Q&A: The future of HIV vaccines

Despite the slew of failures in the past, the most recent $105 million HIV vaccine study among 16,000 Thai volunteers is the first to show any (albeit modest) success. With this first sign of promise in HIV vaccine research, linkurl:Norman Letvin,;http://www.hms.harvard.edu/dms/immunology/fac/Letvin.html professor of Medicine at Beth Israel Deaconess Medical Center, Harvard Medical School, who was not involved in the Thailand trial, weighs in on the topic in an opinion piece published linkurl:online this week in Science;http://www.sciencemag.org/cgi/content/summary/326/5957/1196 . Norman Letvin Image: Harvard Medical SchoolLetvin took time to chat with The Scientist about the new sense of optimism in the field, why statistical significance is not the key issue here, and how, in some groups, the vaccine appeared significantly more effective than others. The Scientist: After the recent HIV vaccine trial in Thailand, what is the mood in the field? Norman Letvin: The vaccine trial has clearly energized researchers in the field. Over the last couple of decades, we've seen a lot of failures and there's been growing pessimism over whether an HIV vaccine would ever be possible. For a while vaccine trials were initiated with the modest hope of decreasing the extent of viral replication, but there was not much optimism about blocking infection. This Thai vaccine trial represents the first in which we're seeing the vaccine actually block initiation of the virus. There is almost a uniform sense of relief in the field because we've shown that an HIV vaccine may, in fact, be possible. Researchers now plan to build on the moderate success of this trial to generate a more effective vaccine. TS: What were the initial controversies associated with the Thai trial? NL: There was a tremendous amount of controversy when the trial was initiated. The volunteers received two vaccines together, each of which had been tested individually in primate and early human trials and were unsuccessful. Despite the poor results observed for each vaccine previously, the Thai trial did go forward using both agents. The hope was that one of the vaccine components -- a recombinant protein found on the surface of HIV called glycoprotein 120 (gp120) -- would generate an antibody response blocking initiation of HIV infection, and the second component -- a canary pox vector expressing three synthetic HIV genes -- would elicit a cellular immune response inhibiting HIV replication. When the study was completed, there was also a little debate over whether the results were statistically significant or not. I would say, however, that it doesn't matter either way. The current vaccine is not potent enough to be used as is, but what we can do is look carefully at the data to create a vaccine with better results. The modest improvements observed with the Thai trial can point a way forward for future vaccine attempts. TS: How do the study findings build on our understanding of the past? NL: The results showed the vaccine protected 31% of the recipients against acquiring the virus. When you break down the data, the vaccine was 40% effective in the lower-risk population (those with limited number of low-risk sex partners and no drug use) but only offered 3.7% protection in the higher-risk population [needle sharing or high-risk sexual activity]. The breakdown of these results is important because it may explain why other trials showed poor results. The previous trials that failed only tested the vaccine in high-risk individuals, while the Thai trial mostly used low-risk subjects. It could be that the immune response required for protection in low-risk populations may be different from those needed in high-risk ones and could reflect the differences we've seen in the outcomes of these trials. TS: Which part of the vaccine conferred the greatest benefit? NL: Once we know which immune response and which component of the vaccine is conferring that 40% protection, we can improve the protection with technology that exists. The general sense in the field right now is that the efficacy we are seeing is probably due to antibodies rather than cellular immune response. TS: What's the next step in HIV vaccine research? NL: The main area that needs to be investigated further is the mechanism that explains the vaccine's effectiveness. There's going to be concerted effort to find out what immune response generated by the vaccine is conferring protection to certain individuals. If the component of the vaccine conferring protection is recombinant gp120 (i.e. the antibody response), there will be straightforward ways to improve the magnitude or durability of eliciting antibodies by developing new types of proteins that enhance the existing recombinant gp120's ability to generate an antibody response. If the canary pox vector component proves to be critical piece of puzzle, there are even more potent vectors in the same family [the pox family] that we can use to improve the cellular immune response. The nature of those studies is in intense discussion right now. **__Related stories:__***linkurl:Modest HIV protection confirmed;http://www.the-scientist.com/blog/display/56067/ [20th October 2009]*linkurl:Hubbub brews for HIV vax data;http://www.the-scientist.com/blog/display/56052/ [12th October 2009]*linkurl:HIV vax testers react to Thai trial;http://www.the-scientist.com/blog/display/55995/ [24th September 2009]

Q&A: The future of HIV vaccines

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