A Novel Immune Modulator/ Adjuvant for HIV Vaccines

描述（由申请人提供）：在过去二十年的艾滋病毒疫苗开发中，已经探索了各种各样的艾滋病疫苗策略。在许多测试中，DNA和基于病毒载体的疫苗激活细胞免疫反应显示出一些希望，尽管它们有局限性。基于质粒DNA的疫苗是理想的候选疫苗，因为它们在各种临床试验中的安全记录，以及在需要时便于大规模免疫接种的制造、储存和交付。此外，DNA疫苗提供了递送代表单一或几种病原体的多个免疫原/表位的有效方法。通过在疫苗配方中加入CpG基序或免疫调节细胞因子等佐剂，可以增强DNA疫苗的效力。这些观察结果有力地表明，用免疫刺激佐剂递送的DNA疫苗可能成为新一代新发传染病的疫苗。

DESCRIPTION (provided by applicant): During the past two decades of HIV vaccine development, a wide variety of AIDS vaccine strategies have been explored. Among the many tested, DNA and viral vector-based vaccines that activate cellular immune responses have shown some promise despite their limitations. Vaccines based on plasmid DNA are ideal candidates as vaccines due to their safety record in various clinical trials as well as ease of manufacturing, storage and delivery for mass immunization when the need arises. Furthermore, DNA vaccines offer an effective method of delivering multiple immunogens/epitopes representing a single or several pathogens. The efficacy of the DNA vaccines can be enhanced by the addition of adjuvants such as CpG motifs or immunomodulatory cytokines to the vaccine formula. These observations strongly indicate that DNA vaccines delivered with immunostimulatory adjuvants could be the new generation of vaccines for emerging infectious diseases. We developed a novel adjuvant consisting of an empty capsid of an adenoviral vector, termed CAP and used it as an immunological adjuvant to a DNA vaccine. Our preliminary studies indicate that CAP activated splenic APC in vitro and induced pro-inflammatory cytokines including IL-12 both in vivo and in vitro. In addition, coadministration of CAP and plasmid DNA coding for gag antigen, resulted in a dramatic increase in gag-specific CD4 and CD8 T cell proliferation and Th1 cytokine production. These data suggest that CAP can function as an immunomodulatory adjuvant with the ability to enhance immunogen-specific Th1 cytokine production. To test our hypothesis, we propose to further evaluate CAP as an immunological adjuvant to HIV vaccines to promote HIV-specific cellular and humoral responses. We will use two types of immunogens 1) plasmid DNA encoding HIV-1 (NL4-3 Clade B) gag, pol, tat and rev and 2) recombinant gag and tat proteins (rGag and rTat) along with CAP and evaluate its potency in prime-boost protocols. The specific aims of the grant are to evaluate CAP as an adjuvant to DNA or protein-based HIV vaccines and to determine the effectiveness of prime-boost combinations in naive as well as mice with pre-existing anti-Ad immunity. PUBLIC HEALTH RELEVANCE: The AIDS epidemic is a global emergency and preventive and therapeutic vaccines for AIDS offer the best hope of ending the pandemic. We are evaluating the use of a preparation derived from a product already approved for human use to enhance the potency of HIV vaccines. The initial results which we plan to extend in this study, show the enhancement is not only due to greater immune responses but also a shift of the type of response to one better suited to protect against HIV.