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BRIAN
DEER: THE VAXGEN EXPERIMENT Page 3
When
Francis returns from his trips to Bangkok, it's to
Brisbane, a community on the San Francisco peninsula,
midway between the city and its airport. His home and
workplace both looks eastward across the bay: towards
Oakland and, beyond that, America. His home is on a
hill and lined with Chinese paintings. His office is
by the shore, in black glass.
He
huddles weekly with his senior colleagues: VaxGen's
vice-president, Dr Phillip Berman, and its chairman,
Dr Robert Nowinski. Berman, aged 49, is a molecular
biologist. He's heavy set with curly hair and has
laboured on the science for 15 years. Nowinski, 52,
is bald and wears glasses. He's a biotechnology
entrepreneur from Seattle. His main claim to fame is
having founded and sold a company, ICOS, which boasts
Microsoft's Bill Gates as an owner.
The
key document at many of their sessions is a
"special issue" of a prestigious journal,
called Aids Research and Human Retroviruses. It's
dated last October. Twenty papers are inside and
they're a rave for VaxGen's ideas. Dr Seth Berkley,
the International Aids Vaccine Initiative's
president, declares that politics and economics are
bigger obstacles to progress than "a scientific
barrier". Dr Mary Lou Clements-Mann, a
researcher for a rival company's vaccine (and who
died in a Swissair plane crash off Nova Scotia last
year), shrugs off pessimistic
"misperceptions". Dr William Heyward, the
CDC's Aids vaccine chief, argues that "only
through such trials" as the Bangkok project
"will further knowledge be gained".
When
visitors drop by, Berman outlines his own paper. It
sets out how AidsVax is meant to work. "Many
lines of evidence suggest that a strong antibody
response to the HIV-1 envelope glycoprotein," he
explains, "will be an essential feature of any
Aids vaccine." Berman sketches what this means
on a board in the conference room, across the
corridor from Francis's office. The billions spent on
Aids have produced unparalleled insights on HIV,
which are the platform on which he builds. The virus
infects. The immune system checks it with, among
other things, specially-tailored antibodies. But the
virus mutates around these adversaries. So the immune
system tailors new defences. The virus then mutates
and immunity responds. It's like a leapfrog
competition. Eventually, the immune system tires of
all this leaping, packs up and then it's Aids.
Of
all the different parts of HIV, the envelope
glycoprotein gp120 is the part that mutates the most.
This sits in blobs around the virus, like loose balls
of wool, on the tips of protruding spikes. Berman
zooms on the moment a blob meets a cell, which is 1m
times bigger than the virus. Part of the blob's
surface locks onto a receptor (like a data-port where
cells get information). The blob then unravels and
locks another of its parts onto a second sort of
receptor on the cell. This cues the cell to pull the
virus inside. Infection is complete.
Here,
Berman argues, is where AidsVax helps: by blocking
this double-lock connection. Summoned in advance, due
to earlier vaccination, antibodies stick to key parts
of the blob and so stop it from locking on the cell.
If the virus is a burglar, these antibodies are
bullterriers, waiting for a leg to appear through the
window on which to snap their jaws. Once they've got
hold, the virus is paralysed, to be disposed of by
other kinds of cell.
He
makes things sound simple. Visitors are impressed.
Investors wonder: why dither in Bangkok? But the
science expounded in the journal issue doesn't
convince many people who grasp the detail. "It's
a waste of time," Dr Robert Gallo, America's
pre-eminent retrovirologist, told me. Prof Andrew
McMichael, Aids vaccine chief at Oxford's Institute
of Molecular Medicine, said: "I wouldn't have
the belief that this will work." And Dr
Jean-Paul Levy, head of France's vaccine programme,
spat: "It forgets one century of science."
For
all the plausibility of the journal's special issue,
the most detailed analysis of VaxGen's approach was
published in February last year in the Journal of
Virology, an even more influential publication. More
than 500 people - mostly American gay men - took part
in preliminary tests of gp120 in the mid-1990s but
experts at seven of America's leading research
centres found that, despite the shots, 16 vaccine
recipients became infected with HIV. That's more than
3% of those getting vaccine, roughly the same
percentage as those on placebo.
Molecular
biologists were not surprised, although their
critique is extremely technical. What it boils down
to is that if HIV leapfrogs the immune system - with
all its astounding complexity - it will easily do the
same with antibodies induced by an off-the-shelf
manufactured product. Inducing antibodies to one B
strain, or two E strains, or five, or fifty XYZ
strains, is like buying insurance against being hit
by cars with specified license plates.
VaxGen's
answer is to develop products from strains it claims
provide "cross-protection" against others.
In Bangkok, for instance, the vaccine is AidsVax B/E,
including gp120 clones from one B and one E strain.
The B strain was isolated from a six-year-old New
Jersey boy in 1984, while the E strain was collected
from a soldier in Chiang Mai about nine years ago.
The plan is to mix 'n' match vaccines in this way to
suit the subtypes in different parts of the world.
Berman zooms closer and claims that parts of gp120
stay sufficiently constant between the mutating
strains to offer a point of attack. Like all
proteins, the blob is made from amino acid molecules,
which string together like beads in a necklace to
make the loose balls of wool. Each bead is made from
one of a possible 20 amino acids. Letters are used to
denote these acids: G stands for glycine, for
instance, R for arginine and Q for glutamine.
Berman
says that the vaccine needs to copy the amino acid
sequence at a key point in this string. Near to where
gp120 locks onto the cell, there is a loose loop of
"wool" - not 100 millionth a cell's size -
which biologists call V3. Berman zooms again: to the
tip of this loop, a string of just six necklace
beads. Here, he argues, is a segment that remains
more constant than most and induces antibodies which
will stick and stop the double-lock connection with
the cell. All it needs is for the vaccine and the
virus to have the same acids at the tip of this loop.
Using
this argument, Berman deduces that the early tests of
gp120 offer hope for the experiment after all.
Mostly, volunteers studied for the Journal of
Virology were injected with gp120 cloned from the New
Jersey strain, in which the necklace in the V3 loop's
tip has the beads GPGRAF (meaning: glycine, proline,
glycine, arginine, alanine, and phenylalanine). It's
a common configuration in North American strains. But
Berman argues that some of the volunteers who became
HIV-positive despite being vaccinated were infected
with strains in which the loop was different: say,
GPGRVL (ending with valine and leucine instead).
This, he suggests, was why the gp120 didn't protect
them. With the commoner strains he believes it did.
At
VaxGen's offices, this bottom-line is dazzling. The
"special issue" paper quickens pulses. But
additional information reveals an oddity, which
Berman's presentation overlooks. At the American
government's Los Alamos National Laboratory, in New
Mexico, staff track amino acid sequences for
thousands of HIV strains. And when I asked them to
print their data from Thailand, a startling
contradiction emerged. The B component in AidsVax B/E
- the shots being given to the junkies - has the New
Jersey V3 loop tip sequence. It goes: GPGRAF.
According
to Berman's argument, the local B strains would need
to have the same string of beads. But only 10% of
Thai B strains have the New Jersey amino acid
sequence. Far more often - in nearly half the strains
- there are two different beads in the loop's tip:
glutamine (Q) and tryptophan (W). They are GPGQAW. By
Berman's own reasoning, the Bangkok junkies are being
injected with the wrong vaccine.
*****
