For the first time, researchers have experimentally induced antibodies that neutralize HIV-1 and simultaneously recognize both HIV-1 envelope protein and lipids. The results were reported by U.S. Military HIV Research Program (MHRP) researchers on Aug. 25 in the online version of AIDS, the official journal of the International AIDS Society.

The lead investigators, Dr. Gary Matyas and Dr. Carl Alving, researchers in the Division of Retrovir ology, MHRP, Walter Reed Army Institute of Research (WRAIR), and their collaborators, conducted the exploratory study using small synthetic HIV-1 peptides encapsulated in liposomes containing lipid A as an adjuvant.

The monoclonal antibodies, produced after immunizing mice, have binding characteristics that look similar to two well-known broadly neutralizing human monoclonal antibodies, known as 2F5 and 4E10, which also bind to HIV-1 protein and lipid. These antibodies, 2F5 and 4E10, are widely viewed as models of the types of neutralizing antibodies that might be useful in an effective HIV-1 vaccine. Until now, the HIV field has been unable to induce neutralizing antibodies that have both protein-binding and lipid-binding characteristics similar to 2F5 or 4E10. This study employed widely used, clinically acceptable, well-tolerated and relatively inexpensive generic antigen-adjuvant constituents that potentially could be used as part of a human formulation.

Dr. Carl Alving, Chief of the Department of Adjuvant and Antigen Research, said, “Some of the strongest naturally occurring antibodies that broadly neutralize HIV have the unique characteristics of recognizing both HIV protein and lipid. It has been believed that it might be difficult to induce such antibodies experimentally, and historically, this has been considered a potential roadblock to creation of an effective HIV vaccine. This study demonstrates that such antibodies might be induced with immuno-stimulating liposomes.”

Source:
Lisa Reilly

Henry M. Jackson Foundation for the Advancement of Military Medicine

Researchers at and associated with the International AIDS Vaccine Initiative (IAVI), at The Scripps Research Institute, and at the biotechnology companies Theraclone Sciences and Monogram Biosciences have discovered two powerful new antibodies to HIV that reveal what may be an Achilles heel on the virus. They published their work in Science this week.

Researchers will now try to exploit the newfound vulnerability on the virus to craft novel approaches to designing an AIDS vaccine. Moreover, the global collaboration and process that led to the discovery of the two new broadly neutralizing antibodies (bNAbs) are likely to produce more such antibodies, which may in turn reveal additional vulnerabilities of HIV, adding still more vitality to the effort to develop a vaccine against AIDS.

“The findings themselves are an exciting advance toward the goal of an effective AIDS vaccine because now we’ve got a new, potentially better target on HIV to focus our efforts for vaccine design,” said Wayne Koff, senior vice president of research and development at IAVI. “And having identified this one, we’re set up to find more, which should further accelerate global efforts in AIDS vaccine development.”

Broadly neutralizing antibodies to HIV are produced by a minority of HIV-infected individuals and are distinct from other antibodies to HIV in that they neutralize a high percentage of the many types of HIV in circulation worldwide. It is widely believed that to prevent HIV infection an AIDS vaccine would need to teach the body to produce these powerful antibodies before exposure to the virus. Animal experiments suggest that conceptually such a vaccine would work. Before this finding only four antibodies to HIV had been discovered that were widely agreed to be broadly neutralizing.

The two newly discovered bNAbs, called PG9 and PG16, are the first to have been identified in more than a decade and are the first to have been isolated from donors in developing countries, where the majority of new HIV infections occur. Moreover, previously identified bNAbs against HIV have functioned by binding to places on HIV that have proven difficult to exploit by means of vaccine design.

“These new antibodies, which are more potent than other antibodies described to date while maintaining great breadth, attach to a novel, and potentially more accessible site on HIV to facilitate vaccine design,” said Dennis Burton, professor of immunology and microbial science and scientific director of the IAVI Neutralizing Antibody Center at The Scripps Research Institute in La Jolla, California. Professor Burton is also a member of the newly established Ragon Institute of MGH, MIT and Harvard. “So now we may have a better chance of designing a vaccine that will elicit such broadly neutralizing antibodies, which we think are key to successful vaccine development.”

Breadth of neutralization is important because any effective AIDS vaccine must provide protection from a diverse range of the most prevalent types of HIV circulating worldwide. High potency suggests that such antibodies will not have to be produced by the body in very large quantities to confer protection.

The two new antibodies target a region of the viral spike used by HIV to infect cells. The viral spike glycoproteins, termed gp120 and gp41, are highly variable and have evolved to thwart immune attack. But biochemical studies suggest that PG9 and PG16 target regions of gp120 that do not change, which probably accounts for their breadth of neutralization. Now researchers at the IAVI-organized Neutralizing Antibody Consortium (NAC), a scientific network focused on designing vaccines capable of eliciting broadly neutralizing antibodies, will turn their attention to studying the molecular structure of PG9 and PG16 and that of the region they target on the HIV spike. They will use this information to try to devise immunogens - the active ingredients of vaccines - that elicit similar antibodies.

How they were discovered

The methods by which PG9 and PG16 were isolated are themselves proving instructive. Their identification represents the first success of an ongoing global hunt launched by IAVI in 2006 to find new bNAbs to support the rational design of novel AIDS vaccine candidates. The effort, named Protocol G, is unprecedented in scale and distinguished by its emphasis on identifying antibodies that neutralize subtypes of HIV circulating primarily in developing countries. IAVI’s clinical research partners have collected blood specimens from upward of 1,800 HIV-infected volunteers from IAVI-supported clinical research centers in seven sub-Saharan countries as well as from centers in Thailand, Australia, the United Kingdom and the United States.

All samples were sent to Monogram Biosciences, which, working with researchers at IAVI’s AIDS Vaccine Design and Development Laboratory in New York City and the IAVI Neutralizing Antibody Center at The Scripps Research Institute, screened the sera for broadly neutralizing activity. Researchers historically have sought bNAbs in serum by testing whether antibodies from such samples bind to soluble versions of gp120 and gp41. It turns out that PG9 and PG16, however, bind to soluble forms of the proteins very weakly, if at all. The antibodies were detected only because a micro-neutralization assay developed by Monogram in partnership with IAVI measuring their ability to block HIV infection of target cells was run in parallel with the standard binding assays used for screening. This has significant implications for the future screening of bNAbs.

“If you think of it as a fishing expedition,” said Christos Petropoulos, chief scientific officer and vice president of virology research and development at Monogram Biosciences, “we and the rest of the field were previously using the wrong bait in the search for HIV-specific broadly neutralizing antibodies. Together with colleagues at IAVI, we reasoned that the best approach to identifying antibodies with the most potent and broad neutralizing activity was to screen directly for their ability to block HIV infection. To do this we developed a new, specialized test known as the micro-neutralization assay, which has opened up new avenues for exploration of additional donors for similar antibodies.”

Once the researchers had ranked the top 10% of serum samples in terms of breadth of neutralization, they needed to isolate the actual bNAbs. This can be painstaking work. But Theraclone Sciences, a company that had been working outside the HIV field, had a relevant and unique high-throughput process that it adapted to HIV work with financing from IAVI’s Innovation Fund, which is co-funded by the Bill & Melinda Gates Foundation. The Theraclone team used a system designed to expose the entire repertoire of antibodies from a blood sample obtained from an HIV-infected individual. Antibodies with broadly neutralizing potential were identified from this pool and traced to their corresponding antibody-forming cells. Using recombinant DNA technology, bNAb genes were then isolated from these cells to enable the production of unlimited quantities of the antibody clones for research.

“It is exciting that we were able to use our technology to identify and isolate these new bNAbs, which may offer important clues that could help create an effective AIDS vaccine. Through this strong scientific partnership, we have rapidly delivered promising results,” said Matthew Moyle, chief scientific officer and senior vice president of Theraclone Sciences. “This project has been a useful demonstration of Theraclone’s antibody discovery platform in infectious disease, and we highly value IAVI’s collaborative approach to solving the AIDS vaccine challenge,” said David Fanning, president and CEO of Theraclone Sciences.

With a large pool of HIV-positive donors from Protocol G now identified whose serum contains HIV-specific broadly neutralizing antibodies, it is likely that this global collaboration will generate more bNAbs that will benefit the vital enterprise of accelerating AIDS vaccine development.

“The story of the discovery of these two new antibodies demonstrates the challenges of AIDS vaccine research but also the power of the collaboration that formed to produce this advance. This is what can happen when you have researchers from the global North and South, from academia and industry, from within and outside the HIV field, working together in a framework to speed innovation,” said Seth Berkley, president and CEO of IAVI. “By working in this manner, I am confident we will continue to move toward solving the AIDS vaccine challenge, one of the greatest scientific and public health challenges of our time.”

The published study on the two new bNAbs is available online at http://www.sciencemag.org.

Source:
Keith McKeown

Scripps Research Institute

Patient / Public:
Health Professional:
Article Opinions:	0 posts

U.S.
Optimistic About Zimbabwe Health System Revitalization

The U.S. plans to support efforts to develop a sustainable health system in Zimbabwe and increase its capacity to treat people, Eric Goosby, U.S. global AIDS Coordinator for PEPFAR, said on Wednesday after a visit to the country with USAID and CDC officials, according to a press release from the U.S. Embassy in Harare, Zimbabwe. Goosby said he is “optimistic” that the Zimbabwe PEPFAR team’s experience will be used “to develop a response that fits the existing health infrastructure, supports it and reinforces it in a way that creates a durable and lasting response” (9/2).

PLoS Medicine Examines Age-Shift Of Dengue Fever Distribution In Thailand

An analysis of data from Thailand’s 72 provinces led researchers from Johns Hopkins University to discover that decreases in birth and death are behind a shift in age distribution of dengue hemorrhagic fever in the country, according to a commentary, authors explore the shifting patterns in dengue and what it means for clinical practice and future vaccination strategies (Simmons/Farrar, 9/1).

Blog: Advance Market Commitments Could Improve U.S. Foreign Aid

Though the idea of the “Advance Market Commitment (AMC), a new market-based financing mechanism that accelerates the delivery of life-saving vaccines for children worldwide,” originated among American global health experts, the U.S. was on “the sidelines observing instead of leading the launch of the first mechanism of this kind,” according a Huffington Post blog entry. “President Obama and our Congress can move the United States from the sidelines to the frontlines of this issue by calling for new AMCs to tackle infectious diseases, and then backing those calls with financial support,” the authors write. “Science is one of the comparative advantages of our knowledge-based economy, and focusing on our prowess in providing better tools to address diseases of poverty is one of the best forms of foreign aid,” they write (Levine/Berkley, 9/2).

Blog: U.S. Global Development Policy, State Department Reviews Are An ‘Important Opportunity’

The recent Presidential Study Directive, which initiates a review of U.S. global development policy and the State Department’s recently launched Quadrennial Diplomacy and Development Review are “an extremely important opportunity to pull all the pieces out there right now aimed at elevating development and modernizing foreign assistance into one smart strategy,” according to a blog post on the Huffington Post. The author outlines how the reviews and foreign assistance reform should ideally proceed. “Key to a successful integration of the three important activities is coordination between and within the executive and legislative branches of government,” she notes (Herrling, 9/1).

Researchers Analyze The Recipients Of A Decade Worth Of Health Aid

A review of 10 years of health aid appearing in the WHO Bulletin (.pdf) revealed “significant imbalances in the allocation of health aid which run counter to internationally recognized principles of ‘effective aid,’” and “[c]ountries with comparable levels of poverty and health need receive remarkably different levels of aid.” Additionally, the authors write, “our findings suggest that control over spending decisions at the country level is limited, as global and regional priorities dominate aid allocation” (Piva/Dodd, 8/25).

This information was reprinted from globalhealth.kff.org with kind permission from the Henry J. Kaiser Family Foundation. You can view the entire Kaiser Daily Global Health Policy Report, search the archives and sign up for email delivery at globalhealth.kff.org.

© Henry J. Kaiser Family Foundation. All rights reserved.