Research in seven sub-Saharan African countries has unearthed two powerful and broadly effective antibodies to the HI virus that promise to give new impetus to the development of an Aids vaccine. Published in this week’s edition of Science, the findings are the result of a worldwide effort launched by the US-based International Aids Vaccine Initiative (IAVI) in 2006 to find new antibodies that neutralize a wide variety of strains of HIV circulating in the world.
HIV, the virus that causes Aids, is the most changeable pathogen encountered by modern science. It mutates at a furious rate, allowing it to evade the body’s immune system. Today, countless variations of the virus infect people around the world. To be effective, an Aids vaccine would have to work against many versions of HIV. The two new broadly neutralizing antibodies are the first to be discovered in more than a decade, and the first to be isolated from donors in developing countries where the pandemic is raging. Now researchers will try to exploit the newfound vulnerability on the virus to craft new approaches to designing an Aids vaccine.
“The findings are an exciting advance 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.” The antibodies are naturally produced by a minority of HIV-positive people. They were discovered in blood specimens collected from over 1 800 volunteers from South Africa, Zambia, Côte d’Ivoire, Kenya, Nigeria, Rwanda and Uganda, as well as from Thailand, Australia, the US and UK.
How it works
Antibodies are infection-fighting protein molecules that tag, neutralize and help destroy toxins and invading pathogens. They are secreted by immune cells known as B lymphocytes – a kind of white blood cell – in response to stimulation by antigens, which are molecules found on the invading pathogen. Each antibody binds only to the specific antigen that stimulated its production. HIV attacks and quickly overwhelms the body’s immune system, but a minority of people naturally produce broadly neutralizing antibodies – ones that target multiple strains of HIV and prevent the virus from infecting cells. Isolating these antibodies gives vaccine researchers valuable insight into fighting the virus. Antibodies from the developing world
Before this discovery, researchers had found just four antibodies widely considered to be broadly neutralizing, but those four were associated with a strain of the virus circulating primarily in the Americas, Europe and Australia. The new antibodies came from a donor in the developing world, where 95% of new infections occur. They also reveal a new vulnerable spot on HIV, binding to a potentially easier-to-reach patch on the virus that no previously known antibodies targeted. This is extremely important as it provides a new target for vaccine designers to exploit. And the antibodies appear to be highly potent as well, which means they bind to the virus tightly.This potency means the body might not have to produce large amounts of the antibodies to gain protection from HIV.
“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 Centre at the Scripps Research Institute in La Jolla, California. “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.” The new antibodies will now be closely studied by researchers in IAVI’s Neutralizing Antibody Consortium, who will work out the molecular structure and the precise mechanism by which the antibodies bind to HIV. With this information they will begin designing novel immunogens – the active ingredient in vaccines – to elicit these antibodies in all people. If they succeed, the immunogens will be put through the preclinical process to produce an industrially viable vaccine candidate for further development.
The discovery is the result of a global collaboration between IAVI, the Scripps Research Institute, private biotech firms and more than a dozen clinical research centres around the world. It began with an IAVI-sponsored clinical study called Protocol G, a global hunt for new broadly neutralizing antibodies against HIV. The effort involved scientists from North America, Europe, Africa and Asia. The study was unprecedented in scope and ambition. The blood samples collected from more than 1 800 HIV-positive people across the world were processed at IAVI’s Human Immunology Laboratory in London. The samples then had to be tested for neutralizing activity against HIV. IAVI scientists suspected that traditional screening methods weren’t picking up the presence of every powerful antibody. They were right. IAVI researchers worked with a private biotech firm, Monogram Biosciences, and an independent biostatistician to create a new process that more accurately predicted whether a given sample contained broadly neutralizing antibodies. Researchers scored the samples in terms of how many types of HIV they neutralized, and separated the top 10% for further study.
These most promising samples then went to four IAVI research partners – HuMabs in Bellinzona, Switzerland; Rockefeller University in New York; the IAVI Neutralizing Antibody Centre at the Scripps Research Institute in La Jolla, California; and Theraclone Sciences in Seattle, Washington. Each would employ a different technology in an effort to pluck out new antibodies. The Theraclone team was the first to succeed, finding the two powerful new antibodies against HIV. Isolating antibodies can be painstaking work. But Theraclone, a company that had been working outside the HIV field, had a unique process that it adapted to HIV work with financing from IAVI’s Innovation Fund, which is co-funded by the Bill and Melinda Gates Foundation.
The team used a system designed to expose the entire array of antibodies from a blood sample. Antibodies with broadly neutralizing potential were identified and traced to their corresponding antibody-forming cells. Using recombinant DNA technology, broadly neutralizing antibody genes were isolated from these cells to enable the production of unlimited quantities of the antibody clones for research. With a large pool of HIV-positive donors from Protocol G now identified whose serum contains broadly neutralizing antibodies to HIV, this global collaboration is likely to generate findings that will benefit the vital enterprise of accelerating Aida vaccine research and development.
“The story of the discovery of these two new antibodies demonstrates the power of the collaboration that formed to produce this advance,” said Seth Berkley, president and CEO of IAVI. “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 up innovation.”