In a sign of the slow progress in the medical fight against the HIV virus and AIDS, a federal health agency has canceled plans for an ambitious clinical trial of an experimental HIV vaccine. Although this candidate vaccine was once thought very promising, researchers lost confidence in it after the failure last September of a similar candidate from drugmaker Merck & Co. that may have left some volunteers more vulnerable to HIV infection [San Francisco Chronicle].
Researchers at the National Institute of Allergy and Infectious Diseases had hoped to begin enrolling 8,500 volunteers in the vaccine trial last fall, but the trial was postponed after the Merck vaccine was shown to be failing in its two main objectives: to prevent infection and to lower the amount of H.I.V. in the blood among those who became infected…. After a safety monitoring committee detected the problems with the Merck vaccine in September, the company quickly halted its study [The New York Times].
Both the Merck vaccine and the new experimental vaccine use the common cold virus, Adenovirus-5, to carry the vaccine’s payload. That approach is now in question, as the Merck trial showed that those who had been previously exposed to the Ad-5 cold virus were more at risk of being infected with HIV.
The disappointing end of the Merck trial has led agencies to renew their emphasis on basic research, rather than on large and costly clinical trials, in hopes that the research will lead to better vaccine candidates for future testing. But it has also prompted some to declare that the vaccine field is in serious trouble; in March, virologist Robert Gallo said the [Merck] results were a catastrophe comparable to the space shuttle Challenger disaster [Nature News].
Although the large clinical trial has been canceled, researchers will go forward with a scaled-down experiment that will study whether the vaccine can lower the amount of HIV in the blood of an infected person. But this downsizing troubled some activists: “After a year of public hand-wringing and unproductive public attacks on the search for an AIDS vaccine, it is essential this decision not be viewed as a vote of no-confidence,” said [AIDS activist] Mitchell Warren [The Wall Street Journal].
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July 20th, 2008 at 11:11 pm
ADJUVANT ACTIVATION COULD EXPLAIN HIV/AIDS VACCINE TRIALS FAILURE
The PAVE 100 trial to test an HIV vaccine will not move forward, according to NIAID. The government vaccine — known as PAVE— was similar to a much-heralded vaccine that failed last year. Both the Merck vaccine and the new experimental vaccine use the common cold virus, Adenovirus-5, to carry the vaccine’s payload. That approach is now in question, as the Merck trial showed that those who had been previously exposed to the Ad-5 cold virus were more at risk of being infected with HIV. On the other hand, in the Boston trial, a new vaccine was designed to overcome the problem of preexisting immunity to common vaccine vectors and is being tested in an early clinical trial at Brigham and Women’s Hospital in Boston. There will be 48 healthy volunteers taking part in the trial of the vaccine, which consists of a replication-incompetent, recombinant adenovirus serotype 26 (rAd26) vector encoding an HIV-1 envelope gene.
We agree with the decision of the NIAID because, as we pointed out in a paper that was published in 2001 (H. C. Grassi, E. D. J. Andrade. HIV infections and AIDS development: the role of adjuvant activation. Medical Hypotheses (2001) 57(6), 693-696), anything that causes uncontrolled activation of CD4+T cells, will promote “adjuvant stimulation” and HIV productive infections. Briefly, we proposed that HIV productive infections of CD4+ T cells occur mainly on activated cells and although the virus can infect both, resting and activated cells, productive infections occur mainly in the latter than in the former. In this paper we conclude that the technological development of vaccines should focus to a highly controlled and specific immune reaction. Similarly, immunotherapeutics could focus towards controlling immune activation. The rational takes into account the role of all the agents that promote cell activation (including vaccination) thus increasing productive infections. This effect was named as “adjuvant activation” or “adjuvant effect” and is consistent with the idea that any immune challenge of an HIV infected person will promote the opportunities for productive infections. Conversely, the infection with HIV of a healthy vaccinated person, will encounter a highly activatable cell population where productive infections can take place, if the vaccine is not properly designed and applied.
In this context, memory T cells that recognize HIV epitopes, will constitute the first target of an incoming HIV infection because they will be the first to become activated. However, preexisting immunity to Adenovirus-5 would be a second problem due to the hypothesized “adjuvant function” described above. In this case, memory T cells that were formed by a previous infection as well as those formed by the vaccine´s cold virus itself, can promote new targets in the T cell population. This would be in agreement with the statement “Preexisting immunity is believed to be a major problem in developing nations” (Robert Preidt in the article “Boston Trial to Test New HIV/AIDS Vaccine” MedicineNet.com). Then, if our reasoning is correct, the new approach using recombinant adenovirus serotype 26 (rAd26) vector encoding an HIV-1 envelope gene, could work better than the Adenovirus-5 based vaccine because the cold virus, if it does not regularly occur in the human population, may not produce the “adjuvant activation”, however this effect could be produced by the HIV epitopes included in the vaccine.
August 11th, 2009 at 1:58 pm
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