Targeted DNA vaccines for enhanced induction of idiotype-specific B and T cells

Abstract

Background: Idiotypes (Id) are antigenic determinants localized in variable (V) regions of Ig. Id-specific T and B cells (antibodies) play a role in immunotherapy of Id+ tumors. However, vaccine strategies that enhance Id-specific responses are needed. Methods: Id+ single-chain fragment variable (scFv) from multiple myelomas and B cell lymphomas were prepared in a fusion format that bivalently target surface molecules on antigen-presenting cells (APC). APC-specific targeting units were either scFv from APC-specific mAb (anti-MHC II, anti-CD40) or chemokines (MIP-1α, RANTES). Homodimeric Id-vaccines were injected intramuscularly or intradermally as plasmids in mice, combined with electroporation. Results: (i) Transfected cells secreted plasmid-encoded Id+ fusion proteins to extracellular fluid followed by binding of vaccine molecules to APC. (ii) Targeted vaccine molecules increased Id-specific B and T cell responses. (iii) Bivalency and xenogeneic sequences both contributed to enhanced responses. (iv) Targeted Id DNA vaccines induced tumor resistance against challenges with Id+ tumors. (v) Human MIP-1α targeting units enhanced Id-specific responses in mice, due to a cross reaction with murine chemokine receptors. Thus, targeted vaccines designed for humans can be quality tested in mice. (vi) Human Id+ scFv from four multiple myeloma patients were inserted into the vaccine format and were successfully tested in mice. (vii) Human MIP-1α vaccine proteins enhanced human T cell responses in vitro. (viii) A hypothetical model for how the APC-targeted vaccine molecules enhance Id-specific T and B cells is presented. Conclusion: Targeted DNA Id-vaccines show promising results in preclinical studies, paving the way for testing in patients.

Antigen Targeting to Human HLA Class II Molecules Increases Efficacy of DNA Vaccination

“…The present data support these observations and expand them to larger animals. The efficiency of MHC-II as a target may be related to the relatively high number of MHC-II molecules on professional APCs, thus enabling display of aggregated vaccine Ag to B cells in a putative APC-B cell synapse (46). In addition to improved Ab responses, it has been shown that targeting of vaccine proteins to MHC-II results in increased CD4 + T cell responses to Ag (7,14,18,22).…”

Simultaneous Targeting of Multiple Hemagglutinins to APCs for Induction of Broad Immunity against Influenza

“…We have hypothesized that this may be due to the formation of APC-B cell synapses in which MHCII-targeted vaccine proteins bridge the two cell types (16,27,28). Indeed, APC-B cell synapses have been demonstrated in vitro (33); however, in vivo evidence is lacking.…”

“…The increased efficacy conferred by MHCII targeting of Ag has recently been translated to influenza vaccination of ferrets and pigs (21). As a mechanism for enhanced Ab induction, it has been suggested that the DNA-encoded anti-MHCII-HA vaccine proteins bridge B cells and APCs in an APC-B cell synapse (16,27,28). In this article, we show that the same MHCII-targeted DNA vaccine format can induce strong Ab responses against H5, H6, H8, H9, H11, and H13 subtypes of group 1 influenza viruses.…”

Immunogenicity of varicella zoster virus glycoprotein E DNA vaccine

“…The naturally formed antigen is then processed and modified in a normal manner prior to presentation to the immune system, which subsequently stimulates an immune response (24,25). Therefore, DNA vaccines possess the safety of recombinant subunit vaccines and the high efficiency of live attenuated vaccines in inducing a comprehensive immune response (26), and these immunogenic and protective effects have been demonstrated in numerous animal models and preliminary human clinical trials (27,28).…”