Recent developments in clinical trial designs for HIV vaccine research

Richert, Laura; Lhomme, Édouard; Fagard, Catherine; Lévy, Yves; Chêne, Geneviève; Thiébaut, Rodolphe

doi:10.1080/21645515.2015.1011974

Cited by 8 publications

(6 citation statements)

References 57 publications

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“…The time points at which different immunogenicity markers are measured in phase I and II HIV vaccine trials vary but are usually selected between two and four weeks after the final vaccine injection [ 13 ]. A better understanding of the dynamics of vaccine-induced immune responses would help facilitate a sampling strategy that can target optimal time points for each immunogenicity marker, to learn more about the vaccine's immunogenicity and increase the efficiency of clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Early CD4+ T Cell Responses Are Associated with Subsequent CD8+ T Cell Responses to an rAd5-Based Prophylactic Prime-Boost HIV Vaccine Strategy

et al. 2016

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IntroductionInitial evaluation of a candidate vaccine against HIV includes an assessment of the vaccine’s ability to generate immune responses. However, the dynamics of vaccine-induced immune responses are unclear. We hypothesized that the IFN-γ producing cytotoxic CD8+ (CD8+ IFN-γ+) T cell responses could be predicted by early IL-2 producing CD4+ (CD4+ IL-2+) helper T cell responses, and we evaluated this hypothesis using data from a phase I/II prophylactic HIV vaccine trial. The objective was to assess the dynamics and correlations between CD4+ IL-2+ T cell and CD8+ IFN-γ+ T cell responses after vaccination with a recombinant adenoviral serotype 5 (rAd5) HIV vaccine.MethodsWe analyzed data from the HVTN 068 HIV vaccine trial, which evaluated the immunogenicity of two different strategies for prime and boost vaccination (rAd5-rAd5 vaccine versus DNA-rAd5) in 66 healthy volunteers. Spearman correlations between immunogenicity markers across time-points were calculated. CD8+ IFN-γ+ T cell response in the rAd5-rAd5 arm was modeled as a function of CD4+ IL-2+ T cell response and time using mixed effects regression models.ResultsModerate to high correlations (r = 0.48–0.76) were observed in the rAd5-rAd5 arm between the CD4+ IL-2+ T cell response at week 2 and later CD8+ IFN-γ+ T cell responses (weeks 2–52). Regression models confirmed this relationship with a significant association between the two markers: for a 1.0% increase in CD4+ IL-2+ T cells at week 2 post-prime, a 0.3% increase in CD8+ IFN-γ+ T cell responses across subsequent time points, including post-boost time points, was observed (p<0.01).ConclusionThese results suggest an early and leading role of CD4+ T cells in the cellular response to the rAd5-rAd5 vaccine and in particular the stimulation of cytotoxic CD8+ T cell responses. These results could inform better timing of CD4+ T cell measurements in future clinical trials.

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Section: Introductionmentioning

confidence: 99%

Early CD4+ T Cell Responses Are Associated with Subsequent CD8+ T Cell Responses to an rAd5-Based Prophylactic Prime-Boost HIV Vaccine Strategy

et al. 2016

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“…Since defense against different infectious diseases requires a balanced combination of unique immune mechanisms, new vaccines will need to elicit an equally fine-tuned immune reaction. Gaps in our knowledge of the qualitative aspects of the human immune response which prevents infection or progression to clinical disease have so far severely hampered the design of efficacious vaccines against several pandemics such as AIDS [34], hepatitis C infection [35,36], and malaria [37,38]. Similarly for TB, the fine-tuned mechanisms that are responsible for sterile eradication or at least lifelong containment of Mtb remain elusive, making it hard to design a vaccine that achieves elimination of Mtb or sustains LTBI lifelong, thereby preventing progression to clinical TB [29,39,40].…”

Section: Biomarkers As Guides For Vaccine Designmentioning

confidence: 99%

Accelerating tuberculosis vaccine trials with diagnostic and prognostic biomarkers

Kaufmann

Weiner

Maertzdorf

2017

Expert Review of Vaccines

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The most recent estimates on tuberculosis (TB) morbidity and mortality reveal that the global disease burden is even higher than previously assumed. Better drugs, diagnostics and vaccines are major requirements to control the ongoing TB pandemic. The high complexity of the infectious process and the underlying pathology, however, challenge elucidation of protective immune mechanisms at the various stages towards active TB disease, which need to be understood for rational design of novel intervention measures. Areas covered: Next to the more classical approaches, host biomarkers increasingly receive attention as promising tools on our way to control the disease. In the area of diagnosis, host biomarkers are recognized as promising new means because the identification of small biosignatures with high discriminatory and even prognostic potential has stimulated the hope that rapid and easy-to-perform diagnosis and prognosis will become possible in the near future. For rational design of new vaccine candidates, correlates of protection are highly desirable. High-throughput systems-vaccinology will boost the identification of such biomarker profiles. Expert commentary: Considering their potential to accelerate development of better diagnostics and vaccines, host biomarkers should be firmly integrated into future TB research.

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“…Therefore, there is a major need for therapeutic strategies as an alternative to the combined antiretroviral drugs [2]. HIV vaccine strategies are expected to be a critical component for controlling the HIV epidemic [3,4]. Immunotherapy, or therapeutic vaccination, aims to enhance existing immune responses against HIV or stimulate immune responses.…”

Section: Hiv Infection and Vaccinationmentioning

confidence: 99%

Which Vaccination Strategies and Immune Responses are More Effective Against HIV Infections?

Bolhassani¹

2016

Advances in Molecular Retrovirology

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Vaccination is one of the most successful approaches for controlling various viral diseases. Novel approaches will be needed to develop highly effective vaccines to prevent infectious diseases such as HIV. There are many aspects of HIV-biology that make the development of an HIV vaccine difficult, including viral diversity, effective type of immune response, and suitable experimental model for preclinical trials. In spite of these challenges, recent published results showed that a vaccine regimen could reduce HIV infection rates by % in Thailand. This vaccine named as RV is composed of a recombinant canarypox vector expressing three HIV-proteins as a prime and two different recombinant HIV-gp envelope glycoproteins with alum adjuvant as a boost. In addition, a subunit vaccine constructed from the viral envelope protein could be efficiently developed using new techniques available through genetic engineering. The current HIV-vaccine development focuses on antibody-based approaches. It was shown that immunization with the viral envelope glycoprotein, gp , should generate neutralizing antibodies that would prevent infection, thereby yielding protective immunity. However, HIV could develop many pathways to escape from antibodies that bind to the different parts of the viral envelope molecules. Thus, the generation of neutralizing antibodies is very difficult after viral infection or immunization protocols. Indeed, the viral envelope molecules Env possess glycosylated residues that cover surface epitopes for binding and neutralizing antibodies, even if the antibodies are produced. Furthermore, the trimeric structures of envelope molecules show rapid conformational changes due to the interaction with viral cell surface receptors, CCR /CXCR and CD thus the transition state is very poor to be recognized by the immune system. Currently, studies focus on generating stable trimeric envelope molecules gp /gp as immunogens that can induce neutralizing antibodies that can compete for binding to the cell surface receptors. "ltogether, it is clear that the design of a vaccine to elicit HIV-neutralizing antibodies is not straightforward, and it causes major challenges in structural biology and immunology, several other studies strongly suggest cytotoxic T-lymphocyte CTL -based immune responses against HIV infections. Indeed, CD +

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Recent developments in clinical trial designs for HIV vaccine research

Cited by 8 publications

References 57 publications

Early CD4+ T Cell Responses Are Associated with Subsequent CD8+ T Cell Responses to an rAd5-Based Prophylactic Prime-Boost HIV Vaccine Strategy

Early CD4+ T Cell Responses Are Associated with Subsequent CD8+ T Cell Responses to an rAd5-Based Prophylactic Prime-Boost HIV Vaccine Strategy

Accelerating tuberculosis vaccine trials with diagnostic and prognostic biomarkers

Which Vaccination Strategies and Immune Responses are More Effective Against HIV Infections?

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