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1.  Efficacy Trial of a DNA/rAd5 HIV-1 Preventive Vaccine 
The New England journal of medicine  2013;369(22):2083-2092.
Background
A safe and effective vaccine for the prevention of human immunodeficiency virus type 1 (HIV-1) infection is a global priority. We tested the efficacy of a DNA prime–recombinant adenovirus type 5 boost (DNA/rAd5) vaccine regimen in persons at increased risk for HIV-1 infection in the United States.
Methods
At 21 sites, we randomly assigned 2504 men or transgender women who have sex with men to receive the DNA/rAd5 vaccine (1253 participants) or placebo (1251 participants). We assessed HIV-1 acquisition from week 28 through month 24 (termed week 28+ infection), viral-load set point (mean plasma HIV-1 RNA level 10 to 20 weeks after diagnosis), and safety. The 6-plasmid DNA vaccine (expressing clade B Gag, Pol, and Nef and Env proteins from clades A, B, and C) was administered at weeks 0, 4, and 8. The rAd5 vector boost (expressing clade B Gag-Pol fusion protein and Env glycoproteins from clades A, B, and C) was administered at week 24.
Results
In April 2013, the data and safety monitoring board recommended halting vaccinations for lack of efficacy. The primary analysis showed that week 28+ infection had been diagnosed in 27 participants in the vaccine group and 21 in the placebo group (vaccine efficacy, −25.0%; 95% confidence interval, −121.2 to 29.3; P = 0.44), with mean viral-load set points of 4.46 and 4.47 HIV-1 RNA log10 copies per milliliter, respectively. Analysis of all infections during the study period (41 in the vaccine group and 31 in the placebo group) also showed lack of vaccine efficacy (P = 0.28). The vaccine regimen had an acceptable side-effect profile.
Conclusions
The DNA/rAd5 vaccine regimen did not reduce either the rate of HIV-1 acquisition or the viral-load set point in the population studied. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00865566.)
doi:10.1056/NEJMoa1310566
PMCID: PMC4030634  PMID: 24099601
2.  Statistical approaches to analyzing HIV-1 neutralizing antibody assay data 
Summary
Neutralizing antibody assays are widely used in research toward development of a preventive HIV-1 vaccine. Currently, the neutralization potency of an antibody is typically quantified by the inhibitory concentration (IC) values (e.g., IC50), and the neutralization breadth is estimated by the empirical method. In this paper, we propose the AUC and pAUC measures for summarizing the titration curve, which complement the commonly used IC measure. We present multiple advantages of AUC over IC50, which include no complications due to censoring, the capability to explore low-level neutralization, and improved coverage probabilities and efficiency of estimators. We also propose statistical methods for determining positive neutralization and for estimating the neutralization breadth. The simulation results suggest that the AUC measure is preferable in particular as IC50s get closer to the highest concentration of antibodies tested. For the majority of the assay data, the AUC method is more powerful than the IC50 method. However, since these methods test different hypotheses, it is not unexpected that some virus-antibody combinations are AUC positive but IC50 negative or vice versa.
doi:10.1080/19466315.2011.633860
PMCID: PMC3959164  PMID: 24660049
AUC; breadth; HIV-1; neutralization assay; polynomial model; titration curve
3.  Vaccine-Induced IgG Antibodies to V1V2 Regions of Multiple HIV-1 Subtypes Correlate with Decreased Risk of HIV-1 Infection 
PLoS ONE  2014;9(2):e87572.
In the RV144 HIV-1 vaccine efficacy trial, IgG antibody (Ab) binding levels to variable regions 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 were an inverse correlate of risk of HIV-1 infection. To determine if V1V2-specific Abs cross-react with V1V2 from different HIV-1 subtypes, if the nature of the V1V2 antigen used to asses cross-reactivity influenced infection risk, and to identify immune assays for upcoming HIV-1 vaccine efficacy trials, new V1V2-scaffold antigens were designed and tested. Protein scaffold antigens carrying the V1V2 regions from HIV-1 subtypes A, B, C, D or CRF01_AE were assayed in pilot studies, and six were selected to assess cross-reactive Abs in the plasma from the original RV144 case-control cohort (41 infected vaccinees, 205 frequency-matched uninfected vaccinees, and 40 placebo recipients) using ELISA and a binding Ab multiplex assay. IgG levels to these antigens were assessed as correlates of risk in vaccine recipients using weighted logistic regression models. Levels of Abs reactive with subtype A, B, C and CRF01_AE V1V2-scaffold antigens were all significant inverse correlates of risk (p-values of 0.0008–0.05; estimated odds ratios of 0.53–0.68 per 1 standard deviation increase). Thus, levels of vaccine-induced IgG Abs recognizing V1V2 regions from multiple HIV-1 subtypes, and presented on different scaffolds, constitute inverse correlates of risk for HIV-1 infection in the RV144 vaccine trial. The V1V2 antigens provide a link between RV144 and upcoming HIV-1 vaccine trials, and identify reagents and methods for evaluating V1V2 Abs as possible correlates of protection against HIV-1 infection.
Trial Registration
ClinicalTrials.gov NCT00223080
doi:10.1371/journal.pone.0087572
PMCID: PMC3913641  PMID: 24504509
4.  Estimating the Efficacy of Preexposure Prophylaxis for HIV Prevention Among Participants With a Threshold Level of Drug Concentration 
American Journal of Epidemiology  2013;177(3):256-263.
Assays for detecting levels of antiretroviral drugs in study participants are increasingly popular in preexposure prophylaxis (PrEP) trials, since they provide an objective measure of adherence. Current correlation analyses of drug concentration data are prone to bias. In this article, we formulate the causal estimand of prevention efficacy among drug compliers, those who would have had a threshold level of drug concentration had they been assigned to the drug arm of the trial. The identifiability of the causal estimand is facilitated by exploiting the exclusion restriction; that is, drug noncompliers do not acquire any prevention benefit. In addition, we develop an approach to sensitivity analysis that relaxes the exclusion restriction. Applications to published data from 2 PrEP trials, namely the Preexposure Prophylaxis Initiative (iPrEx) trial and the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial, suggest high efficacy estimates among drug compliers (in the iPrEx trial, odds ratio = 0.097 (95% confidence interval: 0.027, 0.352); in the CAPRISA 004 trial, odds ratio = 0.104 (95% confidence interval: 0.024, 0.447)). In summary, the proposed inferential method provides an unbiased assessment of PrEP efficacy among drug compliers, thus adding to the primary intention-to-treat analysis and correlation analyses of drug concentration data.
doi:10.1093/aje/kws324
PMCID: PMC3577049  PMID: 23302152
causal inference; compliance; exclusion restriction; potential outcome; principal stratification; two-phase sampling
5.  HIV-1 Conserved-Element Vaccines: Relationship between Sequence Conservation and Replicative Capacity 
Journal of Virology  2013;87(10):5461-5467.
To overcome the problem of HIV-1 variability, candidate vaccine antigens have been designed to be composed of conserved elements of the HIV-1 proteome. Such candidate vaccines could be improved with a better understanding of both HIV-1 evolutionary constraints and the fitness cost of specific mutations. We evaluated the in vitro fitness cost of 23 mutations engineered in the HIV-1 subtype B Gag-p24 Center-of-Tree (COT) protein through fitness competition assays. While some mutations at conserved sites exacted a high fitness cost, as expected under the assumption that the most conserved residue confers the highest fitness, there was no overall strong relationship between sequence conservation and replicative capacity. By comparing sites that have evolved since the beginning of the epidemic to those that have remain unchanged, we found that sites that have evolved over time were more likely to correspond to HLA-associated sites and that their mutation had limited fitness costs. Our data showed no transcendent link between high conservation and high fitness cost, indicating that merely focusing on conserved segments of HIV-1 would not be sufficient for a successful vaccine strategy. Nonetheless, a subset of sites exacted a high fitness cost upon mutation—these sites have been under selective pressure to change since the beginning of the epidemic but have proved virtually nonmutable and could constitute preferred targets for vaccine design.
doi:10.1128/JVI.03033-12
PMCID: PMC3648173  PMID: 23468488
6.  Mark-specific proportional hazards model with multivariate continuous marks and its application to HIV vaccine efficacy trials 
For time-to-event data with finitely many competing risks, the proportional hazards model has been a popular tool for relating the cause-specific outcomes to covariates (Prentice and others, 1978. The analysis of failure time in the presence of competing risks. Biometrics 34, 541–554). Inspired by previous research in HIV vaccine efficacy trials, the cause of failure is replaced by a continuous mark observed only in subjects who fail. This article studies an extension of this approach to allow a multivariate continuum of competing risks, to better account for the fact that the candidate HIV vaccines tested in efficacy trials have contained multiple HIV sequences, with a purpose to elicit multiple types of immune response that recognize and block different types of HIV viruses. We develop inference for the proportional hazards model in which the regression parameters depend parametrically on the marks, to avoid the curse of dimensionality, and the baseline hazard depends nonparametrically on both time and marks. Goodness-of-fit tests are constructed based on generalized weighted martingale residuals. The finite-sample performance of the proposed methods is examined through extensive simulations. The methods are applied to a vaccine efficacy trial to examine whether and how certain antigens represented inside the vaccine are relevant for protection or anti-protection against the exposing HIVs.
doi:10.1093/biostatistics/kxs022
PMCID: PMC3520499  PMID: 22764174
Competing risks; Failure time data; Goodness-of-fit test; HIV vaccine trial; Hypothesis testing; Mark-specific relative risk; Multivariate data; Partial likelihood estimation; Semiparametric model; STEP trial
7.  Sensitivity Analysis of Per-Protocol Time-to-Event Treatment Efficacy in Randomized Clinical Trials 
Journal of the American Statistical Association  2013;108(503):10.1080/01621459.2013.786649.
Summary
Assessing per-protocol treatment effcacy on a time-to-event endpoint is a common objective of randomized clinical trials. The typical analysis uses the same method employed for the intention-to-treat analysis (e.g., standard survival analysis) applied to the subgroup meeting protocol adherence criteria. However, due to potential post-randomization selection bias, this analysis may mislead about treatment efficacy. Moreover, while there is extensive literature on methods for assessing causal treatment effects in compliers, these methods do not apply to a common class of trials where a) the primary objective compares survival curves, b) it is inconceivable to assign participants to be adherent and event-free before adherence is measured, and c) the exclusion restriction assumption fails to hold. HIV vaccine efficacy trials including the recent RV144 trial exemplify this class, because many primary endpoints (e.g., HIV infections) occur before adherence is measured, and nonadherent subjects who receive some of the planned immunizations may be partially protected. Therefore, we develop methods for assessing per-protocol treatment efficacy for this problem class, considering three causal estimands of interest. Because these estimands are not identifiable from the observable data, we develop nonparametric bounds and semiparametric sensitivity analysis methods that yield estimated ignorance and uncertainty intervals. The methods are applied to RV144.
doi:10.1080/01621459.2013.786649
PMCID: PMC3811958  PMID: 24187408
As-treated; Bounds; Causal inference; Exclusion restriction; Ignorance region; Intention to treat; Principal stratification; Selection bias; Survival analysis
8.  Quantile Regression for Competing Risks Data with Missing Cause of Failure 
Statistica Sinica  2012;22(2):703-728.
This paper considers generalized linear quantile regression for competing risks data when the failure type may be missing. Two estimation procedures for the regression co-efficients, including an inverse probability weighted complete-case estimator and an augmented inverse probability weighted estimator, are discussed under the assumption that the failure type is missing at random. The proposed estimation procedures utilize supplemental auxiliary variables for predicting the missing failure type and for informing its distribution. The asymptotic properties of the two estimators are derived and their asymptotic efficiencies are compared. We show that the augmented estimator is more efficient and possesses a double robustness property against misspecification of either the model for missingness or for the failure type. The asymptotic covariances are estimated using the local functional linearity of the estimating functions. The finite sample performance of the proposed estimation procedures are evaluated through a simulation study. The methods are applied to analyze the ‘Mashi’ trial data for investigating the effect of formula-versus breast-feeding plus extended infant zidovudine prophylaxis on HIV-related death of infants born to HIV-infected mothers in Botswana.
doi:10.5705/ss.2010.093
PMCID: PMC3742132  PMID: 23950622
Augmented inverse probability weighted; Auxiliary variables; Competing risks; Double robustness; Efficient estimator; Estimating equation; Inverse probability weighted; Local functional linearity; Logistic regression; Mashi trial; Missing at random; Quantile regression
9.  Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys 
Science translational medicine  2011;3(81):81ra36.
The RV144 vaccine trial in Thailand demonstrated that an HIV vaccine could prevent infection in humans and highlights the importance of understanding protective immunity against HIV. We used a nonhuman primate model to define immune and genetic mechanisms of protection against mucosal infection by the simian immunodeficiency virus (SIV). A plasmid DNA prime/recombinant adenovirus serotype 5 (rAd5) boost vaccine regimen was evaluated for its ability to protect monkeys from infection by SIVmac251 or SIVsmE660 isolates after repeat intrarectal challenges. Although this prime-boost vaccine regimen failed to protect against SIVmac251 infection, 50% of vaccinated monkeys were protected from infection with SIVsmE660. Among SIVsmE660-infected animals, there was an about one-log reduction in peak plasma virus RNA in monkeys expressing the major histocompatibility complex class I allele Mamu-A*01, implicating cytotoxic T lymphocytes in the control of SIV replication once infection is established. Among Mamu-A*01–negative monkeys challenged with SIVsmE660, no CD8+ T cell response or innate immune response was associated with protection against virus acquisition. However, low levels of neutralizing antibodies and an envelope-specific CD4+ T cell response were associated with vaccine protection in these monkeys. Moreover, monkeys that expressed two TRIM5 alleles that restrict SIV replication were more likely to be protected from infection than monkeys that expressed at least one permissive TRIM5 allele. This study begins to elucidate the mechanism of vaccine protection against immunodeficiency viruses and highlights the need to analyze these immune and genetic correlates of protection in future trials of HIV vaccine strategies.
doi:10.1126/scitranslmed.3002351
PMCID: PMC3718279  PMID: 21543722
10.  Design and Estimation for Evaluating Principal Surrogate Markers in Vaccine Trials 
Biometrics  2013;69(2):301-309.
Summary
In vaccine research, immune biomarkers that can reliably predict a vaccine’s effect on the clinical endpoint (i.e., surrogate markers) are important tools for guiding vaccine development. This paper addresses issues on optimizing two-phase sampling study design for evaluating surrogate markers in a principal surrogate framework, motivated by the design of a future HIV vaccine trial. To address the problem of missing potential outcomes in a standard trial design, novel trial designs have been proposed that utilize baseline predictors of the immune response biomarker(s) and/or augment the trial by vaccinating uninfected placebo recipients at the end of the trial and measuring their immune biomarkers. However, inefficient use of the augmented information can lead to counterintuitive results on the precision of estimation. To remedy this problem, we propose a pseudo-score type estimator suitable for the augmented design and characterize its asymptotic properties. This estimator has superior performance compared with existing estimators and allows calculation of analytical variances useful for guiding study design. Based on the new estimator we investigate in detail the problem of optimizing the sampling scheme of a biomarker in a vaccine efficacy trial for efficiently estimating its surrogate effect, as characterized by the vaccine efficacy curve (a causal effect predictiveness curve) and by the predicted overall vaccine efficacy using the biomarker.
doi:10.1111/biom.12014
PMCID: PMC3713795  PMID: 23409839
Closeout placebo vaccination; Estimated likelihood; Immune correlate; Principal surrogate; Pseudo-score; Two-phase sampling design
11.  Nomenclature for Immune Correlates of Protection After Vaccination 
A marker of immune function that statistically correlates with protection after vaccination may be either a mechanistic correlate of protection or a nonmechanistic correlate of protection, which does not cause protection, but predicts protection.
Identification of immune correlates of protection after vaccination is an important part of vaccinology for both theoretical and practical reasons. The terminology and definition of correlates have been confusing, because different authors have used variable terms and concepts. Here, we attempt to give precision to the field by defining 3 terms: correlate of protection (CoP), mechanistic correlate of protection (mCoP), and nonmechanistic correlate of protection (nCoP). A CoP is a marker of immune function that statistically correlates with protection after vaccination that may be either an mCoP, which is a mechanistic cause of protection, or an nCoP, which does not cause protection but nevertheless predicts protection through its (partial) correlation with another immune response(s) that mechanistically protects.
doi:10.1093/cid/cis238
PMCID: PMC3348952  PMID: 22437237
12.  Partially hidden Markov model for time-varying principal stratification in HIV prevention trials 
It is frequently of interest to estimate the intervention effect that adjusts for post-randomization variables in clinical trials. In the recently completed HPTN 035 trial, there is differential condom use between the three microbicide gel arms and the No Gel control arm, so that intention to treat (ITT) analyses only assess the net treatment effect that includes the indirect treatment effect mediated through differential condom use. Various statistical methods in causal inference have been developed to adjust for post-randomization variables. We extend the principal stratification framework to time-varying behavioral variables in HIV prevention trials with a time-to-event endpoint, using a partially hidden Markov model (pHMM). We formulate the causal estimand of interest, establish assumptions that enable identifiability of the causal parameters, and develop maximum likelihood methods for estimation. Application of our model on the HPTN 035 trial reveals an interesting pattern of prevention effectiveness among different condom-use principal strata.
doi:10.1080/01621459.2011.643743
PMCID: PMC3649016  PMID: 23667279
microbicide; causal inference; posttreatment variables; direct effect
13.  Antibody-Dependent Cellular Cytotoxicity-Mediating Antibodies from an HIV-1 Vaccine Efficacy Trial Target Multiple Epitopes and Preferentially Use the VH1 Gene Family 
Journal of Virology  2012;86(21):11521-11532.
The ALVAC-HIV/AIDSVAX-B/E RV144 vaccine trial showed an estimated efficacy of 31%. RV144 secondary immune correlate analysis demonstrated that the combination of low plasma anti-HIV-1 Env IgA antibodies and high levels of antibody-dependent cellular cytotoxicity (ADCC) inversely correlate with infection risk. One hypothesis is that the observed protection in RV144 is partially due to ADCC-mediating antibodies. We found that the majority (73 to 90%) of a representative group of vaccinees displayed plasma ADCC activity, usually (96.2%) blocked by competition with the C1 region-specific A32 Fab fragment. Using memory B-cell cultures and antigen-specific B-cell sorting, we isolated 23 ADCC-mediating nonclonally related antibodies from 6 vaccine recipients. These antibodies targeted A32-blockable conformational epitopes (n = 19), a non-A32-blockable conformational epitope (n = 1), and the gp120 Env variable loops (n = 3). Fourteen antibodies mediated cross-clade target cell killing. ADCC-mediating antibodies displayed modest levels of V-heavy (VH) chain somatic mutation (0.5 to 1.5%) and also displayed a disproportionate usage of VH1 family genes (74%), a phenomenon recently described for CD4-binding site broadly neutralizing antibodies (bNAbs). Maximal ADCC activity of VH1 antibodies correlated with mutation frequency. The polyclonality and low mutation frequency of these VH1 antibodies reveal fundamental differences in the regulation and maturation of these ADCC-mediating responses compared to VH1 bNAbs.
doi:10.1128/JVI.01023-12
PMCID: PMC3486290  PMID: 22896626
14.  Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env-V2 
Nature  2012;490(7420):417-420.
Summary
The RV144 trial demonstrated 31% vaccine efficacy (VE) at preventing HIV-1 infection1. Antibodies against the HIV-1 envelope variable loops 1 and 2 (V1/V2) domain correlated inversely with infection risk2. We hypothesized that vaccine-induced immune responses against V1/V2 would selectively impact, or sieve, HIV-1 breakthrough viruses. 936 HIV-1 genome sequences from 44 vaccine and 66 placebo recipients were examined. We show that vaccine-induced immune responses were associated with two signatures in V1/V2 at amino-acid positions 169 and 181. VE against viruses matching the vaccine at position 169 was 48% (CI: 18 to 66%; p=0.0036), whereas VE against viruses mismatching the vaccine at position 181 was 78% (CI: 35% to 93%; p=0.0028). Residue 169 is in a cationic glycosylated region recognized by broadly neutralizing and RV144-derived antibodies. The predicted distance between the two signatures sites (21±7 Å), and their match/mismatch dichotomy, suggest that multiple factors may be involved in the protection observed in RV144. Genetic signatures of RV144 vaccination in V2 complement the finding of an association between high V1/V2 binding antibodies and reduced risk of HIV-1 acquisition and provide evidence that vaccine-induced V2 responses plausibly played a role in the partial protection conferred by the RV144 regimen.
doi:10.1038/nature11519
PMCID: PMC3551291  PMID: 22960785
15.  Estimation of Stratified Mark-Specific Proportional Hazards Models with Missing Marks 
An objective of randomized placebo-controlled preventive HIV vaccine efficacy trials is to assess the relationship between the vaccine effect to prevent infection and the genetic distance of the exposing HIV to the HIV strain represented in the vaccine construct. Motivated by this objective, recently a mark-specific proportional hazards model with a continuum of competing risks has been studied, where the genetic distance of the transmitting strain is the continuous `mark' defined and observable only in failures. A high percentage of genetic marks of interest may be missing for a variety of reasons, predominantly due to rapid evolution of HIV sequences after transmission before a blood sample is drawn from which HIV sequences are measured. This research investigates the stratified mark-specific proportional hazards model with missing marks where the baseline functions may vary with strata. We develop two consistent estimation approaches, the first based on the inverse probability weighted complete-case (IPW) technique, and the second based on augmenting the IPW estimator by incorporating auxiliary information predictive of the mark. We investigate the asymptotic properties and finite-sample performance of the two estimators, and show that the augmented IPW estimator, which satisfies a double robustness property, is more efficient.
doi:10.1111/j.1467-9469.2011.00746.x
PMCID: PMC3601495  PMID: 23519918
Augmented inverse probability weighted complete-case estimator; auxiliary marks; competing risks; double robustness; failure time data; genetic data; HIV vaccine trial; mark-specific vaccine efficacy; missing at random; semiparametric model
16.  Analysis of V2 Antibody Responses Induced in Vaccinees in the ALVAC/AIDSVAX HIV-1 Vaccine Efficacy Trial 
PLoS ONE  2013;8(1):e53629.
The RV144 clinical trial of a prime/boost immunizing regimen using recombinant canary pox (ALVAC-HIV) and two gp120 proteins (AIDSVAX B and E) was previously shown to have a 31.2% efficacy rate. Plasma specimens from vaccine and placebo recipients were used in an extensive set of assays to identify correlates of HIV-1 infection risk. Of six primary variables that were studied, only one displayed a significant inverse correlation with risk of infection: the antibody (Ab) response to a fusion protein containing the V1 and V2 regions of gp120 (gp70-V1V2). This finding prompted a thorough examination of the results generated with the complete panel of 13 assays measuring various V2 Abs in the stored plasma used in the initial pilot studies and those used in the subsequent case-control study. The studies revealed that the ALVAC-HIV/AIDSVAX vaccine induced V2-specific Abs that cross-react with multiple HIV-1 subgroups and recognize both conformational and linear epitopes. The conformational epitope was present on gp70-V1V2, while the predominant linear V2 epitope mapped to residues 165–178, immediately N-terminal to the putative α4β7 binding motif in the mid-loop region of V2. Odds ratios (ORs) were calculated to compare the risk of infection with data from 12 V2 assays, and in 11 of these, the ORs were ≤1, reaching statistical significance for two of the variables: Ab responses to gp70-V1V2 and to overlapping V2 linear peptides. It remains to be determined whether anti-V2 Ab responses were directly responsible for the reduced infection rate in RV144 and whether anti-V2 Abs will prove to be important with other candidate HIV vaccines that show efficacy, however, the results support continued dissection of Ab responses to the V2 region which may illuminate mechanisms of protection from HIV-1 infection and may facilitate the development of an effective HIV-1 vaccine.
doi:10.1371/journal.pone.0053629
PMCID: PMC3547933  PMID: 23349725
17.  HIV Vaccine Trials Network: activities and achievements of the first decade and beyond 
Clinical investigation  2012;2(3):245-254.
The HIV Vaccine Trials Network (HVTN) is an international collaboration of scientists and educators facilitating the development of HIV/AIDS preventive vaccines. The HVTN conducts all phases of clinical trials, from evaluating experimental vaccines for safety and immunogenicity, to testing vaccine efficacy. Over the past decade, the HVTN has aimed to improve the process of designing, implementing and analyzing vaccine trials. Several major achievements include streamlining protocol development while maintaining input from diverse stakeholders, establishing a laboratory program with standardized assays and systems allowing for reliable immunogenicity assessments across trials, setting statistical standards for the field and actively engaging with site communities. These achievements have allowed the HVTN to conduct over 50 clinical trials and make numerous scientific contributions to the field.
doi:10.4155/cli.12.8
PMCID: PMC3521567  PMID: 23243491
clinical trial network; HIV; HIV Vaccine Trials Network; vaccine
18.  A Sequential Phase 2b Trial Design for Evaluating Vaccine Efficacy and Immune Correlates for Multiple HIV Vaccine Regimens 
Five preventative HIV vaccine efficacy trials have been conducted over the last 12 years, all of which evaluated vaccine efficacy (VE) to prevent HIV infection for a single vaccine regimen versus placebo. Now that one of these trials has supported partial VE of a prime-boost vaccine regimen, there is interest in conducting efficacy trials that simultaneously evaluate multiple prime-boost vaccine regimens against a shared placebo group in the same geographic region, for accelerating the pace of vaccine development. This article proposes such a design, which has main objectives (1) to evaluate VE of each regimen versus placebo against HIV exposures occurring near the time of the immunizations; (2) to evaluate durability of VE for each vaccine regimen showing reliable evidence for positive VE; (3) to expeditiously evaluate the immune correlates of protection if any vaccine regimen shows reliable evidence for positive VE; and (4) to compare VE among the vaccine regimens. The design uses sequential monitoring for the events of vaccine harm, non-efficacy, and high efficacy, selected to weed out poor vaccines as rapidly as possible while guarding against prematurely weeding out a vaccine that does not confer efficacy until most of the immunizations are received. The evaluation of the design shows that testing multiple vaccine regimens is important for providing a well-powered assessment of the correlation of vaccine-induced immune responses with HIV infection, and is critically important for providing a reasonably powered assessment of the value of identified correlates as surrogate endpoints for HIV infection.
PMCID: PMC3502884  PMID: 23181167
HIV vaccine efficacy clinical trial; immune correlate of protection; one-way crossover design; surrogate endpoint for HIV infection; two-phase sampling
19.  Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy Trial 
The New England Journal of Medicine  2012;366(14):1275-1286.
BACKGROUND
In the RV144 trial, the estimated efficacy of a vaccine regimen against human immunodeficiency virus type 1 (HIV-1) was 31.2%. We performed a case–control analysis to identify antibody and cellular immune correlates of infection risk.
METHODS
In pilot studies conducted with RV144 blood samples, 17 antibody or cellular assays met prespecified criteria, of which 6 were chosen for primary analysis to determine the roles of T-cell, IgG antibody, and IgA antibody responses in the modulation of infection risk. Assays were performed on samples from 41 vaccinees who became infected and 205 uninfected vaccinees, obtained 2 weeks after final immunization, to evaluate whether immune-response variables predicted HIV-1 infection through 42 months of follow-up.
RESULTS
Of six primary variables, two correlated significantly with infection risk: the binding of IgG antibodies to variable regions 1 and 2 (V1V2) of HIV-1 envelope proteins (Env) correlated inversely with the rate of HIV-1 infection (estimated odds ratio, 0.57 per 1-SD increase; P = 0.02; q = 0.08), and the binding of plasma IgA antibodies to Env correlated directly with the rate of infection (estimated odds ratio, 1.54 per 1-SD increase; P = 0.03; q = 0.08). Neither low levels of V1V2 antibodies nor high levels of Env-specific IgA antibodies were associated with higher rates of infection than were found in the placebo group. Secondary analyses suggested that Env-specific IgA antibodies may mitigate the effects of potentially protective antibodies.
CONCLUSIONS
This immune-correlates study generated the hypotheses that V1V2 antibodies may have contributed to protection against HIV-1 infection, whereas high levels of Env-specific IgA antibodies may have mitigated the effects of protective antibodies. Vaccines that are designed to induce higher levels of V1V2 antibodies and lower levels of Env-specific IgA antibodies than are induced by the RV144 vaccine may have improved efficacy against HIV-1 infection.
doi:10.1056/NEJMoa1113425
PMCID: PMC3371689  PMID: 22475592
20.  Assessing Treatment-Selection Markers using a Potential Outcomes Framework 
Biometrics  2012;68(3):687-696.
Summary
Treatment-selection markers are biological molecules or patient characteristics associated with one’s response to treatment. They can be used to predict treatment effects for individual subjects and subsequently help deliver treatment to those most likely to benefit from it. Statistical tools are needed to evaluate a marker’s capacity to help with treatment selection. The commonly adopted criterion for a good treatment-selection marker has been the interaction between marker and treatment. While a strong interaction is important, it is, however, not suffcient for good marker performance. In this paper, we develop novel measures for assessing a continuous treatment-selection marker, based on a potential outcomes framework. Under a set of assumptions, we derive the optimal decision rule based on the marker to classify individuals according to treatment benefit, and characterize the marker’s performance using the corresponding classification accuracy as well as the overall distribution of the classifier. We develop a constrained maximum-likelihood method for estimation and testing in a randomized trial setting. Simulation studies are conducted to demonstrate the performance of our methods. Finally, we illustrate the methods using an HIV vaccine trial where we explore the value of the level of pre-existing immunity to Adenovirus serotype 5 for predicting a vaccine-induced increase in the risk of HIV acquisition.
doi:10.1111/j.1541-0420.2011.01722.x
PMCID: PMC3417090  PMID: 22299708
Classification accuracy; Constrained maximum likelihood; Monotone treatment effect; Potential outcomes; Sensitivity analysis; Treatment-selection marker
21.  Commentary on “Principal Stratification — a Goal or a Tool?” by Judea Pearl 
This commentary takes up Pearl's welcome challenge to clearly articulate the scientific value of principal stratification estimands that we and colleagues have investigated, in the area of randomized placebo-controlled preventive vaccine efficacy trials, especially trials of HIV vaccines. After briefly arguing that certain principal stratification estimands for studying vaccine effects on post-infection outcomes are of genuine scientific interest, the bulk of our commentary argues that the “causal effect predictiveness” (CEP) principal stratification estimand for evaluating immune biomarkers as surrogate endpoints is not of ultimate scientific interest, because it evaluates surrogacy restricted to the setting of a particular vaccine efficacy trial, but is nevertheless useful for guiding the selection of primary immune biomarker endpoints in Phase I/II vaccine trials and for facilitating assessment of transportability/bridging surrogacy.
doi:10.2202/1557-4679.1341
PMCID: PMC3204668  PMID: 22049267
principal stratification; causal inference; vaccine trial
22.  Sensitivity Analyses Comparing Time-to-Event Outcomes Only Existing in a Subset Selected Postrandomization and Relaxing Monotonicity 
Biometrics  2010;67(3):1100-1110.
Summary
In randomized studies researchers may be interested in the effect of treatment assignment on a time-to-event outcome that only exists in a subset selected after randomization. For example, in preventative HIV vaccine trials, it is of interest to determine whether randomization to vaccine affects the time from infection diagnosis until initiation of antiretroviral therapy. Earlier work assessed the effect of treatment on outcome among the principal stratum of individuals who would have been selected regardless of treatment assignment. These studies assumed monotonicity, that one of the principal strata was empty (eg, every person infected in the vaccine arm would have been infected if randomized to placebo). Here we present a sensitivity analysis approach for relaxing monotonicity with a time-to-event outcome. We also consider scenarios where selection is unknown for some subjects because of non-informative censoring (e.g., infection status k years after randomization is unknown for some because of staggered study entry). We illustrate our method using data from an HIV vaccine trial.
doi:10.1111/j.1541-0420.2010.01508.x
PMCID: PMC3116075  PMID: 21114663
Causal inference; HIV; Kaplan-Meier; Monotonicity; Principal stratification
23.  Statistical Interpretation of the RV144 HIV Vaccine Efficacy Trial in Thailand: A Case Study for Statistical Issues in Efficacy Trials 
The Journal of Infectious Diseases  2011;203(7):969-975.
Recently, the RV144 randomized, double-blind, efficacy trial in Thailand reported that a prime-boost human immunodeficiency virus (HIV) vaccine regimen conferred ∼30% protection against HIV acquisition. However, different analyses seemed to give conflicting results, and a heated debate ensued as scientists and the broader public struggled with their interpretation. The lack of accounting for statistical principles helped flame the debate, and we leverage these principles to provide a more scientific interpretation. We first address interpretation of frequentist results, including interpretation of P values, synthesis of results from multiple analyses (ie, intention-to-treat versus per-protocol/fully immunized), and accounting for external efficacy trials. Second, we address how Bayesian statistics, which provide clearly interpretable statements about probabilities that the vaccine efficacy takes certain values, provide more information for weighing the evidence about efficacy than do frequentist statistics alone. Third, we evaluate RV144 for completeness of end point ascertainment and integrity of blinding, necessary tasks for establishing robustly interpretable results.
doi:10.1093/infdis/jiq152
PMCID: PMC3068028  PMID: 21402548
24.  Evaluating a surrogate endpoint at three levels, with application to vaccine development 
Statistics in medicine  2008;27(23):4758-4778.
SUMMARY
Identification of an immune response to vaccination that reliably predicts protection from clinically significant infection, i.e. an immunological surrogate endpoint, is a primary goal of vaccine research. Using this problem of evaluating an immunological surrogate as an illustration, we describe a hierarchy of three criteria for a valid surrogate endpoint and statistical analysis frameworks for evaluating them. Based on a placebo-controlled vaccine efficacy trial, the first level entails assessing the correlation of an immune response with a study endpoint in the study groups, and the second level entails evaluating an immune response as a surrogate for the study endpoint that can be used for predicting vaccine efficacy for a setting similar to that of the vaccine trial. We show that baseline covariates, innovative study design, and a potential outcomes formulation can be helpful for this assessment. The third level entails validation of a surrogate endpoint via meta-analysis, where the goal is to evaluate how well the immune response can be used to predict vaccine efficacy for new settings (building bridges). A simulated vaccine trial and two example vaccine trials are presented, one supporting that certain anti-influenza antibody levels are an excellent surrogate for influenza illness and another supporting that certain anti-HIV antibody levels are not useful as a surrogate for HIV infection.
doi:10.1002/sim.3122
PMCID: PMC2646675  PMID: 17979212
clinical trial; counterfactual; immune correlate; meta-analysis; potential outcomes; principal surrogate; statistical surrogate
25.  Low-Dose Penile SIVmac251 Exposure of Rhesus Macaques Infected with Adenovirus Type 5 (Ad5) and Then Immunized with a Replication-Defective Ad5-Based SIV gag/pol/nef Vaccine Recapitulates the Results of the Phase IIb Step Trial of a Similar HIV-1 Vaccine 
Journal of Virology  2012;86(4):2239-2250.
The Step Trial showed that the MRKAd5 HIV-1 subtype B Gag/Pol/Nef vaccine did not protect men from HIV infection or reduce setpoint plasma viral RNA (vRNA) levels but, unexpectedly, it did modestly enhance susceptibility to HIV infection in adenovirus type 5 (Ad5)-seropositive, uncircumcised men. As part of the process to understand the results of the Step Trial, we designed a study to determine whether rhesus macaques chronically infected with a host-range mutant Ad5 (Ad5hr) and then immunized with a replication defective Ad5 SIVmac239 Gag/Pol/Nef vaccine were more resistant or susceptible to SIV infection than unimmunized rhesus macaques challenged with a series of escalating dose penile exposures to SIVmac 251. The Ad5 SIV vaccine induced CD8+ T cell responses in 70% of the monkeys, which is similar to the proportion of humans that responded to the vaccine in the Step Trial. However, the vaccine did not protect vaccinated animals from penile SIV challenge. At the lowest SIV exposure dose (103 50% tissue culture infective doses), 2 of 9 Ad5-seropositive animals immunized with the Ad5 SIV vaccine became infected compared to 0 of 34 animals infected in the other animal groups (naive animals, Ad5-seropositive animals immunized with the empty Ad5 vector, Ad5-seronegative animals immunized with the Ad5 SIV vaccine, and Ad5-seronegative animals immunized with the empty Ad5 vector). Penile exposure to more concentrated virus inocula produced similar rates of infection in all animal groups. Although setpoint viral loads were unaffected in Step vaccinees, the Ad5 SIV-immunized animals had significantly lower acute-phase plasma vRNA levels compared to unimmunized animals. Thus, the results of the nonhuman primate (NHP) study described here recapitulate the lack of protection against HIV acquisition seen in the Step Trial and suggest a greater risk of infection in the Ad5-seropositive animals immunized with the Ad5 SIV vaccine. Further studies are necessary to confirm the enhancement of virus acquisition and to discern associated mechanisms.
doi:10.1128/JVI.06175-11
PMCID: PMC3302390  PMID: 22156519

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