Recruiting innate immune system activity soon after viral transmission could block infection

Margie Ackerman, Professor of Engineering

An international consortium led by investigators from the Ragon Institute of MGH, MIT and Harvard and from Dartmouth have been awarded approximately $8 million from Partners Healthcare through a grant from the Bill & Melinda Gates Foundation-sponsored Collaboration for AIDS Vaccine Discovery in support of an effort to develop a new type of HIV vaccine. The project led by Galit Alter, PhD, of the Ragon Institute and Margaret Ackerman, PhD, of Dartmouth will investigate strategies to induce the production of antibodies that would recruit cells of the innate immune system to block HIV infection soon after viral transmission.

Typical viral infections induce immune responses that eliminate infected cells, ultimately controlling and eliminating the virus. With HIV infection, however, the natural immune response is unable to contain or eradicate the virus. This failure may be due in part to the short period of time, only a few days, before the virus integrates itself into the DNA of infected cells. Inducing immune responses that act this rapidly has not been possible through vaccination.

Galit Alter, Professor in Medicine

Neutralizing antibodies that directly interfere with the activity of a pathogen have been the Holy Grail of HIV vaccine development, but attempts to elicit production of such antibodies have had little success. However, antibodies also act against viruses by recruiting cells of the innate immune system, an early-response system that keeps pathogens in check until the more specialized adaptive immune system can respond. Methods for determining antibodies' innate-immune recruiting properties—also called their effector function—are not currently available on the scale that would be required for vaccine trials. In addition, the metabolic signals responsible for eliciting production of such antibodies are unknown. Therefore developing vaccines that could induce production of potent innate-recruiting antibodies requires both new technologies and better understanding of the required molecular signals.

“The importance of the link between antibodies and innate cells has been long appreciated as a factor in the efficacy of therapeutic antibodies, and the ability to manipulate the strength of this link via vaccination may represent a critical path forward,” said Dr. Ackerman, Assistant Professor of Engineering at Dartmouth.

The project led by Alter and Ackerman seeks to define the required signals, induce the production of innate-immune-recruiting antibodies and evaluate the protection they would afford against HIV in the early days following virus transmission. To meet these ambitious goals, the investigators have assembled a team of scientists—including experts in many facets of immune system biology and computational biology—from Beth Israel Deaconess Medical Center, Tulane University, the University of Oxford, and Friedrich-Alexander University Erlangen-Nuernberg in Germany.

Dr. Alter, who is based at Massachusetts General Hospital and an assistant professor of Medicine at Harvard Medical School, says, "With our spectacular team, I am confident that we will make great strides toward tailoring antibody effector function against HIV. We also hope that the lessons learned from this effort will translate into valuable tools for fine tuning vaccine-induced antibody responses to fight diseases beyond HIV, including cancers and autoimmunity."

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About Ragon Institute:
The Ragon Institute of MGH, MIT and Harvard was established in 2009 with a gift from the Philip T. and Susan M. Ragon Foundation, creating a collaborative scientific mission among these institutions to harness the immune system to combat and cure human diseases. The primary initial focus of the institute is to contribute to the development of an effective AIDS vaccine. The Ragon Institute draws scientists and engineers from diverse backgrounds and area of expertise across the Harvard and MIT communities and throughout the world, in order to apply the full arsenal of scientific knowledge to understanding mechanisms of immune control and immune failure and apply these advances to directly benefit patients. For further information, visit http://www.ragoninstitute.org

About Thayer School of Engineering at Dartmouth:
Thayer School of Engineering at Dartmouth is one of the country's oldest professional schools of engineering offering both undergraduate and graduate programs within a single unified Department of Engineering Sciences. World-class teaching and research is advancing innovation in three focus areas: engineering in medicine; energy technologies; and complex systems. These areas crosscut traditional engineering disciplines and address critical human needs.

Ragon Institute media contact: Sarah Dionne, (617) 726-6126, smdionne@partners.org
Thayer School media contact: Catharine M. Lamm, (603) 646-3943, catharine.m.lamm@dartmouth.edu