Merck HIV vaccine failure puts cold virus on trial
of infection and the latest data raises questions over whether the
cold virus used as a delivery technique was at fault.
The old pharma giant released new data from the STEP study, one of two Phase II trials the investigational vaccine, V520, was undergoing, at a meeting of the HIV vaccine trials network (HVTN). Merck has found that people who have pre-existing immunity to the adenovirus that was used to deliver the vaccine were more likely to become infected with HIV. While analysing the trial results Merck has found that in volunteers who weren't immune to Ad5, there were 20 cases of infection in both the vaccine and placebo arms of the study. However, in the 778 male volunteers who had high levels of pre-existing immunity to Ad5 (greater than 200 units), 21 cases of HIV infection were observed in those who had received vaccine compared to only nine cases of HIV infection observed in those who received placebo. V520 was created using a version of the type 5 adenovirus (Ad5) that had been genetically modified such that it was unable to replicate (and therefore cause a cold). Instead, the virus contains the genetic code for one of three HIV genes, gag, nef and pol, the idea being that the vaccine will teach the immune system to kill the protein products of these genes. The GAG and POL proteins help make up the structure of new virus proteins whereas NEF helps control the ability of HIV to infect new cells. Then, if a person encounters the real HIV virus, their immune system may be able to destroy it before it takes hold. The vaccine does not cause HIV infection. So why did it backfire? The short answer is that nobody really knows. "The data from this trial are remarkably complex. We are analysing the data to try to determine if the results are due to immune responses induced by the vaccine, differences in study populations, or some other biological phenomenon we don't yet understand, or simply due to chance," said Dr Keith Gottesdiener, vice president of Vaccine and Infectious Disease Clinical Research at Merck Research Laboratories. According to a report on Bloomberg, Bruce Walker, a HIV researcher at Harvard University explained that the activated immune system cells are more susceptible to HIV infection and those people with high levels of immunity to the adenovirus had more immune cells activated. "It's possible that repeated immunizations led to repeated transient periods of activation of the immune system that might have made people more susceptible," Walker told Bloomberg. However, he also reportedly cautioned that: "This is real conjecture at this point.'' Should it eventually be shown that the increased levels of infection were directly caused by higher levels of immunity to Ad5, it could cast a shadow over using this subtype in other anti-viral vaccines. Although the director of the International AIDS Vaccine Initiative, Dr Seth Berkley, cautioned against over-reacting. "It's also vital that everybody keeps straight what we know and what we don't know. We know the Merck vaccine didn't work. We don't know why. We know that more people who got the Merck candidate than got the placebo wound up becoming HIV infected. We don't know if that had anything to do with the candidate or not. Given that the trend didn't rise to statistical significance, it could have been chance. And if the vaccine was a factor, we don't know why." The trial itself was initially designed to only test those with low levels of Ad5 immunity as it was recognised that they were likely to respond best. However, volunteers with higher levels of immunity to Ad5 were also subsequently enrolled in the trial because Merck said that new data became available that indicated that the vaccine did work in these people and also, if approved, global vaccination programs would have had to consider any potential effect of pre-existing immunity to Ad5 on the efficacy of the vaccine since frequency of prior natural infection with Ad5 varies. Meanwhile Dr Anthony Fauci, Director of the US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), said that although the new analyses were "both disappointing and puzzling" and offered "no clear explanation" as to why background immunity may have caused more HIV infections, scientists shouldn't give up hope. Especially when you consider that every day, another 12,000 people become infected with HIV, most of whom live in resource-poor countries. Approximately, 40 million people are currently living with HIV infection, and more than 25 million people with AIDS have died. "Historically, vaccines have been the most effective weapon against infectious diseases, such as polio, measles, mumps and smallpox. The goal of developing a safe and effective HIV vaccine is a key goal of HIV research today," he said. "This setback should not and can not diminish our commitment to developing an effective HIV vaccine."