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Human Immunome Program to Push Informatics Boundaries


CHICAGO (GenomeWeb) – Last week, the year-old Human Vaccines Project announced plans to bring in Illumina and the Vanderbilt Vaccine Center at Vanderbilt University Medical Center to make sense of the enormous data sets associated with the human immunome.

"We don't know how big it is," said James Crowe Jr., director of the Vanderbilt Vaccine Center and lead investigator of the Human Immunome Program component of the Human Vaccines Project. "It's like sending a rocket out to the edge of space," he explained.

This project is looking at the "repertoire" of various B cells, which make antibodies, and T cells, which, along with B cells, attack and eliminate viruses. "Each B cell has a receptor that can see a single invader," noted Wayne Koff, president and CEO of the New York-based Human Vaccines Project.

"We don't know exactly how many B-cell and T-cell receptors there are," Koff said.

"There could be as many as 1014 combinations right off the bat," said Crowe, an immunologist and board-certified pediatric infectious diseases specialist. Add mutations and it grows to maybe 1018. "That's just an unfathomable number."

That, according to, Koff, is perhaps 100 billion times larger than the human genome, which contains about 20,000 genes. Because of this difference, the Human Genome Project did not get into sequencing of immune receptors. Back then, in the early 2000s, laboratory and informatics tools were not powerful enough to handle anything like that.

"It's a scale problem for us," Koff said. "We didn't have the instrumentation or computing power we do now."

Behind the complexity is the fact that every person’s immunome is unique. "This could be larger than the Human Genome Project," said Gary Schroth, vice president for product development at Illumina.

The evolution of computation is converging with genomics at a moment when it is most needed, Crowe noted. "It's no longer too big," he said.

In Crowe's estimation, Illumina understands the computational side of this kind of work, even though the scale might be unprecedented. "We need to identify and manage potential mutations at the scale of billions," he said.

That said, this effort will likely stretch current capabilities, since all parties are learning as they go. "We're having to develop new techniques to sequence at this depth," Crowe said.

"This is a nonstandard application for an Illumina sequencer," Schroth said.

From the start, the Human Immunome Program leaned on Illumina sequencing technology, though the San Diego-based sequencing vendor had no direct involvement from a corporate level. "This was a fully formed initiative before we had even heard of it," Schroth said.

"They came to us, as a lot of our customers do," he added. And the new partnership was born. "They really need deep sequencing: millions, even billions of reads," Schroth said.

The Immunome Program seems to fit with the company's mission of improving human health by unlocking the genome. "I personally believe that this will lead to enormous breakthroughs in the areas of vaccines and therapeutics," Schroth said.

The partnership will be using Illumina's older HiSeq sequencing systems in rapid-run mode, a mode not offered on Illumina's new, high-throughput NovaSeq technology that started shipping this month, Schroth said.

"The longer read length is what is important to them," according to Schroth. The Human Vaccines Project is reading 2-by-250 base pairs at a time, he said. "You want to get a lot of elements together in the same read," Schroth said. Illlumina, however, is not committing to having 250-base-pair read lengths in NovaSeq, Schroth noted.

Project leaders hope to open up a new world of precision vaccination, helping immunologists boost the vaccines they currently have and minimize side effects.

Vaccine development, of course, has always been trial-and-error. In the last few years, vaccine researchers have seen failures in their fights against HIV, malaria, dengue and several other infectious diseases, Koff noted. "They failed as a result of our lack of understanding of the human immune system," he said.

"Fundamentally, healthy people don’t make a lot of antibodies to themselves," Crowe noted. The Immunome Program might allow clinicians to winnow down a huge list.

Historically, vaccine researchers have counted on a certain error rate. Consensus from more precise data helps lessen errors. "We are looking at genes that cause errors in themselves," Crowe said.

"In the future, we would envision a time to look at what's at our disposal and design vaccines to those," Crowe explained. "We're trying to determine what's common and good," Crowe said.

And, Koff added, "as we design our next round of vaccines, we want to get as close as possible to 100 percent efficacy." Koff added.

Vanderbilt is performing the laboratory work for the Human Immunome Program. As previously reported, the Human Vaccines Project Bioinformatics and Data Management Core at the Venter Institute and the San Diego Supercomputer Center at the University of California, San Diego, are also supporting the effort.

The Venter Institute and San Diego Supercomputer Center will analyze the data sets with custom software and algorithms to characterize the immunome. “There is no commercial, or otherwise off-the-shelf, software to analyze the details of this data,” Illumina’s Schroth said.

So far, the partners have looked at the immunomes of three donor patients and have, via leukapheresis, identified about 30 to 40 B cells per donor.

"Now we have to begin the analysis," Koff said. "This is a shakedown of the technology."

After the current, initial phase, the plan is to have a pilot lasting a year or two with about 100 donors, involving people from developing countries as well as the developed world, spanning the age spectrum. "That will give us a bird's-eye view of what the immunome looks like," Koff said.

The pilot also will give the project some direction as it enters its planned last phase: analyzing immunomes of 1,000 people.

"We should be able to understand the scale and diversity and commonality of the human immunome," Koff said.

He estimates the whole project to take six to seven years, assuming the funding and resources are available.

Koff has three measures for the program's ultimate success: making immunome analysis a "foundational tool of immunologists and vaccinologists"; accelerating and improving the development of new vaccines; and accelerating the development of new diagnostic tools.

"The Genome Project has ushered in a new era of precision medicine," Koff said. "The Human Immunome Program has the potential to transform public health across the globe."

It has potential in so many areas, including cancer, disease states and the immune system, Crowe explained. "We think it's timely and worth doing."