November 13, 2008

experts comment on study in the Lancet discussing failed HIV vaccine

The US trial of a potentially promising new vaccine for HIV ended in failure when it was found to offer no protection against the virus.

Dr Adriano Boasso, Research Fellow, Department Of Immunology, Imperial College London, said:

“The development of a vaccine against HIV is universally considered the best possible weapon to fight the global HIV epidemic. When approximately one year ago the STEP trial for a vaccine against HIV was halted, research on HIV appeared to have suffered a severe breakdown.”

“The vaccine used in this trial is based on the structure of another virus (adenovirus) as a vehicle to “educate” the immune system to recognize the cells which carry HIV and kill them, a type of immune response which is called cell-mediated.”

“The study by Susan Buchbinder and colleagues published in The Lancet on 13th November 2008, shows that not only the vaccine failed to protect from HIV infection or mitigate the course of the disease, but it also increased rather than reduce the risk of infection in volunteers who had been previously exposed to adenovirus.”

“The second study on today’s issue of The Lancet, by Juliana McElrath and colleagues, shows that the vaccine is capable of inducing cell-mediated immune responses against HIV, yet protection from infection or disease progression was not achieved. The key observation is made that the immune response induced by this vaccine may not have been strong or good enough, epitomizing the need for a better and deeper knowledge of how the immune system functions and how we can manipulate it.”

“These studies and all the future ones which investigate the reasons for the failure of the STEP vaccine trial should be used as the steering wheel to adjust the direction of HIV research and as the backbone on which to design and test new vaccines.”

Prof Jonathan Ball, Professor of Molecular Virology, University Of Nottingham, said:

“The failure of the Merck HIV vaccine trial came as no surprise to some of the HIV research community, and illustrates the magnitude of the challenge that HIV vaccine development poses.

“The Merck vaccine candidate, which consisted of a genetically modified living virus called adenovirus, aimed to stimulate the body’s natural defence system by generating a special kind of white blood cell that is able to kill other HIV infected cells. Early studies had shown that the vaccine candidate was able to produce such “killer” cells. The trial hoped to determine whether the vaccine could deliver the holy grail of absolute protection against infection (so-called sterilising immunity), or at second best, reduce the amount of HIV in individuals who become infected – HIV patients with low levels of virus are known to survive longer and they may be less likely to pass on their infection to others. The second aim was considered, by most, to be the most realistic outcome. Disappointingly, the vaccine, administered to 3000 individuals at high risk of HIV infection, neither protected from infection nor reduced the amount of virus in those who became infected. This was predicted by scientists who had been working within similar vaccines designed to prevent AIDS in monkeys.

“The failure of the Merck trial comes in the wake of other failed attempts, most notably the VaxGen trial, designed to stimulate another part of the defence system called antibodies. HIV is able to mutate very rapidly and this allows it to escape very rapidly from both killer cells and antibodies.

“Certainly it is too premature to assign vaccines that focus on generating cell-mediated immunity to the dustbin. However, most scientists agree that an effective vaccine will probably need to produce both protective killer cells and antibodies at high levels, which target parts of the virus which do not mutate. Information gleaned at the research bench, together with lessons learnt from failed interventions, will help shape the design of future vaccine candidates. However, it is important to safeguard against premature trial until the experimental data indicates that these have a high chance of success; otherwise we may face many more disappointing false new dawns.”

Prof Robin Shattock, Professor of Cellular and Molecular Infection, St George’s, University of London, said:

“While the results of this trial were disappointing, this study was still an important step in determining what is required for an HIV vaccine. We now know that the vaccine approach tested in this trial produced a response against too few viral targets using only one aspect of the immune response – cytotoxic T cells.

“The trial taught us valuable information that can advance our work on HIV vaccines. It demonstrated that there is a need for an HIV vaccine that stimulates stronger and wider immune responses that will induce both broader cytotoxic cells and neutralizing antibodies.

“This is not the end of HIV vaccines, but a closing off of one approach, and a refocusing of effort on others that show promise.

“So far there have been only two HIV vaccine trial failures. To put this in context, it has taken over 20 trials to see any success for malarial vaccines.

“All long journeys are initiated by the first steps. The seriousness of the HIV/AIDS epidemic provides a moral imperative that we should not give up after the first few tentative steps in the long journey towards the goal of an effective HIV vaccine.”

Dr Pat Fast, Chief Medical Officer at the International AIDS Vaccine Initiative, said:

“The authors have done an admirable job of analyzing the data from this important trial. We fully agree with the interpretation that it’s too early to write off cell-mediated immunity as an important component of an effective AIDS vaccine, and that further research is required to determine how to elicit qualitatively different or more broadly reactive T-cell responses.

“To this end, IAVI and others in the field have been working for some time now to understand how to generate more potent T-cell responses and, especially, how to crack the enigma of eliciting broadly neutralizing antibodies that will be effective against many of the HIV subtypes circulating today.”