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      HIV DNA Vaccine: Stepwise Improvements Make a Difference

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          Abstract

          Inefficient DNA delivery methods and low expression of plasmid DNA have been major obstacles for the use of plasmid DNA as vaccine for HIV/AIDS. This review describes successful efforts to improve DNA vaccine methodology over the past ~30 years. DNA vaccination, either alone or in combination with other methods, has the potential to be a rapid, safe, and effective vaccine platform against AIDS. Recent clinical trials suggest the feasibility of its translation to the clinic.

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          DNA vaccines: ready for prime time?

          Michele Kutzler, David B Weiner (2008)
          Since the discovery, over a decade and a half ago, that genetically engineered DNA can be delivered in vaccine form and elicit an immune response, there has been much progress in understanding the basic biology of this platform. A large amount of data has been generated in preclinical model systems, and more sustained cellular responses and more consistent antibody responses are being observed in the clinic. Four DNA vaccine products have recently been approved, all in the area of veterinary medicine. These results suggest a productive future for this technology as more optimized constructs, better trial designs and improved platforms are being brought into the clinic.
          Article 0 comments Cited 286 times – based on 0 reviews     Review now
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            HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis.

            M. Juliana McElrath, Stephen De Rosa, Zoe Moodie … (2008)
            In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated men with pre-existing adenovirus serotype 5 (Ad5) immunity. We assessed vaccine-induced immunity and its potential contributions to infection risk. To assess immunogenicity, we characterised HIV-specific T cells ex vivo with validated interferon-gamma ELISPOT and intracellular cytokine staining assays, using a case-cohort design. To establish effects of vaccine and pre-existing Ad5 immunity on infection risk, we undertook flow cytometric studies to measure Ad5-specific T cells and circulating activated (Ki-67+/BcL-2(lo)) CD4+ T cells expressing CCR5. We detected interferon-gamma-secreting HIV-specific T cells (range 163/10(6) to 686/10(6) peripheral blood mononuclear cells) ex vivo by ELISPOT in 77% (258/354) of people receiving vaccine; 218 of 354 (62%) recognised two to three HIV proteins. We identified HIV-specific CD4+ T cells by intracellular cytokine staining in 58 of 142 (41%) people. In those with reactive CD4+ T cells, the median percentage of CD4+ T cells expressing interleukin 2 was 88%, and the median co-expression of interferon gamma or tumor necrosis factor alpha (TNFalpha), or both, was 72%. We noted HIV-specific CD8+ T cells (range 0.4-1.0%) in 117 of 160 (73%) participants, expressing predominantly either interferon gamma alone or with TNFalpha. Vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile, did not differ between vaccinated male cases (before infection) and non-cases. Ad5-specific T cells were lower in cases than in non-cases in several subgroup analyses. The percentage of circulating Ki-67+BcL-2(lo)/CCR5+CD4+ T cells did not differ between cases and non-cases. Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial.
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              Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env-V2

              Morgane Rolland, Paul T. Edlefsen, Brendan B. Larsen … (2012)
              Summary The RV144 trial demonstrated 31% vaccine efficacy (VE) at preventing HIV-1 infection 1 . Antibodies against the HIV-1 envelope variable loops 1 and 2 (V1/V2) domain correlated inversely with infection risk 2 . We hypothesized that vaccine-induced immune responses against V1/V2 would selectively impact, or sieve, HIV-1 breakthrough viruses. 936 HIV-1 genome sequences from 44 vaccine and 66 placebo recipients were examined. We show that vaccine-induced immune responses were associated with two signatures in V1/V2 at amino-acid positions 169 and 181. VE against viruses matching the vaccine at position 169 was 48% (CI: 18 to 66%; p=0.0036), whereas VE against viruses mismatching the vaccine at position 181 was 78% (CI: 35% to 93%; p=0.0028). Residue 169 is in a cationic glycosylated region recognized by broadly neutralizing and RV144-derived antibodies. The predicted distance between the two signatures sites (21±7 Å), and their match/mismatch dichotomy, suggest that multiple factors may be involved in the protection observed in RV144. Genetic signatures of RV144 vaccination in V2 complement the finding of an association between high V1/V2 binding antibodies and reduced risk of HIV-1 acquisition and provide evidence that vaccine-induced V2 responses plausibly played a role in the partial protection conferred by the RV144 regimen.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Vaccines (Basel)
                Journal ID (iso-abbrev): Vaccines (Basel)
                Journal ID (publisher-id): vaccines
                Title: Vaccines
                Publisher: MDPI
                ISSN (Electronic): 2076-393X
                Publication date (Electronic): 14 May 2014
                Publication date Collection: June 2014
                Volume: 2
                Issue: 2
                Pages: 354-379
                Affiliations
                [1 ]Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, P.O. Box B, Frederick, MD 21702, USA; E-Mail: cristina.bergamaschi@ 123456nih.gov
                [2 ]Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, P.O. Box B, Frederick, MD 21702, USA; E-Mails: antonio.valentin@ 123456nih.gov (A.V.); margherita.rosati@ 123456nih.gov (M.R.); george.pavlakis@ 123456nih.gov (G.N.P.)
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: barbara.felber@ 123456nih.gov ; Tel.: +1-301-846-5159; Fax: +1-301-846-7146.
                Article
                Publisher ID: vaccines-02-00354
                DOI: 10.3390/vaccines2020354
                PMC ID: 4494255
                SO-VID: 87da2ef0-28b6-4871-ad89-10a457f888c1
                Copyright © © 2014 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 21 February 2014
                Date revision received : 11 April 2014
                Date accepted : 18 April 2014
                Categories
                Subject: Review

                Keywords: macaque,cytokine,plasmid,electroporation,immunogenicity,vaccination,dna delivery,dna expression
                Data availability:
                Keywords: macaque, cytokine, plasmid, electroporation, immunogenicity, vaccination, dna delivery, dna expression

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