Scientists have identified two new antibodies that appear to neutralise a wide range of HIV types, blocking their potential for infection. The findings, published today in the journal Science, could open up a new avenue for vaccine research based on neutralising antibodies, say the investigators.
A vaccine that could prevent HIV infection by priming the human body to produce antibodies that can neutralise, or block, HIV infection has proved very difficult to develop. Most antibodies produced against HIV fail to block infection because the virus mutates so rapidly. The only vaccine designed to protect against HIV through an antibody response to be tested in large clinical trials, AIDSVAX, failed to show a protective effect.
In order to develop an antibody-based vaccine, an international consortium of scientists has been searching for antibodies that act against proteins on the virus’s surface that seem less prone to mutate. In particular they have sought to identify antibodies that are effective against a broad range of HIV subtypes present in developing countries, where the need for an HIV vaccine is greatest.
Today’s findings, reported by the Scripps Institute, Theraclone Sciences, Monogram Biosciences and the International AIDS Vaccine Initiative (IAVI), show that antibodies that target two sites on HIV’s envelope have a potent neutralising effect.
“Now we may have a better chance of designing a vaccine that will elicit such broadly neutralising antibodies, which we think are key to successful vaccine development,” said Professor Dennis Burton of the Scripps Institute in La Jolla, California.
The antibodies were identified after screening around 1800 samples from HIV-positive volunteers from IAVI-supported clinical research centres in seven sub-Saharan countries as well as from centres in Thailand, Australia, the United Kingdom and the United States.
The antibodies identified seem to have such a potent anti-HIV effect, say researchers, it is possible that broadly neutralising antibodies with such a specific effect could elicit protection against HIV infection at the modest antibody levels normally achieved after vaccination.
The next step is to design immunogens that can succesfully stimulate the development of these antibodies in animal and human studies. Meanwhile the research group members are optimistic that further screening will identify other broadly neutralising antibodies.
In part this is due to their discovery that previous efforts to identify broadly neutralising antibodies may have been methodologically flawed
In the past, researchers have sought broadly neutralising antibodies by testing whether antibodies from serum samples bind to soluble versions of gp120 and gp41.
However PG9 and PG16, the antibodies identified by the Scripps Institute and their collaborators, bind to soluble forms of the proteins very weakly, if at all.
The antibodies were detected only because a micro-neutralisation assay developed by Monogram Biosciences 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.
“If you think of it as a fishing expedition,” said Chris 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 neutralising antibodies.
"Together with colleagues at IAVI, we reasoned that the best approach to identifying antibodies with the most potent and broad neutralising activity was to screen directly for their ability to block HIV infection. To do this we developed a new, specialised test known as the micro-neutralisation 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 broadly neutralising antibodies. 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 neutralising 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.
Walker LM et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science, online edition, September 3rd, 2009.