DNA/MVA Vaccines for HIV/AIDS

Abstract

Since the initial proof-of-concept studies examining the ability of antigen-encoded plasmid DNA to serve as an immunogen, DNA vaccines have evolved as a clinically safe and effective platform for priming HIV-specific cellular and humoral responses in heterologous "prime-boost" vaccination regimens. Direct injection of plasmid DNA into the muscle induces T- and B-cell responses against foreign antigens. However, the insufficient magnitude of this response has led to the development of approaches for enhancing the immunogenicity of DNA vaccines. The last two decades have seen significant progress in the DNA-based vaccine platform with optimized plasmid constructs, improved delivery methods, such as electroporation, the use of molecular adjuvants and novel strategies combining DNA with viral vectors and subunit proteins. These innovations are paving the way for the clinical application of DNA-based HIV vaccines. Here, we review preclinical studies on the DNA-prime/modified vaccinia Ankara (MVA)-boost vaccine modality for HIV. There is a great deal of interest in enhancing the immunogenicity of DNA by engineering DNA vaccines to co-express immune modulatory adjuvants. Some of these adjuvants have demonstrated encouraging results in preclinical and clinical studies, and these data will be examined, as well.

Keywords: CD40L; GM-CSF; SIV; adjuvant; rhesus macaque.

Figure 1

Phase I/II clinical trials (ongoing/scheduled) of HIV vaccines. (Left) the table shows Phase I/II HIV vaccine trials by vaccine modality obtained from the International AIDS Vaccine Initiative (IAVI) database of vaccine candidates in clinical trials [4].

Figure 2

The timeline of benchmark studies resulting in the development of DNA as a prime for the DNA/MVA HIV vaccine modality. The timeline of key studies resulting in the clinical application of DNA as an immunogen for DNA/MVA HIV vaccines. HGH, human growth hormone; NP, nucleoprotein; CTL, cytotoxic T-cell; Ab, antibody; HA, hemagglutinin; Env, envelope; IM, intramuscular; GM-CSF, granulocyte macrophage colony stimulating factor; SIV, Simian immunodeficiency virus; SHIV, Simian/Human immunodeficiency virus.

Figure 3

Adjuvant activity of GM-CSF in modulating T- and B-cell responses. GM-CSF influences critical steps in antigen presentation, which could enhance vaccine-induced T-and B-cell responses. GM-CSF increases the recruitment of myeloid progenitor cells, induces their differentiation and maturation, resulting in enhanced Class II expression and antigen presentation. Enhanced migration of activated APCs to lymphoid tissue could enhance vaccine-induced T- and B-cell responses.

Figure 4

Immune enhancement by CD40L adjuvanted DNA/MVA HIV vaccines. The schematic conceptualizes the mechanisms by which the co-expression of membrane CD40L on virus-like particles (VLPs; produced by DNA transfected cells or MVA infected cells) expressing HIV Env enhances cellular and humoral responses. DCs and B-cells both receive co-stimulatory signals from VLPs by the ligation of trimeric membrane-bound CD40L (on VLP) and CD40 (on DC or B-cells). VLPs bind to DCs via the interaction of gp120 (on VLP) and CD4 (on DC). This interaction is likely to jump-start CD8 T-cell responses by lowering the threshold for DC activation. Second, VLPs can also bind Env-specific B-cells via the interaction between gp120 (on VLP) and the B-cell receptor (surface Ig). Engagement of the BCR together with CD40 ligation results in the activation and differentiation of naive B-cells. In the germinal center, CD40 signaling enhances affinity maturation, class switch recombination and differentiation to memory B-cells. This model predicts that CD40L-delivered co-stimulation signals will enhance T- and B-cell responses to vaccine antigen. Schematic not drawn to scale; VLPs enlarged relative to immune cells for clarity.