Induction of long‐lasting multi‐specific CD8⁺ T cells by a four‐component DNA‐MVA/HIVA‐RENTA candidate HIV‐1 vaccine in rhesus macaques

Abstract

As a part of a long‐term effort to develop vaccine against HIV‐1 clade A inducing protective T cell responses in humans, we run mutually complementing studies in humans and non‐human primates (NHP) with the aim to maximize vaccine immunogenicity. The candidate vaccine under development has four components, pTHr.HIVA and pTH.RENTA DNA, and modified vaccinia virus Ankara (MVA).HIVA and MVA.RENTA, delivered in a heterologous DNA prime‐MVA boost regimen. While the HIVA (Gag/epitopes) components have been tested in NHP and over 300 human subjects, we plan to test in humans the RENTA (reverse transcriptase, gp41, Nef, Tat) vaccines designed to broaden HIVA‐induced responses in year 2007. Here, we investigated the four‐component vaccine long‐term immunogenicity in Mamu‐A*01‐positive rhesus macaques and demonstrated that the vaccine‐induced T cells were multi‐specific, multi‐functional, readily proliferated to recall peptides and were circulating in the peripheral blood of vaccine recipients over 1 year after vaccine administration. The consensus clade A‐elicited T cells recognized 50% of tested epitope variants from other HIV‐1 clades. Thus, the DNA‐MVA/HIVA‐RENTA vaccine induced memory T cells of desirable characteristics and similarities to those induced in humans by HIVA vaccines alone; however, single‐clade vaccines may not elicit sufficiently cross‐reactive responses.

Naloxone/alum mixture a potent adjuvant for HIV-1 vaccine: induction of cellular and poly-isotypic humoral immune responses

“…Evaluation of vaccine candidates should include multiple parameters such as frequency of vaccine-induced CD4+ and CD8+ T cells, T-cell functionality in terms of their lytic activity, secretion of cytokines and the ability to proliferate on antigen re-exposure, and the longevity of vaccine-induced memory T cells and their anatomical distribution. 15 It is clear that Th1 responses are typically characterized by the secretion of IFN-γ and the generation of delayed type-hypersensitivity responses. In addition, Th1 cells are thought to mediate the killing of intracellular pathogens.…”

Immunization with HIV Gag targeted to dendritic cells followed by recombinant New York vaccinia virus induces robust T-cell immunity in nonhuman primates

“…With respect to prior work using HIV Gag antigens to immunize NHPs, DNA vaccines containing full-length HIV Gag or a specific peptide have been used to prime animals followed by recombinant fowlpox virus (rFPV) (14) or MVA (40) boost. Priming led to increased proliferative responses and CD8 + T-cell immunity as determined by CTL assays (14) or by direct staining with a tetramer or ICS following a prolonged (7-10 d) in vitro culture with antigen (40). Here we show that cross-primed HIV Gag-specific, cytokine-producing, effector CD8 + T cells, induced by DEC HIV Gag and to a lesser extent HIV Gag p24 protein together with poly ICLC, are strongly enhanced following a single boost with NYVAC-HIV Gag/Pol/Nef.…”

Short Communication:Preclinical Evaluation of Candidate HIV Type 1 Vaccines in Inbred Strains and an Outbred Stock of Mice

“…Measurements of T cell induction in isogenic mouse strains provide the most powerful, convenient, and cheapest first-line evaluation of novel vaccine ideas, which if promising need to be confirmed and further characterized in nonhuman primates (NHP) and humans. Although more expensive, NHP have been shown to be better predictors of T cell immunogenicity in humans, [3][4][5][6] perhaps because they are outbred and evolutionarily closer to humans. Moreover, diverse monkey species and simian immunodeficiency viruses offer a spectrum of models distinct from, but very similar to HIV-1 infection of humans and its clinical sequel, the acquired immunodeficiency syndrome, and therefore provide a preclinical indication of vaccine efficacy.…”

“…As immunogens, we use HIV-1 gag-derived HIVA 8 more recently combined with reverse transcriptase-env-nef-tat-derived RENTA. 4,9 The most frequently explored model for both immunogenicity improvements and toxicity has been the BALB/c mice. [8][9][10][11][12] Here, we compared the vaccine performance in BALB/c mice with those in other inbred strains and an outbred stock of mice to assess if any useful additional information or more primate/human-predictive immunogenicity might be obtained in the mouse species.…”