Alex Constantine
[END] THE NEXT PHASE OF ANTHRAX
Sun Feb 20, 2005 01:47
64.140.158.46

 

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. ***** Every six
months, a ten-strong committee of doctors and scientists crowds into
VaxGen's boardroom. This is the "data safety and monitoring board",
recruited to keep an eye on the experiment. On one side of the table
sits a Harvard infectious disease specialist. On the other is a Yale
ethicist. There are three Thai physicians and a Seattle statistician. Dr
Walter Dowdle, a former CDC deputy director, presides. The Americans are
casual, in open-necked shirts, but Dowdle runs proceedings with care.
Piled around the table are printouts on the volunteers, with blood tests
and other results. Using codes which nobody else gets to look at, they
can see who's getting AidsVax and who the placebo and whether any
difference the number of HIV infections has emerged between the groups.

By the convention for vaccines, any difference would be vast for the
product to be declared effective. Measles vaccine, for instance, is 95%
effective, tetanus 90%, and hepatitis B 85%. But the committee's brief
is to watch for just 30% effectiveness. Such is the threat from Aids,
it's argued, that this figure is enough for success.

I asked a professor of medical statistics to number-crunch this
percentage. To reach the 30% mark, he said, there would only need to be
28 more infections among junkies on the placebo than among those
receiving AidsVax. If VaxGen recruits 2,500 - and on its assumption that
in a year about 7% (87 people) on placebo will become infected due to
needle-sharing - then if the number who become infected after getting
AidsVax is 59 (4.7%) or fewer, the committee can rule that the product
works.

VaxGen critics think that even this meagre difference couldn't appear,
and that Dowdle, 68, will one day emerge to drape a consoling arm on
Francis's shoulder. But an alternative scenario is predicted by some
with long research experience. Nobody can recall an HIV product being
ditched after reaching a full-scale efficacy trial. And, such is the
desire for "something to be done" about Aids that science could be
pushed to one side.

The most powerful pressure for something to be done comes from the White
House, anxious to appease the Aids lobby. In May 1997, President Clinton
threw his weight behind urgent action. "If the 21st century is to be the
century of biology," he declared. "Let us make an Aids vaccine its first
great triumph."

How such pressures can translate date back to 1989 and the first
anti-Aids drug, AZT. A board like Dowdle's monitoring a trial among
HIV-positive volunteers with no obvious illness, saw data suggesting
that full-blown Aids could be prevented. At the time, AZT was licensed
only for terminal disease, but this finding caused the trial to be
halted and the product to be approved for this use. But the decision was
based on a transitory data "blip", which had caused the board to act
prematurely. A longer study, published four years later, found no
preventative effect.

Stopping trials in this way before their scheduled completion is now
standard in Aids product development. "If efficacy is observed at the
time of a scheduled interim efficacy analysis," Nowinski explains, "the
monitoring board will recommend termination of the trial."

But could bodies such as the Food and Drug Administration and the
European Medicines Evaluation Agency license a vaccine that doesn't work
on the basis of an AZT-style blip? Evidence suggests that agencies under
political pressure take just such paradoxical steps. The National
Institutes of Health, for instance, vetoed the VaxGen experiment as a
waste of money and volunteers. But after being accused of "a human
rights violation" by Dr Jonathan Mann, 51, former WHO Aids chief (and
who died with his wife, Clements-Mann, also 51, in the Swissair crash),
the institutes not only reversed themselves, but granted Francis $4.6m.

Sometimes the clamour may be marshalled by persons who may not be as
detached as they seem. The Journal of Aids Research and Human
Retroviruses, for instance, has an editorial board that's a Who's Who of
Aids. But Francis paid the publisher $10,000 for the "special issue",
which Berman edited as a "guest". As for some of the contributors,
Francis helped to set up Berkley's international vaccine initiative and
advised Bill Gates's charity foundation to give it $25m. He has done a
deal to supply proteins to the rival manufacturer which employed
Clements-Mann. And he has offered the CDC's Heyward the post of VaxGen
vice-president, starting next January.

Pressure also comes from powerful bodies which have long-held
institutional agendas. The CDC, which mostly collates disease data,
first became a significant health service body due to polio vaccine,
launched in April 1955. The WHO's singular success was smallpox
eradication, accomplished in October 1977. Mass immunisation is what
they know best. It's simply what they do. "Don Francis reminds them of
when they were young," Dr John Moore, of New York's Aaron Diamond Aids
Research Center, told me.

What worries critics such as Moore is that political and institutional
pressures may lead to millions of people being injected with AidsVax
before the benefits and risks are clear. The WHO estimates that annual
demand for the first vaccine will be 650m doses and UNICEF leaders are
thinking about adding it to programmes for 100m children.

Francis anticipates that the CDC, which has already granted him $8m, is
to finance a US immunisation campaign and, in Europe, national health
services will pick up the tab. "In addition, the International Aids
Vaccine Initiative has started a campaign to fund the development and
purchase of an HIV vaccine for the developing world," VaxGen documents
say. "In meetings with us, the World Bank has indicated that it's
exploring the potential for low-interest loans to support the purchase."

One of the snags which may be overlooked in this rush is the effect on
recipients' behaviour. Common sense says that somebody who thinks that
they may be protected is more likely to take chances with risky
activities than a person who knows that they aren't. One study of this
effect in 1997 found that unsafe sexual behaviours doubled among gay men
in preliminary vaccine tests. If this was repeated globally, the impact
of an even vaguely effective AidsVax may be that the Aids epidemic gets
worse. ***** South of VaxGen's offices, the next freeway exit gives
access to its powerhouse: Genentech. This is the world's front-runner in
medical biotechnology, with seven licensed products, from human growth
hormones to a clot-buster, Activase. Twenty years ago the company was
all dreams and venture capital; its few staff snipping and splicing
genes in a wasteland where shipyards had died. Today, their ranks of
Mercs and BMWs surround 26 buildings in biology's Silicon Valley.

Stopping by from time to time are visitors from its master, the
druggernaut Hoffman-La Roche. With twin headquarters in Basle and New
Jersey, and sales last year of SWf24.7bn, this vitamins-to-Valium giant
has the marketing muscle should AidsVax come on stream. At its own labs,
Roche shuns the vaccine race, but with taxes pledged to line-and-jab
Africa and Asia executives doodle in billions on the hope that Francis
pulls it off.

When I flew to San Francisco to quiz Francis for this story, Berman was
ecstatic, in jeans and a check shirt, over a new $1.4m vaccine facility.
The experiment produces a torrent of clinic samples; each volunteer
gives blood on 17 visits, and each sample is split for tests. Giant
freezers were being installed to store bar-coded specimens. There could
be 400,000 in all. There's also a $500,000 microbiology kit going in:
DNA sequencers, PCR machines, centrifuges and the like. Soon he would
direct 30 staff in 20 rooms. He was like a seven-year-old on Christmas
Day.

The first thing that struck me was the push of the spending,
irrespective of scientific achievements. Apart from all the investment
so far, Genentech had a 10,000-litre fermenting tank, half full of New
Jersey strain vaccine. Nobody wanted that, worth $1m, flushed away, much
less the careers of its makers. The next thing I noted was the standard
of safety imposed on the facility's construction. To handle a dangerous
pathogen in California, the brown-and-yellow building, made from
tipped-upright concrete slabs, was stamped with certificates and permits
by the box load before the first plank was sawn. It's both earthquake-
and microbe-proof. And its forests of copper pipes, air ducts and
bio-filters were tested to tolerances few structures could endure.

But while regulations make sure that the building is safe, critics say
that the product itself escapes much rigorous scrutiny. With vaccines,
any problems often don't appear until mass-market use, and such is the
head of steam building up behind Francis that sceptics think that if
AidsVax doesn't join the annals of useless shots, it has the potential
to join, say, a 1960s measles vaccine that made the disease in those
infected worse.

What worries some scientists is that because AidsVax provokes antibodies
to its own specific gp120 strains, there's a risk that it may actually
suppress the immune system's ability to combat other strains. On this
thinking (the principle is sometimes called "deceptive imprinting") even
if the junkies were protected against the New Jersey and Chiang Mai
strains, they might die more quickly if they get infected with one of
the countless other mutations. "There's nothing new in this," Dr Heinz
Kohler, who has led investigations at Kentucky University, said. "It's
just common sense."

At Kansas University, researchers have found that monkeys injected with
gp120 and then a hybrid kind of HIV had more of the virus in their blood
later on than infected animals which weren't vaccinated. "The question
is: will those people who are vaccinated progress to Aids more quickly
if they become infected with HIV than those who were not vaccinated at
all?" Prof McMichael at Oxford summarised. "We might not know the answer
for 10 years."

No such problems were revealed in the preliminary tests, but despite the
importance of long-term follow-up (recipients of the hepatitis B vaccine
that Francis worked on in the early 1980s have been tracked for two
decades), VaxGen no longer monitors what has happened to the people who
received its product in the mid-1990s preliminary tests. Francis argues
that it makes more sense to wait for the full-scale trial results.

This apparent loss of data is surprising to some, because history warns
of the pitfalls of not being thorough. In 1955, just one month after a
near-hysterical press conference in Michigan launched polio vaccine,
reports poured in to the CDC of hundreds of children going down with the
disease, induced by the shots themselves. President Dwight Eisenhower
said that, because of the "great pressure to bring this out", scientists
may have "short-cut a little bit".

AidsVax cannot give volunteers Aids, but there may be something even
more terrifying than the anxiety that it might accelerate their disease
if they are later infected with HIV. Some scientists think that, if it
works at all, the product may have a dangerous effect on the evolution
of HIV. Five years ago, Los Alamos scientists declared that there was
"no simple answer" as to whether Aids could become contagious through
coughs and sneezes - and other researchers argue that, in much the same
way as a partial course of antibiotics can promote resistant bacteria,
so a poorly-effective vaccine may promote more deadly and infectious
strains.

This may sound like journalistic scare, but HIV's best-understood RNA
cousin is influenza virus, which produces devastating mutations every 20
or 30 years. Hepatitis B virus, meanwhile, has already produced mutant
strains accepted as

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