Long peptides induce polyfunctional T cells against conserved regions of HIV‐1 with superior breadth to single‐gene vaccines in macaques

Abstract

A novel T-cell vaccine strategy designed to deal with the enormity of HIV-1 variation is described and tested for the first time in macaques to inform and complement approaching clinical trials. T-cell immunogen HIVconsv, which directs vaccine-induced responses to the most conserved regions of the HIV-1, proteome and thus both targets diverse clades in the population and reduces the chance of escape in infected individuals, was delivered using six different vaccine modalities: plasmid DNA (D), attenuated human (A) and chimpanzee (C) adenoviruses, modified vaccinia virus Ankara (M), synthetic long peptides, and Semliki Forest virus replicons. We confirmed that the initial DDDAM regimen, which mimics one of the clinical schedules (DDDCM), is highly immunogenic in macaques. Furthermore, adjuvanted synthetic long peptides divided into sub-pools and delivered into anatomically separate sites induced T-cell responses that were markedly broader than those elicited by traditional single-open-reading-frame genetic vaccines and increased by 30% the overall response magnitude compared with DDDAM. Thus, by improving both the HIV-1-derived immunogen and vector regimen/delivery, this approach could induce stronger, broader, and theoretically more protective T-cell responses than vaccines previously used in humans. Eur. J. Immunol. 2010. 40: 1973-1984 DOI 10.1002 Immunity to infection 1973 IntroductionDevelopment of an effective, accessible vaccine is the only realistic hope for halting the HIV-1/AIDS epidemic. Ideally, such a vaccine should induce broadly neutralizing antibodies and effective T cells at the same time; however, both of these goals face substantial and very different challenges [1]. A rational scientific strategy tackles and solves these roadblocks separately [2] before combining the two successful solutions into a single vaccine formulation.Here, we focus on the induction of protective T-cell responses. In order to act quickly and efficiently, protective T cells will be required to recognize all HIV-1 variants circulating in the target population as well as all escape mutants generated in individuals who did not repel the virus in the first place. We hypothesized that HIV-1 variation would be best tackled by focusing immune responses on domains that lie within functionally conserved regions of the virus [3]. Thus, we assembled immunogen HIVconsv as a single chimeric protein from the 14 most invariable segments of the HIV-1 proteome, each 27-128 amino acids in length, alternated individual regions among the four major clades (A, B, C, and D) to ensure equal representation and used clade consensus sequences to reflect variation within individual clades. As these regions are functionally conserved, T-cell escape mutations are expected to incur significant costs to viral fitness. Also, relative to non-protective responses induced during natural HIV-1 infection, HIVconsv refocuses T cells to subdominant epitopes, which may be important for protection [4][5][6]. Thus, the HIVconsv immunogen offers a simple and univ...

IgG-Mediated Anaphylaxis to a Synthetic Long Peptide Vaccine Containing a B Cell Epitope Can Be Avoided by Slow-Release Formulation

“…Therefore, we cannot directly extrapolate our data to human vaccination, but our current results show that careful attention has to be given to potential systemic toxicity mediated by Abs after SLP vaccination, which warrants optimizing dose and mode of administration. In particular, formulation in a slow-release system prevents these side effects at immunizing doses, as already demonstrated in human and nonhuman primate studies (10,36).…”

“…For instance, we have used 20 or 50 mg SLP for each effective vaccination, whereas in human patients and nonhuman primates 300 mg per individual SLP is used (10,36). In contrast, comparable amounts of Ag-Ab complexes in humans might cause less severe toxicity, probably owing to larger body size.…”

Clonotypic Diversification of Intratumoral T Cells Following Sipuleucel-T Treatment in Prostate Cancer Subjects

“…This broadening of T-cell responses may reflect processes similar to those seen in the immune response to infectious disease vaccinations (32)(33)(34). However, the specificity and type of T cells recruited to the prostate tissue remain unknown at this time.…”

Superior Induction of T Cell Responses to Conserved HIV-1 Regions by Electroporated Alphavirus Replicon DNA Compared to That with Conventional Plasmid DNA Vaccine

“…HIVconsv is a second-generation T cell immunogen designed to deal with HIV-1 variability and escape by focusing immune responses on the conserved regions of the HIV-1 proteome (25,40). These conventional plasmid or replicon DNA-primed responses were boosted by two heterologous vaccines modalities that are currently being evaluated in clinical trials, modified vaccinia virus Ankara MVA.HIVconsv or attenuated chimpanzee adenovirus ChAdV63.HIVconsv (25,40). The results are discussed in the context of current HIV-1 vaccine development.…”