CVVR

Top HIV Scientists Awarded $42 Million in National Institutes of Health Funding to Improve Efficacy of HIV Vaccine Platforms

BIDMC, OHSU to Lead Consortium Exploring Vaccine Candidate and Cure Strategies

BOSTON – With $42 million in funding from the National Institutes of Health, scientists from Beth Israel Deaconess Medical Center (BIDMC) and Oregon Health & Science University (OHSU) will lead a five-year research initiative to advance efforts to cure and prevent HIV/AIDS.  Dan Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research at BIDMC, and Louis Picker, MD, Assistant Director of the OHSU Vaccine and Gene Therapy Institute, will lead a consortium of researchers from across the country exploring the mechanisms behind promising new HIV vaccine candidates and potential cure strategies.

More than 35 million people worldwide are infected with HIV, and more than 2 million new infections develop each year. “Antiretroviral therapies have allowed people infected with HIV to lead longer, healthier lives, but a vaccine and a definitive cure for infection would accelerate an end to this global epidemic,” said Barouch, who is also Professor of Medicine at Harvard Medical School.

The researchers will focus their work in two key areas: 1) understanding the mechanisms of why the current preventive HIV vaccines developed by Barouch and Picker are providing protection from infection in nonhuman primates; and 2) building on that knowledge to create both an effective preventive and therapeutic (cure) HIV vaccine.

“This grant gives us the opportunity to more closely collaborate with other scientists around the country who have a common goal: to end the HIV epidemic,” said Picker, who is also a Professor of Pathology/Molecular Microbiology and Immunology in the OHSU School of Medicine. “Stopping HIV may require a combination of vaccine approaches to get to full protection. There are just a handful of promising vaccine platforms out there, and if we can better understand why they are working, we’ll have a better shot at getting to the next generation of therapeutic vaccines that could cure current HIV infections.”

Barouch will lead a group of scientists from BIDMC and other institutions to define how candidate HIV vaccines may be able to protect against infection. They will study an adenovirus serotype 26 vectored vaccine with a purified HIV envelope protein (the surface protein of the HIV virus), which enhances the immune responses. This vaccine candidate was developed by Barouch and colleagues at BIDMC and is currently in international Phase 2a clinical trials.

In 2015, Barouch was lead author on a study in Science showing that a novel HIV vaccine using adenovirus serotype 26 (Ad26) regimen he and his research team developed at BIDMC provides robust protection against the virus in non-human primates. The study results showed that in half of the vaccinated non-human primates the prime-boost vaccine regimen provided complete protection against a series of six repeated challenges with the simian immunodeficiency virus (SIV), a virus similar to HIV that occurs in nonhuman primates.

With this new federal funding, Barouch and colleagues will evaluate the types and functions of the antibodies and cell-mediated immune responses induced by this vaccine, which will lead to a deeper understanding of how this vaccine might be able to protect HIV-uninfected individuals and also whether this vaccine could be used in HIV-infected individuals to help control the virus in the long term.

“With this vaccine candidate already in Phase 2a clinical trials, the knowledge gained in this research program will be immediately applicable to the development of clinical interventions,” Barouch said.

Concurrently, Picker will lead a team of investigators from OHSU working to better understand the efficacy of their unique preventive vaccine that uses cytomegalovirus (CMV) as the vector and is heading to Phase 1 human clinical trials next year in Portland, Ore. Picker’s 2013 landmark discovery published in Natureshowed in nonhuman primates that OHSU’s preventive vaccine not only controlled and stopped SIV, the nonhuman primate form of HIV, from spreading, but also cleared the virus in 50% of the primates’ systems.

“What we know so far is that our preventive vaccine using the unique CMV vector is able to control and clear the virus in nonhuman primates, but we haven’t shown why it works. Once we have a better understanding of the mechanisms that are making the preventive vaccine effective, there’s a chance that we could also optimize our vaccine, along with others,” said Picker.

In addition to Barouch and Picker, grant funding from the National Institute of Allergy and Infectious Diseases (UM1 AI124377), part of the NIH, will also support the work of Galit Alter, PhD, Ragon Institute of MGH, MIT and Harvard; R. Paul Johnson, MD, Emory University; Dennis Burton, PhD, Scripps Research Institute; Jeff Lifson, MD, AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research; Rafick Sekaly, PhD, Case Western Reserve University; and Wenjun Li, PhD, University of Massachusetts Medical School.

About Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding.

BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.

About OHSU

Oregon Health & Science University is a nationally prominent research university and Oregon’s only public academic health center. It serves patients throughout the region with a Level 1 trauma center and nationally recognized Doernbecher Children’s Hospital. OHSU operates dental, medical, nursing and pharmacy schools that rank high both in research funding and in meeting the university’s social mission. OHSU’s Knight Cancer Institute helped pioneer personalized medicine through a discovery that identified how to shut down cells that enable cancer to grow without harming healthy ones. OHSU Brain Institute scientists are nationally recognized for discoveries that have led to a better understanding of Alzheimer’s disease and new treatments for Parkinson’s disease, multiple sclerosis and stroke. OHSU’s Casey Eye Institute is a global leader in ophthalmic imaging, and in clinical trials related to eye disease.

CVVR

Researchers Uncover Earliest Events Following HIV Infection, Before Virus Is Detectable

Findings Could Lead to New HIV Prevention Strategies

BOSTON – New research in monkeys exposed to SIV, the animal equivalent of HIV, reveals what happens in the very earliest stages of infection, before virus is even detectable in the blood, which is a critical but difficult period to study in humans. The findings, published online today in the journal Cell, have important implications for vaccine development and other strategies to prevent infection.

“The events during the first few days after exposure to the virus and prior to the initial detection of virus in the blood are critical in determining the course of infection, but this period is essentially impossible to study in humans,” said lead author Dan Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center (BIDMC) and Professor of Medicine at Harvard Medical School. “Our study is the most comprehensive evaluation of acute HIV/SIV infection to date.”

The study was initiated as part of the National Institutes of Health–funded Consortium for AIDS Vaccine Research and involved multiple collaborating laboratories, including those headed by Rafick-Pierre Sekaly, PhD, of Case Western Reserve University and Jeffrey Lifson, MD, of the Frederick National Laboratory for Cancer Research.

When Barouch and his colleagues exposed 44 rhesus monkeys to SIV and conducted analyses of the animals on days 0, 1, 3, 7 and 10 following exposure, they found that SIV could disseminate rapidly through the body, with viral RNA (SIV’s genetic material) present in at least one tissue outside the reproductive tract in most monkeys analyzed 24 hours after exposure.

“In addition to rapid viral dissemination, the virus triggered a local inflammatory response that appears to suppress antiviral innate and adaptive immunity, thus potentially augmenting its own replication,” explained Barouch. “These data provide important insights into the earliest events of infection.”

The inflammatory response occurred in virus-infected tissues soon after exposure to SIV, and increasing amounts of viral RNA correlated with rising amounts of a host protein called NLRX1, which inhibits antiviral immune responses. In addition, the TGF-beta cell-signaling pathway, which suppresses adaptive immune responses, was triggered and correlated with lower levels of antiviral T immune cell responses, as well as higher levels of SIV replication. The researchers observed elevated expression of genes in the TGF-beta pathway in tissues that contained viral RNA as early as day 1 after exposure to the virus.

The findings suggest that there may be a very narrow window of opportunity to contain or eliminate the virus. HIV prevention strategies should take these factors into account. “We believe that these insights into early HIV/SIV infection will be critical for the development of interventions to block infection, such as vaccines, antibodies, microbicides and drugs,” Barouch said. “The next step in this line of research is to evaluate how various interventions may impact these early events.”

Study coauthors include BIDMC investigators Jinyan Liu, Kaitlin Smith, Erica Borducchi, Crystal Cabral, Lauren Peter, Amanda Brinkman, Mayuri Shetty and Hualin Li. Other team members include Khader Ghneim, William J. Bosche, Yuan Li, Brian Berkemeier, Michael Hull, Sanghamitra Bhattacharyya, Mark Cameron, Courtney Gittens, Chantelle Baker, Wendeline Wagner, Mark G. Lewis, Arnaud Colantonio, Hyung-Joo Kang, Wenjun Li, Jeffrey D. Lifson, Michael Piatak, Jr., and Rafick-Pierre Sekaly.

This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the National Institutes of Health (AI060354, AI078526, AI084794, AI095985, AI096040, AI100645 and HHSN261200800001E), and by the Ragon Institute of MGH, MIT and Harvard.

About Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding.

BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.

CVVR

CVVR Volunteer Registry is Now Live!

The Center for Virology and Vaccine Research launched a Volunteer Registry for adults interested in clinical trial participation on December 21st, 2015. The new CVVR Clinical Trials Unit established the Volunteer Registry in anticipation of CVVR clinical trials beginning this year at Beth Israel Deaconess Medical Center. These clinical trials will connect the CVVR lab bench where the research vaccines were developed to the research volunteer’s bedside where the vaccines will be administered, all under the roof of BIDMC. Research volunteers are essential to clinical trials. The Volunteer Registry brings together researchers and volunteers with the common goal of helping others live healthier lives. The purpose of the Volunteer Registry is to collect and maintain information that people voluntarily supply so they may be contacted by the CVVR Clinical Trials Unit about participating in future studies. To find out more information about the Volunteer Registry follow this link: http://cvvr.hms.harvard.edu/registry or to join the Volunteer Registry please call the Clinical Trials Unit at (617)-735-4610 or follow this link:   https://redcap.bidmc.harvard.edu/redcap/surveys/?s=MKTMD7NKLH.

CVVR

amfAR Gives $2 Million to CVVR Researchers to Study HIV Eradication

amfAR, The Foundation for AIDS Research, announced on July 21st that a CVVR research team has been awarded $2 million to pursue a range of strategies aimed at curing HIV. The team of researchers will be led by Dan Barouch, M.D., Ph.D., and will investigate the ability of combinations of antibodies to specifically kill latently infected cells in the lab, in monkeys, and then in people. The researchers will test two promising antibodies alone and together, in combination with a newly described drug that can “shock” the virus out of latently infected cells and possibly enhance the ability of the antibodies to locate the infected cells.

See full press release from amfAR here 

CVVR

Does NK Memory Exist? The Reeves Lab Shows It Does

Keith Reeves and colleagues at CVVR published in Nature Immunology this month that robust, durable, antigen-specific natural killer (NK) cell memory can be induced in primates after both infection and vaccination. This data upsets the long held maxim that NK cells are nonspecific parts of the innate immune system, and raises the possibility that NK cells might be harnessed in the development of vaccines for HIV and other pathogens.

Article at Nature Immunology

CVVR

The Bad Side of CD4 T Cells

CVVR in the News:

Vaccine-Induced CD4 T Cells Lead to Adverse Effect in a Mouse Model of Infection” – Science Daily, Jan 15, 2015

“A study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has found that a vaccine that elicits only CD4 T cells against a mouse model of a chronic viral infection results in an overwhelming — and lethal — inflammatory response. Reported in the January 16, 2015 issue of the journal Science, the new findings provide a cautionary tale for the development of vaccines aimed at eliciting robust CD4 T cell immunity against chronic infections, including HIV.” See full article >

CVVR

New Vaccine Shows Protection in Monkeys

Dan Barouch and colleagues reported in the journal Science on July 17th that an adenovirus-based HIV vaccine demonstrated complete protection in 50% of vaccinated animals against a series of repeated, heterologous, intrarectal SIV challenges that infected all controls. Protective efficacy correlated with the functionality of Env-specific antibody responses. Comparable protection was also observed with a similar Ad/Env vaccine against repeated, heterologous, intrarectal SHIV-SF162P3 challenges. Clinical trials of these vaccine candidates are ongoing, in collaboration with Johnson and Johnson, the U.S. Military HIV Research Program, the International AIDS Vaccine Institute, and the U.S. National Institutes of Health.