Hope in a Vial (AIDS vaccine)

DeepOcean

Will there be an AIDS vaccine anytime soon?







From:  Scientific  American

http://www.sciam.com/article.cfm?articleID=00055C5E-E3B5-1CDA-B4A8809EC588EEDF&catID=2



May 13, 2002

Hope in a Vial

Will there be an AIDS vaccine anytime soon?

By Carol Ezzell



It wasn't supposed to be this hard. When HIV, the virus responsible for AIDS, was first identified

in 1984, Margaret M. Heckler, then secretary of the U.S. Department of Health and Human

Services, predicted that a vaccine to protect against the scourge would be available within two

years. Would that it had been so straightforward.

Roughly 20 years into the pandemic, 40 million people on the planet are

infected with HIV, and three million died from it last year (20,000 in

North America). Although several potential AIDS vaccines are in clinical

tests, so far none has lived up to its early promise. Time and again

researchers have obtained tantalizing preliminary results only to run up

against a brick wall later. As recently as two years ago, AIDS researchers

were saying privately that they doubted whether even a partially

protective vaccine would be available in their lifetime.

No stunning breakthroughs have occurred since that time, but a trickle

of encouraging data is prompting hope to spring anew in the breasts of

even jaded AIDS vaccine hunters. After traveling down blind alleys for

more than a decade, they are emerging battered but not beaten, ready to

strike out in new directions. "It's an interesting time for AIDS vaccine

research," observes Gregg Gonsalves, director of treatment and prevention

advocacy for Gay Men's Health Crisis in New York City. "I feel like it's

Act Two now."

In the theater, Act One serves to introduce the characters and set the

scene; in Act Two, conflict deepens and the real action begins. Act One

of AIDS vaccine research debuted HIV, one of the first so-called retrov

iruses to cause a serious human disease. Unlike most other viruses,

retroviruses insinuate their genetic material into that of the body cells

they invade, causing the viral genes to become a permanent fixture in the

infected cells and in the offspring of those cells. Retroviruses also

reproduce rapidly and sloppily, providing ample opportunity for the

emergence of mutations that allow HIV to shift its identity and thereby

give the immune system or antiretroviral drugs the slip.

Act One also spotlighted HIV's opposition--the body's immune

response--which consists of antibodies (Y-shaped molecules that stick to

and tag invaders such as viruses for destruction) and cytotoxic, or

killer,

T cells (white blood cells charged with destroying virus-infected cells).

For years after infection, the immune system battles mightily against HIV,

pitting millions of new cytotoxic T cells against the billions of virus

particles hatched from infected cells every day. In addition, the immune

system deploys armies of antibodies targeted at HIV, at least early in

the course of HIV infection, although the antibodies prove relatively

ineffectual against this particular foe.

As the curtain rises for Act Two, HIV still has the stage. Results from

the first large-scale trial of an AIDS vaccine should become available

at the end of this year, but few scientists are optimistic about it: a

preliminary analysis suggests that it works poorly. Meanwhile controversy

surrounds a giant, U.S.-government-sponsored trial of another potential

vaccine slated to begin this September in Thailand. But waiting in the

wings are several approaches that are causing the AIDS research community

to sit up and take notice. The strategies are reviving the debate about

whether, to be useful, a vaccine must elicit immune responses that totally

prevent HIV from colonizing a person's cells or whether a vaccine that

falls somewhat short of that mark could be acceptable. Some scientists

see potential value in vaccines that would elicit the kinds of immune

responses that kick in soon after a virus establishes a foothold in cells.

By constraining viral replication more effectively than the body's

natural responses would, such vaccines, they argue, might at least help

prolong the lives of HIV-infected people and delay the onset of the

symptomatic, AIDS phase of the disease.

DeepOcean

In the early 1990s scientists thought they could figure out the best

vaccine strategy for preventing AIDS by studying long-term

nonprogressors,

people who appeared to have harbored HIV for a decade or more but who hadn't

yet fallen ill with AIDS. Sadly, many of the nonprogressors have become

ill after all. The key to their relative longevity seems to have been "a

weakened virus and/or a strengthened immune system," says John P. Moore

of Weill Medical College of Cornell University. In other words, they were

lucky enough to have encountered a slow-growing form of HIV at a time when

their bodies had the ammunition to keep it at bay.





Not Found in Nature?

AIDS vaccine developers have struggled for decades to find the "correlates

of immunity" for HIV--the magic combination of immune responses that, once

induced by a vaccine, would protect someone against infection. But they

keep coming up empty-handed, which leaves them with no road map to guide

them in the search for an AIDS vaccine. "We're trying to elicit an immune

response not found in nature," admits Max Essex of the Harvard School of

Public Health. As a result, the quest for an AIDS vaccine has been a bit

scattershot.



To be proved useful, a candidate AIDS vaccine must successfully pass

through three stages of human testing. In phase I, researchers administer

the vaccine to dozens of people to assess its safety and to establish an

appropriate dose. Phase II involves hundreds of people and looks more

closely at the vaccine's immunogenicity, its ability to prompt an immune

response. In phase III, the potential vaccine is given to thousands of

volunteers who are followed for a long time to see whether it protects

them from infection. Phase III trials for any drug tend to be costly and

difficult to administer. And the AIDS trials are especially challenging

because of an ironic requirement: subjects who receive the vaccine must

be counseled extensively on how to reduce their chances of infection. They

are told, for instance, to use condoms or, in the case of intravenous drug

users, clean needles because HIV is spread through sex or blood-to-blood

contact. Yet the study will yield results only if some people don't heed

the counseling and become exposed anyway.

The first potential vaccine to have reached phase III consists of gp120,

a protein that studs the outer envelope of HIV and that the virus uses

to latch onto and infect cells. In theory, at least, the presence of gp120

in the bloodstream should activate the recipient's immune system, causing

it to quickly mount an attack targeted to gp120 if HIV later finds its

way into the body.

This vaccine, which is produced by VaxGen in Brisbane, Calif.--a spin-off

of biotech juggernaut Genentech in South San Francisco--is being tested

in more than 5,400 people (mostly homosexual men) in North America and

Europe and in roughly 2,500 intravenous drug users in Southeast Asia. The

results from the North American/European trial, which began in 1998, are

expected to be announced near the end of this year.

Many AIDS researchers are skeptical of VaxGen's approach because gp120

normally occurs in clumps of three on the surface of the virus, and the

company's vaccine employs the molecule in its monomeric, or

single-molecule, form. Moreover, vaccines made of just protein generally

elicit only an antibody, or humoral, response, without greatly

stimulating the cellular arm of the immune system, the part that includes

activity by cytotoxic T cells. A growing contingent of investigators

suspect that an antibody response alone is not sufficient; a strong

DeepOcean

Indeed, the early findings do not seem encouraging. Last October

an independent data-monitoring panel did a preliminary analysis

of the results of the North American/European data. Although the

panel conducted the analysis primarily to ascertain that the

vaccine was causing no dangerous side effects in the volunteers,

the reviewers were empowered to recommend halting the trial

early if the vaccine appeared to be working. They did not.

For its part, VaxGen asserts that it will seek U.S. Food and Drug

Administration approval to sell the vaccine even if the phase

III trials show that it reduces a person's likelihood of

infection by as little as 30 percent. Company president and

co-founder Donald P. Francis points out that the first polio

vaccine, developed by Jonas Salk in 1954, was only 60 percent

effective, yet it slashed the incidence of polio in the U.S.



quickly and dramatically.

This approach could backfire, though, if people who receive a

partially effective AIDS vaccine believe they are then protected

from infection and can engage in risky behaviors. Karen M. Kuntz

and Elizabeth Bogard of the Harvard School of Public Health have

constructed a computer model simulating the effects of such a

vaccine in a group of injection drug users in Thailand. According

to their model, a 30 percent effective vaccine would not slow

the spread of AIDS in a community if 90 percent of the people

who received it went back to sharing needles or using dirty

needles. They found that such reversion to risky behavior would

not wash out the public health benefit if a vaccine were at least

75 percent effective.

The controversial study set to begin in Thailand is also a

large-scale phase III trial, involving nearly 16,000 people. It

combines the VaxGen vaccine with a canarypox virus into which

scientists have stitched genes that encode gp120 as well as two

other proteins--one that makes up the HIV core and one that

allows it to reproduce. Because this genetically engineered

canarypox virus (made by Aventis Pasteur, headquartered in Lyons,

France) enters cells and causes them to display fragments of HIV

on their surface, it stimulates the cellular arm of the immune

system.

Political wrangling and questions over its scientific value have

slowed widespread testing of the gp120/canarypox vaccine.

Initially the National Institute of Allergy and Infectious

Diseases (NIAID) and the U.S. Department of Defense were

scheduled to conduct essentially duplicate trials of the

vaccine.

But NIAID pulled the plug on its trial after an examination of

the data from a phase II study showed that fewer than 30 percent

of the volunteers generated cytotoxic T cells against HIV. And

in a bureaucratic twist, this past January the White House

transferred the budget for the Defense Department trial over to

NIAID as part of an effort to streamline AIDS research.

Peggy Johnston, assistant director of AIDS vaccines for NIAID,

says she expects there will be a trial of the vaccine but

emphasizes that "it will be a Thai trial; we won't have any [NIAID]

people there on the ground running things."

Critics cite these machinations as a case study of politics

getting in the way of progress against AIDS. "There's little

science involved" in the trial, claims one skeptic, who wonders

why the Thais aren't asking, "'If it's not good enough for

America, how come it's good enough for us?'" Others point out

that the trial, which was conceived by the Defense Department,

will answer only the question of whether the vaccine works; it

won't collect any data that scientists could use to explain its

potential failure.



Partial Protection



Into this scene comes Merck, which is completing separate phase

I trials of two different vaccine candidates that it has begun

to test together. In February, Emilio A. Emini, Merck's senior

vice president for vaccine research, wowed scientists attending

the Ninth Conference on Retroviruses and Opportunistic

Infections in Seattle with the company's initial data from the

two trials.

DeepOcean

The first trial is investigating a potential vaccine composed

of only the HIV gag gene, which encodes the virus's core protein.

It is administered as a so-called naked DNA vaccine, consisting

solely of DNA. Cells take up the gene and use it as a blueprint

for making the viral protein, which in turn stimulates a mild

(and probably unhelpful) humoral response and a more robust

cellular response. Emini and his colleagues reported that 42

percent of volunteers who received the highest dose of the naked

DNA vaccine raised cytotoxic T cells capable of attacking

HIV-infected cells.

The second trial employs the HIV gag gene spliced into a crippled

adenovirus, the class responsible for many common colds. This

altered adenovirus ferries the gag gene into cells, which then

make the HIV core protein and elicit an immune response targeted

to that protein. Emini told the conference that between 44 and

67 percent of people who received injections of the

adenovirus-based vaccine generated a cellular immune response

that varied in intensity according to the size of the dose the

subjects received and how long ago they got their shots.

Merck is now beginning to test a combination of the DNA and

adenovirus approaches because Emini predicts that the vaccines

will work best when administered as part of the same regimen.

"The concept," he says, "is not that the DNA vaccine will be a

good vaccine on its own, but that it may work as a primer of the

immune system," to be followed months later by a booster shot

of the adenovirus vaccine. A possible stumbling block is that

most people have had colds caused by adenoviruses. Accordingly,

the immune systems of such individuals would already have an

arsenal in place that could wipe out the adenovirus vaccine

before it had a chance to deliver its payload of HIV genes and

stimulate AIDS immunity. Increasing the dose of the adenovirus

vaccine could get around this obstacle.

Emini says he and his co-workers are emphasizing cellular

immunity in part because of the disappointing results so far with

vaccines designed to engender humoral responses. "Antibodies

continue to be a problem," he admits. "There are a handful of

reasonably potent antibodies isolated from HIV-infected people,

but we haven't figured out how to raise those antibodies using

a vaccine."

Lawrence Corey of the Fred Hutchinson Cancer Research Center in

Seattle agrees: "You'd like to have both [a cellular and an

antibody response], but the greatest progress has been in

eliciting a cellular response," says Corey, who is also

principal investigator of the federally funded HIV Vaccine

Trials Network.

Antibodies are important, too, because they are the immune

system's first line of defense and are thought to be the key to

preventing viruses from ever contacting the cells they infect.

Corey says that vaccines that are designed primarily to evoke

cellular immunity (as are Merck's) are not likely to prevent

infection but should give someone a head start in combating the

virus if he or she does become infected. "Instead of progressing

to AIDS in eight years, you progress in 25 years," he predicts.

But, Corey adds, it is unclear whether a vaccine that only slowed

disease progression would stem the AIDS pandemic, because people

would still be able to spread the infection to others despite

having less virus in their bloodstream.



Finding a way to induce the production of antibodies able to neutralize HIV has been

hard slogging for several reasons. For one, the virus's shape-shifting ways allow it to

stay one step ahead of the immune response. "The thing that distinguishes HIV from

all other human viruses is its ability to mutate so fast," Essex says. "By the time you

make a neutralizing antibody [against HIV], it is only against the virus that was in

you a month ago."

DeepOcean

According to many scientists, vaccines using a logical molecule,

gp120--the protein the virus uses to invade immune cells, as

discussed above--haven't worked, probably because the

antibodies that such vaccines elicit bind to the wrong part of

the molecule. Gp120 shields the precise binding site it uses to

latch onto CD4, its docking site on immune cells, until the last

nanosecond, when it snaps open like a jackknife. One way to get

around this problem, suggested in a paper published in Science

three years ago by Jack H. Nunberg of the University of Montana

and his colleagues, would be to make vaccines of gp120 molecules

that have previously been exposed to CD4 and therefore have

already sprung open. But those results have been "difficult to

replicate," according to Corey, making researchers pessimistic

about the approach.

Another possible hurdle to getting an AIDS vaccine that elicits

effective anti-HIV antibodies is the variety of HIV subtypes,

or clades, that affect different areas of the world. There are

five major clades, designated A through E. Although clade B is

the predominant strain in North America and Europe, most of

sub-Saharan Africa--the hardest-hit region of the globe--has

clade C. The ones primarily responsible for AIDS in South and

Southeast Asia--the second biggest AIDS hot spot--are clades B,

C and E.

Several studies indicate that antibodies that recognize AIDS

viruses from one clade might not bind to viruses from other

clades, suggesting that a vaccine made from the strain found in

the U.S. might not protect people in South Africa, for example.

But scientists disagree about the significance of clade

differences and whether only strains that match the most

prevalent clade in a given area can be tested in countries there.

Essex, who is gearing up to lead phase I tests of a clade C-based

vaccine in Botswana later this year, argues that unless

researchers are sure that a vaccine designed against one clade

can cross-react with viruses from another, they must stick to

testing vaccines that use the clade prevalent in the populations

being studied. Cross-reactivity could occur under ideal

circumstances, but, he says, "unless we know that, it's

important for us to use subtype-specific vaccines."

Using the corresponding clade also avoids the appearance that

people in developing countries are being used as guinea pigs for

testing a vaccine that is designed to work only in the U.S. or

Europe. VaxGen's tests in Thailand are based on a combination

of clades B and E, and in April the International AIDS Vaccine

Initiative expanded tests of a clade A-derived vaccine in Kenya,

where clade A is found.

But in January, Malegapuru William Makgoba and Nandipha Solomon

of the Medical Research Council of South Africa, together with

Timothy Johan Paul Tucker of the South African AIDS Vaccine

Initiative, wrote in the British Medical Journal that the

relevance of HIV subtypes "remains unresolved." They assert that

clades "have assumed a political and national importance, which

could interfere with important international trials of

efficacy."

Early data from the Merck vaccine trials suggest that clade

differences blur when it comes to cellular immunity. At the

retrovirus conference in February, Emini reported that killer

cells from 10 of 13 people who received a vaccine based on clade

B also reacted in laboratory tests to viral proteins from clade

A or C viruses. "There is a potential for a substantial

cross-clade response" in cellular immunity, he says, "but that's

not going to hold true for antibodies." Corey concurs that clade

variation "is likely to play much, much less of a role" for killer

cells than for antibodies because most cytotoxic T cells

recognize parts of HIV that are the same from clade to clade.

Johnston of NIAID theorizes that one answer would be to use all

five major clades in every vaccine. Chiron in Emeryville, Calif.,

is developing a multiclade vaccine, which is in early clinical

trials. Such an approach could be overkill, however, Johnston

says. It could be that proteins from only one clade would be

recognized "and the other proteins would be wasted," she warns.





Whatever the outcome on the clade question, Moore of Weill

Medical College says he and fellow researchers are more hopeful

than they were a few years ago about their eventual ability to

devise an AIDS vaccine that would elicit both killer cells and

antibodies. "The problem is not impossible," he says, "just

extremely difficult."

According to many scientists, vaccines using a logical molecule,

gp120--the protein the virus uses to invade immune cells, as

discussed above--haven't worked, probably because the

antibodies that such vaccines elicit bind to the wrong part of

the molecule. Gp120 shields the precise binding site it uses to

latch onto CD4, its docking site on immune cells, until the last

nanosecond, when it snaps open like a jackknife. One way to get

around this problem, suggested in a paper published in Science

three years ago by Jack H. Nunberg of the University of Montana

and his colleagues, would be to make vaccines of gp120 molecules

that have previously been exposed to CD4 and therefore have

already sprung open. But those results have been "difficult to

replicate," according to Corey, making researchers pessimistic

about the approach.

Another possible hurdle to getting an AIDS vaccine that elicits

effective anti-HIV antibodies is the variety of HIV subtypes,

or clades, that affect different areas of the world. There are

five major clades, designated A through E. Although clade B is

the predominant strain in North America and Europe, most of

sub-Saharan Africa--the hardest-hit region of the globe--has

clade C. The ones primarily responsible for AIDS in South and

Southeast Asia--the second biggest AIDS hot spot--are clades B,

C and E.

Several studies indicate that antibodies that recognize AIDS

viruses from one clade might not bind to viruses from other

clades, suggesting that a vaccine made from the strain found in

the U.S. might not protect people in South Africa, for example.

But scientists disagree about the significance of clade

differences and whether only strains that match the most

prevalent clade in a given area can be tested in countries there.

Essex, who is gearing up to lead phase I tests of a clade C-based

vaccine in Botswana later this year, argues that unless

researchers are sure that a vaccine designed against one clade

can cross-react with viruses from another, they must stick to

testing vaccines that use the clade prevalent in the populations

being studied. Cross-reactivity could occur under ideal

circumstances, but, he says, "unless we know that, it's

important for us to use subtype-specific vaccines."

Using the corresponding clade also avoids the appearance that

people in developing countries are being used as guinea pigs for

testing a vaccine that is designed to work only in the U.S. or

Europe. VaxGen's tests in Thailand are based on a combination

of clades B and E, and in April the International AIDS Vaccine

Initiative expanded tests of a clade A-derived vaccine in Kenya,

where clade A is found.

But in January, Malegapuru William Makgoba and Nandipha Solomon

of the Medical Research Council of South Africa, together with

Timothy Johan Paul Tucker of the South African AIDS Vaccine

Initiative, wrote in the British Medical Journal that the

relevance of HIV subtypes "remains unresolved." They assert that

clades "have assumed a political and national importance, which

could interfere with important international trials of

efficacy."

Early data from the Merck vaccine

liver411

"The problem is not possible..."



Thanks.