Advantages Of Using Molecular Adjuvants

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The overall objective of any immunization strategy is to induce specific immune responses that could protect the immunized individual from a given pathogen over his or her lifetime. One major challenge in meeting this goal is that the correlates of protection from an individual pathogen vary from one infectious agent to the next. It would be a distinct advantage to design immunization strategies that can be ''targeted'' according to the correlates of protection known for the particular pathogen (Fig. 8). As summarized in Fig. 9, we observed that significant modulation was possible through the use of molecular adjuvants along with DNA vaccine constructs. This molecular adjuvant network underscores an important level of control in the induction of specific immune responses to tailor vaccination programs more closely to the correlates of protection, which vary from disease to disease. This type of fine control of vaccine and immune therapies was previously very difficult to obtain. Controlling the magnitude and direction of the immune response could be advantageous in a wide variety of vaccine strategies, including HIV-1. Much of the current literature supports that T cell-mediated responses are more critical for providing protective immunity against HIV infection (44,174,175). In such cases where T cell-mediated response is paramount, MCP-1, RANTES, or IL-12 genes could be chosen as the immune modulator to be codelivered with a specific DNA immunogen. However, for building vaccines to target extracellular bacteria, for example, MIP-1a, IL-4, IL-5, IL-10, or GM-CSF genes could be coinjected. In addition, in cases where both CD4 + T helper cells and antibodies play more important roles in protection, IL-2, IL-8, or GM-CSF could be codelivered. Furthermore, these genes can be combined with 1 or more additional cytokine or costimula-tory genes to further control the immune responses. Additional studies in higher animal models such as the primates can further address potential risks and benefits of applying this genetic adjuvant network, ultimately leading to modulation of human diseases.

IX. RECOMBINANT PRIME/BOOST STRATEGIES IN PRIMATES

The generation of potent CTL responses through the utilization of DNA immunization has become an attractive approach against many pathogens, including HIV-1. Specifically, inefficient generation of antibodies possessing high avidity against different HIV strains have determined to be the downfall associated with humoral immune response dominant vaccines (176,177). However, an inverse correlation can be made between HIV viral load and CTL frequency, indicating its importance in both treatment and vaccine applications (174,178). In fact, virus-specific CTLs attribute significantly to the control of acute phase infection and denote the mechanism by which viral loads are controlled (179-181). Furthermore, studies on SIV infection models have also indicated that vire-mia of viral load could be effectively controlled by CD8 + T cells (181,182). As a result, recent applications have concentrated on maximizing the cellular arm of the immune system by generating potent CTLs to target and eliminate virally infected host cells. Previously through DNA vaccines, complete challenges were achieved against nonpathogenic AIDS viruses (118,120) and against pathogenic SHIV-89.6P (183). Collectively, DNA vaccines represent an effective means by which cellular responses can be raised against HIV. In view of this, one of the most promising DNA vaccine models is to manipulate the immune system by employing different prime/ boost strategies. Moreover, studies by differing groups have garnered tremendous enhancement of CTLs by priming with DNA and boosting with attenuated viruses.

There is great intrigue with the immunology of recombinant virus boosting, as the order of application has shown to be crucial in generating potent enhancements. For instance, vaccine regimens in reverse (virus priming and DNA boosting) or merely DNA alone exhibit minimal amplification and fail to provide protective immunity against subsequent challenges (184-186). Historically, the order of application in attenuated prime/boost strategies has also exhibited similar results, as priming with a recombinant influenza virus and boosting with recombinant vaccinia resulted in enhanced CD8+ responses and protective immunity against malaria (187). It was proposed that perhaps the influences of these viruses to preferentially migrate CTLs to sites favored by the boosting virus may influence the overall potency of the vaccine (188). However, another study proposed that the immu-nogenicity may be correlated to the immunodominance of the boosting, as the antigen-specific memory responses from the priming may provide a greater focused isolation of the antigen of interest. Consequently, boosting with recombinant viruses concentrates the primed antigens from the recombinant and may enhance their amplification (186-188). This theory correlates with other reports, indicating that homologous prime/ boosting with the same virus with heterologous antigens fails to proliferate antigen-specific CD8+ cells (189). Meanwhile, heterologous boosting with the modified vaccinia virus Ankara (MVA) and fowlpox viruses, while maintaining the same immunogen, provided significant enhancement of CTLs (190). It is also likely that the enhanced assembly of memory T cells that resulted from the primed immunization may augment the boost's proliferation by providing a larger memory T cell pool.

In addition to its efficacy, attenuated virus boosting specifically with MVA provides a resilient history for safety, as it was employed to vaccinate 120,000 humans during the smallpox eradication campaign (186,191). Furthermore, the inability of the virus to replicate in humans while maintaining efficient viral gene expression makes it a perfect component for recombinant boosting approaches (192,193). Cytokine studies of these viruses indicate an elevated degree of Th1 vs. Th2 responses, corresponding to the potent CTLs essential for an efficacious HIV-1 DNA vaccine (194,195). Further reports on the immunology of the MVA recombinant virus both in vitro and in vivo demonstrate that potent CTLs are generated as indicated by enhanced CD8 + populations and secretion of proinflammatory cytokines IL-6 and TNF-a (196-199). Consequently, the natural immune response of the virus correlates well with essential characteristics of vaccines by compounding the host's cellular responses.

To date, many different viruses have been studied to function as recombinant boosters for DNA vaccines, including the modified vaccinia Ankara, fowlpox, and the adenovirus

Figure 8 The potential utility of the molecular adjuvant network. Tailoring the induction of specific immune responses by vaccination programs against viral, bacterial, or parasitic diseases could be beneficial.

Figure 8 The potential utility of the molecular adjuvant network. Tailoring the induction of specific immune responses by vaccination programs against viral, bacterial, or parasitic diseases could be beneficial.

(200-205). Although most have reported potent CTLs and enhanced Th1-biased cytokine expression, the most promising are recent studies implementing the DNA/MVA boost scheme, as well as the DNA/Adeno5 model. The rhesus macaque from these studies garnered protective responses against subsequent pathogenic SHIV89.6P challenges by preventing clinical AIDS, while displaying low to no viral loads. The overall comparisons indicate that the most promising model is the Ad5 through survival of higher T cell counts and lower viral loads

(205). However, the final judgments for these vaccines are premature until the evaluation of these models in human trials. This is especially of importance as previous challenged primates have been shown to eventually regress and develop clinical AIDS because of mutations within the gag dominant epitope

(206). However, these challenges were conducted with the more pathogenic 89.6 SHIV model, and do not fully signify and mimic the in situ human HIV-1 infection setting.

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