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Can we hope for a curative HIV vaccine? (VACCINE TRIALS, 2009)
Sep 25, 2009

Hi Dr. and thanks for your dedication & permanent support to all of us, you are wonderful. What is your opinion about the new preventive HIV vaccine? Do you think that we can build on it to have a curative vaccine soon? I know that you are optimistic and hopefully we can cure HIV sooner rather than later; can you update us on what is going on with the tests of a curative vaccine and is it possible specially after the recent progress made? Thanks for your answer

Response from Dr. Frascino

Hi,

The news about the limited success of the recent AIDS prevention vaccine trial was unexpected and certainly welcomed, considering the numerous vaccine trial failures over the past decade. However, I agree with Tony Foci that this is not a "breakthrough" so much as an important step forward that will help us with subsequent vaccine development. Both a preventative and therapeutic vaccine are still a very, very long way off. A "curative" vaccine is not even on the distant horizon. I'll post below some information about the recent vaccine trial from New York Times and San Francisco Chronicle.

Stay tuned to The Body. We'll keep you updated as this story evolves.

Dr. Bob

September 25, 2009, New York Times

For First Time, AIDS Vaccine Shows Some Success

By DONALD G. McNEIL Jr. Scientists said Thursday that a new AIDS vaccine, the first ever declared to protect a significant minority of humans against the disease, would be studied to answer two fundamental questions: why it worked in some people but not in others, and why those infected despite vaccination got no benefit at all.

The vaccine known as RV 144, a combination of two genetically engineered vaccines, neither of which had worked before in humans was declared a qualified success after a six-year clinical trial on more than 16,000 volunteers in Thailand. Those who were vaccinated became infected at a rate nearly one-third lower than the others, the sponsors said Thursday morning.

"I don't want to use a word like 'breakthrough,' but I don't think there's any doubt that this is a very important result," said Dr. Anthony S. Fauci, the director of the National Institute of Allergy and Infectious Diseases, which is one of the trial's backers.

"For more than 20 years now, vaccine trials have essentially been failures," Dr. Fauci said. "Now it's like we were groping down an unlit path, and a door has been opened. We can start asking some very important questions."

It will still, however, take years of work before a vaccine that could end the epidemic, which has killed about 25 million people, can even be contemplated.

"We often talk about whether a vaccine is even possible," said Mitchell Warren, the executive director of the AIDS Vaccine Advocacy Coalition, or AVAC. "This is not the vaccine that ends the epidemic and says, 'O.K., let's move on to something else.' But it's a fabulous new step that takes us in a new direction."

In which direction is still unknown. No one including the researchers from the United States Army, the National Institutes of Health, the Thai Ministry of Public Health and two vaccine companies that tested the vaccine knows why the vaccine gave even its weak indicator of success.

Experts generally disdain vaccines that do not protect at least 70 to 80 percent of those getting them. And this vaccine did not lower the viral loads of people who were vaccinated but caught the virus anyway, which was baffling because even mismatched vaccines usually do that.

Simply repeating the trial to confirm the results would be pointless, experts agreed.

The trial, the largest AIDS vaccine trial in history, cost $105 million and followed 16,402 Thai volunteers.

The men and women ages 18 to 30 were recruited from two provinces southeast of the capital, Bangkok, from the general population rather than from high-risk groups like drug injectors or sex workers. Half got six doses of two different vaccines; half were given placebos.

For ethical reasons, all were offered condoms, taught how to avoid infection and promised lifelong antiretroviral treatment if they got AIDS. They were then regularly tested for three years; 74 of those who got placebos became infected, but only 51 of those who got the vaccines did.

Although the difference was a mere 23 people, Col. Jerome H. Kim, a physician and the manager of the Army's H.I.V. vaccine program, said it was statistically significant and meant that the vaccine was 31.2 percent effective.

The results were surprising because both vaccines, one from the French company Sanofi-Aventis and one developed by Genentech but now licensed to Global Solutions for Infectious Diseases, a nonprofit health group, had failed when used individually.

"This came out of the blue," said Chris Viehbacher, Sanofi's chief executive. Even 31 percent protection "was at least twice as good as our own internal experts were predicting," he added.

In 2004, there was so much skepticism about the trial just after it began that 22 top AIDS researchers published an editorial in Science magazine suggesting that it was a waste of money.

One conclusion from the surprising result, said Alan Bernstein, head of the Global HIV Vaccine Enterprise, an alliance of organizations pursuing a vaccine, "is that we're not doing enough work in humans."

Instead of going back to mice or monkeys, he said, different new variants on the two vaccines could be tried on a few hundred people in several countries.

This vaccine was designed to combat the most common strain of the virus in Southeast Asia, so it would have to be modified for the strains circulating in Africa and the United States.

Sanofi's vaccine, Alvac-HIV, is a canarypox virus with three AIDS virus genes grafted onto it. Variations of it were tested in several countries; it was safe but not protective. The other vaccine, Aidsvax, was originally made by Genentech and contains a protein found on the surface of the AIDS virus; it is grown in a broth of hamster ovary cells. It was tested in Thai drug users in 2003 and in gay men in North America and Europe but failed.

In 2007, two trials of a Merck vaccine in about 4,000 people were stopped early; it not only failed to work but for some men also seemed to increase the risk of infection.

Combining Alvac and Aidsvax was simply a hunch: if one was designed to create antibodies and the other to alert white blood cells, might they work together?

One puzzling result those who became infected had as much virus in their blood whether they got the vaccine or a placebo suggests that RV 144 does not produce neutralizing antibodies, as most vaccines do, Dr. Fauci said. Antibodies are Y-shaped proteins formed by the body that clump onto invading viruses, blocking the surface spikes with which they attach to cells and flagging them for destruction.

Instead, he theorized, it might produce "binding antibodies," which latch onto and empower effector cells, a type of white blood cell attacking the virus. Therefore, he said, it might make sense to screen all the stored Thai blood samples for binding antibodies.

"The humbling prospect of this," he said, "is that we may not even be measuring the critical parameter. It may be something you don't normally associate with protection."

Dr. Lawrence Corey, the principal investigator for the HIV Vaccine Trials Network, who was not part of the RV 144 trial, said new work on weakened versions of the smallpox vaccine had produced better pox "spines" that could be substituted for the canarypox. New trials, he added, could be faster and smaller if they were done in African countries where AIDS is more common than in Thailand.

September 25, 2009 In a First, an AIDS Vaccine Shows Some Success

By THE ASSOCIATED PRESS Filed at 2:00 a.m. ET

Scientists and government leaders have already started mapping out how to try to improve the world's first successful AIDS vaccine, which protected one in three people from getting HIV in a large study in Thailand.

That's not good enough for immediate use, researchers say. Yet it is a watershed event in the 26 years since the AIDS virus was discovered. Recent setbacks led many scientists to think a successful vaccine would never be possible.

The World Health Organization and the U.N. agency UNAIDS said the results ''instilled new hope'' in the field, even though it likely will be years before a vaccine might be widely available.

''This is truly a great moment for world medicine,'' said Lt. Gen. Eric Schoomaker, the U.S. Army Surgeon General. The Army helped sponsor the study, the world's largest of an AIDS vaccine.

It was the first time scientists tried preventing HIV the same way they treat it -- with a combination approach. The study used two vaccines that work in different ways, and that may be one reason the strategy worked, even though neither vaccine did when tested individually in earlier trials, scientists say.

The combo cut the risk of becoming infected with HIV by more than 31 percent in the study of more than 16,000 volunteers in Thailand, researchers announced Thursday in Bangkok.

That benefit is modest, yet ''it's the first evidence that we could have a safe and effective preventive vaccine,'' said Col. Jerome Kim, an Army doctor who helped lead the study.

The outcome ''gives me cautious optimism about the possibility of improving this result'' and developing a more effective AIDS vaccine, said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, which co-sponsored the study.

''It's an opening of a new gateway to a road that has brighter lights in it now and maybe some directions,'' he said. ''We need to bring the best minds together and map the way forward.''

That has already started. Dozens of researchers, vaccine makers and deep-pocket donors will meet next week in New York ''to talk about where we go from here,'' said Dr. Alan Bernstein, executive director of the Global HIV Vaccine Enterprise, an alliance of government officials, AIDS scientists, funders such as the Bill & Melinda Gates Foundation, and the WHO. At the meeting will be researchers from the Thai trial, the Army and independent scientists.

Scientists around the world cheered the first taste of victory.

''Since the 1980s, we've been hearing we're going to have an AIDS vaccine in 10 years. For the first time in my lifetime, it feels as though we're actually getting on the right track,'' said Josh Ruxin, a Columbia University public health specialist who runs the Access Project, which helps health centers provide AIDS care in Rwanda.

The Thailand Ministry of Public Health conducted the study. The U.S. Army has long worked with the Thai government and others to develop and test vaccines and medicine to protect troops and the general public.

The study used strains of HIV common in Thailand. Whether such a vaccine would work against other strains in the U.S., Africa or elsewhere in the world is unknown, scientists stressed.

Even a marginally helpful vaccine could have a big impact. Every day, 7,500 people worldwide are newly infected with HIV; 2 million died of AIDS in 2007, UNAIDS estimates.

The study tested the two-vaccine combination in a ''prime-boost'' approach, in which the first one primes the immune system to attack HIV and the second one strengthens the response.

They are ALVAC, from Sanofi Pasteur, the vaccine division of French drugmaker Sanofi-Aventis; and AIDSVAX, originally developed by VaxGen Inc. and now held by Global Solutions for Infectious Diseases, a nonprofit founded by some former VaxGen employees.

ALVAC uses canarypox, a bird virus altered so it can't cause human disease, to ferry synthetic versions of three HIV genes into the body. AIDSVAX contains a genetically engineered version of a protein on HIV's surface. The vaccines are not made from whole virus -- dead or alive -- and cannot cause HIV.

The study tested the combo in HIV-negative Thai men and women aged 18-30 at average risk of becoming infected. Half received four ''priming'' doses of ALVAC and two ''boost'' doses of AIDSVAX over six months. The others received dummy shots. No one knew who got what until the study ended.

Participants volunteered for the study and were told about the potential risks associated with receiving the experimental vaccine before agreeing to participate.

All were given condoms, counseling and treatment for any sexually transmitted infections, and were tested every six months for HIV. Any who became infected were given free treatment with antiviral medicines. All participants continued to receive an HIV test every six months for three years after vaccinations ended.

The results: New infections occurred in 51 of the 8,197 given vaccine and in 74 of the 8,198 who received dummy shots. That worked out to a 31 percent lower risk of infection for the vaccine group. Two of the infected participants who received the placebo died.

Scientists don't know why the vaccine combo worked. It was the Army's idea to test the combination, said Dr. Donald Francis, a former government scientist who helped identify HIV as the cause of AIDS and now heads the nonprofit that holds the rights to AIDSVAX.

AIDSVAX is aimed at prompting antibodies to HIV. The Sanofi vaccine spurs cells to attack the virus directly. The combo strategy ''bridges the two major arms of the immune system,'' Francis said.

Scientists need to look at blood samples from study participants to understand why some became infected and others were protected.

''With the limited amount of vaccine we have right now, we've got a small number of studies that we could do,'' Francis said.

Sanofi officials said the same. The company's Dr. Sanjay Gurunathan said a series of studies ''that will take a few years'' are planned to see if the vaccine can be improved for licensing, and whether new components should be considered to boost effectiveness.

Even AIDS advocates agreed more research was needed.

''We need to take a deep breath and look at all the available evidence from this trial'' before urging that this vaccine be used now, said Julie Davids, a spokeswoman for the Community HIV/AIDS Mobilization Project, a New York-based prevention advocacy group.

The study was done in Thailand because U.S. Army scientists did pivotal research in that country when the AIDS epidemic emerged there, isolating virus strains and providing genetic information on them to vaccine makers. The Thai government also strongly supported the idea of doing the study.

Thailand had a burgeoning AIDS problem when the study began. Aggressive prevention efforts have dramatically cut the rates of new infections there, and only 125 infections occurred in the entire study of more than 16,000 people.

Scientists want to know how long the vaccine's protection will last, whether booster shots will be needed, and whether the vaccine helps prevent infection in gay men and injection drug users, since it was tested mostly in heterosexuals in the Thai trial.

The vaccine had no effect on HIV levels in the blood for those who did become infected. That had been another goal of the study -- seeing whether the vaccine could limit damage to the immune system and help keep infected people from developing full-blown AIDS.

That is ''one of the most important and intriguing findings of this trial,'' Fauci said. It suggests the signs scientists have been using to gauge whether a vaccine was actually giving protection may not be valid.

''It is conceivable that we haven't even identified yet'' what really shows immunity, which is both ''important and humbling'' after decades of research, Fauci said.

AIDS vaccine promising; experts urge caution Victoria Colliver, Chronicle Staff Writer Friday, September 25, 2009

(09-24) 19:20 PDT -- As Bay Area scientists celebrated the first promising results from the largest-ever AIDS vaccine trial, they cautioned that much more research is needed before a vaccine could be available to the public.

The news that an experimental AIDS vaccine tested on 16,000 heterosexual volunteers in Thailand had been shown to be safe and modestly effective surprised researchers, who had become used to failure in the decades-long effort to find a vaccine to protect against HIV infection.

The elusive search for a vaccine has its roots in the Bay Area, where one of the two genetically engineered vaccines used in the Thai trial was developed.

The trial relied on a combination of a modified canary-pox vaccine from Sanofi Pasteur and a drug made from an engineered version of a protein found on the AIDS virus, which was made by a Brisbane biotechnology company called VaxGen Inc. The patent for the VaxGen vaccine is now owned by Global Solutions for Infectious Diseases, a nonprofit in South San Francisco.

"At this point, especially after all the failures, any promising information is exciting," said Dr. Phillip Berman, a VaxGen co-founder and inventor of the vaccine, who woke up to the news Thursday morning. "But it's still a long way to having an approved product and figuring out how to deliver the vaccine to the people who need it the most."

The watershed results announced Thursday in Bangkok came just over a year after the National Institutes of Health dropped plans for a large-scale test of its AIDS vaccine. Two years ago, Merck & Co. halted its vaccine study after results showed the drug may have actually increased some participants' susceptibility to the virus.

one-two punch

The vaccine, known as RV 144, employed a two-pronged or "prime-boost" approach in the Phase 3 trial. The drug made by Sanofi Pasteur "primed" the body's immune system to attack HIV and the drug developed by VaxGen "boosted" the body's response.

According to the Thai Ministry of Health and the study's other backers, the vaccine regimen was safe and 31 percent effective in preventing HIV infection compared with a placebo. Researchers described that result as significant and promising for the future, but not enough to make such a product available to the public soon.

"We are still many years away from a vaccine that will be used universally," said Dr. Jay Levy, professor of medicine at the AIDS Research Institute at UC San Francisco and one of the discoverers of HIV. "But this is encouraging because it says maybe we can derive things from this study and not have to go into something totally different."

Half of the more than 16,000 study participants were given six doses of the vaccines in 2006, and half received placebos. All received condoms, counseling, regular HIV testing and treatment for any sexually transmitted diseases. Of the 8,197 volunteers who were given the vaccine, new infections occurred in 51 people. New infections occurred in 74 of 8,198 participants who received the placebo shot.

uestions remain

The most confusing aspect of the study is that the people who received the vaccine and still got infected had no lower levels of the virus than those who took the placebo and got infected. That indicates the vaccine may be better at preventing the virus than controlling it once it gets into the body.

"That would suggest the immune stimulus isn't very strong," Levy explained. "With that said, it still was enough to block low levels of the virus from coming into the body. We would want a vaccine that would also control the virus if it infects a person."

ne strain rare here

In addition, the trial focused on two subsets of the HIV strain that are common in Thailand and Southeast Asia, only one of which is commonly found in the United States. So it's unclear whether the results of the vaccine combination could be replicated in a different population.

Researchers said many aspects of the trial results are unclear. For example, several scientists said it is uncertain how the drug combination worked and whether one part was more effective than the other.

"We don't really know why and how this vaccine worked and did what it did," said Dr. Alan Bernstein, executive director of the Global HIV Vaccine Enterprise, an alliance of AIDS scientists, governments and donors.

"This trial is raising more questions almost than it's answering," he said. "It's opened the door and it's opened up a whole lot of questions that are answerable and will be answered over the next months and years to come."

Because of the long time frame, health advocates warn that people should not count on a potential vaccine to treat and contain infections.

"It doesn't have a public health impact perhaps for many, many years," said Mark Cloutier, San Francisco AIDS Foundation. "We need to continue to keep our vigilance about prevention, testing and getting people into care."



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