An experiment in Thailand involving 16,000 men and women has demonstrated for the first time a small but measurable protective effect of an AIDS vaccine.
The vaccine, a complicated mixture of six "prime" and "booster" shots, reduced a person's risk of becoming infected by about one-third compared to people getting placebo injections.
The results were barely significant on statistical grounds, perplexing for scientific reasons and unanticipated by most researchers. Nevertheless, the first positive results for an AIDS vaccine after two decades of experimentation was being called a milestone.
"Conceptually, we now know a vaccine is possible," said Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, which paid for most of the six-year trial. "Whether the vaccine is going to look anything like this one I don't know. But at least we know it can be done."
The vaccine is not licensed or being produced in large amounts. It is unlikely -- but not impossible -- that any country would consider it effective enough to be used as a public health measure against HIV.
Instead, the chief usefulness of the so-called ALVAC-AIDSVAX vaccine is likely to be what it can teach virologists about what is happening in the immune system when a person is even somewhat protected from HIV.
"We really need to go through the data to see if there are effects here that are potentially useful," said Col. Jerome Kim, a physician involved in the study, which was run by the U.S. Army, the National Institutes of Health, and Thailand's Ministry of Public Health.
He predicted that information gained from the trial after the results are fully analyzed will have "important implications for the design of future HIV vaccines."
Other researchers were less sanguine about the study, but did not want to be quoted by name as being skeptical when only a few details of the results have been released.
"I just think it's too early really," said one, who spoke on condition of anonymity for that reason. "It is in a kind of gray zone, and I think we should really get the data and look at it and see what it all means."
That the vaccine is at least nominally a success comes as a big surprise.
Early in the decade, more than 20 prominent researchers wrote an open letter to the journal Science urging the federal government to cancel the Thai trial because the vaccine was so unpromising. The study cost $105 million, most of it provided by the National Institutes of Health.
One vaccine component (ALVAC) is made by Sanofi Pasteur. The other (AIDSVAX) is made by Global Solutions for Infectious Diseases, formerly known as VaxGen. The vaccine was tailored to the strains of HIV circulating in Southeast Asia. Whether vaccine made from different strains would have the same effect isn't known.
In the study, volunteers in two provinces in central Thailand were randomly assigned to get vaccine or placebo shots. About 40 percent were women, and many were employed in manufacturing and shipping enterprises along Thailand's coast. They were counseled on ways to avoid HIV infection and advised to use condoms.
There were few intravenous drug users and male homosexuals -- groups at unusually high risk for HIV that make up most of the infected population in North America and Europe. In Africa and much of Asia, however, heterosexual intercourse is the most common route of infection.
Of 8,197 people who got vaccine, 51 became infected in the three years after their shots. Of the 8,198 who got placebo injections, 74 became infected.
While that difference -- 23 infections out of more than 16,000 people studied -- is significant, it could have occurred by chance. For example, if further analysis reveals that many of the infections were from IV drug use and that, by chance, there were more drug users in the placebo group of volunteers, the results would be less noteworthy.
Many details of the trial were not released Wednesday afternoon in briefings to reporters. More information will be presented at an AIDS vaccine meeting in Paris later this fall.
As a practical and scientific matter, two questions bedevil AIDS vaccine researchers, who hope this study may help them find answers.
The questions are: Which of the immune system's several defenses do need to be stimulated to keep someone from getting infected? What can be measured in lab experiments that indicates a "candidate" vaccine is doing that job?
Most vaccines contain parts of a virus or bacterium and stimulate the immune system to make antibodies, the dart-like molecules that attack invaders. Preliminary studies of the ALVAC-AIDSVAX vaccine, however, showed it induced very few antibodies. Human trials in 2003 of the AIDSVAX component, which "presents" the immune system with a protein from HIV's outer shell, showed no protection.
The other component, ALVAC, is a disabled bird virus loaded with three HIV genes. It is principally designed not to prevent infection but to stimulate the immune system to fight HIV more successfully after infection through a mechanism called "cell-mediated immunity."
However, in the Thai study infected people who got the vaccine had on average the same "viral load set-point" as people who got the placebo. Viral load set-point is the amount of HIV circulating in the bloodstream after the immune system's initial battle with the virus. It predicts to some extent how long a person is likely to survive.
How a vaccine that induces both a weak antibody response and a poor cell-mediated one can protect some people from HIV infection is the big initial mystery of this study.
"It tells us how much we have to learn about the correlates [indicators] of immunity," Fauci said.
The search for an AIDS vaccine -- famously predicted by Health and Human Services Secretary Margaret Heckler in 1984 to take two years -- has been a long series of disappointments.
The last big human trial, run on four continents in 2007, was stopped early when results not only showed that the vaccine provided no protection but hinted that it might be increasing a person's risk of infection.
A fuller analysis of that study is leading researchers to believe that it was probably differences in the recipients -- specifically, the rates of circumcision -- and not the vaccine that explain the different rates of infection.
That changed thinking is part of the reason some researchers were unwilling to say much of anything about the preliminary results from Thailand.
"The rush to judgment is something we should try to avoid," said John P. Moore, an AIDS researcher at Weill Cornell Medical College in New York. "We shouldn't be drawing radical conclusions based on a few raw numbers."
The results were barely significant on statistical grounds, perplexing for scientific reasons and unanticipated by most researchers. Nevertheless, the first positive results for an AIDS vaccine after two decades of experimentation was being called a milestone.
"Conceptually, we now know a vaccine is possible," said Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, which paid for most of the six-year trial. "Whether the vaccine is going to look anything like this one I don't know. But at least we know it can be done."
The vaccine is not licensed or being produced in large amounts. It is unlikely -- but not impossible -- that any country would consider it effective enough to be used as a public health measure against HIV.
Instead, the chief usefulness of the so-called ALVAC-AIDSVAX vaccine is likely to be what it can teach virologists about what is happening in the immune system when a person is even somewhat protected from HIV.
"We really need to go through the data to see if there are effects here that are potentially useful," said Col. Jerome Kim, a physician involved in the study, which was run by the U.S. Army, the National Institutes of Health, and Thailand's Ministry of Public Health.
He predicted that information gained from the trial after the results are fully analyzed will have "important implications for the design of future HIV vaccines."
Other researchers were less sanguine about the study, but did not want to be quoted by name as being skeptical when only a few details of the results have been released.
"I just think it's too early really," said one, who spoke on condition of anonymity for that reason. "It is in a kind of gray zone, and I think we should really get the data and look at it and see what it all means."
That the vaccine is at least nominally a success comes as a big surprise.
Early in the decade, more than 20 prominent researchers wrote an open letter to the journal Science urging the federal government to cancel the Thai trial because the vaccine was so unpromising. The study cost $105 million, most of it provided by the National Institutes of Health.
One vaccine component (ALVAC) is made by Sanofi Pasteur. The other (AIDSVAX) is made by Global Solutions for Infectious Diseases, formerly known as VaxGen. The vaccine was tailored to the strains of HIV circulating in Southeast Asia. Whether vaccine made from different strains would have the same effect isn't known.
In the study, volunteers in two provinces in central Thailand were randomly assigned to get vaccine or placebo shots. About 40 percent were women, and many were employed in manufacturing and shipping enterprises along Thailand's coast. They were counseled on ways to avoid HIV infection and advised to use condoms.
There were few intravenous drug users and male homosexuals -- groups at unusually high risk for HIV that make up most of the infected population in North America and Europe. In Africa and much of Asia, however, heterosexual intercourse is the most common route of infection.
Of 8,197 people who got vaccine, 51 became infected in the three years after their shots. Of the 8,198 who got placebo injections, 74 became infected.
While that difference -- 23 infections out of more than 16,000 people studied -- is significant, it could have occurred by chance. For example, if further analysis reveals that many of the infections were from IV drug use and that, by chance, there were more drug users in the placebo group of volunteers, the results would be less noteworthy.
Many details of the trial were not released Wednesday afternoon in briefings to reporters. More information will be presented at an AIDS vaccine meeting in Paris later this fall.
As a practical and scientific matter, two questions bedevil AIDS vaccine researchers, who hope this study may help them find answers.
The questions are: Which of the immune system's several defenses do need to be stimulated to keep someone from getting infected? What can be measured in lab experiments that indicates a "candidate" vaccine is doing that job?
Most vaccines contain parts of a virus or bacterium and stimulate the immune system to make antibodies, the dart-like molecules that attack invaders. Preliminary studies of the ALVAC-AIDSVAX vaccine, however, showed it induced very few antibodies. Human trials in 2003 of the AIDSVAX component, which "presents" the immune system with a protein from HIV's outer shell, showed no protection.
The other component, ALVAC, is a disabled bird virus loaded with three HIV genes. It is principally designed not to prevent infection but to stimulate the immune system to fight HIV more successfully after infection through a mechanism called "cell-mediated immunity."
However, in the Thai study infected people who got the vaccine had on average the same "viral load set-point" as people who got the placebo. Viral load set-point is the amount of HIV circulating in the bloodstream after the immune system's initial battle with the virus. It predicts to some extent how long a person is likely to survive.
How a vaccine that induces both a weak antibody response and a poor cell-mediated one can protect some people from HIV infection is the big initial mystery of this study.
"It tells us how much we have to learn about the correlates [indicators] of immunity," Fauci said.
The search for an AIDS vaccine -- famously predicted by Health and Human Services Secretary Margaret Heckler in 1984 to take two years -- has been a long series of disappointments.
The last big human trial, run on four continents in 2007, was stopped early when results not only showed that the vaccine provided no protection but hinted that it might be increasing a person's risk of infection.
A fuller analysis of that study is leading researchers to believe that it was probably differences in the recipients -- specifically, the rates of circumcision -- and not the vaccine that explain the different rates of infection.
That changed thinking is part of the reason some researchers were unwilling to say much of anything about the preliminary results from Thailand.
"The rush to judgment is something we should try to avoid," said John P. Moore, an AIDS researcher at Weill Cornell Medical College in New York. "We shouldn't be drawing radical conclusions based on a few raw numbers."
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