RACE FOR A VACCINE
Houston-area researchers hope to be ultimate winners in global quest
When Chinese scientists posted the genetic sequence of a novel coronavirus circulating in the province of Wuhan back in January, Peter Hotez knew immediately what he needed to do.
The 62-year-old Houston infectious disease specialist dashed off an email to the National Institutes of Health, then got his Galveston and New York collaborators on a Zoom call to plot out their next step. There was no telling how far the deadly new virus might spread, but they figured they had a good lead on a possible silver bullet.
Four years ago, they had developed a vaccine that in animal models protected against the spread of severe acute respiratory syndrome, or SARS, a closely related coronavirus. The vaccine never made it to human trials because the disease by then had died out, but to them it provided a blueprint for the world’s best hope against a pandemic that’s now killed more than 900,000 people around the globe.
“This is not going to be that difficult,” Hotez, co-director of the Center for Vaccine Development at Texas Children’s Hospital, told the collaborators on Jan. 22, 11 days after the sequence
was posted. “We did it for SARS, and it wasn’t that difficult. I’m pretty sure we can do it for this virus.”
Sixty miles south of the Texas Children’s center, researchers at the University of Texas Medical Branch at Galveston also think they’ve got a great shot at a coronavirus vaccine.
The Galveston National Laboratory at UTMB is the nation’s largest high-security containment facility on an academic campus. More than 150 security cameras monitor the facility — and it’s clear why. The lab houses many potentially dangerous substances — and was the first in the U.S. with the genetic material for the coronavirus.
The UTMB researchers are working with at least 10 different vaccine candidates, some developed by pharmaceutical companies, some by the medical branch.
Scott Weaver, director of the school’s infectious disease research program, notes that several vaccines will be needed to protect against the virus in all populations. Anticipating the need, UTMB scientists are developing and testing a wide range of candidates, taking advantage of innovative techniques developed in-house to determine efficacy.
The Houston-area efforts provide glimpses into the making of a vaccine for SARS-CoV-2 — scientists have nicknamed it SARS2 — the coronavirus that causes COVID-19, the most crippling pandemic since the 1918 Spanish influenza. Never before has such an esoteric field, such a scientific quest, so captured a frightened world’s attention.
The efforts also showcase a frantic race that features more than 170 projects in development around the world, all aiming to be the one whose vaccine brings the virus to heel. The likely achievement, however, will come despite a historic reluctance to invest preemptively in the effort, despite frequent warnings it was only a matter of time before a pandemic hit.
Nothing is stoking expectations from the race like Operation Warp Speed, the Trump administration’s Manhattan Project-like public-private partnership to accelerate the development and distribution of vaccines for the new coronavirus.
The program, still a mystery to most scientists in the field, aims to have 300 million doses of a safe and effective vaccine available for Americans by January.
“If that happens, it’ll be the fastest vaccine development program ever in history,” said Jason Schwartz, a professor of health policy and management at the Yale School of Public Health.
That timeline would ensure the Texas Children’s and UTMB efforts don’t finish first — both have yet to start clinical trials — but it doesn’t mean either can’t still be judged an ultimate winner. In the long run, because latter-generation vaccines typically replace the first ones, the quest is not so much the sprint Trump promises as a marathon.
Low priority
It all started with 18th century folk wisdom and a British doctor eager to connect the dots.
Like others of the time, Edward Jenner had heard the tales that milkmaids who’d contracted cowpox, a mild disease that could be transferred from cattle to humans, were spared the infection of smallpox, then the world’s great scourge. Theorizing that cowpox was similar enough to confer immunity, Jenner scratched pus from a cowpox blister into the skin of an 8-year-old-boy, then six weeks later challenged the cowpox inoculation by exposing the boy to smallpox.
The boy never fell ill. A year later, having repeated the experiment on several other children, Jenner published the results and coined a new term: vaccine (derived from vacca, Latin for cow).
Jenner’s pioneering work led to other advances: Louis Pasteur spearheaded the development of the first successful vaccines for cholera, anthrax and rabies around the turn of the 20th century. Jonas Salk and Albert Sabin created the two polio vaccines in the 1950s.
In modern times, vaccines for smallpox, polio, yellow fever, tetanus, diphtheria, whooping cough and measles are credited with saving an estimated 9 million lives a year.
Yet almost perversely, pandemic preparedness never became an early 21st century priority. In the years before COVID-19, according to an article in the journal Nature, the United States invested less than $1 billion annually on the threat posed by emerging infectious diseases and pandemics, compared to at least $100 billion a year on counterterrorism. No more than a third of the funding went to the NIH for vaccine research.
A congressional group called the Bipartisan Commission on Biodefense led the effort to improve the nation’s preparedness. It had some successes, but few involved spending more on vaccine research and development. Everybody said they supported the effort, one expert noted, but nobody wanted to spend real money on it.
“Had investments been made previously, we potentially could have a vaccine ready to go now,” Hotez testified before the House Committee on Science, Space and Technology in March.
Hotez describes vaccines as a kind of trick on the body, preventing disease by simulating an infection, which the immune system learns to recognize and remember. The vaccine produces such simulation by exposing the subject to harmless molecules that reside on the surface of viruses and bacteria — foreign enough to trigger an immune response, not dangerous enough to cause disease. Immune responses normally learned the hard way — during illness caused by the infection — can be induced painlessly thanks to such tricks.
Scientists historically have made molecules harmless by either killing the bug or by weakening it. Keeping the physical remains intact teaches the immune system what to look for.
The field has advanced exponentially, first the result of new techniques mass producing pieces of a virus, then the result of genetic engineering. Most recently, advances in computers’ abililty to quickly sequence viruses have enabled researchers to build customized snippets of the virus’ own genes to provoke an immune response.
The promise of the method has generated much excitement — first and foremost among Operation Warp Speed’s leaders — even though it’s still experimental. No genetic vaccine has ever been licensed.
But because of the speed of the method, such genetic vaccines lead the COVID-19 vaccine candidate pack. One company says it designed a preliminary model in three hours. In late July, two started late-stage clinical trials.
Previously, the fastest a vaccine — the one for the mumps — has ever made it from bench to doctor’s office was four years. The vaccine for HPV, a sexually transmitted infection, took 15; chickenpox 28.
But researchers are optimistic about a coronavirus vaccine because the concerted effort by the scientific community seems, in the words of many, too big to fail.
The vaccine effect will take time, though. No matter how fast the creation of the new vaccine, clinical testing typically takes at least 12 months, necessary to show that it is safe and effective. The safety bar is particularly high because, unlike therapeutic drugs given to patients battling disease, vaccines are given to healthy people.
Inside the lab
Beyond the impregnable concrete exterior of the Galveston National Laboratory, past the airport-level screening at the entrance and behind steel doors that require key code access, dozens of vials of SARS2 clones sit in a minus-80 degree freezer in a high-security biocontainment lab.
Like she’s done every day for the last several months, Camila Fontes, a graduate student at the University of Texas Medical Branch, steps into a “buffer room” outside of the biocontainment lab to suit up in layers of personal protective equipment before handling the virus clones.
Fontes changes her shoes, puts on gloves and a blue gown, and dons an air-purifying respirator that looks like a big white hood with a glass window covering her entire face. Once she enters the lab, Fontes will put on a second pair of gloves, a second gown and shoe covers.
Thus adequately protected, Fontes retrieves one of the vials from the freezer and places it in a glass of water to thaw. She adds the cloned coronavirus to a plate containing a human blood sample immunized with a vaccine candidate, and places it in an incubator for one hour.
Afterward, Fontes will add the virus mixture to 96 dimesized trays, each filled with 120,000 Vero cells — a lineage of cloned African monkey cells suitable for propagating viruses — and places those trays back in the incubator for 16 to 20 hours.
The medical branch has developed an innovative system that allows scientists to create the SARS2 strain from scratch and manipulate it. Using this technique, UTMB scientists cloned the virus and injected it with a neon green fluorescent protein.
This cloned virus will prove critical for determining whether one of the vaccine candidates under testing has strong enough antibodies to bind to the virus and block it from multiplying in human blood cells.
If the virus is effective in infecting the cells, images of the cell trays will show what looks
“If that happens, it’ll be the fastest vaccine development program ever in history.” Jason Schwartz, a professor of health policy and management at the Yale School of Public Health, on the success of Operation Warp Speed
like a paint splatter of small, day-glo neon green dots attaching to the royal blue Vero cells. If the blood sample is endowed with strong enough antibodies from the vaccine candidate, the cell tray images will show almost no green at all.
“The less green we have, the better,” Fontes said. “That means there is protection.”
For 12 hours a day in small research lab, Fontes prepares millions of the Vero cells for testing. A nine-year Army veteran, Fontes is accustomed to the disciplined, detail-oriented approach her work requires.
“I’m a realist,” Fontes said. “I have an opportunity to help everybody else. I want to see my mom and my dad. They’re in El Paso, and if I want to see them, we need a solution.”
The eight-story national laboratory on the medical branch’s Galveston campus was built in 2008, funded by a $175 million grant from the National Institutes of Health. In the wake of the Sept. 11, 200,1 terrorist attacks, the Bush administration sought to construct research facilities with proper precautions — so-called Biosafety Level 4 lab space — amid mounting concerns about emerging infectious diseases. The Galveston lab has more than 12,000 square feet of such level 4 space.
As the director of UTMB’s infectious disease research programs, Scott Weaver is tasked with helping manage nearly two dozen projects behind the laboratory walls related to the coronavirus. On a summer afternoon in the Galveston lab, Weaver dons a face mask made by his wife that features a pattern of blue spike proteins that characterize the coronavirus.
He guides a reporter through the doors of one of the building’s Biosafety Level 2 labs, which Weaver describes as the workhorse of biomedical research.
“All the work to prepare for the high-containment experiments and then to test samples that come out of there takes place in BSL2,” he said.
Compared to the higher security labs, which require special respiratory protection and, in some cases, biohazard spacesuits, the level 2 labs are almost quaint: three large metal tables separated by aisles of desks piled with papers and shelves of high-tech equipment.
This lab also acts as an outpost of sorts for the university’s World Reference Center for Emerging Viruses and Arboviruses, a library of over 8,000 virus strains encompassing 21 viral families. It was here that the first SARS2 sample to reach U.S. soil was sent by the Centers for Disease Control and Prevention in February, leading to much of the primary research done on the pathogen that was then disseminated to labs across the globe.
With the genetic material of the coronavirus in-house, the Galveston lab developed a major breakthrough in vaccine testing.
Pei-Yong Shi, a professor of human genetics at UTMB, and Xuping Xie, a postdoctoral research scientist, used the initial sample to develop a new way to make the virus in the lab and manipulate it in a petri dish.
The process uses Vero cells to clone the virus. Genetic material from the virus strain is mixed with the cells and “shocked” with an electrical field to open up tiny holes in the cell membrane. Once the viral genetic material permeates the cell, it uses the cell’s machinery to create copies of the virus, effectively cloning itself.
The cloned virus’ monkey DNA allows it to be easily manipulated, which led to the development of the neon green fluorescent protein that could be injected into the virus to allow for high-capacity testing of vaccines and antiviral drugs.
The green protein is a simple concept, Shi explains, like putting on glasses to help you see better. The breakthroughs, he said, opened the door to UTMB partnering with several pharmaceutical companies to test vaccine candidates.
‘Is it still stable?’
Maria Bottazzi was at her 87year-old father’s home in Tegucigalpa, Honduras, for the 2019 Christmas holiday, hanging out on the back porch and listening to his reminiscences about her childhood there, when the news hit about a mysterious pneumonia outbreak in China.
Bottazzi took a break from her dad’s stories to get on the phone with Hotez, who brought her with him to Houston in 2010 as his co-director of the Texas Children’s vaccine lab. The two agreed the outbreak resembled that of SARS, the disease that originated in China in November 2002 and spread to 29 countries. It was particularly virulent, killing 10 percent of people who contracted it before it burned out.
Both immediately thought of the center’s SARS vaccine, developed earlier in the decade using a government bioterrorism preparedness grant. The grant ran out in 2016.
“Is it still stable?” Hotez asked. “Have we been continuously validating it in tests?”
All 20,000 doses manufactured by the Walter Reed Army Institute of Research remained viable in a Houston freezer, replied Bottazzi. She emailed the Texas Children’s research team in Houston, urging them to “be proactive in case we need to deploy it against this mystery virus.”
Bottazzi considers the period after the grant expired “four years of lost time and knowledge,” time during which the team could have produced human safety data and determined if the vaccine generates virus-neutralizing antibodies in people. The team applied for follow-up grants from government agencies, pharmaceutical companies and foundations, all to no avail.
It was the climate at the time. Some politicians called for more government spending on pandemic preparedness, but there were always more pressing priorities. Corrected for inflation, such funding went from over $2 billion in 2003 to a little under $1 billion in 2020.
Coronaviruses represent a departure of sorts for the TCH team, whose other work all targets neglected tropical diseases, a term coined by Hotez to describe debilitating, poverty-related syndromes largely ignored by most of medicine.
The commitment to vaccines for the world’s poorest people and his trademark neckwear have given Hotez the nickname “Bono with a bow tie.” He says that when he tried wearing conventional ties, the outcry was “like when Dylan played electric instruments at Newport.”
It didn’t take long for the Hotez-Bottazzi observation about the resemblance of the SARS virus to the one in Wuhan to be confirmed. The sequence posted two weeks later showed the new virus shared 82 percent of its genes with SARS.
The team decided to proceed on parallel fronts: develop a new vaccine specific to SARS2 but also push for a clinical trial testing the SARS vaccine against the new virus, based on the seeming likelihood it’d provide some cross-protection. After all, it promised help on the immediate front.
In the end, the new vaccine’s development took just a few months. Suddenly, the center’s SARS2 vaccine has become its best candidate, set to begin clinical trials in less than a month in India.
But it remains a David among Goliaths. Operation Warp Speed’s beneficiaries, seven well-heeled, for-profit companies, are each bankrolling efforts with at least $1 billion of their own funds plus more from the Trump administration, which so far has struck deals to send nearly $11 billion their way. The Texas Children’s center effort? It has $3.5 million of funding, all from philanthropy.
Still, Hotez says that’s enough to advance the effort to clinical trials. Meanwhile, he’s still going around, hat in hand, trying to raise money for the effort.
It’s all vexing to Hotez and Bottazzi, who think their vaccine is one of the most likely to work and at a fraction of the cost. When all’s said and done, suspects Hotez, there’ll be a role for the vaccine.
“All the talk portrays this as a race, as if it’s going to be like Jonas Salk in 1956 again — journalists assembled at the University of Michigan auditorium, curtains pulled back like the Wizard of Oz, everyone excitedly dancing off into the streets,” said Hotez. “It’s not going to happen like that. There’s going to be a gradual rollout of vaccines. The first ones will get replaced. Different ones will be used in different places. And no one knows how soon that will happen.”
By the time it does, Hotez hopes to be focused on a more ambitious preparedness project — a universal coronavirus vaccine that would protect against any future variation of the infection that might emerge, an idea the TCH lab first sought funding for a few years ago. Predictably, the NIH rejected the proposal.
“Had investments been made previously, we potentially could have a vaccine ready to go now.” Peter Hotez, Houston infectious disease specialist