binding and neutralizing antibody titers and high avidity for > 1 y. The intradermal DNA delivery regimen induced higher cross-reactive responses able to neutralize the heterologous tier 1B-like SIVsmE660_CG7V. Analysis of cellular immune responses showed induction of Env-specific memory responses and cytotoxic granzyme B⁺ T cells in both vaccine groups, although the magnitude of the responses were ~10x higher in the intramuscular/electroporation group. The cellular responses induced by both regimens were long lasting and could be detected ~1 y after the last vaccination. These data show that both DNA delivery methods are able to induce robust and durable immune responses in macaques.

Keywords: :

• DNA vaccine
• HIV
• SIVmac239
• SIVmac251
• SIVsmE660
• avidity
• binding antibody
• effector memory
• in vivo electroporation
• intradermal
• intramuscular
• neutralizing antibody
• transitional memory
• transmitted Env

Disclosure of Potential Conflicts of Interest

GNP and BKF are inventors on US Government-owned patents and patent applications related to DNA vaccines and gene expression optimization that have been licensed to several companies. There are no further patents, products in development or marketed products to declare. KEB and NS are employed by Inovio Pharmaceuticals, Inc. as such receive salary, and bonuses and stock options as compensation.

BKF, GNP, AV: designed, coordinated the study, analyzed the data, and wrote the paper. VK, MR, JB, GRP, RJ, CB, AKS, CA, BC, G-MZ: performed experiments and analyzed the data. E-YK, SMW: performed Env identification study. WH, YG: performed binding Ab and avidity assays. CL, DCM: performed and analyzed NAb assays. KEB, NYS: contributed electroporation delivery methods and electroporation devices to access IM and ID tissues for immunization.

Acknowledgments

We are grateful to D. Weiss, J. Treece, I. Kalisz, R. Pal and staff at Advanced BioScience Laboratories, Inc., Rockville, for their expert help. We thank A. von Gegerfelt, B. Keele, J.J.S. Cadwell, and E. Chertova for discussions, R. Desrosiers, R. Pal, and NIAID for SIVmac251 virus and macaque plasma samples, and T. Jones for editorial assistance. pNL4-3.LucR-E- was provided by NIH AIDS Research and Reference reagent program, Division of AIDS, NIAID. This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH) and by NIH HHSN 27201100016C.