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. The platform, using all human components, consists of a three-dimensional tissue construct that is able to reproduce immune responses of different populations and age groups. It is designed to enable researchers to evaluate human vaccine candidates for target populations, such as newborns and the elderly, before initiating costly human or animal trials.

Levy, senior author on the paper, hopes the new platform will accelerate and de-risk the development, assessment and selection of vaccines. “We believe this system could disrupt and galvanize the entire field of vaccinology and ultimately save lives,” he says.

Age-specific modeling of immune responses

In 2010, Levy and his colleague Guzman Sanchez-Schmitz, MSc, PhD received a grant from the Bill and Melinda Gates Foundation to create an in vitro model of the human immune system to test vaccines. It was a “man on the moon” effort, says Levy. The team set out to create a system that would not only faithfully replicate human biology, but would also enable the study of targeted age groups.

Infants and the elderly are most at risk from infection, suggesting broad age-based differences in immunity. And while infants receive the most vaccinations, many vaccines don’t provide sufficient protection initially, requiring multiple boosters to confer full immunity.

“We were radically committed to being age-specific in our approach,” said Levy. “Vaccines work differently in kids, and yet they are the group that needs the most protection.”

A personalized human tissue construct for vaccine testing
Step 1: A study participant’s immune cells (monocytes) are applied to the tissue construct, which consists of a layer of human endothelial cells grown over a 3-D network of human proteins. The monocytes migrate down into the protein matrix, mimicking the natural movement of monocytes out of capillaries and into local body tissues. Step 2: A vaccine is added to the construct, which is incubated for 48 hours. Some of the monocytes differentiate to become dendritic cells during this time. Step 3: Mature dendritic cells emerge from the construct, resembling the movement of the body’s dendritic cells to the lymphatic (lymph node) system. Step 4: Dendritic cells are harvested from the construct and cultured with T cells from the same study participant to measure immune response.

Replicating human biology

The construct is designed to replicate a human capillary vein and interstitium — the fluid-filled spaces that line the circulatory system. A layer of endothelial cells, which typically line blood vessels, are grown over a 3D network of human proteins. To model the immune system of a newborn or an adult study participant, the researchers apply the participant’s plasma and immune cells (monocytes) to the surface of the construct.

The monocytes naturally migrate down through the endothelium into the human proteins below. Along the way, many differentiate to dendritic cells, immune cells that initiate specific immune responses from T cells. After two days, these dendritic cells rise back through the endothelial layer, just as in the body they would pass through the walls of lymphatic capillaries en route to the lymph nodes.

When an effective vaccine is added to this system, the emerging dendritic cells pick up the vaccine antigens. These cells are then harvested and cultured with T cells to gauge immune response to the vaccine.

“We relied on only human components, ensuring that the only thing that is not human-derived is the vaccine,” said Sanchez-Schmitz, first author on the paper. “That’s what makes this platform powerful. You can detect small amounts of foreign material in a way that other systems cannot, because you lower the threshold of background noise. Just as nature intended it.”

A personalized platform

The team successfully validated the system using two common, licensed newborn vaccines: Bacillus Calmette–Guérin (BCG), a live-attenuated bacterium widely used to immunize against child tuberculosis, and hepatitis B vaccine (HBV), containing inactivated fragments of the pathogen coupled with alum, added to boost immune response to the vaccine.

“We started with vaccines that are recommended by the World Health Organization and given to newborns in resource-poor settings,” says Levy. “If we were going to model responses by age, it made sense to choose vaccines that are given to newborns, such as BCG and HBV.”

The system will also enable researchers to model the immune systems of other vulnerable populations, such as pregnant women, the elderly or the chronically ill.

“This construct is highly versatile. It can be newborn, if you use newborn cells and plasma. It can be your own cells and plasma. That’s how personalized this system can be,” says Sanchez-Schmitz.

Vaccines for the vulnerable

The system marks a major advancement for Boston Children’s Precision Vaccines Program, which was founded to bring precision medicine principles to vaccinology and catalyze collaboration between academia, government and industry, with the goal of accelerating vaccine development for vulnerable populations.

“Our in vitro systems are part of a larger precision vaccines paradigm that also includes special adjuvant systems to boost immune responses in distinct populations, targeted clinical trials, systems biology and animal modeling,” says Levy. “This is an opportunity to bring molecular biology and innovative immunology to human settings, and to do science that not only is sophisticated, but has a real chance in the near term to enhance human health.”

The study was funded by the Bill and Melinda Gates Foundation, the National Institutes of Health/National Institute of Allergy and Infectious Diseases and the Boston Children’s Technology Development Fund, which is working with Levy and Sanchez-Schmitz to further validate and commercialize the technology. See the paper for a full list of authors and affiliations.

More from the Levy lab

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