ACTIVE VACCINE IMMUNE THERAPY FOR HIV-1 (2006)

The intervention centered on how during the past 13 years DNA vaccines have moved from a laboratory curiosity to an important immunization approach for HIV-1 and other infectious agents and cancers. However, the quality and longevity of the responses induced even with highly optimized plasmid cassettes are still significantly less than that of live vector approaches. There exist enough data to date to indicate that the problem with DNA vaccine immunogenicity is not related to the dose; rather, because it is a nonlive, nonreplicating, and nonspreading antigen delivery technology, there is a need for further improvement of the immune responses. Enhancing cellular immune potency is critically important for both prophylaxis of HIV as well as for potential immune therapy applications. Moreover, there is a strong feeling that studies should prove and quantify immune potency in naive animal systems or infected but highly active antiretroviral therapy (HAART)-treated animals, to have a clear background. For these studies, the rhesus macaque SIV model has many desirable features such as high virus uptake, early infection phenotype is very similar to humans, infection mimics viral set point, whereas low viral load (VL) under HAART permits the measurement of vaccine-induced responses. However it was noted that special attention should be given to animal host factors (haplotype effects), which may predispose the animals to naturally control virus or rapidly progress. Protocols should include a screening phase to insert a mixed population of animals. The goal is to develop a technology with a more than 80% response rate (to multiple epitopes) that may be used alone or in combination with other technologies. The laboratory has produced enhancement strategies in animal systems using pIL-15 and pIL-12 as plasmid encoded adjuvants. They have engineered high-expressing IL-15 and IL-12 expression vectors for these studies. Macaque IL-15 and macaque IL-12 expression vaccine vectors in primate vaccine studies were tested, and these responses were compared with unadjuvanted DNA vaccine cassettes. After 2 immunizations with a low dose (2 mg) of codon-optimized-gag plasmid + IL-15 plasmid, 6 of 6 animals developed CD8 T-cell ELISPOT activity compared with 3 of 6 in the gag-alone group. The IL-15-gag group averaged 400+ spots, whereas the antigen-only group averaged approximately 150 spots. Analysis of plasmid gag + IL-12-vaccinated primates was even more impressive. Plasmid IL-12 (3 immunizations with 1.5 mg DNA) increased immune potency of the DNA vaccine 5- to 8-fold (1400 spots), and these responses were superior to live virus infection. Furthermore, it is accepted that there is an inverse relationship between increased interferon-γ production and control of VL; thus, they compared ELISPOT results and plasma viremia in infected macaques; they saw a relationship between memory response, particularly after boosting. Detailed examination of the T-cell-induced responses demonstrated that not only were the interferon-γ responses increased, but also there were dramatic increases in the production of granzyme B (based on ELISPOT data) induced by the adjuvanted vaccines. Moreover, even 12 weeks after the last boost, memory responses in the IL-12-plus group exceeded the peak response of DNA alone. There is now a study concerning the DNA immune-enhancing potency of the separate or combined adjuvants in a macaque challenge model. In a current challenge study, with the DNA antigens gag, pol, env animals received up to 4 immunizations (3 mg each), the first vaccination was given 1 month after HAART started, then monthly plus or minus IL-12. The IL-12-plus cohort exhibited significantly lower VL and increased protection of CD4 T lymphocytes in vivo. In addition, they have analyzed the macaques memory and naive T-cell subsets after vaccination and observed a clear cytokine adjuvant-driven effect on memory T-cell responses in vivo after each boost. In conclusion, plasmid cytokine adjuvants enhance immune responses in nonreplicating plasmid systems. These DNA plasmid vaccines induce immune responses more commonly associated with live infection. The ability of this approach to impact cellular immunity and ultimately VL in chronic infection is being further explored in the macaque model. In addition, in collaboration with Drs Boyer, Tebas, and MacGregor at Penn and Dr Eldridge and collaborators at Wyeth, a clinical protocol to evaluate the safety and later immunogenicity of these cytokines in chronically infected subjects (on HAART) is in development.