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A new AIDS vaccine tested on more than 16,000 volunteers in Thailand has protected a significant minority against infection, the first time any vaccine against the disease has even partly succeeded in a clinical trial.
Scientists said they were delighted but puzzled by the result. The vaccine — a combination of two genetically engineered vaccines, neither of which had worked before in humans — protected too few people to be declared an unqualified success. And the researchers do not know why it worked.
“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, 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,” he went on. “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.”
Results of the trial of the vaccine, known as RV 144, were released at 2 a.m. Eastern time Thursday in Thailand by the partners that ran the trial, by far the largest of an AIDS vaccine: the United States Army, the Thai Ministry of Public Health, Dr. Fauci’s institute, and the patent-holders in the two parts of the vaccine, Sanofi-Pasteur and Global Solutions for Infectious Diseases.
Col. Jerome H. Kim, a physician who is manager of the army’s H.I.V. vaccine program, said half the 16,402 volunteers were given six doses of two vaccines in 2006 and half were given placebos. They then got regular tests for the AIDS virus for three years. Of those who got placebos, 74 became infected, while only 51 of those who got the vaccines did.
Although the difference was small, Dr. Kim said it was statistically significant and meant the vaccine was 31.2 percent effective.
Dr. Fauci said that scientists would seldom consider licensing a vaccine less than 70 or 80 percent effective, but he added, “If you have a product that’s even a little bit protective, you want to look at the blood samples and figure out what particular response was effective and direct research from there.”
The most confusing aspect of the trial, Dr. Kim said, was that everyone who did become infected developed roughly the same amount of virus in their blood whether they got the vaccine or a placebo.
Normally, any vaccine that gives only partial protection — a mismatched flu shot, for example — at least lowers the viral load.
That suggests that RV 144 does not produce neutralizing antibodies, as most vaccines do, Dr. Fauci said. Antibodies are long 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.
Whatever the vaccine does, he said, it does not seem to mimic the defenses of the rare individuals known to AIDS doctors as “long-term nonprogressors,” who do not get sick even though they are infected. They have low viral loads because they block reproduction in some way that is still mysterious.
“If we knew what immune response did it, we’d be able to be a lot more efficient in targeting it,” Dr. Kim said.
Also, the RV 144 tested in Thailand was designed to combat the most common strain of the virus circulating in Southeast Asia. Different strains circulate in Africa, the United States and elsewhere, and it is not clear that the vaccine would have similar results, even in modified form.
The thousands of Thais chosen were a cross-section of the Thai young adult population, not just high-risk groups like drug injectors or sex workers, Dr. Kim said.
One of the substances that were combined to make RV 144 is Alvac-HIV, from Sanofi-Pasteur, a canarypox virus with three AIDS virus genes grafted onto it. Variations of Alvac were tested in France, Thailand, Uganda and the United States; it was found safe but generated little immune response.
The other, Aidsvax, was originally made by Genentech and is an engineered version of 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 also in gay men in North America and Europe; it did not protect them against infection, and Genentech spun off the rights to develop the vaccine.
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 seemed to increase the risk of infection.
Combining Alvac and Aidsvax was a hunch by scientists: If one was designed to create antibodies and the other to alert white blood cells, might they work together even if neither worked alone?
Mitchell Warren, executive director of AVAC, the AIDS Vaccine Advocacy Coalition, which pushes for vaccines and other forms of prevention, was enthusiastic about the trial data.
“Wow,” he said. “This is a hugely exciting and, frankly, unexpected result. It changes our thinking in ways we hadn’t anticipated.”
“We often talk about whether a vaccine is even possible,” he added. “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.”
Mr. Warren said the finding showed the need for large human trials, expensive as they are. Studies in mice and monkeys have not been good at predicting what would work in people, and small human trials in which researchers test results by looking for antibodies in blood have limited value.
Dr. Fauci agreed.
“This is not the endgame,” he said. “This is the beginning.”
Scientists said they were delighted but puzzled by the result. The vaccine — a combination of two genetically engineered vaccines, neither of which had worked before in humans — protected too few people to be declared an unqualified success. And the researchers do not know why it worked.
“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, 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,” he went on. “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.”
Results of the trial of the vaccine, known as RV 144, were released at 2 a.m. Eastern time Thursday in Thailand by the partners that ran the trial, by far the largest of an AIDS vaccine: the United States Army, the Thai Ministry of Public Health, Dr. Fauci’s institute, and the patent-holders in the two parts of the vaccine, Sanofi-Pasteur and Global Solutions for Infectious Diseases.
Col. Jerome H. Kim, a physician who is manager of the army’s H.I.V. vaccine program, said half the 16,402 volunteers were given six doses of two vaccines in 2006 and half were given placebos. They then got regular tests for the AIDS virus for three years. Of those who got placebos, 74 became infected, while only 51 of those who got the vaccines did.
Although the difference was small, Dr. Kim said it was statistically significant and meant the vaccine was 31.2 percent effective.
Dr. Fauci said that scientists would seldom consider licensing a vaccine less than 70 or 80 percent effective, but he added, “If you have a product that’s even a little bit protective, you want to look at the blood samples and figure out what particular response was effective and direct research from there.”
The most confusing aspect of the trial, Dr. Kim said, was that everyone who did become infected developed roughly the same amount of virus in their blood whether they got the vaccine or a placebo.
Normally, any vaccine that gives only partial protection — a mismatched flu shot, for example — at least lowers the viral load.
That suggests that RV 144 does not produce neutralizing antibodies, as most vaccines do, Dr. Fauci said. Antibodies are long 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.
Whatever the vaccine does, he said, it does not seem to mimic the defenses of the rare individuals known to AIDS doctors as “long-term nonprogressors,” who do not get sick even though they are infected. They have low viral loads because they block reproduction in some way that is still mysterious.
“If we knew what immune response did it, we’d be able to be a lot more efficient in targeting it,” Dr. Kim said.
Also, the RV 144 tested in Thailand was designed to combat the most common strain of the virus circulating in Southeast Asia. Different strains circulate in Africa, the United States and elsewhere, and it is not clear that the vaccine would have similar results, even in modified form.
The thousands of Thais chosen were a cross-section of the Thai young adult population, not just high-risk groups like drug injectors or sex workers, Dr. Kim said.
One of the substances that were combined to make RV 144 is Alvac-HIV, from Sanofi-Pasteur, a canarypox virus with three AIDS virus genes grafted onto it. Variations of Alvac were tested in France, Thailand, Uganda and the United States; it was found safe but generated little immune response.
The other, Aidsvax, was originally made by Genentech and is an engineered version of 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 also in gay men in North America and Europe; it did not protect them against infection, and Genentech spun off the rights to develop the vaccine.
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 seemed to increase the risk of infection.
Combining Alvac and Aidsvax was a hunch by scientists: If one was designed to create antibodies and the other to alert white blood cells, might they work together even if neither worked alone?
Mitchell Warren, executive director of AVAC, the AIDS Vaccine Advocacy Coalition, which pushes for vaccines and other forms of prevention, was enthusiastic about the trial data.
“Wow,” he said. “This is a hugely exciting and, frankly, unexpected result. It changes our thinking in ways we hadn’t anticipated.”
“We often talk about whether a vaccine is even possible,” he added. “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.”
Mr. Warren said the finding showed the need for large human trials, expensive as they are. Studies in mice and monkeys have not been good at predicting what would work in people, and small human trials in which researchers test results by looking for antibodies in blood have limited value.
Dr. Fauci agreed.
“This is not the endgame,” he said. “This is the beginning.”
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