The 2003 “Thai trial” was the first AIDS vaccine trial to demonstrate protection from HIV infection in humans, albeit the reduction of infection risk was modest. Since then, scientists have been endeavoring to find out why the vaccine was effective in some but not others. Finally, we may now have some answers. According to a fascinating new study, host genetics played a significant role in determining whether people’s immune systems would produce the right kind of response and thus provide protection against infection.

Not only is this one of the first really tangible examples to show how a person’s genome will determine how they respond to a vaccine, but it could have huge implications for future trials should the same be observed with different vaccines.

“This study gives us insight into how people are more likely to do better or worse with certain vaccines,” study author Col. Nelson Michael, Director of the U.S. Military HIV Research Program, told IFLScience. “We may even get to the point where we could look forward in time and predict that.”

Back in the ‘90s, two candidate HIV vaccines were developed, which disappointedly proved to be ineffective in clinical trials and were thus deemed failures. But a landmark trial in Thailand, called RV 144, later decided to try them out in combination, which demonstrated that together they could provide protection. After 12 months, the rate of infection was 61% lower in those vaccinated than those with the placebo, but this fell to 31.2% over the next two years.

These findings posed an intriguing question: Why were only some people protected? A follow-up study revealed that the vaccine induced two different immune responses that were associated with HIV-1 acquisition. Some people generated a type of antibody, called IgG, against a spiky outer portion of HIV-1 that decreased the likelihood of becoming infected. Others, however, produced a different type of antibody, IgA, against the same HIV-1 protein, but these were actually associated with an increased risk of infection.

It’s important to point out, however, that the latter does not mean the vaccine made people more likely to become infected, but rather infection rates were similar among this group and those given a placebo, Nelson explains. But what was driving these two different antibody responses? That was the focus of this latest study that set out to examine whether genetics could be playing a part.

The researchers were particularly interested in the genes for molecules called HLA class II, which present bits of pathogens to the immune system and subsequently drive the production of antibodies against them. The genes for these molecules are also highly variable, so scientists wanted to see if differences in these sequences could explain the two responses observed.

As described in Science Translational Medicine, the researchers found that variations in these genes modulated the quantity and quality of antibody responses to the vaccine, which ultimately affected vaccine efficacy and the likelihood of infection. This shows that there exists a genetic predisposition to the kind of immune response that will be generated to the vaccine, which is “really exciting work,” says Michael.

The findings are especially important given the upcoming trial in South Africa that will examine the same vaccine regimen, albeit the design has changed significantly to reflect the dominant HIV strain circulating in this area. In light of this study, scientists are already planning to conduct similar sequencing studies to go hand in hand with the trial data, Michael says. Ultimately, if scientists do these genetic tests alongside all vaccine trials, we may be able to predict whether a vaccine will work prospectively, rather than retrospectively.