HIV-1 Vaccines and Adaptive Trial Designs

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Science translational medicine (Impact Factor: 15.84). 04/2011; 3(79):79ps13. DOI: 10.1126/scitranslmed.3001863
Source: PubMed

ABSTRACT Developing a vaccine against the human immunodeficiency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although nonhuman primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.

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    • "Recently, calls for accelerated clinical development of HIV vaccine strategies have been put forward, advocating the implementation of adaptive trial designs for this purpose [12,13]. Indeed, numerous adaptive or multi-stage clinical trial designs for different phases of clinical development are available in the methodological literature. "
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    ABSTRACT: Many candidate vaccine strategies against human immunodeficiency virus (HIV) infection are under study, but their clinical development is lengthy and iterative. To accelerate HIV vaccine development optimised trial designs are needed. We propose a randomised multi-arm phase I/II design for early stage development of several vaccine strategies, aiming at rapidly discarding those that are unsafe or non-immunogenic. We explored early stage designs to evaluate both the safety and the immunogenicity of four heterologous prime-boost HIV vaccine strategies in parallel. One of the vaccines used as a prime and boost in the different strategies (vaccine 1) has yet to be tested in humans, thus requiring a phase I safety evaluation. However, its toxicity risk is considered minimal based on data from similar vaccines. We newly adapted a randomised phase II trial by integrating an early safety decision rule, emulating that of a phase I study. We evaluated the operating characteristics of the proposed design in simulation studies with either a fixed-sample frequentist or a continuous Bayesian safety decision rule and projected timelines for the trial. We propose a randomised four-arm phase I/II design with two independent binary endpoints for safety and immunogenicity. Immunogenicity evaluation at trial end is based on a single-stage Fleming design per arm, comparing the observed proportion of responders in an immunogenicity screening assay to an unacceptably low proportion, without direct comparisons between arms. Randomisation limits heterogeneity in volunteer characteristics between arms. To avoid exposure of additional participants to an unsafe vaccine during the vaccine boost phase, an early safety decision rule is imposed on the arm starting with vaccine 1 injections. In simulations of the design with either decision rule, the risks of erroneous conclusions were controlled <15%. Flexibility in trial conduct is greater with the continuous Bayesian rule. A 12-month gain in timelines is expected by this optimised design. Other existing designs such as bivariate or seamless phase I/II designs did not offer a clear-cut alternative. By combining phase I and phase II evaluations in a multi-arm trial, the proposed optimised design allows for accelerating early stage clinical development of HIV vaccine strategies.
    Trials 02/2014; 15(1):68. DOI:10.1186/1745-6215-15-68 · 1.73 Impact Factor
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    • "This is especially the case for women because of the increasing feminization of the pandemic epicenter in sub-Saharan Africa where 75 percent of the HIV-1 infected population ages 15–24 are females [1], [2]. Development of a prophylactic vaccine to prevent HIV infection represents the most effective, economical, and universal solution to achieving this goal, but thus far in human trials, vaccine candidates have been at best marginally effective [3], [4]. The SIV-infected rhesus macaque model of HIV is a powerful system being used to gain insights into HIV/SIV pathogenesis and aid in the development of an effective HIV vaccine. "
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    ABSTRACT: Live-attenuated SIV vaccines (LAVs) have been the most effective to date in preventing or partially controlling infection by wild-type SIV in non-human primate models of HIV-1 transmission to women acting by mechanisms of protection that are not well understood. To gain insights into mechanisms of protection by LAVs that could aid development of effective vaccines to prevent HIV-1 transmission to women, we used in situ tetramer staining to determine whether increased densities or changes in the local distribution of SIV-specific CD8 T cells correlated with the maturation of SIVΔnef vaccine-induced protection prior to and after intra-vaginal challenge with wild-type SIVmac251. We evaluated the immunodominant Mamu-A1*001:01/Gag (CM9) and Mamu-A1*001:01/Tat (SL8) epitope response in genital and lymphoid tissues, and found that tetramer+ cells were present at all time points examined. In the cervical vaginal tissues, most tetramer+ cells were distributed diffusely throughout the lamina propria or co-localized with other CD8 T cells within lymphoid aggregates. The distribution and densities of the tetramer+ cells at the portal of entry did not correlate with the maturation of protection or change after challenge. Given these findings, we discuss the possibility that changes in other aspects of the immune system, including the quality of the resident population of virus-specific effector CD8 T cells could contribute to maturation of protection, as well as the potential for vaccine strategies that further increase the size and quality of this effector population to prevent HIV-1 transmission.
    PLoS ONE 12/2013; 8(12):e81623. DOI:10.1371/journal.pone.0081623 · 3.23 Impact Factor
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    • "Numerous reasons to explain this absence have been mentioned in the literature. Scientific challenges are significant [18] but, according to Cohen [19] and Thomas [20], critical causes also include scientific infighting, the lack of co-ordination between institutions, and the lack of funding from pharmaceutical companies. In fact, Harris [21] estimated that in 2008, pharmaceutical companies only invested $33 million in research for an HIV vaccine. "
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    ABSTRACT: Investment by manufacturers in research and development of vaccines is relatively low compared with that of pharmaceuticals. If current evaluation technologies favour drugs over vaccines, then the vaccines market becomes relatively less attractive to manufacturers. We developed a mathematical model simulating the decision-making process of regulators and payers, in order to understand manufacturers' economic incentives to invest in vaccines rather than curative treatments. We analysed the objectives and strategies of manufacturers and payers when considering investment in technologies to combat a disease that affects children, and the interactions between them. The model confirmed that, for rare diseases, the economically justifiable prices of vaccines could be substantially lower than drug prices, and that, for diseases spread across multiple cohorts, the revenues derived from vaccinating one cohort per year (routine vaccination) could be substantially lower than those generated by treating sick individuals. Manufacturers may see higher incentives to invest in curative treatments rather than in routine vaccines. To encourage investment in vaccines, health authorities could potentially revise their incentive schemes by: (1) committing to vaccinate all susceptible cohorts in the first year (catch-up campaign); (2) choosing a long-term horizon for health technology evaluation; (3) committing higher budgets for vaccines than for treatments; and (4) taking into account all intangible values derived from vaccines.
    Cost Effectiveness and Resource Allocation 09/2013; 11(1):23. DOI:10.1186/1478-7547-11-23 · 0.87 Impact Factor
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