In 2009, a study in Thailand proved for the first time that an AIDS vaccine was possible. But scientists were not sure why it offered some protection. Now they have some clues.
The Thailand study looked at a vaccine candidate called RV144. Since the results were announced, researchers have been combing through the data. What was it about this vaccine candidate that offered a protection rate of 31 percent? It was not high enough to go to market, but high enough to cause a lot of excitement for vaccine researchers.
"Once you have a vaccine that works, the next step in terms of the evolution of the vaccine is to try to first understand why it worked, with an idea that if we find out specifically what lab tests seem to correspond with protection we can design a new set of vaccines that might provide better protection," said Col. Jerome Kim, senior author of a new follow-up study on RV144.
Antibodies
Kim, a medical doctor with the U.S. Military HIV Research Program, said when the RV144 results were announced scientists thought the success might be due to antibodies. These are proteins that bind to viruses and disable them.
"But we didn't really know," he said, "and so we looked very, very broadly at a number of different immune responses. And looking very broadly then allowed us to down-select – to pick out only those things which were the most important. Because that statistically gives us the greatest ability to say after all the testing's done, this was important."
The follow-up studies eventually led to two antibodies, one called IgG and the other IgA. Some in the Thai trial had more of one type of antibody than the other. Both, though, were drawn to a part of HIV called the envelope.
Kim said, "HIV is a member of a group of viruses where the outer coat actually is composed of a little bit of what you call membrane and then what we call viral spikes. And these viral spikes stick out of the membrane and envelope is contained in those spikes. And very often when vaccines work, the antibody is directed against these spikes because they're prominent. They stick out and the immune system sees them and says, Ah ha! Let's make an immune response against it."
But when it comes to HIV, Col. Kim said that's easier said than done.
"The virus envelope is very variable. And it's one of the reasons why we were so worried that no vaccine might ever be possible. Because like the flu virus, the HIV virus changes its envelope and does it very quickly, actually many times faster than the flu virus can," he said.
A particular region of the envelope called V2 was the target of antibody response. This region may have something to do with how HIV mutates to avoid detection.
"There is a part of the HIV envelope which exposed to the surface. So that's very important because if it's buried way, way down in the envelope the antibodies aren't going to be able to reach it," he said.
What's going on?
The IgG and the IgA antibodies responded differently to the HIV envelope. But IgG was associated with a better vaccine protection rate by binding to the envelope V2 region. IgA, on the other hand, took a more broad approach to viral envelopes. Initially, it was thought that this resulted in greater risk of infection. Kim says it was both unexpected and confusing, but it raised a number of hypotheses.
"They looked to see, is it actually making infection worse? And in fact it's not. What it's doing is it appears to potentially block the beneficial effects that were being seen with other immune responses. So it's a blocking of the good response rather than something that increases the risk of infection," he said.
The antibodies were apparently competing with each other to bind to the envelope. Initial studies indicated IgA had a binding advantage over IgG. But Kim says that did not mean people were more likely to be infected with HIV.
"Really, the risk of HIV infection in people who had high levels of IgA was similar to the risk of infection to people who got placebos. They knocked down the beneficial response. They didn't create a bad response," he said.
And that could be one reason why the efficacy rate of RV144 was not higher than 31 percent.
Kim said a lot more research is planned on the RV144 vaccine results, including follow-up studies. In fact, two trials are expected next year using similar vaccines. One would be tested in Thailand on the high risk group called men who have sex with men. The other would be tested against HIV Subtype C, which is a virus that's predominantly found in southern Africa. Despite the vaccine breakthroughs, an effective AIDS vaccine is still considered years away.