A closer look at a malaria vaccine trial and controlling HIV-1 viremia

Malaria vaccine trial

The results of a randomized controlled trial of a malaria vaccine called ME-TRAP are published this month in PLoS Medicine. “This first field efficacy trial was an important milestone in the progression of new recombinant vectored vaccines to deployable products,” says Adrian Hill (University of Oxford, United Kingdom), the senior investigator of the study. “The safety profile was excellent and the efficacy data provide a first indication of the levels of cellular immunogenicity that will be required for preventing infection,” he says.

The researchers recruited volunteers from 13 Gambian villages that were close to the alluvial flood plain and so were at high risk of developing malaria. They randomly assigned the 372 volunteers to receive either two doses of the malaria vaccine or three doses of rabies vaccine, which acted as a control. This three-dose schedule is similar to the one used by the World Health Organization/United Nations Children’s Fund Expanded Program on Immunization.

The time to first infection was similar in the two groups, with an estimated vaccine efficacy of only 10%. However, the immune response, measured one week after the third vaccination, was 80 times higher in the DNA/MVA vaccine group than in the rabies vaccine group.

“It is absolutely crucial that results like these are published, since the failures, as well as the successes, need to be documented if we are to move towards rational strategies for optimizing malaria vaccines,” says Tom Smith from the Swiss Tropical Institute, who was not involved in the study. “At the same time, it makes sense to move on quickly without shedding too many tears, in a field that is moving much faster than it was before the recent injections of money from the Gates Foundation, but where it is still impossible to second-guess the results of field trials. This is partly because we do not have any good proxy measures of effective immunity in P. falciparum, and partly because this is a fertile area for trying out new techniques, such as DNA vaccines, where there is still a lot to learn.”

Hill is planning to do further trials that address the important question of whether this type of vaccine can prevent the symptoms of malaria. “The next step,” says Hill, “is to assess newer vaccine regimes that employ two viral vectors rather than DNA and to study prevention of malaria rather than infection.”

Citation: Moorthy VS, Imoukhuede EB, Milligan P, Bojang K, Keating S, et al (2004) A randomised, controlled, double-blind efficacy trial of DNA/MVA ME-TRAP prime-boost immunisation against malaria infection in Gambian adults. PLoS Med 1 (2): e33.

Supervised Treatment Interruptions Fail to Control HIV-1 Viremia

Highly active antiretroviral therapy (HAART) for the treatment of individuals infected by HIV-1 is limited by high costs, drug resistance, and drug-related toxicities. This has led researchers to investigate new treatment options, including ways to boost immune responses to better control HIV. One such approach has been termed supervised treatment interruption (STI)—in which HAART is intermittently stopped once the viral load has been reduced to a low level, in order to boost natural immunity by brief exposure to the virus. The goal is to allow for the eventual discontinuation of drug treatment.

Preliminary evidence, published by Bruce Walker and his colleagues in Nature in 2000, suggested that this approach worked in persons treated in the earliest stages of acute HIV infection. HIV-1 viral loads in newly infected patients remained suppressed for a median of six months after therapy had been stopped. However, a follow up paper, published this month in PLoS Medicine by the same research group, shows that the viral load rebounded in eight of the 14 patients by one year.

“The findings are very straightforward and very important,” comments Danny Douek from the Vaccine Research Center, National Institutes of Health, United States, who was not involved in the study. “In almost every case, the virus rebounded and no clinical benefit from the interruption could be determined.”

Walker’s team first considered the possibility of STI in 1997 after they demonstrated that HAART given to patients recently infected with HIV could protect immune cells, called T helper cells, which are normally destroyed in the earliest stages of infection. They hypothesized that early treatment of acute HIV-1 infection with HAART might boost the immune response, allowing it to control the HIV-1 infection without the need for continuous therapy. “We did not know at that time whether the T helper cells would be functional,” explains Walker, who is director of the Partners AIDS Research Center at Massachusetts General Hospital. “The only way to tell this was to stop medications and see if the immune response could control the virus.”

To test this hypothesis the researchers did an open-label trial of STIs; they published data from a six-month follow-up in the Nature paper. “The key finding was that we were able to get at least transient control of the virus in all eight persons studied, and in five of eight the viral load was less than 500 copies (very low!) at the time of publication,” explains Walker. However, at that point they did not know how long the protective effects would last.

The first evidence that protection was not complete came two years later when Walker’s team reported a case of superinfection; one of the patients in the original experiment was infected with a second strain of HIV, even though the first virus was still well controlled. “This paper was important because it indicated that the amount of immunity might be enough for the person’s own virus, but might not protect against closely related viruses circulating in the population,” says Walker.

The PLoS Medicine study adds more concern since it shows that although most people can indeed transiently control their own virus, they do so for only a limited amount of time. “We expanded the study to 14 persons, and now have about five years of follow-up on some of the patients,” says Walker. “Although we were able to use early treatment and structured treatment interruption to boost immunity and have 11 of 14 patients control their virus, most of the persons ultimately ‘broke through,’ meaning that they had a recurrence of viremia.” At the present time the researchers do not know what causes the loss of viral control.

Walker and colleagues conclude that treatment interruptions should probably be avoided outside the setting of controlled clinical trials, whereas Douek goes a step further: “The study shows that even early short-term treatment and structured treatment interruptions, using current strategies, impart only transient benefit and are unlikely to serve as a reasonable therapeutic option in the future.”

Citation: Kaufmann DE, Lichterfeld M, Altfeld M, Addo MM, Johnston MN, et al. (2004) Limited durability of viral control following treated acute HIV infection. PLoS Med 1 (2): e36.