Tucked in the corner of the University of Hawaii’s seaside John A. Burns School of Medicine, lab manager Teri Wong wields an oversized pipette in one hand and steadies a stack of petri dishes in the other, preparing to feed a line of fruit fly cells.

These microscopic embryo cells are the foundation of a protein-based vaccine candidate that UH researchers hope will prove pivotal in the global fight against Covid-19. Dubbed CiVax (pronounced sigh-vax) by industry-partner Soligenix, this homegrown jab is designed to be shelf-stable and not need refrigeration to make it more useful for unvaccinated populations in areas many miles away from the nearest vaccine freezer.

With vaccines plentiful in the United States, public health experts argue that inoculating people in developing countries should be the highest priority. This is important not only to alleviate inequality as 94% of the population of low-income countries remained unvaccinated as of December, but because large pockets of unvaccinated people can become breeding grounds for immunity-hopping variants like omicron.

But before they are used to make life-saving vaccines, the translucent bubbles of insect-matter float mindlessly in their amber-tinted home, waiting patiently for Wong to finish preparing their meal.

UH JABSOM Microbiology Lab vaccine Lab Technician Teri Wong .
UH microbiology lab manager Teri Wong prepares a batch of fruit fly cells, which are essential to producing the UH Covid vaccine. Cory Lum/Civil Beat/2022

Behind The Curtain

All vaccines function by the same principle: teach the immune system to identify an infectious disease by introducing a harmless antigen – essentially, the pathogen’s calling card – so the body is quicker and better prepared to counter a real infection.

The three Covid-19 vaccines currently authorized by the Food and Drug Administration, the Moderna, Pfizer and Johnson & Johnson vaccines, use genetic code written as either messenger RNA or DNA to instruct the body’s own cells to produce the desired antigen – such as the spike proteins that line the coronavirus.

As UH microbiology professor and CiVax project leader Axel Lehrer explains it, if the code were like a cooking recipe, then the body’s cells are the amateur cook – they make a great dish most the time, but there’s a slim chance something might go wrong.

In contrast, the two-shot UH candidate is one of a range of protein subunit Covid vaccine candidates, including Corbevax and a shot by biotech firm Novavax. Vaccines of this variety skip the middleman by delivering a dose of the spike protein-antigen pre-made, avoiding the risk of a “lousy chef,” Lehrer said.

Embryonic fruit fly cells, pictured at 400x magnification, act as factories for the antigen used in the UH Covid vaccine. Cory Lum/Civil Beat/2022

Production begins with the humble fruit fly cells, which have been genetically programmed to act as factories for the spike proteins. A single five-liter batch made on countertop bio-reactors produces enough antigen for 10,000 vaccine doses when purified and can easily be scaled up to “grow a thousand liters in one batch,” Lehrer said.

The antigen in protein subunit vaccines is injected with a solution called an “adjuvant,” which acts like “little fireworks” provoking the immune system into reacting to the vaccine.

Beyond vaccine function and hesitation, temperature limitations have complicated global vaccine distribution, with the World Health Organization estimating in 2020 approximately 50% of all vaccines were wasted globally, largely due to cold-storage issues.

The genetic code, mRNA, that forms the backbone of the two-shot Moderna and Pfizer vaccines is extremely fragile and requires temperatures as low as negative 76 degrees Fahrenheit during transport and storage – posing a problem even rich countries faced when shipping to places lacking ultracold freezers.

The one-shot Johnson & Johnson and other vaccines developed outside the U.S. can help fill gaps in distribution by needing only a standard refrigerator, but they still require an unbroken “cold chain” of refrigerated shipping containers and ice-lined coolers when being transported to the 3 billion people who live in areas with temperature-control challenges.

UH JABSOM Microbiology Lab Dr. Axel T. Lehrer.
UH JABSOM microbiology professor Axel T. Lehrer stands next to the wave bioreactors on which researchers brew coronavirus spike proteins for their Covid vaccine. Cory Lum/Civil Beat/2022

Hoping to sidestep this logistical nightmare, Lehrer says his team is designing CiVax to withstand temperatures up to 104 degrees Fahrenheit and be storable outside the fridge for up to two years.

CiVax’s secret? Lyophilization – essentially, freeze-drying the vaccine.

Lehrer said his team began developing their protein subunit vaccine platform to immunize against Ebola virus, which exploded into an epidemic in the mid-2010s. Thermostability during shipment and storage in hard-hit West Africa became a priority, so the UH researchers experimented with freeze-drying to lock in freshness.

“We worked with Liberia, and their electricity goes on and off, on and off,” lab manager Wong said. “How do you keep anything stable?”

When Covid emerged, the team began adapting the temperature-stable platform to the coronavirus. Once freeze-dried, the vaccine emerges looking like a “little white muffin,” Lehrer said.

Some freeze-dried protein subunit shots, such as pharmaceutical giant GlaxoSmithKline’s Shingrix shingles vaccine, store the antigen and adjuvant in separate vials. Lehrer’s team is planning for CiVax to be delivered in one vial for simplicity – just add sterile water and inject.

“It takes maybe a minute,” Wong said. “It just goes right in.”

UH JABSOM Microbiology Lab vaccine closeup.
A UH researcher holds a vial of freeze-dried Ebola, Sudan, and Marburg virus vaccine, the precursor to their Covid vaccine. The UH team adapted this vaccine platform for their coronavirus vaccine. Cory Lum/Civil Beat/2022

As the Covid pandemic evolves, Lee Wetzler, Boston University School of Medicine professor of medicine and microbiology who specializes in infectious diseases, said it is important to continue researching CiVax and other vaccines effective at reaching hard-to-reach populations.

“If you can keep the (University of Hawaii) vaccine at room temperature … if it is as stable as they say, getting this around the world is essential if you really want to send off the global pandemic,” said Wetzler, who isn’t involved in the UH research.

So far, CiVax has provoked strong immune responses during mice and primate testing, with protective potential against the alpha, beta, gamma and delta Covid variants and testing underway for omicron.

A lack of funding, however, means the team does not yet have data for humans, Lehrer said. While the researchers have made do with their UH lab budget and by sharing resources with other projects, the team needs approximately $2 million to $3 million more to progress into clinical trials.

“We cannot manufacture the clinical grade material as of yet, and that is mainly a funding situation,” Lehrer said.

Lehrer said his team wrote a “record number of public grant proposals” early on that were “received well” but did not result in additional funding.

This problem is not unique to the UH team, Wetzler said. The federal government pumped $18 billion into Covid projects run by large pharmaceutical firms, but left comparably little for smaller-scale efforts in academia.

“I don’t think (the government) should ignore efforts like this,” Wetzler said. “It’s very important that vaccines like this are allowed to be scaled up and find commercial partners and be used in the ‘armamentarium’ for this disease.”

A batch of freeze dried CiVax vaccine, which was delivered to the lab Thursday. Designed to be shelf-stable and not need refrigeration, Lehrer describes its appearance as a “little white muffin.” Axel T. Lehrer/UH JABSOM/2022

Texas Children’s Hospital and Baylor College of Medicine relied almost entirely on $7 million in philanthropy when developing fellow protein subunit shot Corbevax, which now has emergency use authorization in India.

Philanthropy, Lehrer said, would be a “very attractive option,” as would a partnership with a large pharmaceutical company, even if CiVax comes late to the pandemic fight.

“We are looking to the virus becoming endemic, and we most likely will need at least annual update boosters,” Lehrer said. “There will be a market for these vaccines for a while … I would say definitely a few more years. From that perspective, it would be worth investing.”

Civil Beat’s health coverage is supported by the Atherton Family Foundation, Swayne Family Fund of Hawaii Community Foundation, Cooke Foundation and Papa Ola Lokahi.

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