Researchers Discover Strategy for Predicting the Immunity of Vaccines

In the first study of its kind, researchers at the Yerkes National Primate Research Center and Emory Vaccine Center, Emory University, have developed a multidisciplinary approach involving immunology, genomics and bioinformatics to predict the immunity of a vaccine without exposing individuals to infection. This approach addresses a long-standing challenge in the development of vaccines—that of only being able to determine immunity or effectiveness long after vaccination and, often, only after being exposed to infection.

The study, which used the yellow fever vaccine (YF-17D) as a model, is available in the online edition of Nature Immunology and represents a long awaited step forward in vaccine immunology and predictive health.

YF-17D is one of the most successful vaccines ever developed and has been administered to nearly half a billion people over the last 70 years.

"A single shot of the vaccine induces immunity in many people for nearly 30 years,” says Bali Pulendran, PhD, lead Yerkes researcher of the study and professor in the Department of Pathology and Laboratory Medicine at Emory University School of Medicine. “Despite the great success of the yellow fever vaccine, little has been known about the immunological mechanisms that make it effective,” he continues.

Pulendran’s team, including graduate student Troy Querec, PhD, in collaboration with Rafi Ahmed, PhD, director of the Emory Vaccine Center, Eva Lee, PhD, director of the Center for Operations Research in Medicine and Healthcare at Georgia Institute of Technology and Alan Aderem, PhD, Institute for Systems Biology in Seattle, sought to determine what makes such a vaccine effective so researchers can design new vaccines against global pandemics and emerging infections that repeat the success of this model vaccine.

The researchers used YF-17D to predict the body’s ability shortly after immunization to stimulate a strong and enduring immunity. Researchers vaccinated 15 healthy individuals with YF-17D and studied the T cell and antibody responses in their blood. There was a striking variation in these responses between individuals. Analysis of gene expression patterns in white blood cells revealed in the majority of the individuals the vaccine induced a network of genes involved in the early innate immune response against viruses.

A major challenge in the study involved the identification of discriminatory gene signatures—among over 50,000 genes—that can predict the responses of T cells and antibodies. Lee has developed powerful modeling, computational feature selection and predictive tools that overcome shortcomings of existing techniques, which often have limited ability to handle data sets involving heterogeneous, large-scale, ill-separated and mixed biological and medical data. Her approach offers a very robust classification framework that effectively handles such data sets and derives a classifier that often provides higher prediction accuracy and lower misclassification errors than classifiers derived from other methods.

"Using such a bioinformatics approach, we were able to identify distinct gene signatures that correlated with the T cell response and the antibody response induced by the vaccine,” says Pulendran. “To determine whether these gene signatures could predict immune response, we vaccinated a second group of individuals and were able to predict with up to 90 percent accuracy which of the vaccinated individuals would develop a strong T or B cell immunity to yellow fever,” continues Pulendran.

Pulendran and his colleagues are now working to determine whether this approach can be used to predict the effectiveness of other vaccines, including flu vaccines. The ability to successfully predict the immunity and effectiveness of vaccines would facilitate the rapid evaluation of new and emerging vaccines, and the identification of individuals who are unlikely to be protected by a vaccine.

"This type of research is essential to answer fundamental questions that can lead to better vaccinations and prevention of disease. Yerkes, as one of only eight National Institutes of Health–designated national primate research centers, is uniquely positioned to carry out such diverse research,” says Stuart Zola, PhD, director, Yerkes Research Center.


Funding for this study was provided in part by the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH), as part of the U19 Cooperative Centers for Translational Research on Human Immunology and Biodefense. Dr. Lee’s research is supported partially by the National Science Foundation, and the National Center for Research Resources at the National Institutes of Health, as part of the U54 Clinical and Translational Science Awards.

Reference: Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nature Immunology, early online publication. Troy D. Querec, Rama S. Akondy, Eva K. Lee, Weiping Cao, Helder I. Nakaya, Dirk Teuwen, Ali Pirani, Kim Gernert, Jiusheng Deng, Bruz Marzolf, Kathleen Kennedy, Haiyan Wu, Soumaya Bennouna, Herold Oluoch, Joseph Miller, Ricardo Z. Vencio, Mark Mulligan, Alan Aderem, Rafi Ahmed and Bali Pulendran.

The Center for Operations Research in Medicine and HealthCare, founded in 1999 with partial support from the National Science Foundation and the Whitaker Foundation, is a collaborative education and research center established between the School of Industrial and Systems Engineering at Georgia Institute of Technology and medical and healthcare researchers in different disciplines. The Center’s mission is to foster interdisciplinary education and research efforts involving the development and application of sophisticated techniques from the field of operations research to problems in medicine and healthcare.
Focusing on biomedicine and health systems, researchers in the center perform systems modeling, design and develop algorithms and software, and utilize decision theory analysis to advance various domains within medicine. Specific research areas include computational genomics, health risk prediction, disease diagnosis and early detection, optimal treatment strategies and drug delivery, healthcare outcome analysis and treatment prediction, public health and medical preparedness, large-scale medical decision analysis, quality improvement and clinical operations management.

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Regulatory B Cells Do Exist – and Pack a Punch

Researchers at Duke University Medical Center have uncovered definitive evidence that a small but potent subset of immune system B cells is able to regulate inflammation.

Using a new set of scientific tools to identify and count these cells, the team showed that these B cells can block contact hypersensitivity, the type of skin reactions that many people have when they brush against poison ivy.

The findings may have large implications for scientists and physicians who develop vaccines and study immune-linked diseases, including cancer. Once the cells that regulate inflammatory responses are identified, scientists may have a better way to develop treatments for many diseases, particularly autoimmune diseases such as arthritis, type 1 diabetes and multiple sclerosis.

"While the study of regulatory T cells is a hot area with obvious clinical applications, everyone has been pretty skeptical about whether regulatory B cells exist," said Thomas F. Tedder, Ph.D., chairman of the Immunology Department and lead author of the study published in the May 16 issue of Immunity. "I am converted. They do exist."

Koichi Yanaba and Jean-David Bouaziz identified this unique subset of small white blood cells, which they call B10 cells, in the Tedder laboratory.

The researchers found that B10 cells produce a potent cytokine, called IL-10 (interleukin-10), a protein that can inhibit immune responses. The B10 cells also can affect the function of T cells, which are immune system cells that generally boost immune responses by producing cytokines. T cells also attack tumors and virus-infected cells.

The study was supported by grants from the NIH, the Association pour la Recherche contre le Cancer (ARC), Foundation Rene Touraine, and the Philippe Foundation.

Depleting B10 cells may enhance some immune responses, Tedder said. Enhancing B10 cell function may inhibit inflammation and immune responses in other diseases, like contact hypersensitivity.

"Now that we have been able to identify this regulatory B cell subset, we have already developed treatments that deplete these cells in mice. We are moving to translate these findings to benefit people," he said.

"The discovery of the ability to identify this potent regulatory cell type should provide important clues to how the immune system regulates itself in response to vaccines as well as infectious agents," says Barton F. Haynes, M.D., leader of the international Center for HIV/AIDS Vaccine Immunology (CHAVI), a consortium of universities and academic medical centers, and director of the Duke Human Vaccine Institute. "This information should enable researchers to design ways to help the immune system control infections more effectively, and could be a useful advance as we refine approaches to preventing HIV infection."

There's a huge initiative underway to look at regulatory T cells in autoimmune disease, HIV infection, and cancer therapy," Tedder said. "What we have also shown is that it is not only regulatory T cells, but also regulatory B cells that could prevent a person from making effective immune responses in HIV and many other diseases, particularly cancer."

The Duke researchers developed a way to mark the B10 cells so that they could see that just these cells were producing IL-10. Previously, scientists could only purify a population of B cells and see whether IL-10 could be produced by some of these cells in the population.

In this study, they found that the B10 cells represented only 1-2 percent of all of the B cells in the spleen of a normal mouse. Before this, no one had definitively identified this B cell subset or such regulatory B cells in normal mice, although B cell regulatory function had been described in some genetically altered mice with chronic inflammation.

"In this study, we could directly look at the B cells that were producing IL-10, and figure out what their cell surface molecules looked like, so that we could isolate them. This allowed us to show that this rare subset of B cells controlled immune responses by producing IL-10, which inhibits T cell inflammatory responses," Tedder said.

The scientists studied a special mouse (CD19-deficient) with altered genes that give them an increased contact hypersensitivity reaction. As it turned out, these mice lacked B10 cells, which resulted in exaggerated inflammation reaction. "This allowed us to show that giving CD19-deficient mice a few B10 cells had a big effect on reducing inflammation," Tedder said.

They found that depleting all B cells in the mice also resulted in worse inflammation. Since total B cell depletion therapies are now being used to treat people with B cell cancers and autoimmune disease, these findings help to further explain how these therapies treat disease. They also open the door to creating new therapies that take advantage of the power of B10 cells.

This is the first of several papers that will describe cases in which regulatory B10 cells help control immune responses, Tedder said.

Karen Haas and Jonathan Poe of the Duke Department of Immunology, and Manabu Fujimoto of the Department of Dermatology at Kanazawa University Graduate School of Medical Science in Ishikawa, Japan, were the paper's other authors.