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To Crack the Vaccine Code, UBC Assembles Its Own “Ocean’s Thirteen”

By May 15, 2017No Comments

Vaccines have rightly come to be regarded as one of modern medicine’s greatest accomplishments, having prevented millions of cases of smallpox, yellow fever, polio, tetanus and other debilitating, often deadly diseases.

But UBC vaccine expert Tobias Kollmann would be one of the last people to declare victory.

He sees all of the diseases caused by pathogens for which no vaccine exists despite monumental research efforts: malaria, tuberculosis, HIV, to name just three.

He laments all of the existing vaccines that require more than one dose. Even with booster shots, most vaccines don’t provide life-long immunity.

And he feels hamstrung by the restrictive timing on so many vaccines. For example, there is a narrow window during which babies should receive certain vaccines.

The ideal is a vaccine that needs to be given just once, at any age, and still provide protection for the rest of that person’s days. But getting there will require a different approach than the trial-and-error that has gotten us this far.

“We need to have a better understanding of how vaccines work,” says Dr. Kollmann, a Professor and Acting Head of the Division of Infectious Diseases in the UBC Department of Pediatrics. “To do that, we need to take a systems biology approach – capturing every signal that we can to crack this ‘vaccine code’.”

Dr. Kollmann and Assistant Professor Manish Sadarangani have been tapped by a global consortium, called the Human Vaccines Project, to take that first step.

From their lab at UBC’s Vaccine Evaluation Center, they are leading a small but intensive project aimed at gleaning every bit of relevant data from 10 adults who receive the vaccine for Hepatitis B.

That vaccine, which has been on the market for more than three decades, is hardly experimental. But this would be the first comprehensive examination of how it actually works, examining the whole gamut of fundamental biology – not just the stars of the immune system, white blood cells and antibodies, but the background players as well, including RNA (which reveals gene expression), proteins, metabolites (the catalysts for biochemical reactions) and even the bacteria that live on and in us.

This is also the first vaccine study to look at not only blood, but cells taken from participants’ lymph nodes, “because that is really where the action is,” Dr. Kollmann says.

It’s a demonstration project – hence the tiny sample size. Its main goal is not to find answers to the big questions, but to develop the best strategy for finding answers.

Dr. Kollmann and Dr. Sadarangani, the new Director of the Vaccine Evaluation Center, have rounded up a scientific version of the “Ocean’s Thirteen” gang: 13 faculty members, each of whom has world-class expertise in a specific topic. The crew includes Professor of Medical Genetics Ryan Brinkman, who will find out if the cellular composition of blood predicts the response to vaccination; Professor Bob Hancock from the Department of Microbiology and Immunology, who examines how genes are expressed through RNA; Professor of Biochemistry and Molecular Biology Leonard Foster, who will look for patterns in protein and metabolite levels; Medical Genetics Professor Michael Kobor, who will search for epigenetic changes that switch genes on or off; and Pathology and Laboratory Science Professor Mel Krajden, who will determine the amount of antibody generated in their volunteers following hepatitis B vaccination.

Two of the linchpins on UBC’s team, Dr. Hancock and Associate Professor of Medicine Scott Tebbutt, will help parse the jumble of data that Dr. Kollmann likens to a “hairball.” “They are really like hackers of the secret code hidden in a huge amount of biological data,” Dr. Kollmann says.

“Until now, investigations of vaccine reactions have been as siloed as the scientists doing them, so gene expression, proteins, metabolites and immune cells have been examined separately,” Dr. Sadarangani says. “This is the first time that all of these different tests will be done in the same individuals – the first time anyone has looked at the black box in its entirety, and then tried to integrate all of the data, which is billions of pieces for each person.”

The Human Vaccine Project wants to replicate the success of one of the newest vaccines – the one that protects against the human papillomavirus (HPV), which is the main cause of cervical cancer.

The HPV vaccine is inactivated so it can’t trigger the illness it is meant to protect against. Unlike most other inactivated vaccines, scientists believe that one dose of HPV might be enough to provide lifetime protection. (They aren’t yet sure, because the HPV vaccine has been in widespread use for only a decade, mostly given in three doses. Governments just recently switched to recommending or giving two doses instead of three, based in part on studies by UBC, and there are clinical trials under way to determine if one dose is sufficient.)

Few other vaccines have the kind of one-dose stopping power ascribed to the HPV vaccine. But for the exploratory mission of the Human Vaccine Project, that makes it almost too effective. What the Human Vaccine Project wants to know is why most other vaccines fall short, so they can shore up those weaknesses, and apply those insights to diseases for which no vaccines exist.

The Hepatitis B vaccine fits that “glass half-full” profile. It is an inactivated vaccine, and can be given to someone at any age. But only 30 per cent of people become immune after just one dose, with another 45 per cent needing two doses, and another 15 per cent needing three. (As a result, the standard regimen is to give three doses.)

The Hepatitis B vaccine offers another advantage: Scientists have a better sense of how it works compared with most other vaccines. The antibodies produced by the Hepatitis B vaccine, if extracted, purified and given to an unvaccinated person, are enough to stave off infection. That is not true with most other vaccines: There is something about these other vaccines – not just antibodies – that provides immunity. Scientists don’t know what those other elements might be, and at this stage in the Human Vaccine Project, they want to keep a lid on such variables.

“Hepatitis B vaccine is a perfect model for deciphering how vaccines work,” Dr. Sadarangani says.

The notion of examining not just blood, but lymph node cells, seemed a bit bizarre to Dr. Kollmann at first – and he was the one who proposed doing it.

Even though the lymph nodes are the clearing house for foreign bodies, and most of the reactions that lead to immunity or recovery from infection take place there, blood remains the default source for immunological data.

“We use blood as a proxy for the immune system, but only because it’s so easily accessible,” Dr. Sadarangani says.

Taking samples from the lymph node does require an interventional radiologist – in most cases, that has been Manraj Heran, an Associate Professor in the UBC Department of Radiology. He inserts a needle just below a person’s underarm, and using ultrasound, guides it into the lymph node, then sucks out a small amount of tissue, which he then empties into a vial.

But the procedure actually hurts less than a blood draw because the needle is smaller.

“The only actual pain is putting in the local anesthetic, and it’s just a little pinprick,” says Geoffrey Ainsworth, a 69-year-old volunteer. “The radiologist was extremely skillful, and I could see on the ultrasound screen what was happening. To be able to put a tiny needle like that in the lymph node, it’s amazing. I’m fascinated that you can do things on such a minute scale.”

“I hope our study will open the door to making lymph node biopsies more commonplace for vaccine evaluation,” Dr. Sadarangani says.

In addition to the lymph node and blood cells, the project is collecting multiple nasal, mouth, skin and fecal samples from each participant, with the intention of looking for correlations between immune response and the microbiome.

All of that material is divvied up among various UBC researchers. In addition, some material is sent to Vanderbilt University in Tennessee, the Pasteur Institute in Paris, and three labs in southern California – the J. Craig Venter Institute, the Scripps Research Institute and the University of California, San Diego.

Each of these labs has world-class experts that will extract the most information out of these tiny samples, and then put it together into one coherent biological narrative.

The Human Vaccines Project, the non-profit public-private partnership that chose Dr. Kollmann’s and Dr. Sadarangani’s proposal, is modeling itself on the Human Genome Project – and has similarly lofty ambitions.

The idea took shape at a meeting La Jolla, California, in 2014, when 35 leading global scientists from the public and private sectors gathered to discuss the primary scientific hurdles impeding the development of new vaccines. Recognizing the potential of technological advances in genomics, bioinformatics and systems biology, they called for a decade-long, $1 billion-plus effort to decode the human immune system.

Thus was created the Human Vaccines Project. Initially incubated by the International AIDS Vaccines Initiative (IAVI) with seed funding from the Robert Wood Johnson Foundation, it is supported by a founding Board of Directors and an independent, internationally-recognized Scientific Steering Committee that includes Nobel laureate Peter Doherty of the University of Melbourne. Its funding so far comes from a mix of academic institutions and drug companies.

But progress will also depend on volunteers like Geoffrey Ainsworth, a semi-retired pediatric psychiatrist (and UBC Clinical Instructor) who has agreed to make a dozen visits, giving blood and other samples each time, and lymph node samples twice.

Immunology has intrigued Dr. Ainsworth since his days as a medical student in the U.K. When he worked as a family physician in Fort St. John, he quietly wondered to himself why people overreacted to certain stimuli, but if exposed to a small or altered version of it, they would be able to mount a resistance.

“There are explanations to that, but they don’t really make sense to me,” he says.

He also was impressed to hear that his samples are being scrutinized by experts in three countries on two continents.

“Even though it has been quite time-consuming, the experience has been quite enjoyable,” he says, adding, “They have made it clear I am involved in something that is really important.”