MicrobiologyBytes

Today’s post is from regular guest blogger:

Ed Rybicki, Department of Molecular and Cell Biology, University of Cape Town, South Africa.

It should not have escaped the eye of the interested bystander that there has been a most unfortunate and premature end to a HIV vaccine trial recently – and that something that had been tested as “safe” and “immunogenic” in Phase I and II trials went on to not only to not show any efficacy at all, but may actually have increased susceptibility in recipients to HIV-1 infection. The so-called STEP trial in North and South America, the Caribbean and Australia, and the Phambili trial in South Africa, were “Phase IIB” or international test-of-concept trials in at-risk populations of the efficacy of Merck & Co. Inc. Adenovirus 5-based vectors (MRKAd5) encoding subtype B-derived Gag, Pol and Nef proteins. The outcome was about as gloomy as could possibly have been predicted, and was nothing like what researchers expected from preliminary primate testing.
The trials – more formally designated as “HVTN 502 and HVTN 503 HIV Vaccine Clinical Trials” by the HIV Vaccine Trials Network – were testing a mixture of three replication-defective Adenovirus 5 vectors, containing gag, pol and nef genes respectively, aimed at stimulating mainly CD8+ T-cell responses. There had earlier been some disagreement in the research community about the ethics of trialling a subtype B-specific vaccine in a subtype C-dominated epidemic region – and in a population known to have a high incidence of high titres of antibodies against Ad5, which is after all a common cold virus. However, regulatory bodies were in no doubt that the trials were appropriate, and standard Phase I and II trial results were non-contentious, leaving the way clear for the present exercise.

The study was designed as a randomized, double-blind, placebo-controlled Phase IIB clinical trial, sponsored by Merck and the National Institute of Allergy and Infectious Diseases (NIAID), which enrolled HIV-negative volunteers between 18 and 45 years of age at high risk of HIV infection. Participants were randomly assigned to receive three injections of either the study or a placebo vaccine. Some 3000 participants were planned for each of the two trials; HVTN 502 was closed while 503 was still recruiting, when the Data and Safety Monitoring Board (DSMB) of the STEP trial (HVTN 502) – an independent committee providing oversight of the study – decided on September 18th that “… the trial as originally designed should be discontinued because the trial would not meet its efficacy endpoints”, as there was no evidence for protection. In fact, of people with low anti-adenovirus titres at enrollment who had received one vaccine/placebo dose, 24 of 741 vaccinees became HIV+, while among placebo-vaccinated people, 21 of 762 became infected. Among two-dose trialists, the figures were 19 HIV infections in 672 vaccinated volunteers, and 11 HIV infections among the 691 placebo recipients. This led to the discontinuing of the Phambili trial in South Africa as well, given no additional expectation of success.

And inevitably, things got worse: among male volunteers with high levels of antibodies against Ad5, 21 of 392 vaccinees became infected, but only 9 of 386 in the placebo group. Thus, it could be that pre-existing immunity to the vector virus actually increases susceptibility to HIV infection: one mechanism that has been proposed is that the secondary response to the Ad5 transiently boosts production of CD4+ T-cells – the preferred host cells of HIV.

The upshot of all this is that researchers worldwide are taking a hard look at Adenovirus-based HIV vaccines, even those which do not naturally occur in humans, and to which there should be no immunity: for example the Vaccine Research Center at the NIH has another Adenovirus-vectored candidate about to enter clinical trial, which may yet be delayed as the results of the STEP and Phambili trials are analysed in minute detail. The STEP volunteers are to be informed what they were inoculated with, and all Phambili volunteers have been advised to report back to the clinics for counselling. From the Merck site:

The Phambili DSMB also recommended that Phambili volunteers be told whether they received the vaccine or placebo, be strongly encouraged to return to study sites for protocol-related tests, and be counseled about the possibility that those who received the vaccine might have an increased susceptibility to HIV infections. STEP volunteers will also be counseled about this possibility, and discussions are underway to define the details of continued follow-up for STEP volunteers, including when STEP volunteers will be unblinded. Detailed analyses of the available data are being conducted, including analyses to better understand if there may be an increased susceptibility to HIV infection among those volunteers who received the vaccine.

Inevitably, there has also been political fallout in South Africa: the Minister of Health, Manto Tshabalala-Msimang, announced a moratorium last week on HIV vaccine trials, which could affect the home-grown vaccines due for trial next year.

This is not the only bad news recently on the HIV vaccine front: there seems to be evidence that another hitherto-promising HIV vaccine vector, the adeno-associated viruses (AAVs) may help to exhaust memory T-cells, by over-stimulating them with continuously-produced antigen.

All of this bad news looks, at first sight, to be a major body-blow to efforts to develop viable HIV vaccines. However, this is exactly what clinical trials are for: to test vaccines, for safety, immunogenicity, and efficacy. It is actually encouraging in a perverse sense that the trials work as they should – even though the first two HIV vaccines that have made it as far as efficacy trials are both abject failures. Lessons from the AIDSVAX debacle were that large trials can be done for an HIV vaccine; that HIV infection is a reasonable endpoint for a HIV vaccine trial; that HIV gp120 is not a good vaccine candidate. While it is still too early to be specific, lessons from this trial may be that immunogenicity / efficacy results from monkeys may not be a good predictor of human results, and that Ad5 is not a good HIV vaccine vector in pre-immune populations.

So the search goes on: the longest, most expensive vaccine development exercise in human history, with no clear end in sight.

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Related:

• HIV vaccines – bad news, good news
• The emergence of HIV/AIDS in the Americas and beyond
• How does HIV cause AIDS?

Tags: Biology, Guest, Health, HIV/AIDS, Medicine, Microbiology, Science, Vaccines, Virology

This entry was posted on Wednesday, November 21st, 2007 at 6:11 am and is filed under Biology, Guest, HIV/AIDS, Health, Medicine, Microbiology, Science, Vaccines, Virology. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed.