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Apr 8, 2008

Dear Dr. Bob: Thanks for your sterling job you offer to the community. My question is: the HIV virus is the most studied virus and its behavior as well as functionality is well-known. Why then no vaccine has yet been developed though billions of dollars have been already spent? Recently I have read that no cure will ever be founded as if it ever happened big Pharmas and a great number of researchers will loose the source of huge revenues. Former WW (worried well)

Response from Dr. Frascino

Hello Former WW,

The failure to develop a therapeutic or preventative vaccine against HIV has absolutely nothing to do with Big Pharma's profits or scientific researches' jobs and funding grants. That is conspiracy-theory nonsense. The reason we have not been able to develop an effective HIV vaccine is related to the complexity of the virus and the fact HIV destroys the body's immune system as the disease progresses. Vaccine efficacy requires an effective immune response. There is not doubt vaccine research to date has been disappointing (actually downright depressing!); however, there is also absolutely no doubt a preventative (and hopefully therapeutic) vaccine is essential if we are ever going to control the spreading pandemic. Relatively little research money has been applied to the vaccine research programs until recently. If the vaccine initiative had access to the $5,000 per second we are spending in Iraq (yes, $5,000 per second!!!), there is no doubt we would have solved this and many other pressing medical conundrums (perhaps cancer, diabetes, Parkinson's, Alzheimer's, etc.).

I'll reprint below several posts from the archives that give a brief snapshot of what's been happening with HIV vaccine research (including the failure of Merck's vaccine).

Dr. Bob

What Happened to the Vaccine?

By Richard Jefferys

Summer 2007

When HIV was first discovered in the early 1980s, scientists were optimistic that a vaccine to prevent infection could be developed in a matter of years. Unfortunately, that optimism was misplaced, and HIV has turned out to be a tricky foe for vaccine researchers.

The Antibody Approach Hits a Snag At the time of HIV's discovery, it was thought that most vaccines worked by triggering a type of immune response called an antibody response (we now know that T cells and other parts of the immune system also play a role). Antibodies are tiny Y-shaped molecules made by a type of immune system cell called a B cell. The job of antibodies is to float around the bloodstream and glom onto pathogens, disabling them and marking them for destruction. Initial experiments in the laboratory showed that HIV grown in a lab dish could be effectively blocked by antibodies that would attach to HIV's outer protein, called the envelope protein. Scientists designed vaccines based on a molecule on HIV's envelope called gp120 in the hopes that these vaccines would trigger the development of similar antibodies in people, thereby protecting them if they were exposed to HIV.

But before these vaccines could be tested in clinical trials, researchers realized that HIV adapts itself to life in a lab dish in a way that makes it more vulnerable to antibodies than it is in the human body. HIV taken directly from people could not be blocked by the anti-gp120 antibodies that worked against HIV grown in the lab. One company, VaxGen, that was developing a gp120 vaccine decided to respond to this new information essentially by behaving like a child -- covering its ears and singing "la, la, la" in the hopes of not hearing bad news.

VaxGen took its vaccine, named AIDSVAX, all the way to two huge clinical trials designed to test whether it worked. One trial was conducted mainly in North America and most of the participants were gay men. The second trial took place in Thailand among people at risk for HIV infection because of intravenous drug use.

When the results finally became available in 2003, it turned out that the laboratory studies had been right. There were no differences in the number of people that became HIV infected in the trials whether they received AIDSVAX or a placebo (dummy) vaccination. Shamefully, VaxGen attempted to sift through the results of the North American study and suggest that AIDSVAX had shown some protective effect in people of color; this turned out to be a false claim based on a very small number of nonwhite individuals that had enrolled in the trial.

T Cell Responses Take a Turn While this may sound disastrous, all was not lost because many other scientists continued to work on different vaccine approaches. Over the past decade or so, it has been found that there is another type of immune response against HIV that might be protective. These immune responses are called T cell responses.

T cells come in two main flavors: CD4 cells (which are monitored in people with HIV as a marker of disease progression) and CD8 cells. CD4 cells act like quarterbacks calling the plays for CD8 cells and B cells. CD8 cells have a vitally important function: They can recognize virus-infected cells in the body and zap them with destructive proteins in order to eliminate them. For this reason, they are also sometimes called cytotoxic T cells (cyto comes from the Greek word for cell) or cytotoxic T-lymphocytes (CTL).

Several lines of evidence suggest that CD4 and CD8 cells targeting HIV can play an important role. In monkeys infected with a close relative of HIV called SIV (simian immunodeficiency virus), viral load increases dramatically if researchers artificially deplete the animals of their CD8 cells. People with HIV who do not develop immune deficiency -- long-term nonprogressors -- have been shown to have highly functional CD4 and CD8 cells that target the virus, and their CD8 cells can rapidly kill HIV-infected cells in a lab dish. People with HIV that progresses in the usual way also have CD4 and CD8 cells targeting HIV -- sometimes very large numbers of them -- but when looked at to see how well they work, it turns out they do a poor job of killing infected cells.

Additionally, CD4 and CD8 cells targeting HIV have been found in individuals -- such as sex workers and the uninfected partners of HIV-positive people -- who have been repeatedly exposed to the virus, but remain uninfected (although it is not yet known if these T cell responses are protecting these individuals, or if they just indicate that exposure to HIV has occurred).

The ALVAC Vaccine As a result of this evidence, and because of the difficulty of blocking HIV with antibodies, a major focus of vaccine researchers has been on designing vaccines that can induce production of CD4 and CD8 cells targeting HIV. While CD4 cell responses can be triggered quite easily, it turned out to be tough to trigger the development of CD8 cell responses.

For most of the 1990s, the best that researchers could do was induce CD8 cell responses targeting HIV in around 20% of HIV-negative people who received an experimental vaccine called ALVAC. ALVAC is a type of vaccine called a viral vector. It is a harmless version of a bird virus called canarypox that has been altered so that it makes several different HIV proteins when injected into people (the proteins cannot form infectious HIV).

Although most researchers think it'll be necessary to trigger CD8 cell responses in more than 20% of recipients for a vaccine to have any chance of working, ALVAC is now being tested in a large trial in Thailand to see if it can offer any protection against HIV infection. Anyone in the trial who becomes infected will also be monitored to see if receiving the vaccine improves his or her chances of becoming a long-term nonprogressor.

Merck Makes a Breakthrough The big breakthrough for vaccines aiming to trigger CD8 cell responses came just after the turn of the millennium. Merck & Co. developed a different kind of viral vector vaccine, based on a weakened form of a virus called adenovirus (which in its natural form causes bad colds). This vaccine has been shown to trigger CD4 and CD8 cell responses targeting HIV in the majority (50-70%) of people who receive it. The HIV proteins that the vaccine makes are called gag, pol, and nef. Merck's vaccine is now being tested in a trial involving 3,000 HIV-negative people at risk for HIV infection. The trial got under way in January 2005, and results are expected by 2010 at the latest. As with the ALVAC trial, this study will also evaluate whether the vaccine can completely protect against infection or improve a person's chances of becoming a long-term nonprogressor.

The VRC Weighs In A very similar vaccine has been designed by government researchers at the Vaccine Research Center (VRC) in Bethesda, which is part of the National Institutes of Health. The VRC approach uses a two-pronged strategy called "prime-boost" vaccination. The first vaccine that is given consists of just of a piece of DNA that can make certain HIV proteins when injected into the muscle. This DNA vaccine can induce anti-HIV CD4 and CD8 cells, but only at very low levels. The VRC then uses an adenovirus-based vaccine like Merck's to boost these CD4 and CD8 cells to much higher levels.

The VRC's vaccine includes more HIV proteins: It has gag, pol, and nef, but also includes envelope proteins from three different HIV subtypes from different parts of the world: subtypes A, B, and C. A trial to test the effectiveness of this vaccine involving 8,500 people is just getting under way; preliminary results may be available by 2011.

Therapeutic Vaccines All of the T cell-based vaccines mentioned in this article (and several others) are also being studied as potential therapies. The goal of therapeutic vaccination is to improve the effectiveness of anti-HIV immune responses in people that are already infected with the virus. Studies typically vaccinate people while they are receiving antiretroviral drugs, so that anti-HIV T cell responses can develop while viral load is suppressed. ART is then interrupted to figure out if these new immune responses can control HIV better than it was being controlled before.

To date, some studies using ALVAC have shown a limited impact of therapeutic vaccination, while others have shown no effect (or even a detrimental effect in one case). Results from studies using the Merck and VRC vaccines have not yet been presented.

Conclusion Results from these ongoing trials of T cell-based HIV vaccines will be critical for the future of HIV vaccine research. If some significant evidence of protection -- against either infection or disease progression -- is seen, researchers will be able to try to improve on those results and, depending on the degree of success, submit the results to the FDA for approval of the vaccine.

A vaccine that reduced viral load levels could have a beneficial impact on the spread of HIV infection because people with lower viral loads are less likely to transmit the virus. It would be a challenge, however, to develop educational materials about such partially effective vaccines because recipients would need to be informed that they were not fully protected against HIV. If no hint of an effect emerges from the trials of T cell-based vaccines, vaccine researchers will have to ratchet up efforts to develop antibody-based vaccines or alternative approaches (if any can be discovered).

There is no way of knowing what the outcome of these trials may be; most optimistically, many researchers do feel -- based on results in animal models -- that the vaccines may improve the chance that a vaccine recipient who becomes infected with HIV will become a long-term nonprogressor. More pessimistically, few scientists think that these T cell-based vaccines will offer complete protection against HIV infection, since antibodies are thought to be necessary for this to occur.

If these scientists are correct -- and current evidence strongly suggests they are -- then it is extremely unlikely that a completely protective HIV vaccine will become available in our lifetime. We'll only find out for sure in a few years time, when the results of these trials are in.

For more information, visit the AIDS Vaccine Advocacy Coalition at: Their AIDS Vaccine Handbook: Global Perspectives (2nd edition) contains a wealth of detail on all aspects of the search for a vaccine, from the ethics of clinical trials to the need for community activism.

Richard Jefferys is Coordinator of the Michael Palm Basic Science, Vaccines & Prevention Project at the Treatment Action Group.

Vaccine Questions Nov 17, 2007

Dr. Bob, I've been reading with great disappointment of the effects of the failed Merck AIDS vaccine. All of the data being brought up seems to point to the failure as being directly associated with the Adenovirus delivery vector and Associated Adenovirus Vectors.

I realize Merck was the furthest along and applaud the clinical trial process for halting the testing of a failed avenue of atack, but wonder if there is commonality of the vector being used among the other vaccines in trial. Was the failure of the Adenovirus Vector a major setback in the search for a vaccine? What does this mean for promising candidates like the GeoVax vaccine.

Thank you for all of your support and continued humor. You helped me through the roughest period of my life and have given me hope that my future hasn't been destroyed.

Response from Dr. Frascino


Yes, this was indeed incredibly depressing news! Was this a major setback in the search for a vaccine? Unfortunately yes. What does this mean for other promising vaccine candidates? Well, several other vaccine trials have already been affected by the failure of the Merck vaccine trial. (See below). We are now looking for similarities and hopefully differences in adenoviruses versus adeno-associated viruses. Additional effort may have to be directed at other types of vaccines, such as the dendritic cell therapeutic vaccine. (The French have reported some success with this approach.)

It's also worth noting that despite the fact virtually everyone aggrees we desperately need a preventative and therapeutic HIV vaccine, only a very tiny percentage of the world's HIV research budget is dedicated to vaccine development. (Somewhere around 1%!!!) This must change if we are ever to make significant progress on an HIV vaccine. Of course if we had directed only a small portion of the funds wasted in Iraq toward HIV vaccine development most likely we'd already have both a therapeutic and preventative HIV vaccine!!! (Is it Jan 2009 yet?)

Dr. Bob

Several Vaccine Trials Affected by Halt of Merck's HIV Vaccine Trial

November 16, 2007

Several vaccine trials are being postponed or modified following the halt of Merck's experimental HIV vaccine trial, the Philadelphia Inquirer reports (Stark, Philadelphia Inquirer, 11/16). Merck in September announced that it had ended the Phase II trial, which began in late 2004 and involved HIV-negative volunteers, after the experimental vaccine failed to prevent HIV infection in participants or prove effective in delaying the progression of the virus to AIDS.

New data recently suggested that the vaccine was ineffective among some trial participants with a pre-existing immunity to a common cold virus and that the vaccine might have increased their susceptibility to HIV infection. The Merck vaccine was made from a weakened version of a common cold virus that served as a mode for providing three synthetically produced genes from HIV, known as gag, pol and nef.

After several days of discussions at an HIV Vaccine Trials Network conference last week in Seattle of Merck's trial, leaders of the trial on Monday decided to notify all of the trial's 3,000 participants whether they were given the vaccine or a placebo (Kaiser Daily HIV/AIDS Report, 11/14).

According to the Inquirer, other trials have been affected by Merck's trial because the experimental vaccines have a similar structure to Merck's vaccine. Trial participants now must be warned about the potential risks highlighted in the Merck trail if they participate in experiments that use a cold-virus carrier similar to Merck's product, Anthony Fauci, director of the National Institute of Allergy and Infectious Disease, said.

Gary Nabel, director of NIH's Vaccine Research Center, was scheduled to launch the PAVE 100 HIV vaccine trial early next year, but it recently was postponed until at least mid-2008. The PAVE vaccine uses three shots of DNA followed by a cold-virus booster shot, which has different components than the Merck vaccine. Nabel said he plans to modify the study by testing the vaccine only on people with limited exposure to colds and by increasing monitoring of patients.

Hildegund Ertl -- an immunologist at the Wistar Institute who is preparing to test an experimental HIV vaccine that uses a chimpanzee cold virus -- said the Merck trial also likely will affect her study, which is due to start in a year. "The bar will be raised," she said, adding that she hopes the chimp-based cold virus will not cause complications that the human cold virus might be causing (Philadelphia Inquirer, 11/16).

Vaccines Using Some Viruses Require Further Testing, Study Says Ertl and colleagues on Thursday in the Journal of Clinical Investigation reported that experimental HIV vaccines that typically use harmless viruses called adeno-associated viruses might damage the immune system by exhausting important cells, Reuters reports.

According to the group, AAV vaccines when tested in mice directly interfered with immune cells called CD8 T-cells, which are T-cells that a vaccine is supposed to stimulate to fight HIV. "The immune cells become exhausted," Ertl said, adding, "It is simply a defense mechanism of T-cells -- if there is too much antigen for too long a time they simply turn themselves off." The researchers said AAV vaccines should not be tested on people until more studies are conducted. Ertl said it is unclear whether her findings contributed to the developments in Merck's trial, which used an adenovirus.

Fauci said the study should be taken "with a very heavy dose of caution." He added that adenoviruses and adeno-associated viruses are very different microbes, despite the similarity of their names. "We may be dealing with apples and oranges," he said.

Pat Fast of the International AIDS Vaccine Initiative said the group has stopped testing AAV vaccines. "While we find the AAV study by Dr. Ertl and her group ... very interesting and we'll consider whether it can inform our future studies, their study was conducted in mice and there are fundamental differences between mice and humans in their respective immune responses, particularly with regard to the immune response against HIV," Fast said in a statement (Fox, Reuters, 11/15).

Scientists No Closer To Developing HIV Vaccine Than 20 Years Ago, AAAS President Says [Feb 19, 2008] During the annual American Association for the Advancement of Science meeting on Thursday in Boston, AAAS President David Baltimore said scientists are no closer to developing an HIV vaccine than they were when vaccine research began, BBC News reports (Briggs, BBC News, 2/15).

Baltimore, a biology professor at the California Institute of Technology, said some scientists have begun to openly discuss the possibility of never developing an HIV vaccine because of the virus's ability to weaken the body's immune system while it progresses to AIDS (Connor, Independent, 2/15). "This is a huge challenge because to control HIV immunologically, the scientific community has to beat out nature," Baltimore said (BBC News, 2/15).

Baltimore added that the HIV vaccine development community is "depressed" after recent failed attempts to develop a vaccine but said that will not halt HIV vaccine research. The HIV vaccine community needs to begin "thinking about [vaccine development] in a very different way," he said, adding that scientists are beginning "trendy and difficult" research involving gene therapy, immunotherapy and stem cell therapy (Independent, 2/15). He added that researchers are trying to "design vectors that can carry genes that will be of therapeutic advantage" (BBC News, 2/15).

Baltimore said he is not "prepared" to say that an HIV vaccine will never be developed because he does not want to "take a pessimistic stance. I want to take an optimistic stance and say this is too important to give up on" (Independent, 2/15).

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