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RV144: The Search for Correlates of Protection Begins

June 24, 2010
Samples from RV144 are distributed to laboratories around the world in an effort to find correlates of protection.

When the results of the RV 144 clinical trial were presented at the AIDS Vaccine Meeting in Paris in October 2009, the data suggesting modest vaccine efficacy were greeted with enthusiasm and also raised many questions about how this regimen was able to reduce the risk of HIV infection. 

Initial Laboratory Studies

As the clinical investigation phase of the effort ended, investigators shifted their research focus to laboratory analysis.  MHRP immunologist and virologists quickly mobilized to isolate and characterize the HIV-1 viruses that caused infections and immunologists began to run the standard immunological analysis to determine what caused the effects. Study results challenged conventional assumptions of what type of immune responses correlated with vaccine efficacy, since neither viral load nor CD4+ counts differed in vaccine recipients who became infected with HIV-1.

Initial immunogenicity studies were conducted by Dr. Mark de Souza, head of the MHRP Laboratory at AFRIMS, along with Dr. Alexandra Schuetz, Dr. Chitraporn Karnasuta, and Dr. Silvia Ratto-Kim. Virus characterization began in November, conducted by MHRP researchers Dr. Sodsai Tovanabutra and Eric Sanders-Buell, located in Rockville, Md., and Dr. Jim Mullins at the University of Washington.

New 2010 Studies using RV144 Samples

With the mechanism of protection from HIV-1 infection not yet defined, the search for an immunological correlate of protection from HIV-1 infection is moving into high gear. Throughout the study, blood samples from the 16,000 study participants were carefully collected, coded to preserve patient confidentially and stored for analysis.  An open invitation for research proposals was announced in Paris as well as other large, public scientific meetings and posted on the MHRP website. 

As a result, MHRP and 25 U.S. and international collaborators are initiating intensive laboratory studies of these the patient specimens in an effort to define the immune mechanisms mediating the protection against HIV infection.

To access specimens, investigators were asked to initially submit a research concept sheet. Scientific committees representing wide ranging expertise assisted MHRP by reviewing these concepts and planning further study of these clinical study samples. Investigators were asked to submit hypotheses, experimental methods, and to discuss the proposals with statisticians to ensure that the proposed work was scientifically sound and optimize coordinated use of RV144 samples. 

Research proposals were reviewed by Working Groups (WG), chaired by the following preeminent scientists: Humoral and Innate Immunity by Dr. Bart Haynes, T-cell immunity by Dr. Julia McElrath, Host Genetics by Dr. David Goldstein. The Animal Model working group, chaired by Dr. Genoveffa Franchini, met separately to discuss animal investigations to complement these clinical research efforts.

Starting in November 2009, these scientists, along with their co-chairs, statisticians from SCHARP and MHRP staff organized meetings with more than 50 scientists to review and provide timely scientific and statistical feedback to investigators on their research proposals.  Approved proposals were forwarded to the Scientific Steering Committee (SSC) chaired by Dr. Haynes starting in February 2010. Proposals approved by the SSC were sent to the RV144 Steering Committee, composed of members from each of the collaborators, for approval.  Funding recommendations were made by a joint DAIDS/RV144 Steering Committee, and more than 30 research proposals from 20 institutions were approved. 

TABLE 1. NUMBER OF RV 144 RESEARCH PROJECTS

Approved Proposals

Institutions

Investigators

32

20

3

Thanks to the excellent support from the MHRP staff at AFRIMS and HJF Technology Transfer office, sites are beginning to receive samples for their work, some of which is described below.  We will closely to track reports from what promises to be productive collaborations between MHRP and these creative research teams.

Humoral & Innate Immunity

Since antigen-elicited humoral (antibody) responses are often the hallmark of effective vaccines, it is likely that the RV144 vaccine regimen induced antibodies that contributed to the observed vaccine efficacy. There are many different types of antibody responses. Some can neutralize the virus, preventing cell infection (also sometimes referred to as “sterilizing immunity”), but these highly specific antibodies are extremely difficult to induce for HIV-1. Only modest neutralization was observed study patients who have received the RV144 vaccines in previous studies, so investigators will explore these responses in more detail, using several highly sensitive assays. Other antibodies can bind and cause viruses to aggregate and also interact with immune cells. Still other antibodies preferentially function in certain tissues (i.e. IgA in the mucosa).  Investigators will characterize HIV-specific antibody responses as well as innate responses (naturally present and are not due to specific vaccine antigen) using many new and very interesting assays. 

Cellular Immunity

As cell-mediated immune responses likely contribute to protection against HIV-1 infection, investigators will apply a platform of assays using state-of-the-art technologies to assess cellular immune responses in vaccine and placebo recipients from RV144 to gain a comprehensive view of vaccine-induced cellular immunity. This will include multiparameter flow cytometry and analyses to characterize different immune cell types (T-cells, B-cells, dendritic cells and NK cells), multiplex cytokine secretion and proliferation in response to HIV-1 Gag and Env peptide pools that are representative of the vaccine antigens.

Host Genetics

This group of investigators will explore genetic associations with HIV acquisition in RV144 by from the impact of host genetic factors on vaccine-induced cellular and humoral immunology. A variety of genetic typing assays will be used to characterize patient HLA and other genetic markers and evaluate associations between host genetics and the results of the immune analysis from the other working groups.  As one example, some investigators will examine genetic correlates of antibody induced after RV144 vaccination, since both antibody titers and their capacity to induce ADCC/ADCVI are modulated by particular genetic variations that allow some individuals to induce robust antibody responses while others induce these responses poorly. 

Animal Models

These studies will not directly evaluate immune responses in the RV 144 patients but instead will attempt to reproduce the same effect of vaccination seen on HIV acquisition in RV144 in vaccinated non-human primates, using similar vaccines and challenge viruses.

Conclusion

We are looking forward to collaborating with this group of researchers (in Table 2 below), which includes some of the foremost experts in HIV vaccine research. We will continue to provide updates on these projects over the next year. We would like to thank our many collaborators for these efforts and also the RV 144 study team and study participants who have made this work possible.  

TABLE 2. SUMMARY OF RV144 RESEARCH PROJECTS

Investigator(s)

Institution

Research Focus

   Humoral/Innate

Galit Alter

Dennis Burton

Ragon Institute, Harvard

Scripps Institute

ADCC, epitope mapping, phagocytosis assay

Persephone Borrow

Oxford University

Cytokine, chemokine

Barton Haynes, Georgia Tomaras, Munir Alam, David Montefiore

Vicky Polonis

Chitraporn Karnasutra

John Mascola, Robert Bailor

Duke University

 

 

MHRP

AFRIMS

VRC/NVITAL/NIH

Binding, affinity, neutralizing antibody studies, virus capture

Linda Baum

Mark Connors

Thomas Evans

Guido Ferrari

Stephen Kent

Rush University

NIAID, NIH

Harvard University

Duke University

University of Melbourne

ADCC

Donald Forthal

University of California, Irvine

Fc-Fcy interactions

Susan Zolla-Pazner

New York University

Anti -V2 and -V3 antibody

George Lewis, Anthony Devico, Robert Gallo

Institute of Human Virology, University of Maryland

Anti-CD4i epitope responses

Thomas Hope

Northwestern University

Antibody modulation of HIV transport in cervical mucus

Phillip Berman

University of California, Santa Clara

Blocking antibody, Env specificity

Terri Wrin

Monogram Biologics Inc.

Neutralizing antibody

Daniel Libraty

University of Massachusetts

Innate responses

Dan Barouch

Harvard University

Anti- vector antibody

James Arthos

NIAID, NIH

HIV-1 gp 120 snf a4b7 interaction

Richard Koup

NIAID, NIH

ELISA titers, specificities, and epitope targets of Env antibody

Robin Shattock

St. George's University of London

Viral aggregation

Juliana McElrath

University of Washington

T-cell studies

Rafick Sekaly

Vaccine and Gene Therapy Institute

RNA analysis of T-cells

Daniel Libraty

University of Massachusetts

Innate responses

Thomas Lehner

Kings College London

Innate anti-HIV-1 APOBEC3G and MIP-1

   Host Genetics

Galit Alter

Mary Carrington

David Goldstein

John Moore

Gustavo Kijak

Nelson Michael

Ragon Institue, Harvard

NCI, NIH

Duke University

Cornell University

MHRP

MHRP

Genetic correlates of humoral immunity

   Core MHRP Studies

Mark Desouza

MHRP AFRIMS

Neutralizing and cellular immunity/ADCC

Chitraporn Karnasutra

Vicky Polonis

Ruengpung Sutthent

MHRP AFRIMS

MHRP

MHRP AFRIMS

Neutralizing antibody

Alexandra Schuetz

Silvia Ratto-Kim

Jeff Currier

MHRP AFRIMS

MHRP

MHRP

Cellular immunity

Nelson Michael

MHRP

Genetic Analysis

Gustavo Kijak

Sodsai Tovanabutra

Eric Sanders-Buell

Jerome Kim

Jim Mullins

MHRP

MHRP

MHRP

MHRP

University of Washington

Viral Sequencing