Test Subjects May Have Been Put at Extra Risk Of Contracting HIV
(WP) – The two-decade search for an AIDS vaccine is in crisis after two field tests of the most promising contender not only did not protect people from the virus but may actually have put them at increased risk of becoming infected.
The results of the trials, which enrolled volunteers on four continents, have spurred intense scientific inquiry and unprecedented soul-searching as researchers try to make sense of what happened and assess whether they should have seen it coming.
Both field tests were halted last September, and seven other trials of similarly designed AIDS vaccines have either been stopped or put off indefinitely. Some may be modified and others canceled outright.
Numerous experts are questioning both the scientific premises and the overall strategy of the nearly $500 million in AIDS vaccine research funded annually by the U.S. government.
“This is on the same level of catastrophe as the Challenger disaster” that destroyed a NASA space shuttle, said Robert Gallo, co-discoverer of the human immunodeficiency virus (HIV), which causes AIDS, and head of the Institute for Human Virology in Baltimore.
The recently closed studies, STEP and Phambili, used the same vaccine — made from a common respiratory virus called adenovirus type 5 that had been crippled and then loaded with fragments of HIV. Both studies were halted when it became clear the STEP study was futile and possibly harmful.
The results of the Phambili vaccine trial, which was conducted in South Africa, were revealed last month and only worsened the gloom. Although the number of new HIV infections in that study was far smaller than in STEP — and too few to draw firm conclusions from — those results, too, hinted at a trend toward harm among vaccine recipients.
Many researchers are questioning the scientific premises on which all those studies were based and are wondering, along with AIDS activists, what effect this near-worst-case scenario might have on tests of future vaccines.
The working hypothesis for what went wrong is that the vaccine somehow primed the immune system to be more susceptible to HIV infection — a scenario neither foreseen nor suggested by previous studies.
The National Institutes of Health, which funded the STEP and Phambili trials, is convening a meeting next week to reassess its AIDS vaccine program. But some respected scientists have already reached a verdict.
“None of the products currently in the pipeline has any reasonable chance of being effective in field trials,” Ronald C. Desrosiers, a molecular geneticist at Harvard University, declared last month at an AIDS conference in Boston. “We simply do not know at the present time how to design a vaccine that will be effective against HIV.”
He told a rapt audience that he has reluctantly concluded that the NIH has “lost its way in the vaccine arena” and that he thinks it should redirect its AIDS vaccine funds to basic research and away from human trials.
In this fiscal year, the NIH’s budget for AIDS vaccine research is $497 million. The STEP and Phambili trials were each expected to cost about $32 million. Pharmaceutical giant Merck & Co. has spent an undisclosed amount developing the vaccine and helping to manage the studies.
“We can’t afford to have any more trials like this,” said Mark Harrington, head of the activist Treatment Action Group and a longtime observer of AIDS research. “We have to stop and reassess and recommit to basic science, or people will begin to lose faith.”
At the moment, only two things are certain.
The first is that the vaccine, developed by Merck, could not have caused HIV infection because it contains only three proteins from HIV, not the entire virus. The second is that there are no obvious villains.
“I do not think that what happened in this trial is an example of scientists blindly rushing into dangerous things,” said John P. Moore, an AIDS virologist at Weill Cornell Medical College, who has criticized vaccine trials he considered futile. “In the general HIV-research community, I didn’t know anyone who said this was going to happen.”
Both trials recruited people who were at high risk of HIV infection through sexual activity. The STEP subjects included many male homosexuals; the Phambili volunteers were male and female heterosexuals. Half the people in each trial were randomly assigned to get three shots of vaccine, and half to get three shots of a harmless liquid containing no adenovirus or HIV proteins.
Each trial was to have 3,000 participants. STEP had finished enrolling subjects in North and South America, the Caribbean and Australia. Phambili (which means “moving forward” in the Xhosa language of South Africa) had signed up 801 by the time it was shut down.
While scientists hoped the Merck vaccine might prevent some infections, its chief purpose was to stimulate “cell-mediated” immunity to produce a less severe illness. Specifically, the vaccine was expected to lower the “viral load” of HIV in the bloodstream, which in turn would both prolong survival and lessen the chance the person would infect others.
Many experts are questioning the wisdom of that strategy, even if it had worked perfectly. Urging millions of people to take an AIDS vaccine that probably would not protect them from the virus, they say, would be a hard and confusing task, even in places where the epidemic still rages.
For the moment, that is an academic question. The vaccine failed to achieve any of its goals.
In both studies, people who got vaccine were more likely — not less — to become infected, with trends suggesting roughly a twofold risk. In the STEP study, which has many more cases to evaluate, nearly all that added risk was in people who had high levels of antibodies to adenovirus type 5 before they got their first shot — evidence they had been previously infected with that strain. Uncircumcised men in that group had the highest risk.
So how could this have happened?
The leading theory is that activation of the immune system, a cascade of events that occurs naturally when a person is infected with a virus or bacterium or gets a vaccine against one of them, in some way increased the risk of HIV infection.
Activation causes cells called CD4 T-lymphocytes (among many other things) to proliferate. CD4 cells are the targets of choice for HIV. In their activated state, they are coated with molecules called CCR5 co-receptors, which HIV needs to attach itself to a cell.
The hypothesis is that people who received the vaccine had greater-than-normal activation and consequently produced more and fatter cellular targets for HIV. That then increased their chances of becoming infected should they encounter the virus in unprotected intercourse.
Two things undercut this idea.
People have been suffering immune-activating infections and getting vaccines for years, and there has never been evidence that those events increased a person’s risk of acquiring HIV. These vaccine trials would be odd places to first notice such a thing. Furthermore, people in the STEP study who got the vaccine did not have more activated CD4 cells than people who got placebo — something that Merck vaccine executive Mark B. Feinberg called “kind of an interesting and unexplained observation.”
“There is something very, very peculiar” going on in the vaccine trials, said Anthony S. Fauci, head of the National Institute of Allergy and Infectious Diseases, which sponsored them.
The multiple surprises have reminded researchers how much they still do not know about HIV’s biology. It has also focused attention on questions they never asked.
For example, none of the monkey experiments with the Merck vaccine subjected animals to the kind of sexual exposure that people in the trial had — namely, repeated encounters with low doses of HIV, with no single exposure being especially high-risk.
Why not?
The researchers did not have any reason to believe the vaccine might be harmful (although they acknowledged it might not be effective), and in any case such a study would have required quite a large number of monkeys, which are expensive to acquire and maintain for research.
Instead, researchers vaccinated a relatively small number of monkeys with the Merck vaccine and then injected them with the monkey equivalent of HIV in a manner that guaranteed they would become infected. Those animals did much better over the long run than infected but unvaccinated ones.
That was once enough to move a vaccine into human trials. But it probably never will be again.
Can anyone remember Tuskegee?
Jewish Voters Must Say No to Obama
Posted by morganwrites on March 30, 2008
(TCV) – Little more than 24 hours after Senator Barack Obama (D-IL) stepped to the microphones to address the anti-Semitic, anti-American and anti-white rage of his ‘spiritual advisor’ and pastor, Rev. Jeremiah Wright, many Jews are taking a second look at the junior Senator and Democratic frontrunner.
By Wednesday the Obama campaign was trying to make Jews understand that his 20-year relationship with a preacher and church that gave an award to Louis Eugene Walcott (sorry, Louis Farrakhan, do all racists change their names?) and who blamed America for everything from the AIDS virus to the terrorist attacks of September 11, 2001 was just a relationship of a man sitting in the pew of a preacher from the “old black school.”
Unfortunately for Obama he did not talk until the controversy was out of control and when that happens it is far too late. As of this writing I know Jewish leaders and Israeli politicians who are willing to say that an Obama Administration would be “the worst for Israel” of all the candidates and that Obama was “unacceptable” to the Jewish population not only in Israel, but the Diaspora abroad.
Jewish voters give their votes anywhere between 25 and 27% to Republicans – the balance of Jewish voters in strongholds like New York and California vote in a huge Democratic bloc. Even more than counting on Jewish votes to get Democrats over the top it is almost equally important to get Jewish money. Obama now has a problem: why would any Jew give money to a man who associates with a pastor and a church that awards anti-Semites and bigots?
It is a bit more difficult to tally Jewish money in politics since there is no record kept of the faith of the voter. But, taking the afternoon to compare the directory of membership at my synagogue with records of political contributions it is clear that Jewish political contributions are equally important to Democrats.
So did Obama go far enough in his flag draped explanation about his relationship with a preacher who is willing to honor an anti-Semite and treat Israel like a dirty word? And why all the flags for a guy who won’t wear a flag on his lapel for fear of looking like he was pandering?
Instead of explaining with a condescending “it’s a black thing” and “we all disagree with our pastors” (no we don’t) not quitting his church he brought out of the woodwork people like the Black Panthers and other black separatists who admire anti-Semitism. They also believe that America is a bastion of evil where whites and especially Jews cause there to be inequity in America not unlike that seen during the 1950s in the south.
With friends like Wright, Farrakhan and the Black Panther Party on his side Obama does not need any enemies. The relationship with Wright puts him in the pantheon of black separatism and worse than that is Obama raised more questions than answers when he gave his address. His campaign called his remarks courageous, but courage would have been taking the anti-Semite to task; not telling us that he is like our crazy uncles.
Truth be told I probably would not have voted for Obama whether or not the highlights of Wright’s hate-filled sermons came to the public record or not, but I was willing to give Obama the benefit of the doubt with regard to his judgment. It is that judgment that Obama is using as his only qualification to be Commander-in-Chief and the leader of the free world – a world that has enemies throughout and enemies that would love a person in the White House who did not care if Israel was wiped off the map.
Obama has not explained how in 20 years of sermons, personal contact and experience that he never heard an utterance of an inappropriate or anti-Semitic nature by his own pastor. I’ve not been an adult for 20 years, but in the time I’ve been an adult I would remember well sermons, particularly those during High Holy days, that involved hatred for America or the kind that paint Israel as a demon.
The worst part of Obama’s non-explanation was that he gave it with the hope that it would end the questions concerning his pastor, but it hasn’t. In fact it gave us more to think about. How could a church release a “best-of” DVD of hate and Obama be oblivious to it? How could Wright blame America for everything from AIDS to crack and Obama be oblivious to it? How could Wright be the leader of Obama’s church and be part of his life for 20 years and Obama not be aware that he blamed Israel for the ills of the Middle East – including the fact that Wright and Obama believe that “cynicism” is the reason that there is not peace in the Middle East.
Cynicism? Does Obama, through Wright’s instruction, really believe that the people of Israel want peace so little that it is cynicism rather than the hatred of the Arab governments and people that surround her that keep peace from happening? If Obama misjudges the Middle East in theory – how will he do when he is in the Oval Office and is called upon to judge issues for real?
All Obama did on Tuesday was show just how poor his judgment is. His association with Wright’s church in Chicago may have made him a hero with the black left and helped in a segment of Chicago politics, but for someone that aspired to the highest office in America he should have known better.
Obama knew that Wright was a problem. When he announced his candidacy for the White House – the New York Times reported that Wright was “dis-invited” by an Obama staffer before his announcement. Obama’s knowledge that Wright was a problem a year ago makes it that much more difficult to believe that Obama did not know Wright was a problem ten years ago. That kind of bad judgment cannot be permitted in the White House – particularly when the only thing helping the Jewish vote make a decision is party affiliation.
The Jewish leaders and lay people that I talked to today are just as willing to vote for John McCain, who was at the Western Wall in Jerusalem today, as they would be willing to vote for either of the two Democrats. One unanimous thing that happened today is that I could not find one person in the Jewish leadership willing to say that they support Barack Obama’s run for the White House and it was not lost on Jewish leaders that while McCain was at the Wailing Wall in Jerusalem that Obama was trying to damage control for his association with anti-Semitic and anti-American people that he chose to associate with for two decades.
Jewish people need to examine Obama’s record much more closely and if Obama refuses to not only stand up and “renounce” or “repudiate” the comments and awards that he clearly knew were going on around him then the Jewish vote and Jewish money has an obligation to Israel to stay home or to go to McCain.
Barack Obama’s campaign has done little more than trot out supporters who happen to be Jewish elected leaders in order to explain and disassociate him from his preacher and his church. My microphone is open to the Obama campaign and I suggest that they take me or another Jewish broadcaster up on the offer because two days ago I was willing to go quietly if Obama was the Democratic nominee. Today I am unwilling to see him get to the White House and will do everything in my power to see that Jews are not only aware, but outraged, at his conduct and the pretense that he didn’t know anything untoward was happening right under his nose.
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