Vaccine Failure Is Setback in AIDS Fight

[Guest guest]

Regardless of one's views as to where AIDS comes from -

or doesn't come from - this is an interesting read

..............Lynn

Vaccine Failure Is Setback in AIDS Fight

 

Test Subjects May Have Been Put at

Extra Risk Of Contracting HIVBy

 

David Brown

Washington Post Staff Writer

Friday, March 21, 2008; Page A01

The two-decade search for an AIDS vaccine is in

crisis after two field tests of the most promising contender not only did

not protect people from the virus but may actually have put them at

increased risk of becoming infected.

The results of the trials, which enrolled volunteers on four continents,

have spurred intense scientific inquiry and unprecedented soul-searching

as researchers try to make sense of what happened and assess whether they

should have seen it coming.

Both field tests were halted last September, and seven other trials of

similarly designed AIDS vaccines have either been stopped or put off

indefinitely. Some may be modified and others canceled outright.

 

Numerous experts are questioning both the scientific premises and the

overall strategy of the nearly $500 million in AIDS vaccine research

funded annually by the U.S. government.

" This is on the same level of catastrophe as the Challenger

disaster " that destroyed a

 

NASA space shuttle, said Robert Gallo, co-discoverer of the human

immunodeficiency virus (HIV), which causes AIDS, and head of the

Institute for Human Virology in

 

Baltimore.

The recently closed studies, STEP and Phambili, used the same vaccine --

made from a common respiratory virus called adenovirus type 5 that had

been crippled and then loaded with fragments of HIV. Both studies were

halted when it became clear the STEP study was futile and possibly

harmful.

The results of the Phambili vaccine trial, which was conducted in

 

South Africa, were revealed last month and only worsened the gloom.

Although the number of new HIV infections in that study was far smaller

than in STEP -- and too few to draw firm conclusions from -- those

results, too, hinted at a trend toward harm among vaccine recipients.

 

Many researchers are questioning the scientific premises on which all

those studies were based and are wondering, along with AIDS activists,

what effect this near-worst-case scenario might have on tests of future

vaccines.

The working hypothesis for what went wrong is that the vaccine somehow

primed the immune system to be more susceptible to HIV infection -- a

scenario neither foreseen nor suggested by previous studies.

The

 

National Institutes of Health, which funded the STEP and Phambili

trials, is convening a meeting next week to reassess its AIDS vaccine

program. But some respected scientists have already reached a verdict.

 

" None of the products currently in the pipeline has any reasonable

chance of being effective in field trials, " Ronald C. Desrosiers, a

molecular geneticist at

 

Harvard University, declared last month at an AIDS conference in

 

Boston. " We simply do not know at the present time how to design

a vaccine that will be effective against HIV. "

He told a rapt audience that he has reluctantly concluded that the NIH

has " lost its way in the vaccine arena " and that he thinks it

should redirect its AIDS vaccine funds to basic research and away from

human trials.

In this fiscal year, the NIH's budget for AIDS vaccine research is $497

million. The STEP and Phambili trials were each expected to cost about

$32 million. Pharmaceutical giant Merck & Co. has spent an

undisclosed amount developing the vaccine and helping to manage the

studies.

 

" We can't afford to have any more trials like this, " said Mark

Harrington, head of the activist Treatment Action Group and a longtime

observer of AIDS research. " We have to stop and reassess and

recommit to basic science, or people will begin to lose faith. "

 

At the moment, only two things are certain.

The first is that the vaccine, developed by Merck, could not have caused

HIV infection because it contains only three proteins from HIV, not the

entire virus. The second is that there are no obvious villains.

" I do not think that what happened in this trial is an example of

scientists blindly rushing into dangerous things, " said

 

John P. Moore, an AIDS virologist at Weill Cornell Medical College,

who has criticized vaccine trials he considered futile. " In the

general HIV-research community, I didn't know anyone who said this was

going to happen. "

Both trials recruited people who were at high risk of HIV infection

through sexual activity. The STEP subjects included many male

homosexuals; the Phambili volunteers were male and female heterosexuals.

Half the people in each trial were randomly assigned to get three shots

of vaccine, and half to get three shots of a harmless liquid containing

no adenovirus or HIV proteins.

Each trial was to have 3,000 participants. STEP had finished enrolling

subjects in North and

 

South America, the

 

Caribbean and

 

Australia. Phambili (which means " moving forward " in the

Xhosa language of South Africa) had signed up 801 by the time it was shut

down.

While scientists hoped the Merck vaccine might prevent some infections,

its chief purpose was to stimulate " cell-mediated " immunity to

produce a less severe illness. Specifically, the vaccine was expected to

lower the " viral load " of HIV in the bloodstream, which in turn

would both prolong survival and lessen the chance the person would infect

others.

Many experts are questioning the wisdom of that strategy, even if it had

worked perfectly. Urging millions of people to take an AIDS vaccine that

probably would not protect them from the virus, they say, would be a hard

and confusing task, even in places where the epidemic still rages.

 

For the moment, that is an academic question. The vaccine failed to

achieve any of its goals.

In both studies, people who got vaccine were more likely -- not less --

to become infected, with trends suggesting roughly a twofold risk. In the

STEP study, which has many more cases to evaluate, nearly all that added

risk was in people who had high levels of antibodies to adenovirus type 5

before they got their first shot -- evidence they had been previously

infected with that strain. Uncircumcised men in that group had the

highest risk.

So how could this have happened?

The leading theory is that activation of the immune system, a cascade of

events that occurs naturally when a person is infected with a virus or

bacterium or gets a vaccine against one of them, in some way increased

the risk of HIV infection.

 

Activation causes cells called CD4 T-lymphocytes (among many other

things) to proliferate. CD4 cells are the targets of choice for HIV. In

their activated state, they are coated with molecules called CCR5

co-receptors, which HIV needs to attach itself to a cell.

The hypothesis is that people who received the vaccine had

greater-than-normal activation and consequently produced more and fatter

cellular targets for HIV. That then increased their chances of becoming

infected should they encounter the virus in unprotected intercourse.

 

Two things undercut this idea.

People have been suffering immune-activating infections and getting

vaccines for years, and there has never been evidence that those events

increased a person's risk of acquiring HIV. These vaccine trials would be

odd places to first notice such a thing. Furthermore, people in the STEP

study who got the vaccine did not have more activated CD4 cells than

people who got placebo -- something that Merck vaccine executive Mark B.

Feinberg called " kind of an interesting and unexplained

observation. "

" There is something very, very peculiar " going on in the

vaccine trials, said Anthony S. Fauci, head of the National Institute of

Allergy and Infectious Diseases, which sponsored them.

The multiple surprises have reminded researchers how much they still do

not know about HIV's biology. It has also focused attention on questions

they never asked.

For example, none of the monkey experiments with the Merck vaccine

subjected animals to the kind of sexual exposure that people in the trial

had -- namely, repeated encounters with low doses of HIV, with no single

exposure being especially high-risk.

Why not?

The researchers did not have any reason to believe the vaccine might be

harmful (although they acknowledged it might not be effective), and in

any case such a study would have required quite a large number of

monkeys, which are expensive to acquire and maintain for research.

 

Instead, researchers vaccinated a relatively small number of monkeys with

the Merck vaccine and then injected them with the monkey equivalent of

HIV in a manner that guaranteed they would become infected. Those animals

did much better over the long run than infected but unvaccinated ones.

 

That was once enough to move a vaccine into human trials. But it probably

never will be again.

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