Welcome to the HVTNews

by Jim Kublin, Executive Director, HVTN

Welcome to the HVTNews. With this edition, we would like to welcome new audiences and reintroduce our newsletter. In this and future editions we will clarify why HIV vaccine research in humans provides critical momentum for the discovery and development of effective vaccines. Upcoming newsletter topics include monoclonal antibodies for prevention, electroporation, efficacy trial capacity building, immunotherapy, and community engagement. We will highlight the management of the Network’s many multilateral collaborations and our outstanding clinical sites that work in service to our mission. We are focused on the dynamic field of combination prevention and the role of vaccine development and deployment in control of the HIV pandemic.

A Sequential Two-stage Trial Design for Evaluating Efficacy and Immune Correlates for Multiple Vaccine Regimens

by Peter Gilbert, Doug Grove

Introduction

Of the 5 preventative HIV vaccine efficacy trials that have been conducted to date, 3 (Vax004, Vax003, and Step/HVTN 502) showed a vaccine efficacy (VE) near zero.1,2,3 The fourth trial, RV144, provided an estimated VE = 31%.4 The 5th trial (HVTN 503/Phambili) was halted early and did not yield reliable efficacy data. HIV infection was a primary endpoint in all 5 trials.

This article summarizes a novel efficacy trial design proposed by the HVTN that seeks improvements in four specific aspects of the previous trials, namely: (1) The primary analysis evaluated VE against infections occurring at any time during follow-up, including well after the immunization series; (2) A single vaccine regimen was evaluated; (3) Some of the trials did not monitor for vaccine efficacy futility, resulting in inefficiency; (4) Prospective planning for timely assessment of immune correlates was limited, and correlates, but not surrogates, were assessed.

While the proposed novel design was developed with primary application for future efficacy trials in South Africa5, many of its features are being implemented in the only ongoing efficacy trial, HVTN 505.

Sieve Analysis of HIV Sequences in Vaccine Efficacy Trials

by Peter Gilbert, Allan deCamp, Paul Edlefsen, Craig Magaret, Tomer Hertz

Introduction

Sieve analysis is integral to the evaluation of immune correlates of protection, as vaccine-induced immune responses (whether measurable or not) are the cause of vaccine sieve effects. (Vaccine sieve effects are vaccine-induced adaptive immune responses that may partially block HIV acquisition, and/or alter HIV’s evolution postacquisition.) Sieve analysis can shed light on potential mechanisms of immune protection, as well as generate hypotheses on which immunological measurements may be immune correlates.

The enormous variability of the HIV genome and the spread of multiple HIV genotypes and recombinants has posed a difficult challenge to developing a vaccine.^1,2,3 In preventive HIV vaccine efficacy trials, HIV sequences are measured and characterized from trial participants who become infected. Sieve analysis of these HIV sequences investigates potential vaccine sieve effects.

Training and Mentorship Programs at the HVTN

by Blythe Adamson

The HVTN believes that the continued investment in research and in the next generation of researchers is crucial to the success of our ultimate goal — finding an effective preventive HIV vaccine. To that end, the Network established 3 special programs that address the unique requirements of the HIV vaccine field.

Defining the Targets of HIV-specific T-cell Responses (epitope mapping)

by Nicole Frahm

Epitope mapping determines which regions of a given pathogen (e.g. HIV) are recognized by T cells in response to infection or vaccination. The size and makeup of these mapped regions are characterizedz by the tools used in the process, i.e. the peptides tested in the immune assay of choice. In most cases, the peptides will be relatively short and will cover the protein in question in an overlapping design (e.g. 15-mers overlapping by 11); this approach has been developed to ensure relative sensitivity (longer peptides are less well recognized) as well as good coverage of potential CD8 T-cell epitopes, which are usually 8-12 amino acids (aa) in length (shorter overlaps would lead to truncated epitopes that cannot be recognized). Epitope mapping is mostly carried out in a step-wise manner, with larger pools (encompassing up to 160 15-mers) being tested first and positive pools being deconvoluted, subsequently using smaller pools followed by single peptides. Results are usually presented as the breadth of the T-cell response (i.e. the number of targeted peptides/epitopes), and sometimes as the specific sequences representing the dominant targets of HIV-specific T cells. The assay of choice is predominantly an IFN-γ ELISpot since it allows for testing of large numbers of conditions using relatively few cells; it comes at the cost of not being able to distinguish whether the targeted regions are recognized by CD4 or CD8 T cells unless followed up by intracellular cytokine staining or depletion studies.

HVTN Protocols — Enrolling or in Active Follow Up

Start Date	HVTN#		N	Sites	Description
Jan-09	205	Geovax Phase 1	120	Atlanta; Birmingham; Boston; New York; Iquitos; Lima; Nashville; Rochester; San Francisco; Seattle	This is a phase 2a clinical trial to evaluate the safety and tolerability of a prime-boost regimen of the GeoVax DNA vaccine and modified vaccinia Ankara (MVA) vaccine, or of MVA vaccine alone, in healthy, HIV-1–uninfected, vaccinia-naive individuals. The vaccines express HIV-1 Clade B Gag, Pol and Env. Immune responses will be tested in rectal and genital secretions as well as in blood.
Jan-09	906	US High-Risk Women	800	Chicago; Philadelphia; New York	This is a longitudinal study of women at high risk for HIV-1 infection to inform HIV vaccine trial participation. The primary objectives are 1) To determine the feasibility of recruiting and retaining women at high risk of HIV infection with a focus on women who reside or engage in risk behavior in local risk pockets and/or are partners of men who are from subgroups with a high prevalence of HIV; and 2) To determine whether the HIV incidence rate in the longitudinal cohort is at least 1% per year.

HVTN Annual Network Award Winners

On June 3rd 2011 in Washington DC, the HVTN honored individuals who perform outstanding work at our sites.

HVTN 505: Expansion in Response to an Evolving Field

by Shelly Karuna, Carter Bentley

HVTN 505 is a study of an HIV vaccine regimen developed by the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). In June 2009, the study began enrolling 1350 men and transgender women who have sex with men.

The vaccine regimen in HVTN 505 consists of a DNA prime containing HIV-1 subtype B gag, pol, and nef genes and HIV-1 subtypes A, B, and C env given three times followed by a single recombinant adenovirus type 5 (rAd5) boost containing gag-pol from subtype B and envelope genes from subtypes A, B and C. On the basis of non-human primate (NHP) and human data for this and other vaccine regimens, the primary objectives of the protocol when it opened were: (1) the continued assessment of the safety and tolerability of the regimen; and (2) assessment of the vaccine’s impact on viral load setpoint among participants who became HIV-infected.

Exploring Barriers and Facilitators to Participation of Male-To-Female Transgender Persons in HIV Vaccine Clinical Trials

by Michele Peake Andrasik

Photo by Sarah Stefana Smith

Transgender is a term used to describe a range of individuals with atypical gender characteristics, or with gender identities discordant from their biological sex. Male-to-female (MTF) transgender communities experience high HIV prevalence and African American race has been found to be the strongest risk factor for HIV infection among MTF transgender persons. Additional HIV risk factors in this population include (but are not limited to) depression, homelessness, and having less than a high school degree. MTF transgender persons are often marginalized and have many unmet needs. Behavioral and biomedical HIV prevention strategies are urgently needed for this population.

Enrollment of MTF transgender participants in HIV vaccine trials has been modest. To explore barriers and facilitators to participation, focus groups of MTF transgender women were conducted in four urban areas (Atlanta, Boston, Philadelphia and San Francisco). Forty-two individuals participated in these groups. The figure on page 17 depicts the participants’ major demographic characteristics. In addition, the mean number of unprotected anal sex partners in the 6 months prior to the focus group was 6.5 (range = 0-100). Over half (57%) had never participated in behavioral or biomedical research. Seven (16.7) were unsure of past participation and 2 (5%) chose not to answer. Among those with a confirmed history of biomedical research participation (n=11), 2 reported participating in a PrEP clinical trial and one in a vaccine clinical trial.

Recent HVTN Publications September 2010 – September 2011