LANL SAYS HIV VACCINE SHOWS PROMISE IN MONKEYS

FROM:  LOS ALAMOS NATIONAL LABORATORY 
New Global HIV Vaccine Design Shows Promise in Monkeys
Preclinical study provides strong rationale for clinical trials

LOS ALAMOS, N.M., October 30, 2013—The considerable diversity of HIV worldwide represents a critical challenge for designing an effective HIV vaccine. Now, it appears that that a vaccine bioinformatically optimized for immunologic coverage of global HIV diversity, called a mosaic vaccine and designed by Bette Korber and her team at Los Alamos National Laboratory, may confer protection from infection.

“This is the first time the mosaic antigen inserts were used in a challenge study. In a challenge study, vaccine-elicited protection from infection is tested, versus testing a vaccine for its ability to stimulate good immune responses,” says Bette Korber of Los Alamos.

These vaccines are specifically designed to present the most common forms of parts of the virus that can be recognized by the immune system. This new insight regarding a mosaic vaccine’s ability to protect from infection is the result of work by a scientific team led by Beth Israel Deaconess Medical Center (BIDMC), and including Los Alamos researchers. The study, which was conducted in monkeys, is newly published in the journal Cell.

“To our knowledge, this study represents the first evaluation of the protective efficacy of a candidate global HIV antigen strategy in nonhuman primates,” says lead author Dan H. Barouch, MD, PhD, the director of the Center for Virology and Vaccine Research at BIDMC and professor of medicine at Harvard Medical School. “In this study, we show for the first time that bioinformatically optimized HIV vaccine antigens can afford partial protection in rhesus monkeys against challenges with a stringent simian-human immunodeficiency virus.”

Key defense against HIV infection studied

Barouch and his team studied the immunogenicity of HIV mosaic Env/Gag/Pol antigens administered to monkeys using viral vectors. (Env, Gag, and Pol are three major HIV proteins that help viruses “bind to” or enter host cells and infect them.) Mosaic proteins resemble these natural proteins, therefore increasing efficacy against the HIV diversity. After immunization, the monkeys were repetitively exposed to a simian-human immunodeficiency virus that carried the human Env (envelope, or binding) protein, and the investigators evaluated the ability of the vaccines to block infection by repeatedly exposing the vaccinated animals to the virus.

Although most animals immunized with the mosaic HIV vaccine became infected by the end of the study, the researchers observed an 87 to 90 percent reduction in monkeys’ probability of becoming infected each time they were exposed to the virus. In contrast, monkeys that received sham vaccines became infected quickly.

“These findings indicate that these optimized vaccine antigens can afford partial protection in a stringent animal model,” says Barouch.

The investigators found that the immunized monkeys mounted antibody responses against diverse strains of HIV noting, “Protection was dependent on several different types of antibody responses, suggesting that the coordinated activity of multiple antibody functions may contribute to protection against difficult-to-neutralize viruses.” The monkeys also mounted cellular immune responses to multiple regions of the virus.

Highly infective virus presents challenge

The researchers note that most previous HIV vaccine candidates have typically only been tested for protection against easy-to-neutralize viruses rather than against a difficult-to-neutralize virus like the one used in this study. Also, the viral challenge in the study was approximately 100-fold more infectious than typical sexual HIV exposures in humans.

“These data suggest a path forward for the development of a global HIV vaccine and give us hope that such a vaccine might indeed be possible,” said Barouch. “We are planning to advance this HIV vaccine candidate into clinical trials next year,” he adds.

The research team

Study coauthors include BIDMC investigators Kathryn E. Stephenson, Erica N. Borducchi, Kaitlin Smith, Kelly Stanley, Anna G. McNally, Jinyan Liu, Peter Abbink, Lori F. Maxfield and Michael S. Seaman. Other team members include Anne-Sophie Dugast, Galit Alter, Melissa Ferguson, Wenjun Li, Patricia L. Earl, Bernard Moss, Elena E. Giorgi, James J. Szinger, Leigh Anne Eller, Erik A. Billings, Mangala Rao, Sodsai Tovanabutra, Eric Sanders-Buell, Mo Weijtens, Maria G. Pau, Hanneke Schuitemaker, Merlin L. Robb, Jerome H. Kim, Bette T. Korber and Nelson L. Michael.

This work was supported by the U.S. Military Research and Material Command and the U.S. Military HIV Research Program; the National Institutes of Health; the NIAID Division of Intramural Research; the Ragon Institute of MGH, MIT, and Harvard; and the Bill and Melinda Gates Foundation.

About Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and currently ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox.

ANTIBODY EVOLUTION AND HIV VACCINE DEVELOPMENT

Co-evolution of virus and antibody – The evolution of the viral protein (green) from 14 weeks through 100 weeks post-transmission is compared to the maturation of the human antibody. Image courtesy Los Alamos National Laboratory.

 
FROM: LOS ALAMOS NATIONAL LABORATORY
Antibody Evolution Could Guide HIV Vaccine Development

LOS ALAMOS, N.M., April 4, 2013—Observing the evolution of a particular type of antibody in an infected HIV-1 patient, a study spearheaded by Duke University, including analysis from Los Alamos National Laboratory, has provided insights that will enable vaccination strategies that mimic the actual antibody development within the body.

The kind of antibody studied is called a broadly cross-reactive neutralizing antibody, and details of its generation could provide a blueprint for effective vaccination, according to the study’s authors. In a paper published online in Nature this week, the team reported on the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection.

The observations trace the co-evolution of the virus and antibodies, ultimately leading to the development of a strain of the potent antibodies in this subject, and they could provide insights into strategies to elicit similar antibodies by vaccination.

Patients early in HIV-1 infection have primarily a single "founder" form of the virus that has been strong enough to infect the patient, even though the population in the originating patient is usually far more diverse and contains a wide variety of HIV mutations. Once the founder virus is involved in the new patient’s system, the surrounding environment stimulates the HIV to mutate and form a unique, tailored population of virus that is specific to the individual.

The team, including Bette Korber, Peter Hraber, and S. Gnanakaran, of Los Alamos National Laboratory, led by Barton Haynes of Duke University School of Medicine in Durham, North Carolina, with colleagues at Boston University, the National Institutes of Health, and other institutions as part of a large collaboration, showed that broadly neutralizing antibodies developed only after the population of viruses in the individual had matured and become more diverse.

"Our hope is that a vaccine based on the series of HIV variants that evolved within this subject, that were together capable of stimulating this potent broad antibody response in his natural infection, may enable triggering similar protective antibody responses in vaccines," said Bette Korber, leader of the Los Alamos team.

This study was supported by the National Institutes of Allergy and Infectious Diseases (NIAID) and by intramural National Institutes of Health (NIH) support for the NIAID Vaccine Research Center, by grants from the NIH, NIAID, AI067854 (the Center for HIV/AIDS Vaccine Immunology) and AI100645 (the Center for Vaccine Immunology-Immunogen Discovery). Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source at Argonne National Laboratory was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38.