The positive results of the Thai HIV vaccine study announced today are surprising to many, since it was widely predicted that the study would fail to show a protective effect.
About the study
The vaccine regimen was designed to stimulate both the cellular and the antibody-producing arms of the immune system (for further informationa about vaccines and how they work, see our guide to HIV vaccines).
First, participants would receive ALVAC, a vaccine that used a canarypox vector to deliver selected recombinant HIV sequences in order to stimulate the cellular arm of the immune system to produce HIV-specific cytotoxic T-lymphocytes (CD8+ cells).
Participants received four doses of ALVAC over six months, and vaccinations at months 3 and 6 with AIDSVAX B/E, a vaccine designed to produce an antibody response against the gp120 protein on HIV’s surface, using sequences from two HIV subtypes present in Thailand, B and E.
All participants received counselling on how to protect themselves against infection at the beginning of the study and every six months, as well as being tested for HIV every six months. Anyone who seroconverted during the study received free care and treatment for HIV infection.
The study recruited 16,402 volunteers aged 18-30 in Thailand. All participants were followed for at least three and a half years.
An unpopular study
The RV-144 trial was the biggest HIV vaccine study conducted to date, dwarfing all the other efficacy studies that have taken place, and one that many advocates and scientists said should never have gone ahead.
Back in 2004, as the first participants began to receive vaccinations in Thailand, a group of some of the biggest names in US vaccine research published a letter in Science magazine in which they called for the study to be abandoned.
In particular, researchers were concerned that the products being tested in the vaccination regimen, ALVAC and AIDSVAX, had little chance of producing robust immune responses that would protect against HIV infection, based on the results of previous studies.
They expressed concern over the use of AIDSVAX, after phase III trials in the United States and Thailand reporting in 2003 had shown the vaccine to be “completely incapable of preventing or ameliorating HIV-1 infection.”
The trial was going ahead, at a cost of over $119 million over six years, they said, without a clear scientific rationale. They feared that failure of the study would erode the confidence of public and politicians in HIV vaccine research. Plans for a similar study in the US had been cancelled following the results of the AIDSVAX studies.
Instead, they argued, money should be invested in vaccine prospects that showed evidence of strong immunologic responses in phase I and II studies. (For further information on the debate over the Thai trial, see Types of HIV vaccines).
The RV 144 study continued, despite the controversy, but with little expectation in the wider HIV vaccine field that it would yield a positive result showing a protective effect.
Instead, there was growing optimism that a new vaccine candidate that elicited promising immune responses, developed by Merck, would prove successful in proof of concept studies taking place in the US, Latin America and South Africa.
It was thus a huge shock to the field, when almost exactly two years ago, the investigators in the major study of the Merck vaccine decided to halt the STEP trial following evidence that the vaccine was not effective.
Worse was to follow, as subsequent analysis showed that a subset of participants who received the vaccine were at higher risk of infection. The mechanisms that placed these individuals at higher risk are still not understood.
So, today’s announcement that the `Thai trial` resulted in a reduced risk of infection for those who got the vaccine is one of the bigger surprises in a field that is becoming accustomed to results that upset the conventional wisdom.
However the design of the Thai trial still leaves a major question unanswered. What part of the vaccine regimen induced protection? Was it ALVAC, which had never been tested in an efficacy trial in HIV-negative individuals? Was it AIDSVAX, despite its failure to protect in two large trials in the US and Thailand? Or was it the combination of the two, despite no clear scientific rationale for why the two vaccines together would be expected to produce a greater protective effect than ALVAC alone?
Some of these questions may be answered when further results from the study are presented at the 2009 AIDS Vaccine Conference next month in Paris, but others will require further clinical studies before the mechanisms that led to a modest level of protection in the Thai study are fully understood.
More information and analysis
See aidsmap.com's guide to The search for an HIV vaccine for further background information.
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