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Vaccine Development Stands to Benefit From Results of New Human Immune System Sequencing Project

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NEW YORK (GenomeWeb) – As part of the first phase of the Human Vaccines Project, researchers at Vanderbilt University have started enrolling subjects for the Human Immunome Program — a study aimed at untangling genetic features of the immune system that influence response to everything from invading pathogens to vaccines.

"Ultimately, the plan is to … get an estimate of the world's immunome, the world's collection of antibodies, if not get them all into the database," James Crowe Jr., Vanderbilt Vaccine Center director and leader of the Human Immunome Program, told GenomeWeb.

Just as the human genome project has had applications that may not have been anticipated originally, Crowe said the immunome aims to create a catalog with a wide range of potential uses, including future vaccine design. "We're aiming to broadly expand our knowledge about how things work in the immune system," he said.

Crowe and his collaborators will start by profiling immune patterns in two or three healthy individuals — sequencing B-cell receptors, which are membrane-bound antibodies, and T-cell receptors to saturation in each individual — to test the approach and refine their protocol.

From there, the researchers plan to enroll 100 individuals from diverse ethnic and geographic backgrounds and different age groups to identify as many antibodies and T-cell receptors as possible. Finally, they hope to profile immune features in 1,000 or more individuals, including some receiving established or experimental vaccines who will be tested sequentially over time.

"With those kinds of numbers, you could begin to then think about the common elements found across individuals, which is going to facilitate rational vaccine design," explained Wayne Koff, president and CEO of the Human Vaccines Project, noting that "the future of vaccine design is largely going to be [structure-based]."

"If we only have a few antibodies identified, and vaccine design is based on these rare antibodies, it's likely that they're not going to work in the majority of individuals," Koff said. "So the desire here is to design vaccines against the real human immunome."

The immunome effort falls within the Human Vaccines Project, an international collaboration of academic and nonprofit organizations, industry, and government agencies in a not-for-profit public-private partnership that has seed money from vaccine and immunotherapy developers such GlaxoSmithKline, AstraZeneca's MedImmune, Sanofi Pasteur, Crucell/Janssen, Regeneron, and Pfizer, as well as from philanthropic or nonprofit organizations, including the MacArthur Foundation, the Robert Wood Johnson Foundation, and Aeras.

The effort was proposed in a 2014 commentary in Nature Immunology. Through a series of workshops, investigators discussed potential gaps in immune system knowledge, strategies for using insights into the immune system to accelerate the development of effective and durable vaccines, and scientific approaches for addressing these problems, Koff explained.

"What came out of that was that if one could do a decoding of the human immune system, one had the opportunity to really make huge advances and to have potential for a new way, a new paradigm, of vaccine development," Koff said.

The general strategy and goals of the Human Vaccines Project are further outlined in a perspective article published in Science Translational Medicine in April, where members of the team discussed the effort within the context of cancer vaccine development.

"The recent discovery of immune checkpoint inhibitors has demonstrated that the immune system can effectively control a wide range of cancer in a subset of patients," Koff and his colleagues wrote in that article.

"Building on these discoveries, and harnessing recent technological advances in genetic and immune monitoring," they explained, "successful achievement of the Human Vaccines Project's major objective — to decode the human immune system — will provide the foundational knowledge to accelerate therapeutic cancer vaccine development into clinically useful, powerful therapies."

In particular, Human Vaccines Project members are interested in deciphering the naïve and adaptive aspects of the human immune repertoire across different age groups and populations, along with the neoantigens presented by cancer cells, for example.

For another upcoming arm of the project, the group hopes to untangle what it calls the "Rules of Immunogenicity," or immunological features that produce a durable, long-lasting immune response. That work will be carried out through several small clinical trials.

"If we look a decade ahead, if we really understand the components of the human immune system at the molecular level, and we understand how to drive the immune system to stimulate a specific and durable immune response, then one can begin to think — like our smallpox vaccine and like a couple of other vaccines — of a single shot and a lifetime of protective immunity," Koff said.

He noted that insights from the human immunome effort are expected to help in developing vaccines against existing and emerging infectious diseases, and in coming up with cancer vaccines that can be used alone or in combination with other treatments, such as checkpoint blockade immunotherapy. Understanding the immune system may also highlight processes that go awry in autoimmune conditions such as multiple sclerosis, Crohn's disease, or type 1 diabetes.

For the Human Immunome Program arm of the project, Crowe and his colleagues at Vanderbilt University are teaming up with Human Vaccine Project members at the J. Craig Venter Institute, the La Jolla Institute for Allergy and Immunology, the University of California, San Diego, and the Scripps Research Institute.

Using DNA from white blood cells obtained using a blood donation method called leukapheresis, which nabs some white blood cells by filtration and returns red blood cells and other blood components to the donor, the team plans to do exhaustive amplicon sequencing on T-cell and B-cell receptors.

"That's part of the demo project that we're doing here," Koff said, "to really get the scale of sequencing down and to look at strategies to eliminate errors in the sequencing."

The team estimates that the price tag will come in at around $100,000 per person, though that will depend on the extent of immune diversity present and the sequencing depth needed to capture it, Crowe explained.

"We really have no idea how many sequences an individual has," he said. "To our knowledge, no one has pushed to the very bottom to keep sequencing parallel aliquots from a single individual."

"It may not be that we get every last sequence possible, and we're only looking at a single time point," he added. "But if we keep doing more sequencing and the frequency of identifying new sequences begins to reduce over time, minimally we'll be able to estimate new sequences that that person actually has in their sample."

Crowe said the initial effort will likely rely on the Illumina HiSeq 2500 with V2 chemistry, which appears to give greater amplicon sequencing depth. But because the 250-base paired-end reads that can be achieved with that approach will cover only the heavy chain or light chain of a given antibody, he explained, researchers are looking at ways to incorporate longer Pacific Biosciences reads as well.

"It's desirable to link the heavy chain and light chain [of an antibody] from a single cell," Crowe said. "That is technically very demanding right now, and the Illumina platform isn't easily used for that, so we've also been using PacBio sequencing to get longer read lengths."

Due to the vast number of T-cell and B-cell receptors that can theoretically be produced through recombination, the scale of the human immunome will likely dwarf that of the human genome, according to Koff.

"We couldn't have thought of doing this years ago because we didn't have the bioinformatics approaches to handle this large amount of data, and we didn't have the computational approaches to do the rational vaccine design," he noted.

Crowe said some of the informatics work for the immunome project may be done at Vanderbilt, though JCVI and UCSD's San Diego Supercomputer Center will act as bioinformatics hubs for the larger Human Vaccine Project, owing to the large amounts of data storage and processing needed.

Because leukapheresis typically yields some 40 billion white blood cells for each individual, the immunome team plans to make aliquots of the sample available for collaborators keen to analyze them with other approaches, such as 5'-RACE.

"The intention is to engage the broader community to sequence aliquots of these cells in parallel, to benchmark all of the techniques," Crowe said.

For the moment, the team is focusing on leukocytes in the blood, though Koff explained that there may be an advantage in doing tissue-specific testing — particularly lymph node profiling — in the future.

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