Author: Paul Goldsmith

3D human tissue construct could de-risk vaccine development

Ofer Levy (L) with Guzman Sanchez-Schmitz (PHOTO: MICHAEL GODERRE)

Immunization is one of modern medicine’s greatest success stories. Yet we still lack vaccines for common diseases such as HIV and respiratory syncytial virus. Other vaccines are only moderately effective, like those against tuberculosis or pertussis. The average vaccine can take a decade or more to develop, at a cost of hundreds of millions of dollars, and vaccines that worked flawlessly in mice regularly fail in clinical trials. As a result, many companies are reluctant to enter into vaccine development.

“We need a way to rapidly assess vaccine candidates earlier in the process,” says Ofer Levy, MD, PhD, a physician-scientist in the Division of Infectious Diseases at Boston Children’s Hospital and director of the Precision Vaccines Program. “It’s simply not possible to conduct large-scale, phase 3, double-blind, placebo-controlled studies of every potential vaccine for every pathogen we want to protect against.”

In a paper published today in Frontiers in ImmunologyLevy’s team describes the first modeling laboratory system for testing human immune responses to vaccines — outside the body.

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From the ashes of a failed pain drug, potential treatments for autoimmunity and cancer

BH4 pathway - orchestra concept
ORCHESTRATING T-CELL RESPONSES: The BH4 pathway can be quieted with a small-molecule inhibitor to calm T-cell responses in autoimmune disease, or tuned up to activate T cells in cancer. (ILLUSTRATION: TIBOR KULCSAR/IMBA)

In 2013, renowned Boston Children’s Hospital pain researcher Clifford Woolf, MD, PhD, and Kai Johnsson, PhD, his fellow co-founder at Quartet Medicine, believed they held the key to non-narcotic pain relief. Woolf had shown that tetrahydrobioptrin — a protein also known as BH4 — is a primary natural modulator of neuropathic and inflammatory pain sensitivity. Quartet was founded on the premise that inhibiting BH4 production could prevent the progression of acute pain to chronic pain in millions of patients, without threat of addiction or tolerance.

With solid human genetic data and chemical biology, plus $17 million in series A funding, Quartet looked primed for success. But in the summer of 2017, toxicology studies of the company’s lead candidate revealed neurologic side effects. Hope for the promising pain drug cratered, taking Quartet with it.

Now, however, a surprising discovery about BH4 will likely rekindle interest in the once-promising pathway and could have profound implications for treating autoimmunity and cancer. In yesterday’s Nature, Woolf and his team at Boston Children’s Hospital, together with immunologists from the Institute of Molecular Biotechnology (IMBA) in Vienna report that BH4 also functions as a kind of immunological thermostat in the body, raising and lowering the activity levels of T cells.

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