Sunday, February 2, 2014

AIDS VACCINES LURCH FORWARD

SCIENCE & TECHNOLOGY
August 27, 2001
Volume 79, Number 35
CENEAR 79 35 pp. 37-44
ISSN 0009-2347
 

After years of stagnation, new results and better organization have scientists hopeful

ELIZABETH K. WILSON, C&EN WEST COAST NEWS BUREAU
It's been 20 years since physicians first reported that a handful of gay men were dying of diseases such as pneumocystis pneumonia, maladies that shouldn't fell healthy young people.

"Hope [for an AIDS vaccine] is high now because researchers have changed the goal posts."
7935scit1.ce
HIV STRUCTURE Vaccines mimic or replicate combinations of the virus' parts.
Scientists swiftly identified the culprit, in 1984, which they named the human immunodeficiency virus (HIV). The disease it causes, acquired immunodeficiency syndrome (AIDS), lays waste to the human immune system, leaving its victims vulnerable to a host of horrible illnesses: pneumonia, Kaposi's sarcoma, and out-of-control fungal infections.
Prejudice and ignorance blighted the early years of the epidemic. Victims died alone, shunned by their families and friends. The government, under the Reagan Administration, all but ignored the disease. Science put forth its first anti-HIV drugs such as AZT, but their ability to beat back the virus was short-lived.
Gradually, at least in the U.S., the picture brightened. The gay community spearheaded organized, aggressive education campaigns, which drastically slowed the rate of new infections. They demanded the government take the disease seriously, giving birth to a new wave of highly effective political activism. And in 1996, protease inhibitor drugs burst on the scene, proving so effective in keeping the virus under submission that many began to see AIDS as a chronic but manageable disease, like diabetes.
But the optimism and even complacency that resulted from the progress are, unfortunately, misplaced, as statistics bear out. There's still no cure in sight, and AIDS continues to kill Americans. The intense barrage of public education that marked the early years of AIDS has faded, and the U.S. is once again seeing an increase in the rate of new HIV infections.
But most serious of all is the devastating impact of AIDS on developing nations. Nearly 35 million people worldwide are estimated to be infected with HIV. In some sub-Saharan African countries, one in three adults is infected.
THE ONLY REAL CHANCE of stopping the plague, most scientists believe, is with a vaccine. Health education by itself clearly won't do the trick. And drug treatments-- which traditionally are only moderately effective against viruses--are unlikely to ever completely beat the ever-mutable HIV, which can sequester itself for years in the body's cells.
Humans have vanquished smallpox with vaccines; polio is likely soon to follow. Vaccines can disarm influenza and hepatitis B. But unfortunately, despite the ingenious, almost miraculous inventions of biological and genetic engineering, no successful AIDS vaccine has yet emerged.
Almost immediately after scientists identified HIV, they began talking about a vaccine, hopeful that one could be found within a few years.
But the virus has proved a slippery target. With each promising new candidate, it seems, spring ever more complicated revelations about HIV and the immune system: that the virus can lie undetected in reservoirs in the body, for example, or that, paradoxically, immunity to HIV in some people might require their immune systems to be kept in shape by a constant assault from the invader. The virus mutates rapidly--there are five different major subtypes, or clades, of HIV throughout the world and many more variations.
And although it might hasten the process, we can't adopt the methods, now deemed unethical, of the famous physician Edward Jenner, who ushered in vaccinology in 1800 when he inoculated humans with cowpox in hopes of staving off smallpox. Because HIV eventually kills almost all its infectees, no AIDS vaccine can be tested by giving people a dose of HIV.
If that weren't enough, AIDS vaccine research has been beset almost from the beginning by a lack of funding and organization. Researchers had no infrastructure for comparing and contrasting their results and for accelerating promising vaccines into clinical trials.
Given all these hurdles, some scientists began to despair that a vaccine could ever be developed. But in the past half decade, scientists have gradually begun to lift the grim veil from the countenance of AIDS vaccine research.
A surge of promising results of DNA vaccines in animal models has stirred the scientific waters. Funding for AIDS vaccine research at the National Institutes of Health (NIH) has more than doubled, from $130 million in 1997 to $282 million in 2001. New organizations like the International AIDS Vaccine Initiative, fed up with the paralysis of analysis permeating the field, are mobilizing to strong-arm potential vaccines into clinical trials in record time.
"The climate for trying to do AIDS vaccine work has improved tremendously," says John Donnelly, senior director of immunology and infectious diseases at Chiron, a biotech company in Emeryville, Calif., with an active AIDS vaccine research program.
That HIV hasn't yielded to researchers' attempts to foil it is perhaps not surprising. For an organism of such apparent simplicity--a blob of nine genes encased in a protein sack--HIV has an ingenious and complicated modus operandi. HIV belongs to the retrovirus family, which carries its genetic material in the form of RNA rather than the DNA used by many other viruses.
Once it gets inside its host, HIV seeks out its preferred target, a white blood cell known as a CD4, or T4-lymphocyte. HIV grabs the cell, muscles open a portal in the cell surface, and injects its guts into the cell. Once inside, an HIV enzyme called reverse transcriptase converts HIV's RNA to DNA. The HIV-derived DNA then worms its way into the cell nucleus to mingle with the cell's own DNA.

"One of the problems that plagues vaccine development is that we're so busy trying to guess which one works better, we've been reluctant to go forward and finish any of the experiments we've started."
THUS HIJACKED, the cell begins producing the scripted HIV proteins. These proteins eventually assemble outside the cell nucleus into brand new HIV viruses, which migrate toward the surface of the cell, where they "bud" off like bubbles coming up out of water. They escape into the bloodstream to begin the infection cycle anew, and the spent cell dies. What makes HIV so insidious is that it kills the very cells the body uses to fight infection. The CD4 cells are responsible for activating all of the most important elements of the immune system.
Two potential strategies exist to stop HIV once it gets inside the body. One is to scavenge the virus that's circulating in the blood, looking for cells to infect. The other is to search out and destroy the cells that are already infected. The immune system has the wherewithal to do both.
But it needs a fighting chance. Once the virus invades, the immune system has little time to develop the skill it needs to recognize and take the enemy out. By the time it gears up, the virus has already taken hold. A vaccine, however, would give the immune system that needed practice. Once trained, the immune system "remembers" what the virus looks like and so can quickly remobilize should the invader appear again.
VACCINES WORK because they fool the immune system into thinking it's under attack by the real culprit. One of the better ways to accomplish this trickery is to simply expose the body to a dead version of the virus. If the virus is intact, it will look just like the live, disease-causing version. Because it's dead, it can't replicate. But the immune system will still react, furiously churning out Y-shaped proteins known as antibodies that lock on to the virus, immobilizing it. Once the body has made these antibodies, it should remember--at least for a while--how to do it again. This is the strategy behind Jonas Salk's polio vaccine.
But in the case of HIV, some technical hurdles make this approach difficult right now. HIV is a lethal virus--the chance of even a few live particles accidentally slipping through during the chemical or radiation processes designed to kill it is too risky. And techniques that unequivocally kill all the virus often destroy its structure.
If the virus is merely hobbled so that it can't replicate or cause disease, but is still alive, the vaccine is potentially even more powerful. This so-called live attenuated virus approach works like Albert Sabin's vaccine for polio. In the past, viruses were weakened with heat or by passing them through cell lines. Nowadays, scientists delete some key genes. Because it's still alive, the attenuated HIV can infect cells. And so not only does the virus bring on a rush of antibodies, it also alerts another part of the immune system, one that acts to thin the herd of sick and dying cells.
When a cell is infected, viral proteins work their way to the cell surface, where they sit, poking out of the cell like beacons. The beacons draw a fleet of immune cells, known as cytotoxic lymphocytes (CTLs), or killer T-cells, that learn to recognize the infected cells and then destroy them.
Unfortunately, a live attenuated virus can sometimes revert to an infectious form. Some initial research showed that monkeys were incredibly well protected from the simian immunodeficiency virus--SIV, analogous to HIV in humans--after being vaccinated with live attenuated SIV. But some monkeys vaccinated with live attenuated SIV eventually became sick with AIDS. So the live attenuated approach is "absolutely a no-no for us at this moment," says Jorge Flores, chief of the vaccine clinical branch of the National Institute of Allergy & Infectious Diseases' (NIAID) Division of AIDS.
BUT THIS IS THE AGE of biotechnology, and we've had recombinant DNA techniques around for 25 years. And so when scientists set out to develop a vaccine against HIV, they turned to genetic engineering. HIV's key to entering cells is a mushroom-shaped protein complex that studs its surface. The cap of the complex, known as gp120, was seen as a likely candidate for vaccine. If the body developed antibodies against gp120, those same antibodies should bind to gp120 on the real HIV, entirely frustrating its attempt to infect cells.
Scientists already had a hugely successful precedent for this strategy: the first genetically engineered vaccine, for hepatitis B, developed by Chiron in the 1980s. Chiron used the nascent recombinant DNA technology to cut and paste genes that coded for portions of hepatitis B's coat into cells that would churn out the protein. The purified protein, when injected into people, stimulates antibodies that prevent hepatitis B. It was reasonable to expect the same thing might be applied to HIV.
Both Chiron and biotech company Genentech immediately began developing gp120-based vaccines.
But unlike the hepatitis B vaccine, the results for HIV were less than stellar. Chimps and macaque monkeys were only modestly protected from the HIV virus. Different virus subtypes, for one, could be complicating the picture. It was well known that clade B, for example, which predominates in the Americas and Europe, has a different enough structure from Thailand's clade E or Africa's clade A to likely necessitate different vaccines for each. But even the strains grown for generations in laboratories had possibly evolved to become different enough from primary isolates--strains isolated from infected people's blood--to complicate experimental results.

7935scit2.ce
NEVERTHELESS, Genentech's vaccine, AIDSVAX, passed both a Phase I trial for safety and a larger Phase II study. But in 1994, NIH declined to fund Phase III efficacy trials for AIDSVAX, over the protests of some in the scientific community who felt that a vaccine needed to get through the testing process in order to cogently direct future research.
Scientists were beginning to turn away from the antibody--or humoral--arm of the immune system in favor of priming the cell-mediated arm, the one responsible for clearing out infected cells. But rather than work with a dangerous live HIV that moves into cells to produce proteins, why not do the same thing by using instead a harmless virus that carries some HIV genes along with it?
These benign viruses that infect human cells but exist solely to shuttle genetic material are known as vectors. Again calling on biotechnology, researchers can insert HIV genes into the virus' genetic material and inject the modified virus into an animal. The hope is that when the virus infects cells that in turn produce HIV proteins that migrate to the surface, the immune system will charge in and slay the infected cells.
For example, the world's largest vaccine manufacturer, Aventis Pasteur in France, has a number of AIDS vaccine candidates, some in Phase I clinical trials, based on canarypox--a cousin of smallpox that infects birds.
DNA vaccines approach the problem differently. The technology was first explored in the early '90s by several researchers, including David B. Weiner, professor of pathology at the University of Pennsylvania; Margaret Liu, a former scientist at Merck, now a consultant for the Bill & Melinda Gates Foundation; and Harriet L. Robinson, professor of microbiology and immunology at Emory University in Atlanta.
Instead of saddling a viral vector with HIV genes, researchers call upon tiny rings of DNA found in bacteria, called plasmids. Plasmids are bacteria's idea of sex--they transmit useful genetic information between the organisms. The plasmid migrates from one cell into another and merges with the cell's DNA, which begins producing proteins. It's a relatively simple feat to splice a few HIV genes into a plasmid.
DNA vaccines also circumvent a potential snag wherein the immune system develops antibodies to viral vectors, Weiner notes. A vaccination program frequently involves one or more booster shots after the first, to keep training the immune system. But once the viral vector enters the bloodstream on its mission to infect cells, the immune system is going to begin mounting an antibody response to the vector itself. The response may not interfere with the vaccine initially, but by the second shot, the antibodies are primed and ready. DNA itself elicits no antibodies, however, and can be used again and again.
Though these approaches primarily stimulate the cell-mediated immune arm, they do, to a certain extent, stimulate the humoral arm as well, Weiner says. The HIV proteins sloshing around inside cells sometimes leak out into the bloodstream, where they encounter antibodies.
Although some Phase I trials in humans of some DNA vaccines have failed to produce an army of killer T-cells, striking new research inoculating monkeys with DNA vaccines, followed by a viral vector boost, has some researchers excited.
For example, Robinson showed that monkeys given this sort of two-pronged vaccine stayed healthy after being exposed rectally to a lethal form of the virus. Her lab is working with NIAID to begin Phase I clinical trials of the vaccine in January 2002. The two-pronged regimen "raises both better cellular and humoral immune responses than either DNA or [the viral vector] alone," Robinson says.
THE RELATIONSHIP between HIV and CTL immunity is by no means clear-cut. For example, a group of about 100 prostitutes in Nairobi have somehow remained uninfected despite hundreds of yearly HIV exposures. Curiously, however, when some of the women stopped being sex workers, they then became infected. The implication is sobering: The women may have needed to keep their immune systems constantly stimulated in order to stave off infection. Researchers have documented a similar phenomenon in people continuously exposed to malaria.
Some combination vaccines are designed to stimulate both arms of the immune system. One of the vaccines farthest along in the clinical process is one such example. Chiron and VaxGen are partnering with Aventis on a canarypox vector prime plus a gp120 protein subunit boost vaccine. They're in Phase II trials in Thailand, Haiti, Trinidad, and Brazil.
"From our way of thinking, a vaccine that induces both [antibody and CTL response] is better than either alone, because we don't have a clue" which will work, says John McNeil, chief of HIV vaccine development at the Walter Reed Army Institute of Research, which is collaborating with the three companies on the trials.
"There's been a remarkable amount of convergent evolution in the past three to four years," Chiron's Donnelly says. "Everybody's sensitized to the idea that you need a balanced response."
With the focus on CTL response also has come a shift in sentiment about what constitutes efficacy. At one point, the only acceptable result was that immunity was completely "sterilizing"--that is, that the virus never takes hold in the body. But in a number of recent studies, monkeys that received vaccines still became infected and carried the virus, but either they didn't become sick or they got sick more slowly than if they hadn't been vaccinated. Some scientists think that outcome might be good enough right now in light of the seriousness of the epidemic.

FRANCIS8
FRANCIS


"HOPE IS HIGH NOW because researchers have changed the goal posts," notes Jon Cohen, a reporter who covers AIDS for Science and author of a book published this year by W. W. Norton & Co., "Shots in the Dark: The Wayward Search for an AIDS Vaccine." "The sentiment in the community is that you do not have to prevent infection to have a useful vaccine," he says. But despite all this heady research and numerous different strategies, none of the many proposed vaccines has managed to make it through the system to Phase III efficacy trials, except for one.
Phase III is the final clinical step, the one that tests the actual efficacy of a vaccine. It requires a huge number of volunteers because the results are highly statistical--success at this stage is based on a comparison of the number of infections among populations.
When NIH in 1994 turned down VaxGen's request for Phase III trial funding for AIDSVAX, the company set out to show that it could do the study without government support. Led by VaxGen's president, Donald Francis--immortalized in Randy Shilts's 1987 chronicle of the AIDS epidemic, "And the Band Played On"--the company raised the necessary millions from private donors.
In 1999, VaxGen launched two Phase III trials of a gp120-based vaccine: One, in the U.S., enrolled 5,000 gay men and 400 heterosexual women; and one, in Thailand, enrolled 2,500 intravenous drug users. In November, the firm will announce interim results that will determine whether the vaccine is effective enough to warrant stopping the trial and moving ahead with distribution.
Nobody, including the scientists at VaxGen, expects AIDSVAX to be the final answer in AIDS vaccines. "I think to hit a home run on this--the first go-around--would be a lot to ask," Francis says. Nevertheless, if AIDSVAX is even slightly effective, the field as a whole will have a much-needed springboard.
"I think one of the problems that plagues vaccine development is that we're so busy trying to guess which one works better, we've been reluctant to go forward and finish any of the experiments we've started," says Patricia Thomas, medical journalist and author of "Big Shot: Passion, Politics, and the Struggle for an AIDS Vaccine," a book that will be published next month by Perseus Books Group. "That's why the VaxGen [trial] is so important--because they are finishing the experiment."
Nonetheless, there are signs that the ice is shifting. Big pharmaceutical companies, which for years had little interest in AIDS vaccines, have suddenly emerged as significant players. Merck in particular has an extensive AIDS vaccine program, and it has just begun Phase I trials with a DNA prime/vector boost vaccine.
AND INCREASINGLY in both public and government consciousness is the realization that unless something is done quickly about AIDS, whole nations will likely be populated largely by orphans.
The New York City-based International AIDS Vaccine Initiative is moving a number of AIDS vaccine strategies speedily toward clinical trials. One of its projects--with Oxford University and the University of Nairobi--is already in Phase I testing in the U.K. and Kenya, with a DNA prime and viral vector boost.
Bill Snow is a longtime AIDS vaccine activist and a cofounder of the AIDS Vaccine Advocacy Coalition who has also served on NIAID's AIDS Vaccine Research Committee and NIH's Office of AIDS Research Advisory Council. He points out that, as of right now, the merits of debating individual vaccines are perhaps less important than getting them tested.
"I have very little reason to think one strategy is better than the other. Clearly right now, the thing scientists are most excited about and working hardest on are the DNA plus vector boosts," Snow says. But what's most important, he says, is to "get things into efficacy trials--as many and as quickly as possible, so we'll have some grounds to say what does or doesn't work."

Under scrutiny
AIDS vaccine candidates in clinical trials
PRODUCT MANUFACTURER
OR SPONSOR
HIV SUBTYPE PHASE LOCATION OF TRIAL
RECOMBINANT PROTEIN SUBUNIT
Bivalent rgp120 VaxGen B+E 3 Thailand
Bivalent rgp120 VaxGen B 3 VaxGen B 3 U.S., Canada, the Netherlands
Oligomeric rgp140 Aventis E 1 U.S.
rgp120 Chiron E 1 Thailand
rp24 Chiron B 1 U.S.
DNA
gag Merck B 1 U.S.
env-rev Wyeth B 1 U.S.
VIRAL VECTOR
Vaccinia--env, gag, pol Therion B 1 U.S.
Vaccinia--multi-env St. Jude's B 1 U.S.
Canarypox--env, gag-pr, nef, pol Aventis B 1 U.S.
BACTERIAL VECTOR
Salmonella--env U. of Maryland B 1 U.S.
VECTOR PRIME PLUS SUBUNIT BOOST COMBINATIONS
Canarypox--env, gag-pr, nef, pol Aventis E 2 Thailand
rgp 120 Chiron E

rgp120 VaxGen B+E

Oligomeric rgp140 Aventis E

Canarypox--env, gag-pr Aventis B 2 Haiti, Trinidad, Brazil
Canarypox--env, gag-pr, nef, pol Aventis B

rgp120 VaxGen B

Salmonella--env U. of Maryland B 1 U.S.
rgp120 VaxGen B

DNA PRIME PLUS VECTOR BOOST COMBINATIONS
DNA--gag, pol Wyeth B 1 U.S.
Canarypox--env, gag-pr Aventis B

DNA--env-rev Wyeth B 1 U.S.
Canarypox--env, gag-pr Aventis B

DNA--env, gag, nef, pol Oxford U. A 1 U.K.
Vaccinia--env, gag, nef, pol Oxford U.


DNA--env, gag, nef, pol Oxford U./U. of Nairobi A 1 Kenya
Vaccinia--env, gag, nef, pol Oxford U./U. of Nairobi


DNA--gag Merck B 1 U.S.
Adenovirus--gag Merck


PEPTIDE
C4-V3 peptide Wyeth B 1 U.S.
V3 peptides CIBG B 1 Cuba
p17 Cel-Sci B 1 U.S./Europe
Lipopeptides: env, gag, nef ANRS B 1 France
NOTE: Prefix r denotes recombinant protein. env, gag, nef, and pol refer to major proteins encoded by the HIV genome. This table is not intended to be comprehensive. SOURCE: International AIDS Vaccine Initiative

Top

FUNDING
International AIDS Vaccine Initiative's Unusual 'Social Venture Capital' Model

Seth Berkley
BERKELEY
David Gold pic-1
GOLD
Wayne Koff pic
KOFF
In the mid-1990s, the AIDS vaccine effort was floundering. In the years since scientists had identified the AIDS virus, they had made little progress in finding a way to prevent it from infecting humans. Some spectacular successes came from therapeutic drugs--protease inhibitors in particular have been credited with extending the lives of AIDS patients by years.
But promising leads for vaccines hadn't panned out. Big pharmaceutical companies had little interest in pursuing a product with limited potential for profit. Lackluster federal support and uncoordinated research programs thwarted attempts to test candidate vaccines. In the meantime, the virus was wreaking devastation in developing countries.
It was in this discouraging climate in 1994 that the Rockefeller Foundation assembled a group of scientists, led by epidemiologist Seth Berkeley, to take a hard look at the field. It was time, they decided, to fill a much-needed leadership gap. And so they launched the International AIDS Vaccine Initiative (IAVI) in 1996 to speed a broad spectrum of vaccine strategies from the lab into clinical trials. They've also taken some unusual steps to ensure that, if successful, the vaccines are made available to poor developing countries.
"The whole reason IAVI formed is market failure," says David Gold, the organization's vice president for policy and public sector support.
The Rockefeller Foundation seeded the New York City-based IAVI, with Berkeley in charge. Thanks in large part to Berkeley's unflagging fund-raising, IAVI last year received $25 million and this year, a $100 million challenge grant from the Bill & Melinda Gates Foundation. Though IAVI still needs a lot more money to accomplish its goals, the $100 million grant--the largest ever for AIDS research--gave IAVI significant clout.
In addition to doing its own research, IAVI has so far invested $20 million in six different vaccine research programs at small companies and academic labs. A vaccine developed by Oxford University and the University of Nairobi has already entered Phase I clinical trials in the U.K. and Kenya.
IAVI intends to help sponsor up to 12 of these potential vaccines. Ultimately, it would like to see a vaccine licensed in eight to 10 years, a much shorter timeline than the more usual 12 to 15 years.
IAVI's priority is developing economies like Africa and India, where the effects of the virus are most devastating. IAVI's partners develop their vaccines using strains of HIV from those countries and run clinical trials there, using IAVI as a bridge to connect with the countries' governments.
"Nobody's ever run large-scale efficacy trials in regions where the epidemic is, with the exception of Thailand," says Wayne Koff, IAVI's senior vice president for research and development.
In exchange for their support, IAVI insists the companies pledge to make their vaccine--if it pans out--available at very low cost to developing nations. This "social venture capitalism" is unusual, Koff says, although some organizations dealing with diseases like malaria and tuberculosis have adopted similar policies.
Because of this requirement, the companies and labs that enter into partnerships with IAVI typically are small outfits. A Merck or a Wyeth, for example, has plenty of its own money and resources, and isn't likely to surrender any of its intellectual property rights.
That doesn't mean IAVI's negotiations with the small companies have been easy. "It's probably easier to extract teeth," Gold acknowledges. "Anything that impinges on pure intellectual property rights will be viewed with some concern."
One example is AlphaVax, a company in Research Triangle Park, N.C., that is partnering with IAVI to develop its vaccine in South Africa. AlphaVax inserts HIV genes into the Venezuelan equine encephalitis virus, a combination that produces viral particles in the body that can't reproduce, but can elicit a strong immune response. IAVI's agreement with AlphaVax includes the pledge that, should the company be unable to keep its costs down, IAVI will have the right to seek bids to manufacture the vaccine from regional or local companies, says Peter Young, chief executive officer of AlphaVax.
"For the conventional big pharma way of thinking, that's a very difficult set of commercial commitments to take on," Young says. "But conventional big pharma is self-sufficient. Small biotechs like ours are not."
AlphaVax does get something out of the deal besides immediate support, Young says, in that IAVI's sponsorship has allowed the firm to create a springboard for its entire technology. AlphaVax will be able to harness the organization, manufacturing, and regulatory platforms it's developed for its South Africa AIDS vaccine for any other type of product, be it vaccines for AIDS, herpes, or cancer. "That's attractive, not only in-house, but also for our partners, because it shaves two to three years off development," he says.
One of IAVI's newest partnerships, with Cambridge, Mass.-based Therion Biologics, will test a vaccine for India. Therion's strategy is to stuff almost all of the proteins found in HIV into a vaccinia virus. Once injected, the virus makes the body express the HIV proteins that will hopefully prime the immune system.
Even though IAVI approached Therion with a collaboration proposal, working out the intellectual property agreement was difficult, notes Dennis L. Panicali, president and CEO of Therion Biologics. But, he says, "we also recognize that, particularly as a small company, we don't intend to be a manufacturer and distributor for Asia or South Africa. We're happy to have IAVI take that role."

Top

BATTLE PLAN
Developing Vaccine Strategies For War Against AIDS
Whole killed virus. Like Jonas Salk's polio vaccine, this type of vaccine consists of the intact virus, killed, or "inactivated," by chemicals or radiation. The advantage to this approach is that the body tends to mount strong antibody responses when it sees the intact virus. Other recombinant vaccine techniques use only parts of the virus, which don't prepare the body as well for an attack by real HIV.
Live attenuated virus. Even more risky than whole killed virus but potentially even more effective, live attenuated virus is stripped of some of its genes. It then can't cause disease but can still infect cells, thus training the immune system with the closest thing possible to actual HIV.
Recombinant protein subunit. Borrowing from the strategy of the successful hepatitis B vaccine, scientists surmise that the immune system recognizes structural features on a virus--pieces of its coat, in particular. Using recombinant DNA technology, scientists clip pieces of the HIV gene that code for certain proteins, most notably, a spike on HIV's coat known as gp120. They insert the genes into bacteria, which start expressing the protein en masse. The harvested proteins are injected into the body, where it is hoped they'll stimulate antibodies that recognize and latch onto HIV, rendering it inactive.
Viral vector. This approach targets the so-called cell-mediated arm of the immune system that clears out already infected cells, rather than the humoral arm that produces antibodies. Pieces of HIV genes are cut and pasted into a harmless virus, such as vaccinia. The virus then infects human cells and harnesses the cells' machinery to produce viral proteins. These proteins pop up on the surface of the cell, like beacons on a hill. The beacons alert special killer immune cells known as cytotoxic T-lymphocytes (CTLs), or killer T-cells, which rush in to destroy the infected cell.
Bacterial vector. Used in the same manner as viruses in viral vectors, bacteria are easier to work with than viruses and more genetic material can be crammed inside, proponents say.
DNA vaccine. DNA vaccines are based on relatively new technology that harnesses DNA plasmids--rings of DNA that live in bacteria. Scientists insert pieces of HIV DNA into plasmids, then inject the "naked" DNA into a person. Once the plasmids enter a human cell, they migrate to the nucleus and begin expressing proteins. The proteins then migrate to the surface, as they do with viral vectors, alerting killer T-cells.
Combinations. Numerous animal and human studies now consist of various combinations of an initial vaccine--known as a prime--followed by a "boost" of a different vaccine. Examples include a DNA vaccine prime and a viral vector boost. Some combinations are designed to activate both arms of the immune system--cell-mediated and antibody--with, for example, a DNA vaccine prime and protein subunit boost.

Top

VOLUNTEERING
Journalist's Participation In AIDS Vaccine Trial Is More than Just Book Research
More than four years ago, while journalist Patricia Thomas was doing research for a book on AIDS vaccines, a scientist mentioned that the National Institutes of Health (NIH) was recruiting volunteers for a new vaccine trial.
The organization was testing a new DNA vaccine developed by the company Apollon. At this stage of the game--Phase I--they needed to inject only a few people to test the vaccine for safety and for signature immune responses.
More was at stake than an opportunity for a journalist to get an intimate glimpse of the clinical science. Because while it might be relatively easy to recruit subjects to swallow pills that might cure their migraines or reduce their blood pressure, it's much more difficult to find perfectly healthy people who would agree to be injected with a mixture that might have untoward effects.
Thomas, whose book "Big Shot: Passion, Politics, and the Struggle for an AIDS Vaccine" will be released by Perseus Books Group in September, decided to proffer her arm to the NIH. She fit the bill for a Phase I volunteer in this trial: a non-IV-drug-using woman, at very low risk for AIDS, in the correct age group of between 18 and 60 years. And Thomas wanted to help the cause. "Already in my research I'd decided that clearly one of the real rate-limiting steps in vaccine development was clinical testing," she says.
This DNA vaccine--the first ever to be tested against HIV--consisted of snippets of DNA that code for two HIV proteins, pasted into a ring of DNA known as a plasmid. Cells in the body take up the plasmid and express the proteins. The theory is that the body will mount an immune response against them that will also be effective against real, whole HIV.

7935sci1x
THOMAS
PHOTO BY ELSA WILKINS



The very first step for Thomas--indeed, for anyone volunteering for such a trial--was to review and sign the informed consent form. "When I volunteered, intellectually I was pretty sure that the DNA vaccine concept was safe," Thomas says. Nevertheless, the 14-page-long list of possible adverse effects gave her pause. Because the Food & Drug Administration requires that volunteers be told of anything that could possibly occur, no matter how remote the chance, Thomas found herself contemplating the possibility not only of trivial effects like local soreness at the injection site, but dire ones such as cancer 20 years down the road. The document was "pretty ominous," she says. "I couldn't help but think what a deterrent that sort of form would be to many people."
After a battery of tests (which included drawing prodigious amounts of blood into a multitude of test tubes, one "about the size of a kielbasa") showed she was not infected with HIV, or pregnant, to name just two criteria, she was accepted into the trial. Over the next year and a half, Thomas made 17 treks from her Boston home to the NIH campus in Bethesda, Md., for a total of four injections and many more exams.
Vaccine volunteers are a special breed, a staff member told Thomas on one of her visits. Unlike drug trial volunteers, who hope they'll be helped immediately, members of vaccine trials are investing in the future of humankind.
More sobering was Thomas' realization that class plays a role in trial volunteering. Although NIH paid for plane fare and a per diem, she spent money from her own pocket on each trip. Volunteers need to have flexibility in their work schedules, as well as the ability to make up costs not covered by the per diem, she notes. "I thought, 'Boy, if I wasn't somewhat middle class, I'd never be able to do this.' "
Meanwhile, Thomas was attending scientific meetings to gather material for her book. "I'd hear a lot of gossip about the trial I was in," she says. Unfortunately, what she heard was disappointing. The immune responses were less powerful and of shorter duration than the researchers had hoped.
Eventually, the trial coordinator told Thomas that they believed the dose they were using was too low. While finishing the study Thomas was in, NIH began recruiting another group of Phase I volunteers to be injected at a higher dose. Finally, on the first of this year, the trial was officially unblinded: Because the results were so lackluster, they would not proceed to a larger, Phase II study, at least with this version of the DNA vaccine. (A new version of the vaccine, in which the DNA injection is followed by a "booster" of a different vaccine form, is now being tested by Wyeth-Lederle, which acquired Apollon.)
Yet that trial and many others like it that will undoubtedly fail before a working vaccine emerges are a vital part of the scientific process, Thomas concludes in a journal she kept about the experience. "Each clinic visit, each vial of blood is like a tile in a huge mosaic--inconsequential in itself but part of a larger pattern," she writes. "For now, it is enough to know that I rolled up my sleeve for something I believed in."

No comments:

Post a Comment