Peter B Gilbert

Publications of Peter B Gilbert

• Immune-correlates analysis of an HIV-1 vaccine efficacy trial.

  Authors: Barton F Haynes, Peter B Gilbert, M Juliana McElrath, Susan Zolla-Pazner, Georgia D Tomaras, S Munir Alam, David T Evans, David C Montefiori, Chitraporn Karnasuta, Ruengpueng Sutthent [......] Michael D Alpert, Nicole L Yates, Xiaoying Shen, Richard A Koup, Punnee Pitisuttithum, Jaranit Kaewkungwal, Sorachai Nitayaphan, Supachai Rerks-Ngarm, Nelson L Michael, Jerome H Kim

  The New England journal of medicine. 04/2012; 366(14):1275-86.

  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 cellularIn 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. 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. 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. 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.

• Assessing Treatment-Selection Markers using a Potential Outcomes Framework.

  Authors: Ying Huang, Peter B Gilbert, Holly Janes

  Biometrics. 02/2012;

  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 individualSummary 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 sufficient for good marker performance. In this article, 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 preexisting immunity to adenovirus serotype 5 for predicting a vaccine-induced increase in the risk of HIV acquisition.

• 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.

  Authors: Huma Qureshi, Zhong-Min Ma, Ying Huang, Gregory Hodge, Michael A Thomas, Janet DiPasquale, Veronique DeSilva, Linda Fritts, Andrew J Bett, Danilo R Casimiro, John W Shiver, Marjorie Robert-Guroff, Michael N Robertson, Michael B McChesney, Peter B Gilbert, Christopher J Miller

  Journal of virology. 12/2011; 86(4):2239-50.

  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 modestlyThe 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 (10(3) 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.

• Recurrent signature patterns in HIV-1 B clade envelope glycoproteins associated with either early or chronic infections.

  Authors: S Gnanakaran, Tanmoy Bhattacharya, Marcus Daniels, Brandon F Keele, Peter T Hraber, Alan S Lapedes, Tongye Shen, Brian Gaschen, Mohan Krishnamoorthy, Hui Li [......] Craig A Magaret, William R Schief, Yih-En Andrew Ban, Ming Zhang, Kelly A Soderberg, Joseph G Sodroski, Barton F Haynes, George M Shaw, Beatrice H Hahn, Bette Korber

  PLoS pathogens. 09/2011; 7(9):e1002209.

  Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infectionHere we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413-415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response.

• Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys.

  Authors: Norman L Letvin, Srinivas S Rao, David C Montefiori, Michael S Seaman, Yue Sun, So-Yon Lim, Wendy W Yeh, Mohammed Asmal, Rebecca S Gelman, Ling Shen [......] Adam P Buzby, Linh V Mach, Jinrong Zhang, Harikrishnan Balachandran, George M Shaw, Stephen D Schmidt, John-Paul Todd, Alan Dodson, John R Mascola, Gary J Nabel

  Science translational medicine. 05/2011; 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 aThe 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 about a 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 mechanisms 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.

• Comparing biomarkers as principal surrogate endpoints.

  Authors: Ying Huang, Peter B Gilbert

  Biometrics. 04/2011; 67(4):1442-51.

  Recently a new definition of surrogate endpoint, the "principal surrogate," was proposed based on causal associations between treatment effects on the biomarker and on the clinical endpoint. DespiteRecently a new definition of surrogate endpoint, the "principal surrogate," was proposed based on causal associations between treatment effects on the biomarker and on the clinical endpoint. Despite its appealing interpretation, limited research has been conducted to evaluate principal surrogates, and existing methods focus on risk models that consider a single biomarker. How to compare principal surrogate value of biomarkers or general risk models that consider multiple biomarkers remains an open research question. We propose to characterize a marker or risk model's principal surrogate value based on the distribution of risk difference between interventions. In addition, we propose a novel summary measure (the standardized total gain) that can be used to compare markers and to assess the incremental value of a new marker. We develop a semiparametric estimated-likelihood method to estimate the joint surrogate value of multiple biomarkers. This method accommodates two-phase sampling of biomarkers and is more widely applicable than existing nonparametric methods by incorporating continuous baseline covariates to predict the biomarker(s), and is more robust than existing parametric methods by leaving the error distribution of markers unspecified. The methodology is illustrated using a simulated example set and a real data set in the context of HIV vaccine trials.

• Statistical interpretation of the RV144 HIV vaccine efficacy trial in Thailand: a case study for statistical issues in efficacy trials.

  Authors: Peter B Gilbert, James O Berger, Donald Stablein, Stephen Becker, Max Essex, Scott M Hammer, Jerome H Kim, Victor G Degruttola

  The Journal of infectious diseases. 04/2011; 203(7):969-75.

  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 HIVRecently, 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.

• Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial.

  Authors: Morgane Rolland, Sodsai Tovanabutra, Allan C deCamp, Nicole Frahm, Peter B Gilbert, Eric Sanders-Buell, Laura Heath, Craig A Magaret, Meera Bose, Andrea Bradfield [......] Fusheng Li, Steve G Self, Jerome Kim, Susan Buchbinder, Danilo R Casimiro, Michael N Robertson, Ann Duerr, M Juliana McElrath, Francine E McCutchan, James I Mullins

  Nature medicine. 02/2011; 17(3):366-71.

  We analyzed HIV-1 genome sequences from 68 newly infected volunteers in the STEP HIV-1 vaccine trial. To determine whether the vaccine exerted selective T cell pressure on breakthrough viruses, weWe analyzed HIV-1 genome sequences from 68 newly infected volunteers in the STEP HIV-1 vaccine trial. To determine whether the vaccine exerted selective T cell pressure on breakthrough viruses, we identified potential T cell epitopes in the founder sequences and compared them to epitopes in the vaccine. We found greater distances to the vaccine sequence for sequences from vaccine recipients than from placebo recipients. The most significant signature site distinguishing vaccine from placebo recipients was Gag amino acid 84, a site encompassed by several epitopes contained in the vaccine and restricted by human leukocyte antigen (HLA) alleles common in the study cohort. Moreover, the extended divergence was confined to the vaccine components of the virus (HIV-1 Gag, Pol and Nef) and not found in other HIV-1 proteins. These results represent what is to our knowledge the first evidence of selective pressure from vaccine-induced T cell responses on HIV-1 infection in humans.

• Commentary on "Principal stratification - a goal or a tool?" by Judea Pearl.

  Authors: Peter B Gilbert, Michael G Hudgens, Julian Wolfson

  The international journal of biostatistics. 01/2011; 7(1):Article 36.

  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 randomizedThis 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.

• Sensitivity analyses comparing time-to-event outcomes only existing in a subset selected postrandomization and relaxing monotonicity.

  Authors: Bryan E Shepherd, Peter B Gilbert, Charles T Dupont

  Biometrics. 11/2010; 67(3):1100-10.

  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, inIn 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 (e.g., 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 noninformative 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.

• Some design issues in phase 2B vs phase 3 prevention trials for testing efficacy of products or concepts.

  Authors: Peter B Gilbert

  Statistics in medicine. 05/2010; 29(10):1061-71.

  After one or more Phase 2 trials show that a candidate preventive vaccine induces immune responses that putatively protect against an infectious disease for which there is no licensed vaccine, theAfter one or more Phase 2 trials show that a candidate preventive vaccine induces immune responses that putatively protect against an infectious disease for which there is no licensed vaccine, the next step is to evaluate the efficacy of the candidate. The trial-designer faces the question of what is the optimal size of the initial efficacy trial? Part of the answer will entail deciding between a large Phase 3 licensure trial or an intermediate-sized Phase 2b screening trial, the latter of which may be designed to directly contribute to the evidence-base for licensing the candidate, or, to test a scientific concept for moving the vaccine field forward, acknowledging that the particular candidate will never be licensable. Using the HIV vaccine field as a case study, we describe distinguishing marks of Phase 2b and Phase 3 prevention efficacy trials, and compare the expected utility of these trial types using Pascal's decision-theoretic framework. By integrating values/utilities on (1) correct or incorrect conclusions resulting from the trial; (2) timeliness of obtaining the trial results; (3) precision for estimating the intervention effect; and (4) resources expended; this decision framework provides a more complete approach to selecting the optimal efficacy trial size than a traditional approach that is based primarily on power calculations. Our objective is to help inform the decision-process for planning an initial efficacy trial design.

• Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Neutralizing Antibody Assessment.

  Authors: Michael S Seaman, Holly Janes, Natalie Hawkins, Lauren E Grandpre, Colleen Devoy, Ayush Giri, Rory T Coffey, Linda Harris, Blake Wood, Marcus G Daniels, Tanmoy Bhattacharya, Alan Lapedes, Victoria R Polonis, Francine E McCutchan, Peter B Gilbert, Steve G Self, Bette T Korber, David C Montefiori, John R Mascola

  Journal of virology. 11/2009;

  The restricted neutralization breadth of vaccine-elicited antibodies is a major limitation of current human immunodeficiency virus-1 (HIV-1) candidate vaccines. In order to permit the efficientThe restricted neutralization breadth of vaccine-elicited antibodies is a major limitation of current human immunodeficiency virus-1 (HIV-1) candidate vaccines. In order to permit the efficient identification of vaccines with enhanced capacity for eliciting cross-reactive neutralizing antibodies (NAbs), and to assess the overall breadth and potency of vaccine-elicited NAb reactivity, we assembled a panel of 109 molecularly cloned HIV-1 Env pseudoviruses representing a broad range of genetic and geographic diversity. Viral isolates from all major circulating genetic subtypes were included, as were viruses derived shortly after transmission, and during the early and chronic stages of infection. We assembled a panel of genetically diverse HIV-1(+) plasma pools to assess neutralization sensitivity of the entire virus panel. When the viruses were rank ordered according to average neutralization sensitivity to the HIV-1(+) plasmas, a continuum of average sensitivity was observed. Clustering analysis on the patterns of sensitivity defined four subgroups of viruses: those having very high (Tier 1A), above average (Tier 1B), moderate (Tier 2), or low (Tier 3) sensitivity to antibody-mediated neutralization. We also investigated potential associations between characteristics of the viral isolates (clade, stage of infection, and source of virus) and sensitivity to NAb. In particular, higher levels of NAb activity were observed when the virus and plasma pool were matched in clade. These data provide the first systematic assessment of the overall neutralization sensitivity of a genetically and geographically diverse panel of circulating HIV-1 strains. These reference viruses can facilitate the systematic characterization of NAb responses elicited by candidate vaccine immunogens.

• Semiparametric estimation of the average causal effect of treatment on an outcome measured after a postrandomization event, with missing outcome data.

  Authors: Peter B Gilbert, Yuying Jin

  Biostatistics (Oxford, England). 10/2009;

  In the past decade, several principal stratification-based statistical methods have been developed for testing and estimation of a treatment effect on an outcome measured after a postrandomizationIn the past decade, several principal stratification-based statistical methods have been developed for testing and estimation of a treatment effect on an outcome measured after a postrandomization event. Two examples are the evaluation of the effect of a cancer treatment on quality of life in subjects who remain alive and the evaluation of the effect of an HIV vaccine on viral load in subjects who acquire HIV infection. However, in general the developed methods have not addressed the issue of missing outcome data, and hence their validity relies on a missing completely at random (MCAR) assumption. Because in many applications the MCAR assumption is untenable, while a missing at random (MAR) assumption is defensible, we extend the semiparametric likelihood sensitivity analysis approach of Gilbert and others (2003) and Jemiai and Rotnitzky (2005) to allow the outcome to be MAR. We combine these methods with the robust likelihood-based method of Little and An (2004) for handling MAR data to provide semiparametric estimation of the average causal effect of treatment on the outcome. The new method, which does not require a monotonicity assumption, is evaluated in a simulation study and is applied to data from the first HIV vaccine efficacy trial.

• Power to Detect the Effects of HIV Vaccination in Repeated Low-Dose Challenge Experiments.

  Authors: Michael G Hudgens, Peter B Gilbert, John R Mascola, Chih-Da Wu, Dan H Barouch, Steven G Self

  The Journal of infectious diseases. 09/2009; 200(4):609-613.

  Simulation studies were conducted to estimate the statistical power of repeated low-dose challenge experiments performed in nonhuman primates to detect the effect of a candidate humanSimulation studies were conducted to estimate the statistical power of repeated low-dose challenge experiments performed in nonhuman primates to detect the effect of a candidate human immunodeficiency virus vaccine. The effect of various design parameters on power was explored. Results of simulation studies indicate that repeated low-dose challenge studies with a total sample of size 50 (25 animals/arm) typically provide adequate power to detect a 50% reduction in the per-exposure probability of infection resulting from vaccination. Power generally increases with the maximum number of allowable challenges per animal, the per-exposure risk of infection in control animals, and the proportion of animals susceptible to infection.

• Antibody specificities associated with neutralization breadth in plasma from HIV-1 subtype C infected blood donors.

  Authors: Elin S Gray, Natasha Taylor, Diane Wycuff, Penny L Moore, Georgia D Tomaras, Constantinos Kurt Wibmer, Adrian Puren, Allan Decamp, Peter B Gilbert, Blake Wood, David C Montefiori, James M Binley, George M Shaw, Barton F Haynes, John R Mascola, Lynn Morris

  Journal of virology. 06/2009;

  Defining the specificities of the anti-HIV-1 envelope antibodies able to mediate broad heterologous neutralization will assist in identifying targets for an HIV-1 vaccine. We screened 70 plasmas fromDefining the specificities of the anti-HIV-1 envelope antibodies able to mediate broad heterologous neutralization will assist in identifying targets for an HIV-1 vaccine. We screened 70 plasmas from HIV-1 chronically infected individuals for neutralization breadth. Of these, 16 (23%) were found to neutralize 80% or more of the viruses tested. Anti-CD4bs antibodies were found in almost all plasmas independent of their neutralization breadth, but they mainly mediated neutralization of the laboratory strain HxB2 with little effect over the primary virus Du151. Adsorption with Du151 monomeric gp120 reduced neutralizing activity to some extent in most plasma samples when tested against the matched virus, although these antibodies did not always confer cross-neutralization. For one plasma this activity was mapped to a site overlapping the CD4i epitope and CD4bs. Anti-MPER (r=0.69, P<0.001) and anti-CD4i (r=0.49, P<0.001) antibody titers were found to correlate with neutralization breadth. These anti-MPER antibodies were not 4E10 or 2F5-like but spanned the 4E10 epitope. Furthermore, we found anti-cardiolipin antibodies correlated with neutralization breadth (r=0.67, P<0.001) and anti-MPER antibodies (r=0.6, P<0.001). Our study suggests that more than one epitope on the envelope glycoprotein is involved in the cross-reactive neutralization elicited during HIV-1 natural infection, many of which are yet to be determined, and the possible involvement of polyreactive antibodies in this phenomenon.

• Assessing Vaccine Effects in Repeated Low-Dose Challenge Experiments.

  Authors: Michael G Hudgens, Peter B Gilbert

  Biometrics. 05/2009;

  Evaluation of HIV vaccine candidates in nonhuman primates (NHPs) is a critical step toward developing a successful vaccine to control the HIV pandemic. Historically, HIV vaccine regimens have beenEvaluation of HIV vaccine candidates in nonhuman primates (NHPs) is a critical step toward developing a successful vaccine to control the HIV pandemic. Historically, HIV vaccine regimens have been tested in NHPs by administering a single high dose of the challenge virus. More recently, evaluation of candidate HIV vaccines has entailed repeated low-dose challenges, which more closely mimic typical exposure in natural transmission settings. In this article, we consider evaluation of the type and magnitude of vaccine efficacy from such experiments. Based on the principal stratification framework, we also address evaluation of potential immunological surrogate endpoints for infection.

• Response to Andrew Dunning's comment on 'Evaluating a surrogate endpoint at three levels, with application to vaccine development'

  Authors: Peter B Gilbert, Li Qin, Steven G Self

  Statistics in medicine. 02/2009; 28(4):716-719.

• Simultaneous Evaluation of the Magnitude and Breadth of a Left and Right Censored Multivariate Response, with Application to HIV Vaccine Development.

  Authors: Yunda Huang, Peter B Gilbert, David C Montefiori, Steve G Self

  Statistics in biopharmaceutical research. 02/2009; 1(1):81-91.

  Both the magnitude and breadth of neutralization against multiple strains of virus are main endpoints for comparing antibody-based HIV-1 vaccine candidates in Phase I and II trials, and are keyBoth the magnitude and breadth of neutralization against multiple strains of virus are main endpoints for comparing antibody-based HIV-1 vaccine candidates in Phase I and II trials, and are key markers to be evaluated in vaccine efficacy trials as immune correlates of protection against HIV-1 infection. More generally, consideration of both magnitude and breadth is encountered when there is interest in comparing quantitative multivariate response data between groups. In this paper, we discuss two approaches to simultaneously evaluating the magnitude and breadth of a multivariate response. We suggest methods for the summarization and group comparison of multivariate response data that are subject to left and/or right censoring. Applications to data from a phase III clinical trial (Vax004) are discussed. Simulation-based sample size calculations and power analyses of the described methods also are presented.

• PROPORTIONAL HAZARDS MODELS WITH CONTINUOUS MARKS.

  Authors: Yanqing Sun, Peter B Gilbert, Ian W McKeague

  Annals of statistics. 02/2009; 37(1):394-426.

  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 et al. Biometrics34For 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 et al. Biometrics34 (1978) 541-554]. This article studies an extension of this approach to allow a continuum of competing risks, in which the cause of failure is replaced by a continuous mark only observed at the failure time. We develop inference for the proportional hazards model in which the regression parameters depend nonparametrically on the mark and the baseline hazard depends nonparametrically on both time and mark. This work is motivated by the need to assess HIV vaccine efficacy, while taking into account the genetic divergence of infecting HIV viruses in trial participants from the HIV strain that is contained in the vaccine, and adjusting for covariate effects. Mark-specific vaccine efficacy is expressed in terms of one of the regression functions in the mark-specific proportional hazards model. The new approach is evaluated in simulations and applied to the first HIV vaccine efficacy trial.

• Predicting the Impact of Blocking HIV-1 Nef In vivo.

  Authors: W David Wick, Peter B Gilbert, Otto O Yang

  Journal of virology. 01/2009;

  HIV-1 Nef is a multifunctional protein that confers an ability to evade killing by CTLs as well as other advantages for the virus in vivo. Here we exploit mathematical modeling and relatedHIV-1 Nef is a multifunctional protein that confers an ability to evade killing by CTLs as well as other advantages for the virus in vivo. Here we exploit mathematical modeling and related statistical methods to estimate the impact of Nef activity on viral replication in vivo in relation to CTLs. Our results indicate that downregulation of MHC class-I, A and B by wild-type Nef confers an advantage to the virus of about 82 percent in decreased CTL killing efficiency, on average-meaning that abolishing the MHC-I downregulation function of Nef would increase killing by more than five-fold. We incorporated this estimate, as well as prior estimates of replicative enhancement by Nef, in a previously-published model of HIV-1 and CTLs in vivo, generalized to permit CTL recognition of multiple epitopes. A sequence data-base analysis revealed that 92.9 percent of HIV-1 epitopes are A- or B-restricted and a previous study found an average of about 19 epitopes recognized. We combined these estimates in the model in order to predict the impact of inhibiting Nef function in the general (chronically-infected) population by a drug. The predicted impact on viral load ranged from negligible to 2.4 orders of magnitude, depending on the effects of the drug and the CTL dynamical-scenario assumed. We conclude that inhibiting Nef could make a substantial reduction in disease burden, lengthening the time before the necessity to undertake combination therapy with other antiretroviral drugs.