Selected approaches for increasing HIV DNA vaccine immunogenicity in vivo

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The safety, stability, and ability for repeat homologous vaccination makes the DNA vaccine platform an excellent candidate for an effective HIV-1 vaccine. However, the immunogenicity of early DNA vaccines did not translate from small animal models into larger non-human primates and was markedly lower than viral vectors. In addition to improvements to the DNA vector itself, delivery with electroporation, the inclusion of molecular adjuvants, and heterologous prime-boost strategies have dramatically improved the immunogenicity of DNA vaccines for HIV and currently makes them a leading platform with many areas warranting further research and clinical development.

Highlights

► HIV-specific cellular and humoral immune responses are improved by delivering HIV-DNA vaccines with electroporation. ► Co-immunization of a HIV-DNA vaccine with molecular adjuvants can modulate HIV-specific immune responses. ► Heterologous prime-boost strategies with DNA and viral vectors or recombinant protein outperform any single platform.

Introduction

Owing to recent technical improvements, which have shown improved immune potency in vivo, plasmid DNA vaccines are again gaining importance as parts of potential HIV-vaccine platforms. DNA vaccines have an impeccable safety profile, are relatively easy to manufacture and to manipulate, and are remarkably stable making for ideal distribution in developing nations. Despite promising initial studies in small animal models [1, 2, 3, 4], immunogenicity in larger species including non-human primates (NHP) and humans was disappointing [5, 6]. Following up on these early studies, improvements to the vectors, insert sequence optimization, novel delivery methods and the inclusion of gene adjuvants has greatly improved both cellular and humoral immune responses induced by this platform so that HIV DNA vaccines are now performing as well as highly immunogenic viral vectors [7••]. These improvements make DNA vaccines more attractive as components of prime-boost platforms as well as in particular stand alone situations. This brief review will illustrate some important ways that have served to improve the immunogenicity of DNA vaccines to HIV-1 such as improved delivery, the inclusion of molecular adjuvants, as well as prime-boosting.

Section snippets

Delivery

An important approach to improve DNA vaccine immunogenicity is to increase the amount of DNA/plasmid delivered to cells, as this increases antigen expression. Various plasmid needle-free delivery devices have been studied in this regard, such as the gene gun, patch systems or jet injection devices. Jet injection involves using high pressure to deliver a liquid formulation of DNA mm to cm below the skin's surface. It has been reported effective in delivery of DNA through the skin deep into the

Molecular adjuvants

Molecular adjuvants are commonly used to increase or modify the immunogenicity of DNA-based vaccines. Molecular adjuvants can be divided into two groups: cytokine and chemokine molecules. Unlike traditional adjuvants, molecular adjuvants are delivered as plasmid vector along with the antigen-encoded vector. Upon delivery, the vector encoding the molecular adjuvant transduces cells at the site of vaccination that can then secrete the adjuvant molecule.

Cytokine molecular adjuvants can be

Chemokine adjuvants

Chemokines are molecules that control the trafficking of lymphocytes and direct them to sites of inflammation. By utilizing chemokine molecular adjuvants, it is possible to modulate the magnitude and characteristics of DNA vaccine-induced mucosal immunity. This may be particularly important for an HIV vaccine that needs to induce mucosal protection to prevent infection. CCL27 (CTECK) has been shown to increase mucosal homing of antigen-specific cells in mice and monkeys following a HIV-1 DNA

Prime-boosting

An effective HIV-1 vaccine will probably need to induce robust effector T-cell responses as well as broadly neutralizing and binding antibody responses. One method of improving the magnitude and quality of the overall HIV-specific response is the use of heterologous prime-boost strategies. By combining DNA vaccines with either viral vectors or a recombinant protein a synergistic enhancement of immunity can improve challenge outcome. This concept has received a significant boost in attention

Conclusions

Intensive research over the past 20 years has lead to remarkable improvements in the immunogenicity of HIV DNA vaccines. Following years of failures, the recent RV-144 trial, showing a modest prevention of heterosexual transmission, has been viewed as an important achievement that is refocusing efforts in the HIV vaccine field, and engendered a renewed interest in prime-boost strategies. Many clinical trials are ongoing and will provide important data for further development. New developments

Disclosure statement

DBW notes that he has important commercial relationships that should be taken into consideration when reviewing this publication. These are associated with this work from consulting fees, stock ownership, Advisory Board or Review Board Service, speaking support that include the following companies: Pfizer, Inovio, BMS, VGXI, Virxsys, Ichor, Merck, Althea, Aldevron, Novartis, and possibly others.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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