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.