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MIT Better World

By Leda Zimmerman

“Pursuing a Covid-19 vaccine has been the perfect chance to advance these ideas—a real live-fire test for us.”

Under pressure from the pandemic, Love and his team worked not only to design and build potentially life-saving vaccine candidates but also to further his larger vision: changing the drug-development pipeline to get treatments to patients faster. On June 22, in the midst of Covid-19 research, he announced the AltHost Consortium, an MIT-led group for open-access sharing of research and information with pharmaceutical giants Amgen, Biogen, Pfizer, Roche, and Sanofi. By leveraging contributions from this consortium, and harnessing his lab’s novel methods for evaluating and rapidly manufacturing biologically based medicines, Love was able to fashion coronavirus vaccine possibilities in record time.

“Our work thinking about how to respond most efficiently in urgent circumstances prepared us for the current crisis,” says Love. “We were able get out of the gate very quickly.”

Tackling Covid-19

Prior to the pandemic, the Love Lab, supported by the Bill and Melinda Gates Foundation (also an AltHost member), had been devising ways to produce and disseminate millions of doses of low-cost vaccines, especially for infectious diseases affecting the world’s most vulnerable populations. Such capabilities for generating vaccine candidates might also, Love and his team recognized, be necessary in case of a pandemic. That need arrived sooner than they imagined. In February 2020, research sponsors presented an urgent challenge to Love: Could you create a Covid-19 vaccine candidate by the end of the month?

Love’s lab, which resides in the Koch Institute for Integrative Cancer Research, brings together graduate research assistants and technical experts in chemical and biological engineering, immunology, and the genomic sciences. This multidisciplinary compass underpins the team’s pathbreaking approach to both drug discovery and manufacturing, an approach intended to skirt the pitfalls of the conventional process for bringing new drug candidates to production.

Currently, vaccines are manufactured in centralized facilities that make large quantities of a single type at a time. If something goes wrong during production, millions of doses can be lost. Manufacturers cannot respond quickly to new disease threats because it can take many months to grow the necessary biological components in such conventional facilities or to reconfigure these facilities to accommodate a different vaccine product.

“To avoid these kinds of bottlenecks, we must invent a simple, efficient method for manufacturing,” says Sergio A. Rodriguez, a third-year PhD student in biological engineering and a member of the Love Lab. “That is precisely what our lab has set out to accomplish.”

The Love Lab’s platform uses genetically engineered yeasts as biofactories for proteins that are the core constituents of many pharmaceuticals. Applying techniques such as CRISPRCas9, a genome editor, the lab can modify yeasts in a matter of days. “We are essentially tuning strains of yeast to produce specific kinds of drugs such as vaccine candidates,” says Neil Dalvie, a fifth-year PhD student in chemical engineering and a graduate research assistant.

Through a series of iterations, researchers test and tweak target proteins, focusing simultaneously on the effectiveness of their products and on whether the manufacturing process yields these products reliably and in sufficient volume to ramp up production.

This kind of innovative drug development, which Love describes as “on-demand biomanufacturing,” could one day enable smaller pharmaceutical companies, stocked with the right ingredients and genetic information, to generate products wherever they are needed.

“It is a streamlined approach where engineering, host biology, immune response, and manufacturability are integrated, giving us an opportunity to design for low-cost medicines that could reach potentially billions of patients,” says Love.

Pandemic work

When MIT shut down research facilities in March, the Love team continued its vital efforts on Covid-19 vaccine discovery and manufacture. Only four staff at a time were allowed in the lab. While Love and the rest of the group contributed from home, Dalvie and three other graduate students were deemed essential workers and stayed on campus. They seized the chance to play leading roles in significant research. “Once the Covid-19 work began, all of us realized the broader impact of our research on the world, and that we must do our best, and quickly,” says Rodriguez. The immediate goal was to produce a vaccine based on the spike protein used by the coronavirus to latch onto receptors in human cells, the first interaction of the virus in its attack. “The idea is that a vaccine that resembles this spike protein would prevent this interaction by generating an immune response where antibodies would neutralize the spike before it binds to the cell,” says Dalvie. The core team set out to transform Pichia pastoris, the host yeast, into an effective biofactory for this target protein.

This work proved a major change of pace for all of them—longer-than-usual days with the added burden of social distancing and constant pressure. The scene on campus sometimes seemed surreal.

“It was weird to see everything so empty and quiet,” says Elvin Yang, a third-year chemical engineering PhD student. “But I was really glad to be in the lab, where it felt like I was working on tangible things and generating results.”

This intense round of research leveraged the Love Lab’s interdisciplinary culture. “Our lab is designed to encourage collaboration, and to ensure that each of us gains a holistic understanding of the host organism and biomanufacturing process,” says Rodriguez. “We didn’t get to say, ‘I’m the one who does yeast purification.’”

“Challenges in production can best be solved when everyone knows the molecular design, host biology, and engineering processes,” says Love. “This is what makes our lab different.”

Vaccine candidate

In just 28 days, the Love Lab managed to produce its first version of a Covid-19 vaccine candidate. But creating a potential vaccine is far from the conclusion of drug R&D. Researchers must also demonstrate that the vaccine can safely engender an effective immune response in animal models and humans. Just as important, the team must prove that its manufacturing approach is agile enough to respond rapidly to potential virus mutations and that its biomanufacturing platform can scale up sufficiently. “To address the pandemic, the world will need billions of doses,” says Love.

To that end, last spring the lab began sending out vaccine components, including its engineered yeast cell lines, to multiple partners around the world for trial manufacturing and evaluation—progress made possible, in part, by the collective research of the AltHost Consortium.

“With our Covid-19 work, we have begun modeling ideas for sharing cell strains and providing access to advanced tools so we can all move forward together on the development of life-saving drugs,” says Love. “I feel fortunate that in these incredibly challenging circumstances, we are able to demonstrate our vision for how we might transform the conventional state of biopharmaceutical manufacturing.”