In the nearly 30-year hunt for a working HIV vaccine, researchers have fiercely debated what that vaccine will look like — and, when people receive the shot, what kind of immune response their bodies will mount that ultimately protects them from infection.
There are several kinds of immune responses that could protect against HIV infection. Researchers at Fred Hutchinson Cancer Research Center have now found that a small but important subset of the immune cells known as T cells may be important for a working HIV vaccine.
Dr. Raphael Gottardo, a computational biologist at Fred Hutch who specializes in vaccine research, led an international research team that devised a unique, computational method to detect a tiny fraction of T cells in HIV-vaccine recipients — cells dubbed “polyfunctional T cells” for their ability to produce several different immune molecules. These polyfunctional T cells, Gottardo's team found, were linked to a lower risk of infection. The team published its findings Monday in the journal Nature Biotechnology.
“It’s not the quantity that matters, but it’s the quality of the cells,” Gottardo said. “And, in fact, we’ve known that for a very long time.”
Gottardo and his team weren’t the first to look for T cells correlated with HIV protection in a vaccine study, but they were the first to find them.
Their finding, Gottardo said, is a big shift from the current paradigm in vaccine research, which has centered in recent years on immune proteins known as antibodies. That focus was due to a study known as the Thai trial, a large clinical trial of an HIV vaccine conducted in Thailand and published in 2009 that showed the first example of an HIV vaccine that actually protected against HIV/AIDS, albeit modestly. Those who received the Thai vaccine had a 31 percent reduced risk of infection with the virus, not enough protection for the vaccine to move to market, and the vaccine’s protection has further waned over time, Gottardo said.
But still, the Thai trial’s partial success was a huge step for the HIV vaccine field – at last, researchers had a concrete, working vaccine to study. Scientists around the world quickly began to try and understand why that vaccine worked while others had failed. In 2012, international research teams (including those involving several Fred Hutch scientists) published studies showing that Thai vaccine recipients who’d remained uninfected had higher levels of a special antibody that binds to one spot in the virus’ outer coating.
Since those findings came out, T cells have taken a bit of a back seat to antibodies in new vaccine studies, Gottardo said, even though their importance in immune protection is undeniable. For example, T cells are needed to help the antibodies work.
“Once the original analysis was done, everyone said, ‘We need to look at antibodies’ … all the novel vaccines have looked at that,” Gottardo said. “There wasn’t a whole lot said about the T-cell side of things.”
That’s because nobody had found any T cells linked to protection from HIV infection — until now.
To look for such T cells, scientists sort cells taken from a trial participant’s blood into multiple categories defined by the immune molecules they produce in a test tube in response to pieces of viral proteins. That test tells researchers which cells are likely to respond to HIV in the body. It’s a powerful approach, Gottardo said, but the problem comes when scientists break those cells up into too many different subsets.
It then becomes challenging to analyze those many results computationally, and researchers may be left with only a few cells in each category, meaning it’s hard to say definitively whether that minute collection of cells has any biological meaning.
“You’re basically slicing your data very thin,” Gottardo said. “The more functions you measure, the harder it is to deal with [the information].”
Other computational approaches aiming to link T cells with HIV protection all looked for larger immune responses, Gottardo said. Even though researchers understand the inherent value of HIV-specific T cells that can make several different immune molecules, nobody had thought of a way to capture that value when the cells were rare.
Gottardo and his team designed a method which, rather than measuring the number of cells in each category, asked whether those cells were or were not present. Using a very sensitive computational approach, the team gathered a simple "yes" or "no" for each subset. That tactic allowed them to level the playing field, Gottardo said, and assess the importance of those rare, polyfunctional T cells.
“Whether it’s very abundant or not so abundant doesn’t matter, as long as you see it,” he said, describing how their approach works. “And that really puts all the different [cells] and their functions at the same level.”
When they analyzed them this way, they found that polyfunctional T cells did matter, and that they seem to work independently from the protective antibodies. That is, the same uninfected people didn’t necessarily have both antibodies and polyfunctional T cells, although Gottardo pointed out that the number of people they analyzed in their study might not have been large enough to find a subtle connection between the two immune responses.
Understanding which cells or proteins are needed to protect people from HIV infection is not just an academic question, it’s critical to the ultimate development of an HIV vaccine effective enough to bring to the public, Gottardo said. Defining the immune signature of protection will help researchers screen new candidate vaccines faster — they can halt trials that aren’t working earlier if that signature is not elicited, saving precious time and money. It also will guide researchers in the design of new vaccines to specifically prompt the right immune response.
“[It helps] us understand what are the things that we need to make a better vaccine,” Gottardo said.
Though just published, their work is already having an impact. Gottardo is part of the international HIV Vaccine Trials Network headquartered at the Hutch, the world’s largest group working to develop an HIV vaccine. All the new HVTN trials will now incorporate tests for polyfunctional T cells, Gottardo said, although researchers will still test for antibodies as well.
“This is huge,” he said. “This is basically guiding future vaccine development.”
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.