Safety and Immunogenicity of DNA Prime and Modified Vaccinia Ankara Virus-HIV Subtype C Vaccine Boost in Healthy Adults

Hayes, Peter; Gilmour, Jill; Lieven, Andrea von; Gill, Dilbinder K.; Clark, Lorna; Kopycinski, Jakub; Cheeseman, Hannah; Chung, Amy W.; Alter, Galit; Dally, Len; Zachariah, Devika; Lombardo, Angela; Ackland, James; Sayeed, Eddy; Jackson, Akil; Boffito, Marta; Gazzard, Brian; Fast, Patricia E.; Cox, Josephine H.; Laufer, Dagna

doi:10.1128/cvi.00637-12

Cited by 25 publications

(21 citation statements)

References 60 publications

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“…Priming with DNA vaccines is an approach studied by VRC/NIAID/NIH as a preventive vaccination strategy against multiple pathogens [9,13] as well as by others for different pathogens and cancer [14–17]. The DNA vaccine priming appears to expand the antibody epitope repertoire and increase affinity maturation, and to direct development of T cells with effector memory phenotype [18–20].…”

Section: Introductionmentioning

confidence: 99%

Phase I clinical evaluation of seasonal influenza hemagglutinin (HA) DNA vaccine prime followed by trivalent influenza inactivated vaccine (IIV3) boost

Ledgerwood

Costner

et al. 2015

Contemporary Clinical Trials

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Annual influenza vaccination reduces the risks of influenza when the vaccines are well matched to circulating strains, but development of an approach that induces broader and more durable immune responses would be beneficial. We conducted two companion Phase 1 studies, VRC 307 and VRC 309, over sequential seasons (2008–2009 and 2009–2010) in which only the influenza B strain component of the vaccines differed. Objectives were safety and immunogenicity of prime–boost vaccination schedules. A schedule of DNA vaccine encoding for seasonal influenza hemagglutinins (HA) prime followed by seasonal trivalent influenza inactivated vaccine (IIV3) boost (HA DNA–IIV3) was compared to placebo (PBS)–IIV3 or IIV3–IIV3. Cumulatively, 111 adults were randomized to HA DNA–IIV3 (n = 66), PBS–IIV3 (n = 25) or IIV3–IIV3 (n = 20). Safety was assessed by clinical observations, laboratory parameters and 7-day solicited reactogenicity. The seasonal HA DNA prime–IIV3 boost regimen was evaluated as safe and well tolerated. There were no serious adverse events. The local and systemic reactogenicity for HA DNA, IIV and placebo were reported predominantly as none or mild within the first 5 days post-vaccination. There was no significant difference in immunogenicity detected between the treatment groups as evaluated by hemagglutination inhibition (HAI) assay. The studies demonstrated the safety and immunogenicity of seasonal HA DNA–IIV3 regimen, but the 3–4 week prime–boost interval was suboptimal for improving influenza-specific immune responses. This is consistent with observations in avian H5 DNA vaccine prime–boost studies in which a long interval, but not a short interval, was associated with improved immunogenicity. Trial Registration: NCT00858611 for VRC 307 and NCT00995982 for VRC 309.

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Section: Introductionmentioning

confidence: 99%

Phase I clinical evaluation of seasonal influenza hemagglutinin (HA) DNA vaccine prime followed by trivalent influenza inactivated vaccine (IIV3) boost

Ledgerwood

Costner

et al. 2015

Contemporary Clinical Trials

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“…Our initial efforts have focused on the development of a VIA that determines the p24 release in cell culture supernatant as a measure of HIV-1 replication, and this assay has proven valuable for testing samples from several HIV-1 vaccine trials (Spentzou et al, 2010; Hayes et al, 2013; N Borthwick et al manuscript in preparation). However, we recognized certain limitations and thus pursued technological advances towards the development and optimization of a second generation VIA, referred to throughout the manuscript as the IMC LucR VIA.…”

Section: Introductionmentioning

confidence: 99%

Development of a luciferase based viral inhibition assay to evaluate vaccine induced CD8 T-cell responses

Naarding

Fernández

Kappes

et al. 2014

Journal of Immunological Methods

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Emergence of SIV and HIV specific CD8 T cells has been shown to correlate with control of in vivo replication. Poor correlation between IFN-γ ELISPOT responses and in vivo control of the virus has triggered the development of more relevant assays to assess functional HIV-1 specific CD8 T-cell responses for the evaluation and prioritization of new HIV-1 vaccine candidates. We previously established a viral inhibition assay (VIA) that measures the ability of vaccine-induced CD8 T-cell responses to inhibit viral replication in autologous CD4 T cells. In this assay, viral replication is determined by measuring p24 in the culture supernatant. Here we describe the development of a novel VIA, referred to as IMC LucR VIA that exploits replication-competent HIV-1 infectious molecular clones (IMCs) in which the complete proviral genome is strain-specific and which express the Renilla luciferase (LucR) gene to determine viral growth and inhibition. The introduction of the luciferase readout does provide significant improvement of the read out time. In addition to switching to the LucR read out, changes made to the overall protocol resulted in the miniaturization of the assay from a 48 to a 96-well plate format, which preserved sample and allowed for the introduction of replicates. The overall assay time was reduced from 13 to 8 days. The assay has a high degree of specificity, and the previously observed non-specific background inhibition in cells from HIV-1 negative volunteers has been reduced dramatically. Importantly, we observed an increase in positive responses, indicating an improvement in sensitivity compared to the original VIA. Currently, only a limited number of “whole-genome” IMC-LucR viruses are available and our efforts will focus on expanding the panel to better evaluate anti-viral breadth. Overall, we believe the IMC LucR VIA provides a platform to assess functional CD8 T-cell responses in large-scale clinical trial testing, which will enhance the ability to select the most promising HIV-1 vaccine candidates capable of controlling HIV-1 replication in vivo.

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“…Other groups have also tested DNA/MVA HIV vaccines in humans [39,41,43,95,122–125]. These studies differ with regard to number of doses of DNA primes and MVA boosts, the immunogens used, and their expression levels [95,122,123].…”

Section: Immunogenicity Of Dna/mva Hiv Vaccines In Humansmentioning

confidence: 99%

Section: Immunogenicity Of Dna/mva Hiv Vaccines In Humansmentioning

confidence: 99%

“…These studies differ with regard to number of doses of DNA primes and MVA boosts, the immunogens used, and their expression levels [95,122,123]. Hayes et al utilized a DDDM regimen in healthy adults that exhibited enhanced breadth and magnitude of the cellular response and better viral inhibition in vitro compared to immunization with MVA alone [122]. A multi-gene, multi-clade DDDM Phase I study performed in Sweden demonstrated generation of HIV-specific CD4 + and CD8 + T cell responses, but poor development of Env antibody responses [39,41].…”

Section: Immunogenicity Of Dna/mva Hiv Vaccines In Humansmentioning

confidence: 99%

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Immunogenicity and efficacy of DNA/MVA HIV vaccines in rhesus macaque models

Chea

Amara

2017

Expert Review of Vaccines

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Introduction: Despite 30 years of research on HIV, a vaccine to prevent infection and limit disease progression remains elusive. The RV144 trial showed moderate, but significant protection in humans and highlighted the contribution of antibody responses directed against HIV envelope as an important immune correlate for protection. Efforts to further build upon the progress include the use of a heterologous prime-boost regimen using DNA as the priming agent and the attenuated vaccinia virus, Modified Vaccinia Ankara (MVA), as a boosting vector for generating protective HIV-specific immunity. Areas Covered: In this review, we summarize the immunogenicity of DNA/MVA vaccines in non-human primate models and describe the efficacy seen in SIV infection models. We discuss immunological correlates of protection determined by these studies and potential approaches for improving the protective immunity. Additionally, we describe the current progress of DNA/MVA vaccines in human trials. Expert Commentary: Efforts over the past decade have provided the opportunity to better understand the dynamics of vaccine-induced immune responses and immune correlates of protection against HIV. Based on what we have learned, we outline multiple areas where the field will likely focus on in the next five years.

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Safety and Immunogenicity of DNA Prime and Modified Vaccinia Ankara Virus-HIV Subtype C Vaccine Boost in Healthy Adults

Cited by 25 publications

References 60 publications

Phase I clinical evaluation of seasonal influenza hemagglutinin (HA) DNA vaccine prime followed by trivalent influenza inactivated vaccine (IIV3) boost

Phase I clinical evaluation of seasonal influenza hemagglutinin (HA) DNA vaccine prime followed by trivalent influenza inactivated vaccine (IIV3) boost

Development of a luciferase based viral inhibition assay to evaluate vaccine induced CD8 T-cell responses

Immunogenicity and efficacy of DNA/MVA HIV vaccines in rhesus macaque models

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