Editor’s note: Although best known as a cancer research center, Fred Hutch also is a hub of HIV research. This is one of a series leading up to World AIDS Day on the breadth of our work, from investigating HIV at a molecular level to searching for a cure to running the world’s largest HIV vaccine clinical trials network.
More than three decades have passed since the discovery of the AIDS virus and the famously flawed prediction of an HIV vaccine within two years. Yet scientists have never stopped trying, and now they are enlisting a surprising new ally in their quest for an effective vaccine: the microbiome.
At Fred Hutchinson Cancer Research Center, Dr. James Kublin and his colleagues are in their second year of a five-year federal grant to study how the microbiome — the diverse community of bacteria and other microbes that inhabit our bodies, particularly our gut — alters the immune system’s response to vaccines.
Their study is already providing new insights into the complex interactions between gut bugs and the immune system, with implications that could lead to improved vaccines of all kinds.
“I am entranced by this,” said Kublin, a principal staff scientist for the Vaccine and Infectious Disease Division who also serves as executive director of the HIV Vaccine Trials Network, the largest publicly funded global network developing HIV/AIDS vaccines, headquartered at the Hutch.
Now Kublin wants to know exactly what happens to the body’s ability to develop immunity from a vaccine — against, say, HIV, tuberculosis or polio — in people with different communities of bacteria in their gut.
Research has already shown that a rotavirus vaccine, which protects against severe diarrhea, works well in Africa among infants whose gut microbiomes are similar to those of children in industrial countries but not so well in those whose gut-bug composition is commonly found in children who are malnourished. The microbiome can profoundly influence the body’s array of white blood cells and antibodies that defend against hostile invaders. These microbial communities also may determine how well vaccines, often designed to resemble the dangerous bugs they target, might work.
That is why a Duke University study of a failed HIV vaccine has become so important. In 2013 one of the largest vaccine trials conducted by HVTN was halted after an early look at the data showed it did not block HIV infection. Two years later, the Duke team, including HVTN researchers and biostatisticians, reported that a component of the vaccine known as gp41 — meant to stir up protective antibodies against a surface feature of the AIDS virus — instead “cross-reacted” to a similarly shaped protein found on common gut bacteria. It is as if the immune system was lured off-target by a decoy.
Kublin and his team are following up on that discovery with evidence of cross-reactivity with the same gp41 protein in other HIV vaccine trials. Under their federal grant, they are determining from genetic sequencing of stool samples what gut bugs comprise the microbiomes of more than 1,000 participants who have volunteered in one of five different HIV vaccine trials. Within just a few months, they will begin collecting data measuring each participant’s response to the vaccines. “Then, it is a matter of analyzing the relationship between their microbiomes and the vaccines,” said Kublin.
Meanwhile, they are also embarked on an ambitious preclinical study to understand how common gut bug species interact with vaccines. Using mice bred in sterile environments so they begin life with no gut bacteria, the researchers can carefully construct a microbiome for them with one specific bug, or five, or a community of 50. These mice then receive one of several different types of vaccines — including several varieties of HIV vaccines previously tested or currently in human clinical trials. Some mice will also be given immune-stimulating adjuvants, often added to vaccines to increase their effectiveness.
These mice studies are exploring in a very systematic fashion how specific gut bugs, or communities of them, interact with the mouse immune system and to specific vaccines. While it is too early to draw conclusions from these studies, there are clearly different vaccine responses with different microbial communities. Kublin said investigating a variety of vaccines, adjuvants and microbial communities will be “a great analytical challenge and opportunity.”
The outcomes of these studies could lead to new strategies in vaccine design to overcome decoys such as the gp41-like protein found in gut bacteria, or to the development of bacterial cocktails — probiotics — tailored to produce a more favorable response in advance of a vaccine. Researchers are considering strategies to immunize children with HIV vaccines early, before their microbiomes are fully developed, so that they might avoid the microbial tamp-down of immunity.
It will take years to tease out information from these studies about the complex interactions between gut bacteria and the immune system, but it is becoming clear that all vaccine development in the future will have to consider the influence of the bacteria that live within us.
“The immune system exists in a delicate balance between tolerance and immunity,” said Kublin, “and the development of the immune system is inextricably linked to the development of the microbiome.”
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Sabin Russell is a staff writer at Fred Hutchinson Cancer Research Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT, and a freelance writer for the New York Times and Health Affairs. Reach him at firstname.lastname@example.org.