An unpopular vaccine study produces surprising result

This article is more than 10 years old. Click here for more recent articles on this topic

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.

Glossary

immune system

The body's mechanisms for fighting infections and eradicating dysfunctional cells.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

phase I

The first stage of human testing of a new drug or intervention, typically involving a small number (10-100) of participants who do not have the condition the drug is intended to treat. Phase I clinical trials evaluate safety, side-effects, dosage and how a drug is metabolised and excreted in the body.

gp120

A glycoprotein on the HIV envelope. gp120 binds to a CD4 receptor on a host cell, such as a CD4 T lymphocyte (CD4 cell). This starts the process by which HIV fuses its viral membrane with the host cell membrane and enters the host cell.

cytotoxic

Harmful to cells.

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 also Vaccine reduces risk of HIV infection by one-third in large trial.

See also Vaccine trial "is the beginning" of a new path of research, says US health chief.

Further information

See aidsmap.com's guide to The search for an HIV vaccine for further background information.

Note to editors

We are happy for you to link to this article on aidsmap.com