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STEP study: disappointing, but not a failure
Editorial
On Sept 18, the independent data monitoring and safety board for the STEP (towards developing an HIV vaccine) trial convened for a pre-planned interim analysis. The study was a randomised, double-blind phase II trial of an HIV vaccine sponsored by the HIV Vaccine Trials Network, the US National Institute of Allergy and Infectious Disease, and Merck & Co—the vaccine’s developer. The vaccine, V520, uses a replication-defective adenovirus type 5 as a vector to deliver three synthetically produced HIV genes, gag, pol, and nef, and is designed to provoke an HIV-specific immune response mediated by CD8 T cells. The trial was designed to answer two questions: could the vaccine prevent HIV infection and, in those who did become infected, would the vaccine lower viral load. 3000 HIV-negative volunteers were enrolled in North and South America, the Caribbean, and Australia. All were from groups at high risk of HIV infection. All were counselled on ways to reduce their risk of HIV prevention. Initially, only patients with low titres to the adenovirus type 5 (Ad5), a common cold virus, were entered into the trial, but when testing indicated that there seemed to be no ill effects in patients who had evidence of prior immunity to Ad5, patients with higher titres were allowed to start the injections. A second “sister” study, called Phambili, which means “to move forward” in Xhosa, had recently been launched in South Africa. The interim analysis focused only on volunteers from the low Ad5 titre group, who, because they had been injected earlier, were further along in the study. The findings were surprising—and disconcerting. Not only had the vaccine failed to prevent infection or to reduce viral load, but also further analysis suggested that the vaccine might have actually increased susceptibility to infection. Both the STEP study and the Phambili study were immediately halted and word of the results was promptly sent out to all the trial participants. Researchers are already looking at the immune responses to the vaccine in these volunteers to determine why it seemed to be ineffective. And genetic studies of the virus are also underway to determine whether these strains were somehow capable of eluding the vaccine-generated immune responses. Last week, at a meeting of the HIV Vaccine Trials Network in Seattle (Nov 7–8), trial investigators came together to discuss the trial’s findings. The data www.thelancet.com Vol 370 November 17, 2007
presented at the meeting were to be posted on the Network website by Nov 14. In their presentation, the investigators repeatedly cautioned that much of what was discussed was preliminary, based on post-hoc analysis and small numbers. Of particular interest were analyses that suggest that volunteers who started the trial with higher titres against Ad5 and received the vaccine seemed to be more susceptible to HIV infection. Why higher Ad5 titres might be associated with higher risk of infection clearly puzzled the investigators. If the association proves true, it might be, according to one hypothesis, that the Ad5 vector stimulates an immune system already primed for Ad5 and, as a result, expands the population of target cells for HIV, thus increasing the risk of infection. But it is also possible that Ad5 titres are, instead, an indirect marker of some other as yet unidentified biological, demographic, or behavioural factor. For example, fewer men in the study with higher Ad5 titres had been circumcised and they tended to live outside of the USA. And, given the low numbers involved, the findings related to Ad5 titres might be due to chance. In any case, the trend associating susceptibility to HIV infection with higher Ad5 titres suggests that trial protocols that use this vector or other vectors might need to be redesigned so that they can help answer some of the questions raised about vectors by this study. The failure of the vaccine to provide protection or to reduce viral load also raises a more fundamental question: whether vaccines that only induce cellmediated responses will prove effective. Given the elusive nature of any HIV vaccine, it is important that other prevention measures are promoted vigorously, including HIV/AIDS education, condom programmes, and, to reduce the risk among intravenous drug users, needle exchange. Currently, fewer than 20% of the world’s population has access to effective HIV prevention programmes. But though disappointing, the STEP study is not a failure. It shows that it is possible to work with diverse communities to do a well-designed trial that quickly answered the questions it was designed to, while at the same time protecting the safety of the volunteers. The investigators, clinical staff, and volunteers have reason to be proud to have been part of this trial. ■ The Lancet
Photolibrary
STEP study: disappointing, but not a failure
For more on the HIV Vaccine Trial Network see http://www.htvn.org For more on the Phambili study see http://www.phambili.org.za/
1665
On Sept 18, the independent data monitoring and safety board for the STEP (towards developing an HIV vaccine) trial convened for a pre-planned interim analysis. The study was a randomised, double-blind phase II trial of an HIV vaccine sponsored by the HIV Vaccine Trials Network, the US National Institute of Allergy and Infectious Disease, and Merck & Co—the vaccine’s developer. The vaccine, V520, uses a replication-defective adenovirus type 5 as a vector to deliver three synthetically produced HIV genes, gag, pol, and nef, and is designed to provoke an HIV-specific immune response mediated by CD8 T cells. The trial was designed to answer two questions: could the vaccine prevent HIV infection and, in those who did become infected, would the vaccine lower viral load. 3000 HIV-negative volunteers were enrolled in North and South America, the Caribbean, and Australia. All were from groups at high risk of HIV infection. All were counselled on ways to reduce their risk of HIV prevention. Initially, only patients with low titres to the adenovirus type 5 (Ad5), a common cold virus, were entered into the trial, but when testing indicated that there seemed to be no ill effects in patients who had evidence of prior immunity to Ad5, patients with higher titres were allowed to start the injections. A second “sister” study, called Phambili, which means “to move forward” in Xhosa, had recently been launched in South Africa. The interim analysis focused only on volunteers from the low Ad5 titre group, who, because they had been injected earlier, were further along in the study. The findings were surprising—and disconcerting. Not only had the vaccine failed to prevent infection or to reduce viral load, but also further analysis suggested that the vaccine might have actually increased susceptibility to infection. Both the STEP study and the Phambili study were immediately halted and word of the results was promptly sent out to all the trial participants. Researchers are already looking at the immune responses to the vaccine in these volunteers to determine why it seemed to be ineffective. And genetic studies of the virus are also underway to determine whether these strains were somehow capable of eluding the vaccine-generated immune responses. Last week, at a meeting of the HIV Vaccine Trials Network in Seattle (Nov 7–8), trial investigators came together to discuss the trial’s findings. The data www.thelancet.com Vol 370 November 17, 2007
presented at the meeting were to be posted on the Network website by Nov 14. In their presentation, the investigators repeatedly cautioned that much of what was discussed was preliminary, based on post-hoc analysis and small numbers. Of particular interest were analyses that suggest that volunteers who started the trial with higher titres against Ad5 and received the vaccine seemed to be more susceptible to HIV infection. Why higher Ad5 titres might be associated with higher risk of infection clearly puzzled the investigators. If the association proves true, it might be, according to one hypothesis, that the Ad5 vector stimulates an immune system already primed for Ad5 and, as a result, expands the population of target cells for HIV, thus increasing the risk of infection. But it is also possible that Ad5 titres are, instead, an indirect marker of some other as yet unidentified biological, demographic, or behavioural factor. For example, fewer men in the study with higher Ad5 titres had been circumcised and they tended to live outside of the USA. And, given the low numbers involved, the findings related to Ad5 titres might be due to chance. In any case, the trend associating susceptibility to HIV infection with higher Ad5 titres suggests that trial protocols that use this vector or other vectors might need to be redesigned so that they can help answer some of the questions raised about vectors by this study. The failure of the vaccine to provide protection or to reduce viral load also raises a more fundamental question: whether vaccines that only induce cellmediated responses will prove effective. Given the elusive nature of any HIV vaccine, it is important that other prevention measures are promoted vigorously, including HIV/AIDS education, condom programmes, and, to reduce the risk among intravenous drug users, needle exchange. Currently, fewer than 20% of the world’s population has access to effective HIV prevention programmes. But though disappointing, the STEP study is not a failure. It shows that it is possible to work with diverse communities to do a well-designed trial that quickly answered the questions it was designed to, while at the same time protecting the safety of the volunteers. The investigators, clinical staff, and volunteers have reason to be proud to have been part of this trial. ■ The Lancet
Photolibrary
STEP study: disappointing, but not a failure
For more on the HIV Vaccine Trial Network see http://www.htvn.org For more on the Phambili study see http://www.phambili.org.za/
1665