a Publication of the HIV Vaccine Trials Network VOLUME 3, ISSUE 1 | SEPTEMBER, 2011 Welcome to the HVTNews Jim Kublin, Executive Director, HVTN Welcome to the HVTNews. With this immune system’s response to it grows, the edition, we would like to welcome new au- Network and its partners are developing diences and reintroduce our newsletter. In vaccine candidates that elicit promising im- this and future editions we will clarify why mune responses, with new vectors, proteins, HIV vaccine research in humans provides inserts, and new vaccine delivery mecha- critical momentum for the discovery and nisms; an important scientific milestone in development of effective vaccines. Upcom- our trials this past year was the use of elec- ing newsletter topics include monoclonal troporation of DNA plasmids, which nearly antibodies for prevention, electroporation, doubled the detectable immune response to efficacy trial capacity building, immu- the study’s vaccine candidate. notherapy, and community engagement. We will highlight the management of the Though the promising results of the latest Network’s many multilateral collaborations biomedical prevention trials are great news, Photo by Sarah Stefana Smith and our outstanding clinical sites that work the search for a vaccine is as relevant and Exploring Barriers: Participation of Male-to-Female Transgender Persons in HIV Vaccine Trials [p.16] in service to our mission. We are focused on urgent today as it was at the outset of the the dynamic field of combination preven- epidemic. Several factors must be consid- tion and the role of vaccine development ered in the context of an effective bio- activism and innovation the field deserves, plays and deployment in control of the HIV medical prevention regimen -- compliance, a major role in the ultimate control of this pan- pandemic. cost, and resistance are among the most demic. As you read this issue, we hope you will important. gain a perspective about where we are going as We are currently developing novel trial a field and as an organization, in our quest for designs that, combined with new analy- The best biomedical prevention regimen is this ultimate goal. ses tools, will speed up clinical trials and still only as good as its users’ compliance. allow us to zoom in quicker on the most When compliance is spotty or inconsistent, promising candidates, and identify the new infections will still occur. Additionally, MISSION OF THE HVTN much needed correlates and surrogates of the regular use of antiviral drugs as prophy- TO ENHANCE THE DISCOVERY AND DRIVE THE protection. Epitope mapping allows us to laxis may result in resistant strains of the DEVELOPMENT OF A SAFE AND GLOBALLY characterize the breadth and depth of T cell virus, complicating the already challenging EFFECTIVE VACCINE TO PREVENT HIV. responses to specific epitopes in our vaccine picture of HIV treatment and preven- candidates, and sieve analyses enables us to tion. On top of that, when considering the We will do this through well-designed clinical more accurately recognize vaccine candi- global distribution of HIV infections, it is research trials that objectively and ethically dates that exert pressure on the virus. These clear that the cost of preventive medica- address the critical questions of the field. topics are discussed more in depth in the tions will figure prominently in many of the Our objective clinical trial platform lets us following pages. hardest hit communities. evaluate safety, immunogenicity and efficacy of candidate vaccines, as well as design clinical The search for an HIV vaccine, as with Considering the enormous toll exerted trials that will provide clues on ways to enhance other vaccines, has been long and, for many globally by the HIV pandemic, in terms of the effectiveness of new vaccines. years, frustrating. At the moment, however, human suffering and social and economic we find ourselves in the midst of a very ex- devastation, it is clear that definitive, reli- We promote the use of new innovations such as adaptive trial designs, which may help us citing time in the HIV prevention field in able methods to halt the spread of HIV get closer to a safe and effective vaccine more general, and the vaccine field in particular. are needed. A preventive vaccine, building quickly. As our understanding of the virus and the on recent advances, with the continued IN THIS ISSUE ARTICLES 2 A Sequential Two-stage Trial Design for Evaluating Efficacy and Immune 15 HVTN 505: Expansion in Response to an Evolving Field Correlates for Multiple Vaccine Regimens 16 Exploring Barriers and Facilitators to Participation of Male-To-Female 5 Sieve Analysis of HIV Sequences in Vaccine Efficacy Trials Transgender Persons in HIV Vaccine Clinical Trials 7 Training and Mentorship Programs at the HVTN 12 PROTOCOLS 10 Defining the Targets of HIV-specific T-cell Responses (Epitope Mapping) 19 PUBLICATIONS 20 14 HVTN Annual Network Award Winners CALENDAR [Back Cover] A Sequential Two-stage Trial Design for Evaluating Efficacy and Immune Correlates for Multiple Vaccine Regimens Peter Gilbert, Doug Grove Of the 5 preventive HIV vaccine efficacy trials that have been Multiple Concurrent Two-stage Designs with a conducted to date, 3 (Vax004, Vax003, and Step/HVTN Shared Placebo Group 502) showed a vaccine efficacy (VE) near zero.1,2,3 The fourth trial, RV144, provided an estimated VE = 31%.4 The 5th trial The new trial design may be viewed as multiple concurrent (Phambili/HVTN 503) was halted early and did not yield two-stage vaccine-versus-placebo trials, with resource savings reliable efficacy data. HIV infection was a primary endpoint in accrued via a shared placebo group. For each vaccine regimen, all 5 trials. stage 1 evaluates VE over 18 months. Only if positive efficacy is demonstrated, stage 2 occurs and evaluates VE through 36 This article summarizes a novel efficacy trial design proposed months. Such adaptive assessment of VE durability is by the HVTN that seeks improvements in 4 specific aspects of motivated by the supposition that only vaccines conferring the previous trials, namely: (1) The primary analysis evaluated protection over 18 months merit longer-term assessment. VE against infections occurring at any time during follow- This is because durability largely influences a vaccine’s public health utility,6, 7, 8 and HIV vaccine-induced immune responses up, including well after the immunization series; (2) A single 4 vaccine regimen was evaluated; (3) Some of the trials did not can wane over time (eg, RV144) . The 2 stages are also used monitor for vaccine efficacy futility, resulting in inefficiency; for adaptively assessing immune correlates, as this assessment (4) Prospective planning for timely assessment of immune becomes a priority once a vaccine shows positive VE(0-18). correlates was limited, and correlates, but not surrogates, were assessed. Prospectively Planned and More Rigorous Evaluation of Immune Correlates While the proposed novel design was developed with primary 5 An ultimate goal for HIV vaccine research is development application for future efficacy trials in South Africa , many of of an immune response biomarker that reliably predicts VE, its features are being implemented in the only ongoing efficacy 9 a so-called “surrogate of protection (SoP).” An identified trial, HVTN 505. SoP would guide vaccine development as an evidence-based Objectives of the Proposed Design primary endpoint in subsequent phase I/II trials. For each of 1 to 3 vaccine regimens versus a shared placebo Identification of SoPs proceeds in two steps. First, immune group, the new design’s primary objective is the timely evalu- biomarkers are assessed as correlates of infection rate among 10 ation of VE against HIV infections diagnosed within 18 vaccinated subjects, named correlates of risk (CoRs). Howev- months of entry [a parameter we refer to as VE(0-18)]. This er, a discovered CoR may have no value to predict VE, because design uses sequential monitoring to maximize efficiency and it may merely correlate with an intrinsic factor that actually 11 ethics. Trial efficiency is maximized by restricting the assess- determines relative resistance to infection. Because of this ment to HIV exposures near the immunization series before limitation, statistical methods have been developed to assess immune responses wane. The trial is event-driven, with sample whether an identified CoR reliably predicts VE, and, if it does, 12-16 sizes chosen to ensure high probability that the trial will it is called a SoP. identify vaccines with VE(0-18) of at least 40%. The second- ary objectives include: (1) to evaluate durability of VE for each Assessing a SoP requires predicting the vaccine-induced im- regimen showing reliable evidence for positive VE(0-18); (2) mune biomarker for placebo recipients; these predictions may to expeditiously and rigorously evaluate immune correlates of be derived either by (1) Modeling the relationship between protection if any of the vaccine regimens show positive VE(0- baseline subject characteristics and the immune biomarker 18); (3) to compare VE among the vaccine regimens, aiding (baseline immunogenicity predictor approach, BIP), and/or by decisions about whether and which regimen to advance to a (2) Vaccinating uninfected placebo recipients at study close- licensure trial; and (4) to evaluate vaccine effects on HIV-1 out and directly measuring their vaccine-induced biomarkers 12 infection progression. (closeout placebo vaccination approach, CPV). Accordingly, 2 SEPTEMBER