HIV vaccine a step closer with discovery of new potent antibodies
22 September 2009
Two powerful new antibodies to HIV that reveal what may be an
Achilles heel on the virus have been found by 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.
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
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
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
“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
“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
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