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Recent developments in clinical trial designs for HIV vaccine research abcde
Laura Richert abce
Chêne
, Edouard Lhomme
abcd
, Catherine Fagard
abe
, Yves Lévy
efgh
, Geneviève
abcde
& Rodolphe Thiébaut
a
Univ. Bordeaux, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, F-33000 Bordeaux, France b
INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, and CIC1401-EC (Clinical epidemiology), F-33000 Bordeaux, France c
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CHU de Bordeaux, Pole de sante publique, F-33000 Bordeaux, France
d
INRIA SISTM, F-33405 Talence, France
e
Vaccine Research Institute (VRI), F-94010 Créteil, France
f
INSERM U955, F-94010 Créteil, France
g
Univ. Paris Est Créteil, Faculté de Médecine, F-94010 Créteil, France
h
Groupe Henri-Mondor Albert-Chenevier, Immunologie clinique, F-94010 Créteil, France Accepted author version posted online: 09 Mar 2015.
To cite this article: Laura Richert, Edouard Lhomme, Catherine Fagard, Yves Lévy, Geneviève Chêne & Rodolphe Thiébaut (2015): Recent developments in clinical trial designs for HIV vaccine research , Human Vaccines & Immunotherapeutics To link to this article: http://dx.doi.org/10.1080/21645515.2015.1011974
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Recent developments in clinical trial designs for HIV vaccine research Review
Laura Richert1,2,3,4,5, Edouard Lhomme1,2,3,4, Catherine Fagard1,2,5, Yves Lévy5,6,7,8, Geneviève
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Chêne1,2,3,5, Rodolphe Thiébaut1,2,3,4,5; for the Vaccine Research Institute (VRI)
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Univ. Bordeaux, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, F-33000
INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, and CIC1401-EC
an
2
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Bordeaux, France
(Clinical epidemiology), F-33000 Bordeaux, France
CHU de Bordeaux, Pole de sante publique, F-33000 Bordeaux, France
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INRIA SISTM, F-33405 Talence, France
5
Vaccine Research Institute (VRI), F-94010 Créteil, France
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INSERM U955, F-94010 Créteil, France
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Univ. Paris Est Créteil, Faculté de Médecine, F-94010 Créteil, France
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Groupe Henri-Mondor Albert-Chenevier, Immunologie clinique, F-94010 Créteil, France
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Affiliations:
Corresponding author: Pr Rodolphe Thiébaut, MD, PhD; Centre INSERM U897 ; Université Bordeaux Segalen, 146, rue Léo Saignat – case 11, F-33076 Bordeaux cedex, FRANCE. [email protected]
1
Key words: AIDS vaccines, clinical trials, epidemiologic research design, treatment outcome, HIV, prevention, therapeutic use
Adenovirus 5
DNA
deoxyribonucleic acid
HIV
human immunodeficiency virus
IDU
intravenous drug users
IFN-γ
interferon-gamma
MSM
men having sex with men
PrEP
pre-exposure prophylaxis
RNA
ribonucleic acid
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Abstract
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Ad5
HIV vaccine strategies are expected to be a crucial component for controlling the HIV
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List of abbreviations
epidemic. Despite the large spectrum of potential candidate vaccines for both prophylactic and therapeutic use, the overall development process of an efficacious HIV vaccine strategy is lengthy. The design of clinical trials and the progression of a candidate strategy through the different clinical development stages remain methodologically challenging, mainly due to the lack of validated correlates of protection. In this review, we describe recent advances in clinical trial designs to increase the efficiency of the clinical development of candidate HIV
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vaccine strategies. The methodological aspects of the designs for early- (phase I and II) and later –stage (phase IIB and III) development are discussed, taking into account the
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specificities of both prophylactic and therapeutic HIV vaccine development.
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Background Despite considerable advances in HIV prevention and treatment, HIV infection still remains a threatening infectious disease with important public health consequences. To control the HIV epidemic, two principal issues would need to be resolved: i) efficacious and feasible largescale measures for HIV prevention, and ii) strategies for a cure from infection. To achieve
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each of these aims, complex integrated strategies may be required, of which HIV vaccines
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expected to be crucial components.1
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No prophylactic or therapeutic HIV vaccine strategies with satisfactory efficacy are available
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to date, but the research field has been encouraged by the first report of a protective vaccine effect against HIV in 2009. Results of a randomized phase IIB trial in 16402 healthy
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volunteers in Thailand (RV144 trial), evaluating a combination of two HIV candidate vaccines in a prime-boost strategy against placebo, showed promising results with a reduction
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of HIV acquisition in the active vaccine arm.2 However, estimated vaccine efficacy was modest (approximately 30%) and seemed to wane over time.2-4
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In therapeutic approaches, the efficacy of vaccine strategies to control viral replication or to reduce the viral reservoir has been evaluated in proof-of-concept trials with varying results
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(reviewed in 5, 6).
To disentangle the results of the RV144 trial and to improve the efficacy of HIV candidate
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(prophylactic vaccines for the first issue and therapeutic vaccines for the second one) are
vaccines, research is currently very active, with a multitude of potential vaccine strategies under development for both prophylactic and therapeutic applications. Candidate vaccines
against HIV include protein or sub-unit vaccines, recombinant viral vector, deoxyribonucleic acid (DNA) and dendritic-cell based vaccines.7 As the results of the RV144 trial suggest that heterologous prime-boost strategies are a promising approach, the number of strategies to be evaluated is potentially large.
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Despite this spectrum of candidate vaccines, the development of efficacious HIV vaccine strategies remains a major scientific challenge. In addition to aspects related to viral diversity and escape, HIV vaccine development is complicated as there is limited knowledge about the potential immunological correlates of clinical vaccine efficacy, that is protection from infection or post-infection viral load in the case of a prophylactic strategy or virological
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control or stable disease without antiretroviral treatment in the case of a therapeutic strategy.
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immunogenicity markers. The overall development process is lengthy, and it is difficult to
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correctly appreciate the worthiness of a new HIV vaccine strategy before the first clinical efficacy trials.8 This has resulted in only six prophylactic HIV vaccine efficacy trials
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implemented so far, with the phase IIB RV144 trial in Thailand mentioned above being the only trial with a promising result. The remaining trials showed disappointing results with no
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evidence for a protective vaccine effect (Table 1).
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Results of an exploratory case-control analysis nested in the RV144 trial suggested that the modest clinical efficacy of the prime-boost strategy under evaluation may have been mediated
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by humoral responses,9 but cellular responses may also contribute to this association.10 Despite the encouraging results of the RV144 trial, it is, however, premature to conclude
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which components of cellular or humoral immunity should be generated by a HIV vaccine strategy. Moreover, it is likely that the immunological correlates of HIV vaccine efficacy will
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This means that it is not yet possible to predict these clinical outcomes based on
be different for prophylactic vaccine strategies versus therapeutic vaccine strategies.
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Principles of clinical development in HIV vaccine research HIV vaccine development currently relies on iterative loops between animal studies and clinical studies in humans. Phase I and II clinical trials are conducted to determine the safety and to assess the immunogenicity of the vaccine strategies in early clinical development. As correlates of protection are not well known to date, a large number of immunogenicity
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markers are measured. This implies a considerable uncertainty about the interpretation of
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early clinical development. Immunogenicity results in early clinical development stages in
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humans often entail a return to the animal model to optimize tested strategies.
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To obtain preliminary evidence based on a clinical endpoint (that is HIV acquisition or postinfection viremia), HIV vaccine development nowadays usually includes phase IIB test-of-
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concept trials before deciding whether further clinical efficacy testing is reasonable.11 In contrast to large phase III trials, phase IIB trials do not aim at directly supporting a licensure
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decision. Endpoint definitions and allowable type I and II error rates may be different between phase IIB and III trials. In particular, in test-of-concept trials higher false positive rates (type I
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error) and lower false negative rates (type II error) than in confirmatory trials may be
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desirable in order to increase the probability to detect a vaccine effect.11, 12 However, even these phase IIB trials typically require a large sample size with several thousand participants and prolonged follow-up.2, 13, 14 If results of a phase IIB trial are promising enough, phase III
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immunogenicity results and the potential value of a vaccine strategy as it proceeds through
trials are conducted to confirm clinical vaccine efficacy with stringent methods aiming at licensure requests.
To evaluate potential surrogate markers the first step is to assess correlates of risk, i.e. immunological markers that correlate with the clinical endpoint of interest.15-17 Evaluation of correlates of risk requires variability in the marker and the clinical endpoint, but not
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necessarily a protective vaccine effect. Correlates of risk can thus be analyzed in various datasets, such as observational data from HIV controllers,18-20 single arm vaccine trials or randomized trials. Once correlates of risks are identified, they can be evaluated with regards to their value as correlates of protection, which implies their evaluation as surrogate endpoints. Plotkin and
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Gilbert have defined a correlate of protection as an immune marker statistically associated
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vaccine effect on the clinical endpoint. This definition incorporates “surrogate endpoints” in
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the terminology used by Prentice.21 For the analysis of a surrogate endpoint, one needs datasets of randomized phase IIB or III trials having demonstrated a protective vaccine effect.
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As RV144 is the only trial having shown a modest protective effect of a prophylactic HIV vaccine strategy so far, this dataset constitutes a unique opportunity to search for correlates of
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protection for prophylactic HIV vaccine strategies,2, 9 although vaccine studies in non-human
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primates may also contribute to this search.22, 23
The sample size of the RV144 trial (16402 participants) and the trial’s timelines, with
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approximately ten years between trial planning and the publication of the main correlate
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results also illustrate the efforts required to conduct prophylactic HIV vaccine efficacy trials.24
Trial designs to accelerate clinical development of HIV vaccine strategies
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with clinical vaccine efficacy.15 In other words, a correlate of protection must capture the
A relevant impetus for rethinking HIV vaccine trial designs today is the demand to accelerate the clinical development of candidate vaccine strategies. In the methodological literature numerous clinical trial designs exist that allow for increased efficiency, by reducing sample size or allowing more rapid decision making within the clinical development plan than with classical designs, while maintaining desired operating characteristics and trial validity. Many
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of these designs have been in longstanding use in fields other than HIV vaccine research, especially in cancer research.25-27 Multi-arm trials have more than two arms, which can increase efficiency in terms of sample size, for example by comparing more than one active vaccine arm to a common control arm or by using factorial designs (Figure 1).
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Group-sequential or sequential trials allow for stopping the trial early in case of efficacy,
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methods to define the stopping rules, and review by an Independent Data Monitoring
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Committee.28 Recent prophylactic HIV vaccine efficacy trials used such designs, which resulted in the STEP and HVTN 505 trials, respectively, being stopped for futility.13, 29
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More sophisticated adaptive designs accommodate greater flexibility for modifications during trial conduct while controlling bias and the rates of erroneous conclusions, in particular the
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type I error rate.30 Design modifications in adaptive trials are prospectively planned and based
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on analyses of data accumulated during the trial and can concern different adaptations, such as selecting a treatment dose, stopping or adding a trial arm, enriching a participant sub-group,
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modifying the sample size or changing the random allocation ratio.31 Seamless adaptive designs allow for combining several development phases in one single trial. Well-defined
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endpoints but also extensive simulation studies are usually necessary to set up complex adaptive designs with adequate operating characteristics.32 The conduct of such trials also
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futility (that is lack of efficacy), or harm. This requires interim analyses, appropriate statistical
requires thorough planning of all operational aspects, for example the practical implementation of the design modifications in the trial’s logistics and the timing of unblinding. As is also the case in group-sequential trials, a proficient Independent Data Monitoring Committee plays a key role in the rigorous conduct of adaptive designs. Development of adaptive designs is currently a vast field of statistical research with a multitude of methods proposed in the recent literature, although the scientific and ethical
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challenges of such trials are also subject to debate,33,
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and acceptability by regulatory
authorities may need upfront consultations. To accelerate the clinical development of efficacious prophylactic HIV vaccine strategies several authors have recently called for the use of adaptive trial designs.8, 24, 35, 36 As most adaptive designs existing in the literature have been devised for other indications, mainly
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oncology trials, thorough methodological consideration is needed before being adapted to
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including but not limited to the acceptable toxicity rates of interventions and the rates of
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clinical efficacy endpoints.
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Designs for clinical efficacy vaccine trials
The only adaptive design in the literature developed for HIV vaccine trials relates to a multi-
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arm two-stage phase IIB design, in which adaptive decisions during the trial are based on a
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clinical HIV acquisition endpoint.12 This design allows for evaluating the efficacy of several prophylactic vaccine strategies in parallel with a common placebo arm. Interim analyses
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monitor futility of vaccine efficacy compared to placebo and aim at stopping inefficacious strategies during the first stage, that is in the first 18 months of follow-up. For all strategies
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that are not stopped, adaptations in the proposed design include i) the assessment of durability of vaccine efficacy in the second stage, ii) preparations to analyze correlates of protection in a
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HIV vaccine research. Many differences distinguish cancer and HIV vaccine research,
timely manner, and iii) head-to-head comparisons of promising vaccine strategies. Furthermore, interim analyses are planned to monitor for high efficacy, albeit it is unlikely that this type of stopping criterion be met with the currently developed HIV vaccine strategies, as well as continuous monitoring of harm. This design has thus many desirable features to accelerate HIV vaccine efficacy trials, but it remains yet to be implemented in practice.
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Specific methods for correlate discovery called “augmented designs” have been developed independently from adaptive trial designs, but can be combined with the latter. Such augmentations aim at deducing immune responses to the vaccine in placebo recipients, which are required for the statistical evaluation of surrogate endpoints in a counterfactual model. This can be achieved by imputing the non-observed immune response using baseline variables
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as predictors (baseline immunogenicity predictor approach) and/or administrating the vaccine
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To evaluate prophylactic HIV vaccine strategies together with other available partially
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effective prevention measures, such as pre-exposure prophylaxis (PrEP), several types of multi-arm efficacy trial designs have been proposed in the literature.38, 39 These include a two-
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by-two factorial four-arm design, with a first group receiving a combination of the vaccine and the other prevention measure, a second and third group receiving either the vaccine or the
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prevention measure, respectively, and the relevant placebo, and the fourth group receiving
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double placebo, which allows to assess not only the efficacy of each intervention but also possible synergies if the trial is adequately powered. Design options accommodating for the
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willingness of the participants to adhere to the non-vaccine prevention measure also exist, performing randomization in two stages. In the first stage, all participants are randomized to
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either vaccine or placebo. In the second stage, use of the other prevention measure is randomized only for those being willing. However, this increases the required sample sizes.39
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to a sample of placebo recipients at the end of the trial (close-out placebo vaccination).37
Designs including only a subset of the above mentioned arms also exist (reviewed in
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).
Some of these multi-arm designs could also be used should a non-inferiority hypothesis of a vaccine strategy alone compared to the combination strategy become relevant.39 How to best
perform group-sequential monitoring, or even adaptive modifications, in these combination trials requires further consideration.
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Therapeutic HIV vaccine efficacy trials require their own specific methodological considerations. Availability of highly effective antiretroviral treatment as standard of care raises questions about the acceptability and risk-benefit ratio of analytical treatment interruption to assess the vaccine effect on virological control in proof-of-concept trials.41 Whether virological control or disease progression events should be the primary endpoint in
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confirmatory trials would also need scrutiny. The level of intracellular HIV DNA, which is a
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endpoint. As therapeutic HIV vaccine development is currently mainly in early development
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stages, to our knowledge, few specific methodological papers related to efficacy trials have
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been published to date.
Immunogenicity assessments in early stage clinical HIV vaccine development
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In early stage clinical HIV vaccine development, that is phase I and II trials, the main
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limitation is currently the lack of validated surrogate endpoints that could be used to reliably explore vaccine efficacy based on immunogenicity markers. As adaptive designs require a
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clear consensual endpoint definition for progression between stages, application of such designs to early clinical development stages in HIV vaccine research is difficult.
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Nevertheless, phase II immunogenicity trials could benefit from other features of design optimizations but few authors have so far addressed design considerations in early stage HIV
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measure of the ‘reservoir’ of the latently infected cells, could also be considered as an
vaccine trials beyond endpoint definitions. Randomized multi-arm trials are valuable in early stage trials to allow for an unbiased assessment of the safety and immunogenicity of several candidate vaccine strategies in
parallel, with the standardized immunogenicity assays and endpoint definitions across arms. For instance, a non-comparative multi-arm phase IB selection design can be used to screen several strategies and prioritize among them for further development the most promising
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one.42 In this type of design, the arms are not compared directly to each other by statistical testing but are ranked based on a binary immunogenicity endpoint, and the arm(s) with the top-rank is/are selected. This allows for having adequate statistical power for selecting the strategy with the highest immunological response rate of the defined endpoint, while keeping the sample size reasonable for a phase II trial, usually comprising between twenty and fifty
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participants per arm. A minimum required response rate of the selected strategy can also be
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Another type of non-comparative multi-arm design aims at moving all strategies with
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immunogenicity response rate above such a minimum required rate forward to the next development stage. The minimum required rate is defined a priori, and the one-sided 95%
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confidence interval of the observed response rate in a trial arm must lie above this minimal rate in order to consider it promising. Such a design has recently been proposed in the
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literature for a phase II prophylactic HIV vaccine trial of four heterologous prime-boost
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strategies. Furthermore, as one of the vaccines to be studied in this design also required a phase I evaluation, the possibility to integrate a phase I safety stage in one arm of the
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randomized phase II design has been established (Figure 2). This is achieved by a sequential analyses of an early safety endpoint of the concerned vaccine with the aim to stop the vaccine
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before the boost phase should it be unsafe.43 The applicability of the integrated phase I evaluation relies on prior knowledge of the safety of similar vaccines and quick participant
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incorporated in the design.
accrual in the trial.
After such non-comparative trials, a randomized comparative phase II design can be set up as the next development step with direct statistical head-to-head comparisons of immunogenicity between strategies. Inclusion of a placebo arm is debatable in early stage prophylactic HIV vaccine trials in low-risk populations, where HIV-specific immune responses can be
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considered close to zero in the absence of exposure or vaccination for assays with high specificity. As a vaccine strategy proceeds further through clinical development stages, a randomized placebo arm will become important for head-to-head comparisons. In the absence of validated correlates of protection, endpoint definitions in immunogenicity trials are subject to more or less empirical choices. Several authors have put forward statistical
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methods for the creation of binary endpoints from IFN-γ ELISpot and intracellular cytokine
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quantitative immunogenicity variables have been proposed for IFN-γ ELISpot data and 51
and summary measures have also been developed for
multivariate broadly neutralizing antibody data.52
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multiplex bead array assays,50,
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Nevertheless, all currently established designs for early stage HIV vaccine trials, be they comparative or not, rely on the definition of a single immunogenicity primary endpoint.43
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Secondary immunogenicity endpoints thus play an important role in these designs.
The definition of appropriate statistical analysis methods is crucial for HIV vaccine
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immunogenicity trials, which are characterized by a relatively small sample size and a broad spectrum of assessed immunogenicity markers. In particular, the analysis of markers of HIV-
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specific cellular response is intricate due to their multidimensionality (numerous markers assessed in different stimulation conditions). The statistical analysis of multidimensional data
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staining data,44-48 but the use of binary endpoints is subject to debate.49 Analysis methods of
requires careful considerations related to the large numbers of variables measured and the correlations between different markers. This also implies questions regarding the adjustment for test multiplicity and the use of analysis methods allowing to integrate and summarize the immune responses across different markers, such as statistical methods for dimensionreduction and systems biology approaches.53
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For the early stage development of therapeutic HIV vaccine strategies, additional aspects need to be taken into account. As these strategies are administered to HIV-infected persons, virological endpoints are assessable in addition to immunogenicity endpoints from early development on. Although these are not validated surrogates for clinical endpoints, HIV RNA or DNA can be measured. If HIV RNA is measured after short-term antiretroviral treatment
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interruption, methodological consideration is required for defining a standardized viral load
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rebound etc. are examples of endpoint definitions, the potential clinical relevance of which
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needs to be discussed. The underlying assumption of the vaccine effect varies according to the chosen endpoint. For instance, establishing an immune response that delays the start of the
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viral rebound is not the same as limiting the maximum observed value of viral load.54 The handling of patients having restarted antiretroviral treatment before measurement of the
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endpoint is critical, as these could correspond to the ones with the weakest viro-
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immunological control. Randomized placebo groups are also important from early development on, as HIV-specific immune responses exist prior to trial entry and regardless of
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vaccination in HIV-infected participants. The integrative analysis of the data in therapeutic HIV vaccine research requires the consideration of viral parameters in addition to the
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immunological measures.5 A recently published example used several statistical approaches for the dimension-reduction in a phase I therapeutic HIV vaccine trial.54
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endpoint. Viral load set point, maximum viral load, area under the curve of viral load, time to
Definition of dose and schedules in HIV vaccine trials In first-in-human phase I trials the safety of different doses of a single vaccine or of a combination is often assessed in a dose-escalation design. In contrast to phase I trials of therapeutic drugs, the estimation of the maximum tolerated dose is likely not the relevant paradigm in phase I trials of vaccines, as dose-toxicity and dose-immunogenicity relationships 14
may not both be sigmoid shaped. The low expected rate of vaccine-related toxicity events requires a trade-off between risk minimization, commensurability and statistical operating characteristics. Ten participants per dose level have been recommended in vaccine dose escalation trials,42, 55 and the number of potential doses is often limited. More than one safe dose level can be selected after phase I dose escalation and be moved forward to randomized
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phase II trials to search for the optimal biologically active and safe dose.
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complex vaccine strategy, and it is likely that the timing of the repeated vaccine injections
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also plays a role. As the large number of possible injection schedules makes it prohibitive to test them all in clinical trials, the timing has often been defined empirically. Recently,
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mathematical models have been used to predict the effect of an exogenous IL-7 immunotherapy on CD4 T-cells in HIV infected persons and to define the number of
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treatment cycles to be tested in future trials of this therapy.56 HIV vaccine research could also
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benefit from such modeling to narrow down the best time points for vaccine injections and also for immunogenicity assessments. These so-called in-silico trials have already been
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proposed in other areas.57, 58
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Conclusion
Despite the large number of potential candidate strategies, the selection of HIV vaccine
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However, dose finding and selection of candidate vaccines is only one aspect when defining a
strategies for clinical efficacy testing remains a major methodological challenge, related to the lack of validated correlates of protection and the considerable human and financial resources required for efficacy trials. Although several clinical trials designs have recently been proposed to make vaccine evaluation more efficient at different development stages, the progression from phase II immunogenicity trials to phase IIB efficacy trials remains the most critical point. Decision criteria for this progression can currently not be based on a clear
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surrogate marker but take into account a large spectrum of immunogenicity variables and are thus implicitly multivariate. Standardisation of various immune assays as well as the use of statistical methods for multivariate data are thus relevant areas for progress in decision making in HIV vaccine development in the absence of well established surrogate
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immunogenicity markers.
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39. Janes H, Gilbert P, Buchbinder S, Kublin J, Sobieszczyk ME, Hammer SM. In pursuit of an HIV vaccine: designing efficacy trials in the context of partially effective nonvaccine prevention modalities. AIDS Res Hum Retroviruses 2013; 29(11): 1513-23. 40. Moodie Z, Janes H, Huang Y. New clinical trial designs for HIV vaccine evaluation. Curr Opin HIV AIDS 2013; 8(5): 437-42.
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44. Horton H, Thomas EP, Stucky JA, Frank I, Moodie Z, Huang Y, et al. Optimization and
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46. Moodie Z, Huang Y, Gu L, Hural J, Self SG. Statistical positivity criteria for the analysis of ELISpot assay data in HIV-1 vaccine trials. J Immunol Methods 2006; 315(1-2): 12132.
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47. Alexander N, Fox A, Lien VT, Dong T, Lee LY, Hang Nle K, et al. Defining ELISpot cut-offs from unreplicated test and control wells. J Immunol Methods 2013; 392(1-2): 5762. 48. Finak G, McDavid A, Chattopadhyay P, Dominguez M, De Rosa S, Roederer M, et al. Mixture models for single-cell assays with applications to vaccine studies. Biostatistics
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Application to HIV Vaccine Development. Stat Biopharm Res 2009; 1(1): 81-91. 53. De Gregorio E, Rappuoli R. From empiricism to rational design: a personal perspective
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54. Levy Y, Thiebaut R, Montes M, Lacabaratz C, Sloan L, King B, et al. Dendritic cell-
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based therapeutic vaccine elicits polyfunctional HIV-specific T-cell immunity associated with control of viral load. Eur J Immunol 2014. Epub ahead of print.
55. Saul A. Models of Phase 1 vaccine trials: optimization of trial design to minimize risks of multiple serious adverse events. Vaccine 2005; 23(23): 3068-75.
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56. Thiebaut R, Drylewicz J, Prague M, Lacabaratz C, Beq S, Jarne A, et al. Quantifying and predicting the effect of exogenous interleukin-7 on CD4+ T cells in HIV-1 infection. PLoS Comput Biol 2014; 10(5): e1003630. 57. Magni L, Raimondo DM, Bossi L, Man CD, De Nicolao G, Kovatchev B, et al. Model predictive control of type 1 diabetes: an in silico trial. J Diabetes Sci Technol 2007; 1(6):
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804-12.
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Results of a multicentric in silico clinical trial (ROCOCO): comparing radiotherapy with
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photons and protons for non-small cell lung cancer. J Thorac Oncol 2012; 7(1): 165-76. 59. Pitisuttithum P, Gilbert P, Gurwith M, Heyward W, Martin M, van Griensven F, et al.
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Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J
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Infect Dis 2006; 194(12): 1661-71.
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60. Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J
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58. Roelofs E, Engelsman M, Rasch C, Persoon L, Qamhiyeh S, de Ruysscher D, et al.
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Table 1. Overview of phase IIB and III trials of prophylactic HIV vaccine strategies
III
III
STEP 13
IIB
Main result
IDU
Protein subunit
No protective
vaccine
vaccine effect
MSM, high-risk
Protein subunit
heterosexual women
vaccine
MSM, high-risk
Ad5 vector vaccine
heterosexual men
IIB
PHAMBILI 14
High-risk
vaccine effect
vaccine effect*
Ad5 vector vaccine
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heterosexual men and women
RV144 2
General population
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IIB
pt IIB
Non-significant trend for deleterious vaccine effect**
Canarypox virus
≈ 30% vaccine
vector prime,
efficacy
subunit boost
MSM
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HVTN 505 29
Non-significant trend
for deleterious
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and women
No protective
DNA prime, Ad5
Non-significant trend
boost
for deleterious vaccine effect*
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VAX004 60
Vaccine strategy
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VAX003 59
Trial population
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Trial phase
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Trial name
Ad5: Adenovirus 5. DNA: deoxyribonucleic acid. IDU: intravenous drug users. MSM: men having sex with men.
* Trial stopped for futility at interim analysis. ** Recruitment halted when the STEP trial results became available; results before unblinding of participants.
24
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ce Ac Figure 1. Schematic illustration of different trial designs. A) Multi-arm design Example of a design comparing three different vaccine strategies to a common placebo arm
B) Two-by-two factorial four-arm design 25
Example of a design evaluating a vaccine strategy, another intervention and the combination of both. The other intervention could for instance be pre-exposure prophylaxis (PrEP) in case of a HIV prevention trial or a drug to mobilize the viral reservoir in case of a therapeutic trial.
C) Two-arm group-sequential design Example of a design with one interim analysis and stopping rule
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D) Seamless adaptive design Example of an adaptive design with a seamless progression between phase II and phase III, integrating a
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selection of trial arms during phase II and additional design adaptations at the beginning of phase III
26
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in parallel and integrating an early safety decision rule for one of the vaccines (vaccine
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Figure 2. Illustration of a multi-arm phase I-II design evaluating four vaccine strategies
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Human Vaccines & Immunotherapeutics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/khvi20
Recent developments in clinical trial designs for HIV vaccine research abcde
Laura Richert abce
Chêne
, Edouard Lhomme
abcd
, Catherine Fagard
abe
, Yves Lévy
efgh
, Geneviève
abcde
& Rodolphe Thiébaut
a
Univ. Bordeaux, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, F-33000 Bordeaux, France b
INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, and CIC1401-EC (Clinical epidemiology), F-33000 Bordeaux, France c
Click for updates
CHU de Bordeaux, Pole de sante publique, F-33000 Bordeaux, France
d
INRIA SISTM, F-33405 Talence, France
e
Vaccine Research Institute (VRI), F-94010 Créteil, France
f
INSERM U955, F-94010 Créteil, France
g
Univ. Paris Est Créteil, Faculté de Médecine, F-94010 Créteil, France
h
Groupe Henri-Mondor Albert-Chenevier, Immunologie clinique, F-94010 Créteil, France Accepted author version posted online: 09 Mar 2015.
To cite this article: Laura Richert, Edouard Lhomme, Catherine Fagard, Yves Lévy, Geneviève Chêne & Rodolphe Thiébaut (2015): Recent developments in clinical trial designs for HIV vaccine research , Human Vaccines & Immunotherapeutics To link to this article: http://dx.doi.org/10.1080/21645515.2015.1011974
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Recent developments in clinical trial designs for HIV vaccine research Review
Laura Richert1,2,3,4,5, Edouard Lhomme1,2,3,4, Catherine Fagard1,2,5, Yves Lévy5,6,7,8, Geneviève
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Chêne1,2,3,5, Rodolphe Thiébaut1,2,3,4,5; for the Vaccine Research Institute (VRI)
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1
Univ. Bordeaux, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, F-33000
INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, and CIC1401-EC
an
2
us
Bordeaux, France
(Clinical epidemiology), F-33000 Bordeaux, France
CHU de Bordeaux, Pole de sante publique, F-33000 Bordeaux, France
4
INRIA SISTM, F-33405 Talence, France
5
Vaccine Research Institute (VRI), F-94010 Créteil, France
6
INSERM U955, F-94010 Créteil, France
7
Univ. Paris Est Créteil, Faculté de Médecine, F-94010 Créteil, France
8
Groupe Henri-Mondor Albert-Chenevier, Immunologie clinique, F-94010 Créteil, France
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Affiliations:
Corresponding author: Pr Rodolphe Thiébaut, MD, PhD; Centre INSERM U897 ; Université Bordeaux Segalen, 146, rue Léo Saignat – case 11, F-33076 Bordeaux cedex, FRANCE. [email protected]
1
Key words: AIDS vaccines, clinical trials, epidemiologic research design, treatment outcome, HIV, prevention, therapeutic use
Adenovirus 5
DNA
deoxyribonucleic acid
HIV
human immunodeficiency virus
IDU
intravenous drug users
IFN-γ
interferon-gamma
MSM
men having sex with men
PrEP
pre-exposure prophylaxis
RNA
ribonucleic acid
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Abstract
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Ad5
HIV vaccine strategies are expected to be a crucial component for controlling the HIV
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List of abbreviations
epidemic. Despite the large spectrum of potential candidate vaccines for both prophylactic and therapeutic use, the overall development process of an efficacious HIV vaccine strategy is lengthy. The design of clinical trials and the progression of a candidate strategy through the different clinical development stages remain methodologically challenging, mainly due to the lack of validated correlates of protection. In this review, we describe recent advances in clinical trial designs to increase the efficiency of the clinical development of candidate HIV
2
vaccine strategies. The methodological aspects of the designs for early- (phase I and II) and later –stage (phase IIB and III) development are discussed, taking into account the
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specificities of both prophylactic and therapeutic HIV vaccine development.
3
Background Despite considerable advances in HIV prevention and treatment, HIV infection still remains a threatening infectious disease with important public health consequences. To control the HIV epidemic, two principal issues would need to be resolved: i) efficacious and feasible largescale measures for HIV prevention, and ii) strategies for a cure from infection. To achieve
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each of these aims, complex integrated strategies may be required, of which HIV vaccines
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expected to be crucial components.1
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No prophylactic or therapeutic HIV vaccine strategies with satisfactory efficacy are available
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to date, but the research field has been encouraged by the first report of a protective vaccine effect against HIV in 2009. Results of a randomized phase IIB trial in 16402 healthy
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volunteers in Thailand (RV144 trial), evaluating a combination of two HIV candidate vaccines in a prime-boost strategy against placebo, showed promising results with a reduction
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of HIV acquisition in the active vaccine arm.2 However, estimated vaccine efficacy was modest (approximately 30%) and seemed to wane over time.2-4
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In therapeutic approaches, the efficacy of vaccine strategies to control viral replication or to reduce the viral reservoir has been evaluated in proof-of-concept trials with varying results
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(reviewed in 5, 6).
To disentangle the results of the RV144 trial and to improve the efficacy of HIV candidate
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(prophylactic vaccines for the first issue and therapeutic vaccines for the second one) are
vaccines, research is currently very active, with a multitude of potential vaccine strategies under development for both prophylactic and therapeutic applications. Candidate vaccines
against HIV include protein or sub-unit vaccines, recombinant viral vector, deoxyribonucleic acid (DNA) and dendritic-cell based vaccines.7 As the results of the RV144 trial suggest that heterologous prime-boost strategies are a promising approach, the number of strategies to be evaluated is potentially large.
4
Despite this spectrum of candidate vaccines, the development of efficacious HIV vaccine strategies remains a major scientific challenge. In addition to aspects related to viral diversity and escape, HIV vaccine development is complicated as there is limited knowledge about the potential immunological correlates of clinical vaccine efficacy, that is protection from infection or post-infection viral load in the case of a prophylactic strategy or virological
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control or stable disease without antiretroviral treatment in the case of a therapeutic strategy.
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immunogenicity markers. The overall development process is lengthy, and it is difficult to
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correctly appreciate the worthiness of a new HIV vaccine strategy before the first clinical efficacy trials.8 This has resulted in only six prophylactic HIV vaccine efficacy trials
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implemented so far, with the phase IIB RV144 trial in Thailand mentioned above being the only trial with a promising result. The remaining trials showed disappointing results with no
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evidence for a protective vaccine effect (Table 1).
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Results of an exploratory case-control analysis nested in the RV144 trial suggested that the modest clinical efficacy of the prime-boost strategy under evaluation may have been mediated
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by humoral responses,9 but cellular responses may also contribute to this association.10 Despite the encouraging results of the RV144 trial, it is, however, premature to conclude
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which components of cellular or humoral immunity should be generated by a HIV vaccine strategy. Moreover, it is likely that the immunological correlates of HIV vaccine efficacy will
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This means that it is not yet possible to predict these clinical outcomes based on
be different for prophylactic vaccine strategies versus therapeutic vaccine strategies.
5
Principles of clinical development in HIV vaccine research HIV vaccine development currently relies on iterative loops between animal studies and clinical studies in humans. Phase I and II clinical trials are conducted to determine the safety and to assess the immunogenicity of the vaccine strategies in early clinical development. As correlates of protection are not well known to date, a large number of immunogenicity
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markers are measured. This implies a considerable uncertainty about the interpretation of
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early clinical development. Immunogenicity results in early clinical development stages in
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humans often entail a return to the animal model to optimize tested strategies.
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To obtain preliminary evidence based on a clinical endpoint (that is HIV acquisition or postinfection viremia), HIV vaccine development nowadays usually includes phase IIB test-of-
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concept trials before deciding whether further clinical efficacy testing is reasonable.11 In contrast to large phase III trials, phase IIB trials do not aim at directly supporting a licensure
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decision. Endpoint definitions and allowable type I and II error rates may be different between phase IIB and III trials. In particular, in test-of-concept trials higher false positive rates (type I
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error) and lower false negative rates (type II error) than in confirmatory trials may be
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desirable in order to increase the probability to detect a vaccine effect.11, 12 However, even these phase IIB trials typically require a large sample size with several thousand participants and prolonged follow-up.2, 13, 14 If results of a phase IIB trial are promising enough, phase III
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immunogenicity results and the potential value of a vaccine strategy as it proceeds through
trials are conducted to confirm clinical vaccine efficacy with stringent methods aiming at licensure requests.
To evaluate potential surrogate markers the first step is to assess correlates of risk, i.e. immunological markers that correlate with the clinical endpoint of interest.15-17 Evaluation of correlates of risk requires variability in the marker and the clinical endpoint, but not
6
necessarily a protective vaccine effect. Correlates of risk can thus be analyzed in various datasets, such as observational data from HIV controllers,18-20 single arm vaccine trials or randomized trials. Once correlates of risks are identified, they can be evaluated with regards to their value as correlates of protection, which implies their evaluation as surrogate endpoints. Plotkin and
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Gilbert have defined a correlate of protection as an immune marker statistically associated
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vaccine effect on the clinical endpoint. This definition incorporates “surrogate endpoints” in
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the terminology used by Prentice.21 For the analysis of a surrogate endpoint, one needs datasets of randomized phase IIB or III trials having demonstrated a protective vaccine effect.
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As RV144 is the only trial having shown a modest protective effect of a prophylactic HIV vaccine strategy so far, this dataset constitutes a unique opportunity to search for correlates of
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protection for prophylactic HIV vaccine strategies,2, 9 although vaccine studies in non-human
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primates may also contribute to this search.22, 23
The sample size of the RV144 trial (16402 participants) and the trial’s timelines, with
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approximately ten years between trial planning and the publication of the main correlate
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results also illustrate the efforts required to conduct prophylactic HIV vaccine efficacy trials.24
Trial designs to accelerate clinical development of HIV vaccine strategies
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with clinical vaccine efficacy.15 In other words, a correlate of protection must capture the
A relevant impetus for rethinking HIV vaccine trial designs today is the demand to accelerate the clinical development of candidate vaccine strategies. In the methodological literature numerous clinical trial designs exist that allow for increased efficiency, by reducing sample size or allowing more rapid decision making within the clinical development plan than with classical designs, while maintaining desired operating characteristics and trial validity. Many
7
of these designs have been in longstanding use in fields other than HIV vaccine research, especially in cancer research.25-27 Multi-arm trials have more than two arms, which can increase efficiency in terms of sample size, for example by comparing more than one active vaccine arm to a common control arm or by using factorial designs (Figure 1).
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Group-sequential or sequential trials allow for stopping the trial early in case of efficacy,
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methods to define the stopping rules, and review by an Independent Data Monitoring
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Committee.28 Recent prophylactic HIV vaccine efficacy trials used such designs, which resulted in the STEP and HVTN 505 trials, respectively, being stopped for futility.13, 29
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More sophisticated adaptive designs accommodate greater flexibility for modifications during trial conduct while controlling bias and the rates of erroneous conclusions, in particular the
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type I error rate.30 Design modifications in adaptive trials are prospectively planned and based
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on analyses of data accumulated during the trial and can concern different adaptations, such as selecting a treatment dose, stopping or adding a trial arm, enriching a participant sub-group,
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modifying the sample size or changing the random allocation ratio.31 Seamless adaptive designs allow for combining several development phases in one single trial. Well-defined
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endpoints but also extensive simulation studies are usually necessary to set up complex adaptive designs with adequate operating characteristics.32 The conduct of such trials also
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futility (that is lack of efficacy), or harm. This requires interim analyses, appropriate statistical
requires thorough planning of all operational aspects, for example the practical implementation of the design modifications in the trial’s logistics and the timing of unblinding. As is also the case in group-sequential trials, a proficient Independent Data Monitoring Committee plays a key role in the rigorous conduct of adaptive designs. Development of adaptive designs is currently a vast field of statistical research with a multitude of methods proposed in the recent literature, although the scientific and ethical
8
challenges of such trials are also subject to debate,33,
34
and acceptability by regulatory
authorities may need upfront consultations. To accelerate the clinical development of efficacious prophylactic HIV vaccine strategies several authors have recently called for the use of adaptive trial designs.8, 24, 35, 36 As most adaptive designs existing in the literature have been devised for other indications, mainly
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oncology trials, thorough methodological consideration is needed before being adapted to
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including but not limited to the acceptable toxicity rates of interventions and the rates of
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clinical efficacy endpoints.
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Designs for clinical efficacy vaccine trials
The only adaptive design in the literature developed for HIV vaccine trials relates to a multi-
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arm two-stage phase IIB design, in which adaptive decisions during the trial are based on a
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clinical HIV acquisition endpoint.12 This design allows for evaluating the efficacy of several prophylactic vaccine strategies in parallel with a common placebo arm. Interim analyses
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monitor futility of vaccine efficacy compared to placebo and aim at stopping inefficacious strategies during the first stage, that is in the first 18 months of follow-up. For all strategies
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that are not stopped, adaptations in the proposed design include i) the assessment of durability of vaccine efficacy in the second stage, ii) preparations to analyze correlates of protection in a
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HIV vaccine research. Many differences distinguish cancer and HIV vaccine research,
timely manner, and iii) head-to-head comparisons of promising vaccine strategies. Furthermore, interim analyses are planned to monitor for high efficacy, albeit it is unlikely that this type of stopping criterion be met with the currently developed HIV vaccine strategies, as well as continuous monitoring of harm. This design has thus many desirable features to accelerate HIV vaccine efficacy trials, but it remains yet to be implemented in practice.
9
Specific methods for correlate discovery called “augmented designs” have been developed independently from adaptive trial designs, but can be combined with the latter. Such augmentations aim at deducing immune responses to the vaccine in placebo recipients, which are required for the statistical evaluation of surrogate endpoints in a counterfactual model. This can be achieved by imputing the non-observed immune response using baseline variables
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as predictors (baseline immunogenicity predictor approach) and/or administrating the vaccine
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To evaluate prophylactic HIV vaccine strategies together with other available partially
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effective prevention measures, such as pre-exposure prophylaxis (PrEP), several types of multi-arm efficacy trial designs have been proposed in the literature.38, 39 These include a two-
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by-two factorial four-arm design, with a first group receiving a combination of the vaccine and the other prevention measure, a second and third group receiving either the vaccine or the
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prevention measure, respectively, and the relevant placebo, and the fourth group receiving
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double placebo, which allows to assess not only the efficacy of each intervention but also possible synergies if the trial is adequately powered. Design options accommodating for the
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willingness of the participants to adhere to the non-vaccine prevention measure also exist, performing randomization in two stages. In the first stage, all participants are randomized to
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either vaccine or placebo. In the second stage, use of the other prevention measure is randomized only for those being willing. However, this increases the required sample sizes.39
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to a sample of placebo recipients at the end of the trial (close-out placebo vaccination).37
Designs including only a subset of the above mentioned arms also exist (reviewed in
40
).
Some of these multi-arm designs could also be used should a non-inferiority hypothesis of a vaccine strategy alone compared to the combination strategy become relevant.39 How to best
perform group-sequential monitoring, or even adaptive modifications, in these combination trials requires further consideration.
10
Therapeutic HIV vaccine efficacy trials require their own specific methodological considerations. Availability of highly effective antiretroviral treatment as standard of care raises questions about the acceptability and risk-benefit ratio of analytical treatment interruption to assess the vaccine effect on virological control in proof-of-concept trials.41 Whether virological control or disease progression events should be the primary endpoint in
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confirmatory trials would also need scrutiny. The level of intracellular HIV DNA, which is a
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endpoint. As therapeutic HIV vaccine development is currently mainly in early development
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stages, to our knowledge, few specific methodological papers related to efficacy trials have
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been published to date.
Immunogenicity assessments in early stage clinical HIV vaccine development
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In early stage clinical HIV vaccine development, that is phase I and II trials, the main
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limitation is currently the lack of validated surrogate endpoints that could be used to reliably explore vaccine efficacy based on immunogenicity markers. As adaptive designs require a
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clear consensual endpoint definition for progression between stages, application of such designs to early clinical development stages in HIV vaccine research is difficult.
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Nevertheless, phase II immunogenicity trials could benefit from other features of design optimizations but few authors have so far addressed design considerations in early stage HIV
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measure of the ‘reservoir’ of the latently infected cells, could also be considered as an
vaccine trials beyond endpoint definitions. Randomized multi-arm trials are valuable in early stage trials to allow for an unbiased assessment of the safety and immunogenicity of several candidate vaccine strategies in
parallel, with the standardized immunogenicity assays and endpoint definitions across arms. For instance, a non-comparative multi-arm phase IB selection design can be used to screen several strategies and prioritize among them for further development the most promising
11
one.42 In this type of design, the arms are not compared directly to each other by statistical testing but are ranked based on a binary immunogenicity endpoint, and the arm(s) with the top-rank is/are selected. This allows for having adequate statistical power for selecting the strategy with the highest immunological response rate of the defined endpoint, while keeping the sample size reasonable for a phase II trial, usually comprising between twenty and fifty
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participants per arm. A minimum required response rate of the selected strategy can also be
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Another type of non-comparative multi-arm design aims at moving all strategies with
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immunogenicity response rate above such a minimum required rate forward to the next development stage. The minimum required rate is defined a priori, and the one-sided 95%
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confidence interval of the observed response rate in a trial arm must lie above this minimal rate in order to consider it promising. Such a design has recently been proposed in the
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literature for a phase II prophylactic HIV vaccine trial of four heterologous prime-boost
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strategies. Furthermore, as one of the vaccines to be studied in this design also required a phase I evaluation, the possibility to integrate a phase I safety stage in one arm of the
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randomized phase II design has been established (Figure 2). This is achieved by a sequential analyses of an early safety endpoint of the concerned vaccine with the aim to stop the vaccine
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before the boost phase should it be unsafe.43 The applicability of the integrated phase I evaluation relies on prior knowledge of the safety of similar vaccines and quick participant
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incorporated in the design.
accrual in the trial.
After such non-comparative trials, a randomized comparative phase II design can be set up as the next development step with direct statistical head-to-head comparisons of immunogenicity between strategies. Inclusion of a placebo arm is debatable in early stage prophylactic HIV vaccine trials in low-risk populations, where HIV-specific immune responses can be
12
considered close to zero in the absence of exposure or vaccination for assays with high specificity. As a vaccine strategy proceeds further through clinical development stages, a randomized placebo arm will become important for head-to-head comparisons. In the absence of validated correlates of protection, endpoint definitions in immunogenicity trials are subject to more or less empirical choices. Several authors have put forward statistical
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methods for the creation of binary endpoints from IFN-γ ELISpot and intracellular cytokine
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quantitative immunogenicity variables have been proposed for IFN-γ ELISpot data and 51
and summary measures have also been developed for
multivariate broadly neutralizing antibody data.52
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multiplex bead array assays,50,
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Nevertheless, all currently established designs for early stage HIV vaccine trials, be they comparative or not, rely on the definition of a single immunogenicity primary endpoint.43
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Secondary immunogenicity endpoints thus play an important role in these designs.
The definition of appropriate statistical analysis methods is crucial for HIV vaccine
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immunogenicity trials, which are characterized by a relatively small sample size and a broad spectrum of assessed immunogenicity markers. In particular, the analysis of markers of HIV-
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specific cellular response is intricate due to their multidimensionality (numerous markers assessed in different stimulation conditions). The statistical analysis of multidimensional data
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staining data,44-48 but the use of binary endpoints is subject to debate.49 Analysis methods of
requires careful considerations related to the large numbers of variables measured and the correlations between different markers. This also implies questions regarding the adjustment for test multiplicity and the use of analysis methods allowing to integrate and summarize the immune responses across different markers, such as statistical methods for dimensionreduction and systems biology approaches.53
13
For the early stage development of therapeutic HIV vaccine strategies, additional aspects need to be taken into account. As these strategies are administered to HIV-infected persons, virological endpoints are assessable in addition to immunogenicity endpoints from early development on. Although these are not validated surrogates for clinical endpoints, HIV RNA or DNA can be measured. If HIV RNA is measured after short-term antiretroviral treatment
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interruption, methodological consideration is required for defining a standardized viral load
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rebound etc. are examples of endpoint definitions, the potential clinical relevance of which
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needs to be discussed. The underlying assumption of the vaccine effect varies according to the chosen endpoint. For instance, establishing an immune response that delays the start of the
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viral rebound is not the same as limiting the maximum observed value of viral load.54 The handling of patients having restarted antiretroviral treatment before measurement of the
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endpoint is critical, as these could correspond to the ones with the weakest viro-
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immunological control. Randomized placebo groups are also important from early development on, as HIV-specific immune responses exist prior to trial entry and regardless of
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vaccination in HIV-infected participants. The integrative analysis of the data in therapeutic HIV vaccine research requires the consideration of viral parameters in addition to the
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immunological measures.5 A recently published example used several statistical approaches for the dimension-reduction in a phase I therapeutic HIV vaccine trial.54
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endpoint. Viral load set point, maximum viral load, area under the curve of viral load, time to
Definition of dose and schedules in HIV vaccine trials In first-in-human phase I trials the safety of different doses of a single vaccine or of a combination is often assessed in a dose-escalation design. In contrast to phase I trials of therapeutic drugs, the estimation of the maximum tolerated dose is likely not the relevant paradigm in phase I trials of vaccines, as dose-toxicity and dose-immunogenicity relationships 14
may not both be sigmoid shaped. The low expected rate of vaccine-related toxicity events requires a trade-off between risk minimization, commensurability and statistical operating characteristics. Ten participants per dose level have been recommended in vaccine dose escalation trials,42, 55 and the number of potential doses is often limited. More than one safe dose level can be selected after phase I dose escalation and be moved forward to randomized
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phase II trials to search for the optimal biologically active and safe dose.
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complex vaccine strategy, and it is likely that the timing of the repeated vaccine injections
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also plays a role. As the large number of possible injection schedules makes it prohibitive to test them all in clinical trials, the timing has often been defined empirically. Recently,
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mathematical models have been used to predict the effect of an exogenous IL-7 immunotherapy on CD4 T-cells in HIV infected persons and to define the number of
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treatment cycles to be tested in future trials of this therapy.56 HIV vaccine research could also
ed
benefit from such modeling to narrow down the best time points for vaccine injections and also for immunogenicity assessments. These so-called in-silico trials have already been
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proposed in other areas.57, 58
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Conclusion
Despite the large number of potential candidate strategies, the selection of HIV vaccine
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However, dose finding and selection of candidate vaccines is only one aspect when defining a
strategies for clinical efficacy testing remains a major methodological challenge, related to the lack of validated correlates of protection and the considerable human and financial resources required for efficacy trials. Although several clinical trials designs have recently been proposed to make vaccine evaluation more efficient at different development stages, the progression from phase II immunogenicity trials to phase IIB efficacy trials remains the most critical point. Decision criteria for this progression can currently not be based on a clear
15
surrogate marker but take into account a large spectrum of immunogenicity variables and are thus implicitly multivariate. Standardisation of various immune assays as well as the use of statistical methods for multivariate data are thus relevant areas for progress in decision making in HIV vaccine development in the absence of well established surrogate
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immunogenicity markers.
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Table 1. Overview of phase IIB and III trials of prophylactic HIV vaccine strategies
III
III
STEP 13
IIB
Main result
IDU
Protein subunit
No protective
vaccine
vaccine effect
MSM, high-risk
Protein subunit
heterosexual women
vaccine
MSM, high-risk
Ad5 vector vaccine
heterosexual men
IIB
PHAMBILI 14
High-risk
vaccine effect
vaccine effect*
Ad5 vector vaccine
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heterosexual men and women
RV144 2
General population
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IIB
pt IIB
Non-significant trend for deleterious vaccine effect**
Canarypox virus
≈ 30% vaccine
vector prime,
efficacy
subunit boost
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HVTN 505 29
Non-significant trend
for deleterious
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and women
No protective
DNA prime, Ad5
Non-significant trend
boost
for deleterious vaccine effect*
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VAX004 60
Vaccine strategy
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VAX003 59
Trial population
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Trial phase
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Trial name
Ad5: Adenovirus 5. DNA: deoxyribonucleic acid. IDU: intravenous drug users. MSM: men having sex with men.
* Trial stopped for futility at interim analysis. ** Recruitment halted when the STEP trial results became available; results before unblinding of participants.
24
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ce Ac Figure 1. Schematic illustration of different trial designs. A) Multi-arm design Example of a design comparing three different vaccine strategies to a common placebo arm
B) Two-by-two factorial four-arm design 25
Example of a design evaluating a vaccine strategy, another intervention and the combination of both. The other intervention could for instance be pre-exposure prophylaxis (PrEP) in case of a HIV prevention trial or a drug to mobilize the viral reservoir in case of a therapeutic trial.
C) Two-arm group-sequential design Example of a design with one interim analysis and stopping rule
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D) Seamless adaptive design Example of an adaptive design with a seamless progression between phase II and phase III, integrating a
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selection of trial arms during phase II and additional design adaptations at the beginning of phase III
26
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in parallel and integrating an early safety decision rule for one of the vaccines (vaccine
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1)
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Figure 2. Illustration of a multi-arm phase I-II design evaluating four vaccine strategies
27
