labrat's notebook: HIV

ARTICLE 1:
Title: Eulogy for a Doomed Vaccine
Author: Kennedy, Sean
Source: Advocate, 1.29.2008; Issue 1001, p39-42

It was bad enough when a promising HIV vaccine's global trial was halted last September because the drug under study failed to prevent infection. But it got even worse when scientists discovered in November that in some of its recipients the vaccine might actually have promoted HIV infection. The twist was like a sick joke: A product designed to protect people from HIV could instead help them get it?

LABRAT ARTICLE 1 QUESTION 1: WHAT IS THE NAME OF THIS DRUG AND, RESEARCH ABOUT IT SINCE 2008?

The vaccine under study--only the second ever to garner a critical Phase II clinical trial--was expected to be a major breakthrough in the fight against HIV. Developed over the course of a decade by drug company heavyweight Merck & Co. and being tested in nearly 3,000 people from North and South America, the Caribbean, and Australia, the vaccine was designed to stimulate the body's T cells in order to better ward off the insatiable virus. The previous vaccine to reach the Phase II stage had targeted antibodies, the immune system's other set of defenders, but it had proved a bust in 2003. Hopes were high that the T-cell approach would succeed.

LABRAT ARTICLE 1 QUESTION 2: WHAT HAPPENED WITH THIS DRUG IN 2003?

LABRAT ARTICLE 1 QUESTION 3: WHAT TYPE OF T-CELLS ARE THEY TALKING ABOUT HERE AND WITH HIV?

Instead, a midpoint analysis made public on September 21 showed statistically comparable rates of infection for volunteers (all HIV-negative at the start of the trial) who had received the vaccine and those in the placebo group. What's more, in those vaccine recipients who became infected with HIV, the vaccine also failed to lower their virus levels--another area of inquiry for investigators. The vaccine was a loser, and there was nothing to do but stop the three-year-old trial.

It was a devastating denouement for anyone aware of the stakes--experts widely believe that a vaccine, if not a cure, is the only thing that can turn around the runaway HIV/AIDS pandemic. But like a thriller, this trial held one last plot surprise in store: People who had received the vaccine were in fact becoming infected with HIV at a higher rate than those in the placebo group. According to the latest data available, 49 of the 914 men who received the vaccine became infected with the virus, while 33 of the 922 who received the placebo tested positive. (The remaining 839 volunteers were women, only one of whom became infected.)

Suddenly what had been a straightforward story of loss became a vexing mystery. Although the vaccine was made with three HIV genes, they were synthetic--like Xerox copies of original documents--so it was impossible to get infected from the vaccine itself. That left two possible explanations: Either vaccine recipients who contracted the virus guessed that they had been vaccinated--like any legitimate scientific study, the trial was double-blind, meaning neither subjects nor researchers knew who received what--and, assuming they were protected, consequently engaged in riskier behavior. Or, more probably, the vaccine facilitated infection in some way.

LABRAT ARTICLE 1 QUESTION 4: WHAT DOES THE AUTHOR MEAN BY “SYNTHETIC” GENES?

LABRAT ARTICLE 1 QUESTION 5: WHAT DO THEY MEAN BY THREE HIV GENES, HOW MANY TYPES OF HIV ARE THERE?

Indeed, the leading hypothesis among investigators is that the vaccine somehow made the immune system more susceptible to infection. However, the increased susceptibility appears to be limited only to those vaccine recipients who had a preexisting immunity to the cold virus used in the vaccine to transport the HIV genes into the body. For reasons that still need to be determined, that was the group that saw an increase in HIV infection. If you had been given the vaccine but had lower immunity to the cold virus, your risk was likely no greater than that of the placebo recipients.
Either way, as a study participant, this was the last thing I wanted to hear.
I have always felt guilty for being HIV-negative. As much as we know about safe sex, the importance of protecting ourselves, and the ravages of AIDS, accidents still happen--including the accident of birth. What if I had been born early enough to arrive in New York City as a young man in the early 1980s, when the virus was just beginning to circulate, incubating among a generation of men who had no idea what was about to befall them? Fresh-eyed and adventurous, I would surely have died. Instead, I came to the city after college in 2000, having never met anyone who was positive. That difference in fates weighed heavily on me, a kind of spiritual survivor's guilt.

So when I learned three years ago in the course of my work as a journalist that an international HIV vaccine trial was enrolling gay men and other people at "high risk" (such as heterosexual black women) for contracting the virus, I decided to participate. I knew it would make a good story, but I also hoped it would assuage my feelings of guilt. Instead of helping just one person, as the save-a-starving-child proselytizers constantly beseech us to do, a viable HIV vaccine could benefit an untold number of people. It could even end the global epidemic. Medical progress so often relies on human guinea pigs--it seemed like my duty to participate.
Still, it was not a decision I made lightly. During the initial consultation at the trial site in a nondescript office suite in New York City's Union Square, one of 25 cities where the HIV Vaccine Trials Network conducted the study, a staffer apprised me of what lay ahead. Although the gist was simple enough--three injections of the vaccine over the course of six months, then follow-up visits that would slowly dwindle before ending 4 1/2 years later--the details were harder to comprehend. For one thing, I would have to give a lot of blood, sometimes filling as many as 32 vials, which would be sent to a lab for analysis. For someone squeamish about needles, let alone seeing my own red liquid outside my body, the prospect made me want to throw up.

Then there were more practical considerations, like the fact that because of the HIV genes that would be injected into my body, I would turn up as positive in routine HIV screenings. Consequently, I could be tested only at the study site (and as part of the study, I was, on a regular basis). If I needed to prove that I was negative for any reason--say, to visit a country that currently bars HIV-positive visitors, such as China--I would have to disclose my participation in the trial and provide documentation. I doubted people would understand. (In fact, they didn't: When I would bring up the subject in casual conversation, I realized that many people assumed I was HIV-positive, even though by definition a vaccine is given to those who don't have the target of prevention.)

But my biggest concern, as attested to by the mounds of paperwork I signed, was that there was no telling what could happen to me in this unprecedented experiment. Though I was reassured that the vaccine was innocuous, no one had received it before, so there was no long-term knowledge of its effects. If it worked (and I had received it), then great--I would be biologically protected from a most nefarious scourge. But what if it didn't work--or worse, had some unforeseen negative consequences? The staffer had no answers for me. That's how it is on the leading edge of science: murky and uncertain.

Yet my hand was forced when a friend of mine, nearing 30, suddenly became infected with HIV. Thanks to a single unsafe sexual encounter, his life was changed forever. It was too late to save him from infection, but maybe I could save others--maybe even myself.

Until this fall, the whole experience was as smooth as could be. The injections were akin to getting a flu shot, and the various sums of money I collected at the end of each appointment, between $25 and $75, were welcome pocket change. I would leave the study site, get a Jamba Juice around the corner, and go on with my life. I rarely thought about the trial; it was a nonissue.

The only time it became a problem was when I told a boyfriend about it. Normally I didn't disclose my participation to sex partners, since the vaccine couldn't affect them, but he was different. We were in a relationship, and I felt like he should know. So one night, in the middle of a certain sex act, I blurted it out. "Now you're telling me?!" he practically yelled. I shrugged. It seemed like an opportune time.

Being in the trial, I even learned a valuable lesson: that my own safe-sex regimen works. I've been tested more than a dozen times since I enrolled in the study, and every time the result has been negative. It's embarrassing to admit now, but I didn't get my first HIV test until I was 25 because I was irrationally afraid that it would come back positive, even though I had never engaged in unsafe behaviors. To know that I was effectively shielding myself was tremendously reassuring.
And then, of course, I discovered that maybe I hadn't shielded myself at all--that maybe, instead, I had inadvertently thrown myself into the lion's den. When a trial staffer called in November to inform me that the vaccine might have promoted HIV infection and that all study volunteers would be "unblinded" so they would know what they got, I didn't quite understand her. "Isn't an HIV vaccine supposed to prevent infection?" I asked. The staffer nervously laughed.

It wasn't until the following day that the reality of what had happened started to sink in. There, on the front page of The Waft Street Journal's Marketplace section, was a story whose headline said it all: "Canceled Vaccine May Have Boosted HIV Risk." I started to feel anxious. All my initial concerns about participating in the study came roaring back to the forefront of my mind. Had I put my body on the line for science only to have harmed it?

I didn't know the answer to that yet, but the vaccine effort itself was clearly damaged. As Anthony Fauci, the well-known HIV researcher who directs the National Institute of Allergy and Infectious Diseases, which provided funding for the trial, told the Journal, the vaccine's failure will force the field to "relook at everything."

"It's just extraordinarily disappointing to be faced with another vaccine that is not effective," epidemiologist Beryl Koblin, the principal investigator for two of the study sites in New York City, told me recently. "Sometimes it's hard to find the words because of the urgency, and that desire to be able to find a vaccine as quickly as possible." Indeed, at an HIV Vaccine Trials Network conference in Seattle in November, where the troubling results were announced, one staffer told me she had never seen such grief.
As for the apparent increased risk of infection, Koblin said, "For me, personally, that is just really hard. You never want to put people at more risk than is already there." But she cautions that there's still a "huge amount of data that needs to be sorted through to see whether there's a true biological effect going on." A special committee has been charged with assessing the results; study participants will also be tracked. There are lots of factors to consider. Among the clues: People from outside the United States or Europe tend to have a higher prevalence of immunity to the cold virus used in the vaccine; non-Americans in the study were also less likely to be circumcised. What does it all mean? Only time will tell.

From a public relations standpoint, however, this has to be a disaster, right? Koblin said that so far, recruitment for the various Phase I trials she oversees--there are more than 30 currently under way worldwide--hasn't been affected, but she knows there may be problems down the road, when volunteers are needed for a Phase II trial of a new vaccine. One had been set to start last September, but it was scrubbed when the Merck vaccine failed. It's now being redesigned, and she thinks it could begin in another year.

LABRAT ARTICLE 1 QUESTION 6: WHAT ARE THE DIFFERENT PHASES OF VACCINATION AND MEDICATION TRIALS?

"We have to keep going," Koblin said. "But we need to be really careful about how we proceed."

In December, I went to the study site to find out whether or not I had received the vaccine. Volunteers who had been given the placebo would be eligible to participate in future vaccine trials, and before my appointment, I wondered if I would want to. I was hoping I had been given the placebo simply because I wouldn't be at higher risk of contracting HIV, which would be a relief. But it would also mean I would have to decide whether to put my life on the line again. It seemed like a game of Russian roulette; Spin the barrel of the gun and you could be fine--but maybe not.

"What do you think you got?" Leah Strock, a nurse practitioner and the resident clinician, asked me. Over the last three years I had grown quite fond of Strock, a doting big-sister type and former punk rocker who had dated the cartoonist R. Crumb in the 1980s. I told her I hadn't really thought about it. "You'd be the only one," she said with a laugh. (Jokes aside, all the study participants have been very understanding about the turn of events, Strock told me. One who learned he was at increased risk took the news in stride, pragmatically deciding to use condoms for every kind of sex act going forward.)

Strock was waiting for an answer to write down on the sheet in front of her, so I said "placebo," which is what I was praying for. She turned to a spreadsheet that listed all the participants at the site, coded by numbers. Next to my number it said "vaccine." My stomach turned over. "But you don't have the immunity to the cold virus, so you're fine!" Strock quickly added. My mood lurched again. I wanted to hug her.

As happy as I was, it also meant that, for better or worse, I could never again participate in an HIV vaccine study. The decision was made for me--and I can't say I'm unhappy about it.

LABRAT 303, 7/11/2012 1729

LABRAT ARTICLE 1 ANSWER 1:

The vaccine is called V520. Pubmed search for "V520" returns 4 results:
(2010) Safety and Immunogenicity of the MRKAd5 gag HIV Type 1 Vaccine in a Worldwide Phase 1 Study of Healthy Adults.
(2009) Safety and immunogenicity of adenovirus-vectored near-consensus HIV type 1 clade B gag vaccines in healthy adults.
(2008) Why vaccines are not the answer - the failure of V520 and the importance of cell-mediated immunity in the fight against HIV.
(2008) Safety and immunogenicity of a replication-incompetent adenovirus type 5 HIV-1 clade B gag/pol/nef vaccine in healthy adults.

LABRAT 303, 7/11/2012 1758

LABRAT ARTICLE 1 ANSWER 2:

ARTICLE 2
TITLE: AIDS vaccine fails in Thai trial.
AUTHOR: McCarthy M
SOURCE: [Lancet] Lancet 2003 Nov 22; Vol. 362 (9397), pp. 1728.

“The vaccine neither prevented infection nor slowed disease progression in those who became infected after receiving the vaccine.

In the phase III trial, 2546 injecting drug users in Bangkok, Thailand, were randomised to receive seven injections of either the vaccine or placebo. The vaccine, AIDS/VAX B/E, contained recombinant forms of the HIV surface protein, gp120, which resemble the gp120 proteins found on HIV strain subtypes B and E, common in Asia.”

LABRAT ARTICLE 2 QUESTION 1: WHAT ARE SURFACE PROTEINS IN VIRUSES?

LABRAT 303, 7/11/2012 1833

LABRAT ARTICLE 1 QUESTION 3: WHAT TYPE OF T-CELLS ARE THEY TALKING ABOUT HERE AND WITH HIV?

The answer seems to be CD4 cells; however, the concept of "T-Cells" needs to be looked at more closely after the rest of ARTICLE 1 questions are answered. Therefore, this question has not yet been answered.

LABRAT ARTICLE 1 ANSWER 4: WHAT DOES THE AUTHOR MEAN BY “SYNTHETIC” GENES?

http://youtu.be/hfElVabRh2Y

http://youtu.be/1S0x3aRCviM

CONCEPT STILL ISN'T CLEAR. REVISIT LATER.

LABRAT ARTICLE 1 ANSWER 5: HOW MANY TYPES OF HIV ARE THERE?

http://www.ehow.com/about_5068053_many-strains-hiv-virus-

NOT THE MOST CREDIBLE SOURCE, BUT THE EXPLANATION SEEMS TO LINE UP WITH OTHER STUFF I HAVE BEEN READING.

(NOTE: QUESTIONS AND ANSWERS WILL JUST BE NUMBERED FROM THIS POINT ON)

QUESTION 7: IS THE RECOMBINANT NATURE OF HIV PART OF THE REASON THAT VACCINE IS SO DIFFICULT TO DEVELOP?

QUESTION 8: WHAT WERE THE THREE GENES USED IN V520 VACCINE?

Why did you use the word "recombinant" here? Recombinant usually refers viruses that are formed in the lab.

The author calls them "recombinant strains."

I didn't read the article. Be careful with what sources you base your knowledge upon. Also, a little bit of knowledge....well, you know.

Later on, if you start to examine some of the technical details of the HIV and drug therapy, clarity in your understanding of vocabulary is going to become increasingly important.

I believe that a simple but more accurate way to think about the HIV strains, at this point in your study, is that two main types of HIV exist, these strains tend to mutate, and these mutations sometimes recombine. 1)HIV1 and HIV2, 2) the mutations (prior to recombining), and 3) the “recombinant strains,” each pose different but related challenges to HIV pharmacological treatment.

I suggest that you examine both HIV mutations and circulating recombinant forms (CRFs) further.

ANSWER 6:
http://www.nlm.nih.gov/services/ctphases.html

Clinical trials are conducted in a series of steps, called phases - each phase is designed to answer a separate research question.


•Phase I: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.


•Phase II: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.


•Phase III: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.


•Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug's effect in various populations and any side effects associated with long-term use.



Additional Resource Information on clinical trials can be found at http://clinicaltrials.gov/info/resources

Scientists see AIDS vaccine within reach after decades.
By Julie Steenhuysen
CHICAGO | Sun Jul 15, 2012 11:03am EDT

(Reuters) - At an ill-fated press conference in 1984, U.S. Health and Human Services Secretary Margaret Heckler boldly predicted an effective AIDS vaccine would be available within just two years.

But a string of failed attempts - punctuated by a 2007 trial in which a Merck vaccine appeared to make people more vulnerable to infection, not less - cast a shadow over AIDS vaccine research that has taken years to dispel.

A 2009 clinical trial in Thailand was the first to show it was possible to prevent HIV infection in humans. Since then, discoveries have pointed to even more powerful vaccines using HIV-fighting antibodies. Now scientists believe a licensed vaccine is within reach.

"We know the face of the enemy," said Dr. Barton Haynes, of Duke University in Durham, North Carolina, and recent director of the Center for HIV AIDS Vaccine Immunology (CHAVI). The research consortium was funded by the National Institute of Allergy and Infectious Diseases (NIAID), founded in 2005 by the National Institutes of Health to identify and overcome roadblocks in the design of vaccines for the human immunodeficiency virus, which causes AIDS. NIAID's funding of CHAVI ended in June.

Unlike many viruses behind infectious disease, HIV is a moving target, constantly spitting out slightly different versions of itself, with different strains affecting different populations around the world. The virus is especially pernicious since it attacks the immune system, the very mechanism the body needs to fight back.

"The virus is far more crafty than we ever thought," said Haynes, who will outline progress in vaccine research at the International AIDS Society's 2012 conference being held in Washington from July 22-27.

FIRST SIGN OF HOPE

Thanks to drugs that can control the virus for decades, AIDS is no longer a death sentence. New infections have fallen by 21 percent since the peak of the pandemic in 1997 and advances in prevention - through voluntary circumcision programs, prevention of mother-to-child transmission and early treatment - promise to cut that rate even more.

Still, as many as 34 million people are infected with HIV worldwide. And with 2.7 million new infections in 2010 alone, experts say a vaccine is still the best hope for eradicating AIDS.

Teams have been working on a vaccine for nearly three decades, but it wasn't until RV144, the 2009 clinical trial involving more than 16,000 adults in Thailand, that researchers achieved any hint of success.

The test of a combination of two vaccines followed several big failures, including the stunning news that Merck's vaccine may have increased the risk of infection among men who were both uncircumcised and had prior exposure to the virus used in the vaccine.

"It had an extremely chilling effect on the whole field," said Colonel Nelson Michael, director of the U.S. Military HIV Research Program at the Walter Reed Army Institute of Research, which led the RV144 trial.

The Thai study tested Sanofi's ALVAC, a weakened canary pox virus used to sneak three HIV genes into the body, and AIDSVAX, a vaccine originally made by Roche Holding's Genentech that carried an HIV surface protein.

Both vaccines had poor showings in individual trials. Researchers were so convinced the Thai trial would fail that 22 scientists wrote an editorial in Science calling it a waste of money.

Then came the shocker. Results of the study published in 2009 showed the vaccine combination cut HIV infections by 31.2 percent. According to Michael and many other experts, the result was not big enough to be considered effective, but its impact on researchers was huge, says Wayne Koff, chief scientific officer of the International AIDS Vaccine Initiative (IAVI) based in New York.

An extensive analysis of the Thai trial published this year in the New England Journal of Medicine offered clues about why some volunteers responded.

The study, led by Haynes, scientists at Walter Reed and 25 other institutions, found men and women who were vaccinated made antibodies to a specific region of the virus's outer coat, suggesting this region provides an important vaccine target.

Preparations are under way for a follow-up trial testing beefed-up versions of the vaccines among heterosexuals in South Africa and men who have sex with men in Thailand.

Once again, the trial will use a Sanofi vaccine, but instead of AIDSVAX, researchers will use a different vaccine candidate with a boosting agent from Novartis.

Michael said it has been a major effort to secure new research partners and funding, including support from host countries, as well as to persuade rivals Novartis and Sanofi to work together. The teams still need to retool the vaccines to work in South Africa, where the strain of HIV is different.

"We're really working as fast as we can," said Michael, who expects large-scale effectiveness studies to start in 2016.

The hope is to have at least 50 percent effectiveness, a level that mathematical modelers say could have a major impact on the epidemic. Michael thinks this might be the pathway for getting the first HIV vaccine licensed, possibly by 2019.

Vaccine experts are equally excited about a vaccine that Michael's team is developing with Harvard University and Johnson & Johnson's Crucell unit, which uses weakened versions of a common cold virus and a smallpox virus.

A study published in February showed this vaccine protected monkeys from a virulent strain of HIV. Animals that did become infected after repeated exposure also had low levels of virus in their blood. Safety studies in human patients are just starting, with large-scale efficacy studies slated for 2016.

NEXT-GENERATION VACCINES

The current crop of vaccines is largely designed to train immune system cells known as T-cells to recognize and kill cells already infected with HIV. While these trials progress, scientists are working on even more advanced vaccines that activate powerful antibodies to prevent HIV from infecting cells in the first place. Both would be administered before a person becomes exposed to the virus.

Most modern vaccines use this antibody approach, but HIV's extreme skill at mutating makes it difficult for specifically targeted antibodies to identify and neutralize the virus.

Teams led by Dr. Dennis Burton of the Scripps Research Institute in La Jolla, California, Dr. Michel Nussenzweig at Rockefeller University in New York, Dr. Gary Nabel of NIAID's Vaccine Research Center, Haynes at Duke and others have focused on rare antibodies made by 10 to 20 percent of people with HIV that can neutralize a broad array of strains.

Researchers think a vaccine that can coax the body into making these antibodies before HIV exposure would offer a powerful foil to many forms of the virus.

Such antibodies seek out and latch on to regions of the virus that are highly "conserved," meaning they are so critical to the virus that they appear in nearly every HIV strain. By attaching to the virus they make it incapable of infecting other cells.

Until 2009, scientists had identified only a few broadly neutralizing antibodies, but in the past few years teams have found dozens.

So far, scientists have isolated the antibodies, identified what part of HIV they target and even know the exact shape they make, Koff said. Researchers are now using this information to design vaccines that prompt the immune system to make them.

"We're not there yet," Nabel said.

NIAID this month said it will spend up to $186 million over the next seven years to fund the Centers for HIV/AIDS Vaccine Immunology & Immunogen Discovery. The new consortium is focused on making vaccines that induce these protective antibodies, with major grants going to Duke and Scripps.

Nabel said no vaccine being tested today "is likely to hit it out of the park," but many researchers do feel advances in broadly neutralizing antibodies are key to developing a highly successful HIV vaccine.

"It's really a new day when we start to think about where we are with AIDS vaccines," Nabel said.

QUESTION 9: WHAT IS DIFFERENT ABOUT RV144?

QUESTION 10: WHY ARE THEY USING ALVAC?

QUESTION 11: WHY ARE THEY NOT USING AIDSVAX?

QUESTION 12: WHAT IS MEANT BY THESE HIGHLY "CONSERVED" REGIONS?

ANSWER 9:

The Phase III HIV Vaccine Trial, also known as RV144, was the largest HIV vaccine study ever conducted in humans and involved more than 16,000 volunteers in Thailand. The trial tested a “prime-boost” combination of two vaccines: ALVAC® HIV vaccine (the prime), and AIDSVAX®B/E vaccine (the boost). The vaccine combination was based on HIV strains that commonly circulate in Thailand.2. .... Additional research is needed to better understand how the regimen reduced study volunteers’ risk of HIV infection.
https://www01.hjf.org/apps/internet/hivnewscenter.nsf/phase3faqs

The first finding is that antibodies specific to a particular region of the HIV envelope (outside coat) protein, called V1V2, correlated with lower infection rates among those who were vaccinated. Antibodies are proteins that the body produces to defend against harmful agents such as viruses or bacteria. The hypothesis is that when these IgG antibodies bind to the V1V2 region of the outer coat of the virus, they might help prevent infection.

A second finding indicates that vaccine recipients with the highest blood levels of a different type of envelope protein binding antibody, known as IgA, had less protection from HIV than those with low levels. When compared with the placebo group, there was no difference in the rate of infection among the vaccinated group with high IgA antibodies and volunteers who received placebo, so the scientists believe that these IgA antibodies may have interfered with other vaccine-induced protective responses.

These findings, and the laboratory tests used in the studies, may help to explain the efficacy seen in RV144, and they will be tested in future studies to assess their importance to the protective effect of the vaccine.
http://www.eurekalert.org/pub_releases/2012-04/dumc-fst040212.php