Scientists at Baylor College of Medicine developed a vaccine called Corbevax that, unlike mRNA vaccines, can be mass produced using technology already in place in low- and middle-income countries. It's now being administered in India to children aged 12-14.
When the COVID-19 pandemic began invading the world in late 2019, Peter Hotez and Maria Elena Bottazzi set out to create a low-cost vaccine that would help inoculate populations in low- and middle-income countries. The scientists, with their prior experience of developing inexpensive vaccines for the world’s poor, had anticipated that the global rollout of Covid-19 jabs would be marked with several inequities. They wanted to create a patent-free vaccine to bridge this gap, but the U.S. government did not seem impressed, forcing the researchers to turn to private philanthropies for funds.
Hotez and Bottazzi, both scientists at the Texas Children’s Hospital Center for Vaccine Development at Baylor College of Medicine, raised about $9 million in private funds. Meanwhile, the U.S. government’s contribution stood at $400,000.
“That was a very tough time early on in the pandemic, you know, trying to do the work and raise the money for it at the same time,” says Hotez, who was nominated in February for a Nobel Peace Prize with Bottazzi for their COVID-19 vaccine. He adds that at the beginning of the pandemic, governments emphasized speed, innovation and rapidly immunizing populations in North America and Europe with little consideration for poorer countries. “We knew this [vaccine] was going to be the answer to global vaccine inequality, but I just wish the policymakers had felt the same,” says Hotez.
Over the past two years, the world has witnessed 488 million COVID-19 infections and over 61 million deaths. Over 11 billion vaccine doses have been administered worldwide; however, the global rollout of COVID-19 vaccines is marked with alarming socio-economic inequities. For instance, 72 percent of the population in high-income countries has received at least one dose of the vaccine, whereas the number stands at 15 percent in low-income countries.
This inequity is worsening vulnerabilities across the world, says Lawrence Young, a virologist and co-lead of the Warwick Health Global Research Priority at the UK-based University of Warwick. “As long as the virus continues to spread and replicate, particularly in populations who are under-vaccinated, it will throw up new variants and these will remain a continual threat even to those countries with high rates of vaccination,” says Young, “Therefore, it is in all our interests to ensure that vaccines are distributed equitably across the world.”
“When your house is on fire, you don't call the patent attorney,” says Hotez. “We wanted to be the fire department.”
The vaccine developed by Hotez and Bottazzi recently received emergency use authorisation in India, which plans to manufacture 100 million doses every month. Dubbed ‘Corbevax’ by its Indian maker, Biological E Limited, the vaccine is now being administered in India to children aged 12-14. The patent-free arrangement means that other low- and middle-income countries could also produce and distribute the vaccine locally.
“When your house is on fire, you don't call the patent attorney, you call the fire department,” says Hotez, commenting on the intellectual property rights waiver. “We wanted to be the fire department.”
The Inequity
Vaccine equity simply means that all people, irrespective of their location, should have equal access to vaccines. However, data suggests that the global COVID-19 vaccine rollout has favoured those in richer countries. For instance, high-income countries like the UAE, Portugal, Chile, Singapore, Australia, Malta, Hong Kong and Canada have partially vaccinated over 85 percent of their populations. This percentage in poorer countries, meanwhile, is abysmally low – 2.1 percent in Yemen, 4.6 in South Sudan, 5 in Cameroon, 9.9 in Burkina Faso, 10 in Nigeria, 12 in Somalia, 12 in Congo, 13 in Afghanistan and 21 in Ethiopia.
In late 2019, scientists Peter Hotez and Maria Elena Bottazzi set out to create a low-cost vaccine that would help inoculate populations in low- and middle-income countries. In February, they were nominated for a Nobel Peace Prize.
Texas Children's Hospital
The COVID-19 vaccination coverage is particularly low in African countries, and according to Shabir Madhi, a vaccinologist at the University of the Witwatersrand, Johannesburg and co-director of African Local Initiative for Vaccinology Expertise, vaccine access and inequity remains a challenge in Africa. Madhi adds that a lack of vaccine access has affected the pandemic’s trajectory on the continent, but a majority of its people have now developed immunity through natural infection. “This has come at a high cost of loss of lives,” he says.
COVID-19 vaccines mean a significant financial burden for poorer countries, which spend an average of $41 per capita annually on health, while the average cost of every COVID-19 vaccine dose ranges between $2 and $40 in addition to a distribution cost of $3.70 per person for two doses. In December last year, the World Health Organisation (WHO) set a goal of immunizing 70 percent of the population of all countries by mid-2022. This, however, means that low-income countries would have to increase their health expenditure by an average of 56.6 percent to cover the cost, as opposed to 0.8 per cent in high-income countries.
Reflecting on the factors that have driven global inequity in COVID-19 vaccine distribution, Andrea Taylor, assistant director of programs at the Duke Global Health Innovation Center, says that wealthy nations took the risk of investing heavily in the development and scaling up of COVID-19 vaccines – at a time when there was little evidence to show that vaccines would work. This reserved a place for these nations at the front of the queue when doses started rolling off production lines. Lower-income countries, meanwhile, could not afford such investments.
“Now, however, global supply is not the issue,” says Taylor. “We are making plenty of doses to meet global need. The main problem is infrastructure to get the vaccine where it is most needed in a predictable and timely way and to ensure that countries have all the support they need to store, transport, and use the vaccine once it is received.”
Taufique Joarder, vice-chairperson of Bangladesh's Public Health Foundation, sees the need for more trials and data before Corbevax is made available to the general population.
In addition to global inequities in vaccination coverage, there are inequities within nations. Taufique Joarder, vice-chairperson of Bangladesh’s Public Health Foundation, points to the situation in his country, where vaccination coverage in rural and economically disadvantaged communities has suffered owing to weak vaccine-promotion initiatives and the difficulty many people face in registering online for jabs.
Joarder also cites the example of the COVID-19 immunization drive for children aged 12 years and above. “[Children] are given the Pfizer vaccine, which requires an ultralow temperature for storage. This is almost impossible to administer in many parts of the country, especially the rural areas. So, a large proportion of the children are being left out of vaccination,” says Joarder, adding that Corbevax, which is cheaper and requires regular temperature refrigeration “can be an excellent alternative to Pfizer for vaccinating rural children.”
Corbevax vs. mRNA Vaccines
As opposed to most other COVID-19 vaccines, which use the new Messenger RNA (mRNA) vaccine technology, Corbevax is an “old school” vaccine, says Hotez. The vaccine is made through microbial fermentation in yeast, similar to the process used to produce the recombinant hepatitis B vaccine, which has been administered to children in several countries for decades. Hence, says Hotez, the technology to produce Corbevax at large scales is already in place in countries like Vietnam, Bangladesh, India, Indonesia, Brazil, Argentina, among many others.
“So if you want to rapidly develop and produce and empower low- and middle-income countries, this is the technology to do it,” he says.
“Global access to high-quality vaccines will require serious investment in other types of COVID-19 vaccines," says Andrea Taylor.
The COVID-19 vaccines created by Pfizer-BioNTech and Moderna marked the first time that mRNA vaccine technology was approved for use. However, scientists like Young feel that there is “a need to be pragmatic and not seduced by new technologies when older, tried and tested approaches can also be effective.” Taylor, meanwhile, says that although mRNA vaccines have dominated the COVID-19 vaccine market in the U.S., “there is no clear grounding for this preference in the data we have so far.” She adds that there is also growing evidence that the immunity from these shots may not hold up as well over time as that of vaccines using different platforms.
“The mRNA vaccines are well suited to wealthy countries with sufficient ultra-cold storage and transportation infrastructure, but these vaccines are divas and do not travel well in the rest of the world,” says Taylor. “Global access to high-quality vaccines will require serious investment in other types of COVID-19 vaccines, such as the protein subunit platform used by Novavax and Corbevax. These require only standard refrigeration, can be manufactured using existing facilities all over the world, and are easy to transport.”
Joarder adds that Corbevax is cheaper due to the developers’ waived intellectual rights. It could also be used as a booster vaccine in Bangladesh, where only five per cent of the population has currently received booster doses. “If this vaccine is proved effective for heterologous boosting, [meaning] it works well and is well tolerated as a booster with other vaccines that are available in Bangladesh, this can be useful,” says Joarder.
According to Hotez, Corbevax can play several important roles - as a standalone adult or paediatric vaccine, and as a booster for other vaccines. Studies are underway to determine Corbevax’s effectiveness in these regards, he says.
Need for More Data
Biological E conducted two clinical trials involving 3000 subjects in India, and found Corbevax to be “safe and immunogenic,” with 90 percent effectiveness in preventing symptomatic infections from the original strain of COVID-19 and over 80 percent effectiveness against the Delta variant. The vaccine is currently in use in India, and according to Hotez, it’s in the pipeline at different stages in Indonesia, Bangladesh and Botswana.
However, Corbevax is yet to receive emergency use approval from the WHO. Experts such as Joarder see the need for more trials and data before it is made available to the general population. He says that while the WHO’s emergency approval is essential for global scale-up of the vaccine, we need data to determine age-stratified efficacy of the vaccine and whether it can be used for heterologous boosting with other vaccines. “According to the most recent data, the 100 percent circulating variant in Bangladesh is Omicron. We need to know how effective is Corbevax against the Omicron variant,” says Joarder.
Shabir Madhi, a vaccinologist at the University of the Witwatersrand, Johannesburg and co-director of the African Local Initiative for Vaccinology Expertise, says that a majority of people in Africa have now developed immunity through natural infection. “This has come at a high cost of loss of lives."
Shivan Parusnath
Others, meanwhile, believe that availing vaccines to poorer countries is not enough to resolve the inequity. Young, the Warwick virologist, says that the global vaccination rollout has also suffered from a degree of vaccine hesitancy, echoing similar observations by President Biden and Pfizer’s CEO. The problem can be blamed on poor communication about the benefits of vaccination. “The Corbevax vaccine [helps with the issues of] patent protection, vaccine storage and distribution, but governments need to ensure that their people are clearly informed.” Notably, however, some research has found higher vaccine willingness in lower-income countries than in the U.S.
Young also emphasized the importance of establishing local vaccination stations to improve access. For some countries, meanwhile, it may be too late. Speaking about the African continent, Madhi says that Corbevax has arrived following the peak of the crisis and won’t reverse the suffering and death that has transpired because of vaccine hoarding by high-income countries.
“The same goes for all the sudden donations from countries such as France - pretty much of little to no value when the pandemic is at its tail end,” says Madhi. “This, unfortunately, is a repeat of the swine flu pandemic in 2009, when vaccines only became available to Africa after the pandemic had very much subsided.”
The Cocoanut Grove fire in Boston in 1942 tragically claimed 490 lives, but was the catalyst for several important medical advances.
The scene of the fire.
Boston Public Library
Tragic Losses Prompted Revolutionary Leaps
But there is a silver lining: this horrific disaster prompted dramatic changes in safety regulations to prevent another catastrophe of this magnitude and led to the development of medical techniques that eventually saved millions of lives. It transformed burn care treatment and the use of plasma on burn victims, but most importantly, it introduced to the public a new wonder drug that revolutionized medicine, midwifed the birth of the modern pharmaceutical industry, and nearly doubled life expectancy, from 48 years at the turn of the 20th century to 78 years in the post-World War II years.
The devastating grief of the survivors also led to the first published study of post-traumatic stress disorder by pioneering psychiatrist Alexandra Adler, daughter of famed Viennese psychoanalyst Alfred Adler, who was a student of Freud. Dr. Adler studied the anxiety and depression that followed this catastrophe, according to the New York Times, and "later applied her findings to the treatment World War II veterans."
Dr. Ken Marshall is intimately familiar with the lingering psychological trauma of enduring such a disaster. His mother, an Irish immigrant and a nurse in the surgical wards at Boston City Hospital, was on duty that cold Thanksgiving weekend night, and didn't come home for four days. "For years afterward, she'd wake up screaming in the middle of the night," recalls Dr. Marshall, who was four years old at the time. "Seeing all those bodies lined up in neat rows across the City Hospital's parking lot, still in their evening clothes. It was always on her mind and memories of the horrors plagued her for the rest of her life."
The sheer magnitude of casualties prompted overwhelmed physicians to try experimental new procedures that were later successfully used to treat thousands of battlefield casualties. Instead of cutting off blisters and using dyes and tannic acid to treat burned tissues, which can harden the skin, they applied gauze coated with petroleum jelly. Doctors also refined the formula for using plasma--the fluid portion of blood and a medical technology that was just four years old--to replenish bodily liquids that evaporated because of the loss of the protective covering of skin.
"Every war has given us a new medical advance. And penicillin was the great scientific advance of World War II."
"The initial insult with burns is a loss of fluids and patients can die of shock," says Dr. Ken Marshall. "The scientific progress that was made by the two institutions revolutionized fluid management and topical management of burn care forever."
Still, they could not halt the staph infections that kill most burn victims—which prompted the first civilian use of a miracle elixir that was being secretly developed in government-sponsored labs and that ultimately ushered in a new age in therapeutics. Military officials quickly realized this disaster could provide an excellent natural laboratory to test the effectiveness of this drug and see if it could be used to treat the acute traumas of combat in this unfortunate civilian approximation of battlefield conditions. At the time, the very existence of this wondrous medicine—penicillin—was a closely guarded military secret.
From Forgotten Lab Experiment to Wonder Drug
In 1928, Alexander Fleming discovered the curative powers of penicillin, which promised to eradicate infectious pathogens that killed millions every year. But the road to mass producing enough of the highly unstable mold was littered with seemingly unsurmountable obstacles and it remained a forgotten laboratory curiosity for over a decade. But Fleming never gave up and penicillin's eventual rescue from obscurity was a landmark in scientific history.
In 1940, a group at Oxford University, funded in part by the Rockefeller Foundation, isolated enough penicillin to test it on twenty-five mice, which had been infected with lethal doses of streptococci. Its therapeutic effects were miraculous—the untreated mice died within hours, while the treated ones played merrily in their cages, undisturbed. Subsequent tests on a handful of patients, who were brought back from the brink of death, confirmed that penicillin was indeed a wonder drug. But Britain was then being ravaged by the German Luftwaffe during the Blitz, and there were simply no resources to devote to penicillin during the Nazi onslaught.
In June of 1941, two of the Oxford researchers, Howard Florey and Ernst Chain, embarked on a clandestine mission to enlist American aid. Samples of the temperamental mold were stored in their coats. By October, the Roosevelt Administration had recruited four companies—Merck, Squibb, Pfizer and Lederle—to team up in a massive, top-secret development program. Merck, which had more experience with fermentation procedures, swiftly pulled away from the pack and every milligram they produced was zealously hoarded.
After the nightclub fire, the government ordered Merck to dispatch to Boston whatever supplies of penicillin that they could spare and to refine any crude penicillin broth brewing in Merck's fermentation vats. After working in round-the-clock relays over the course of three days, on the evening of December 1st, 1942, a refrigerated truck containing thirty-two liters of injectable penicillin left Merck's Rahway, New Jersey plant. It was accompanied by a convoy of police escorts through four states before arriving in the pre-dawn hours at Massachusetts General Hospital. Dozens of people were rescued from near-certain death in the first public demonstration of the powers of the antibiotic, and the existence of penicillin could no longer be kept secret from inquisitive reporters and an exultant public. The next day, the Boston Globe called it "priceless" and Time magazine dubbed it a "wonder drug."
Within fourteen months, penicillin production escalated exponentially, churning out enough to save the lives of thousands of soldiers, including many from the Normandy invasion. And in October 1945, just weeks after the Japanese surrender ended World War II, Alexander Fleming, Howard Florey and Ernst Chain were awarded the Nobel Prize in medicine. But penicillin didn't just save lives—it helped build some of the most innovative medical and scientific companies in history, including Merck, Pfizer, Glaxo and Sandoz.
"Every war has given us a new medical advance," concludes Marshall. "And penicillin was the great scientific advance of World War II."
Conner Curran, now 10 years old, can walk more than two miles after gene therapy treatment for his Duchenne's muscular dystrophy.
That the medical world is on the cusp of a successful treatment for a crippling and deadly disease is the culmination of more than 35 years of work by Dr. Jude Samulski, a professor of pharmacology at the University of North Carolina School of Medicine in Chapel Hill. More recently, he's become a leading gene therapy entrepreneur.
But Samulski likens this breakthrough to the frustrations of solving a Rubik's cube. "Just because one side is now all the color yellow does not mean that it is completely aligned," he says.
Although Conner's life and future have dramatically improved, he's not cured. The gene therapy tamed but did not extinguish his disorder: Conner is now suffering from the equivalent of Becker's muscular dystrophy, a milder form of the disease with symptoms that appear later in life and progress more slowly. Moreover, the loss of muscle cells Conner suffered prior to the treatment is permanent.
"It will take more time and more innovations," Samulski says of finding an even more effective gene therapy for muscular dystrophy.
Conner's family is still overjoyed with the results. "Jude's grit and determination gave Conner a chance at a new life, one that was not in his cards before gene therapy," says his mother Jessica Curran. She adds that "Conner is more confident than before and enjoys life, even though he has limitations, if compared to his brothers or peers."
Conner Curran holding a football post gene therapy treatment.
Courtesy of the Curran family
For now, the use of gene therapy as a treatment for diseases and disorders remains relatively isolated. On paper at least, progress appears glacially slow. In 2018, there were four FDA-approved gene therapies (excluding those reliant on bone marrow/stem cell transplants or implants). Today, there are 10. One therapy is solely for the cosmetic purpose of reducing facial lines and folds.
Nevertheless, experts in the space believe gene therapy is poised to expand dramatically.
"Certainly in the next three to five years you will see dozens of gene therapies and cell therapies be approved," says Dr. Pavan Cheruvu, who is CEO of Sio Gene Therapies in New York. The company is developing treatments for Parkinson's disease and Tay-Sachs, among other diseases.
Cheruvu's conclusion is supported by NEWDIGS, a think tank at the Massachusetts Institute of Technology that keeps tabs on gene therapy developments. NEWDIGS predicts there will be at least 60 gene therapies approved for use in the U.S. by the end of the decade. That number could be closer to 100 if Chinese researchers and biotech ventures decide the American market is a good fit for the therapies they develop.
"We are watching something of a conditional evolution, like a dot-com, or cellphones that were sizes of shoeboxes that have now matured to the size of wafers. Our space will follow along very similarly."
Dr. Carsten Brunn, a chemist by training and CEO of Selecta Biosciences outside of Boston, is developing ways to reduce the immune responses in patients who receive gene therapy. He observes that there are more than 300 therapies in development and thousands of clinical trials underway. "It's definitely an exciting time in the field," he says.
That's a far cry from the environment of little more than a decade ago. Research and investment in gene therapy had been brought low for years after the death of teenager Jesse Gelsinger in 1999 while he had been enrolled in a clinical trial to treat a liver disease. Gene therapy was a completely novel concept back then, and his death created existential questions about whether it was a proper pathway to pursue. Cheruvu, a cardiologist, calls the years after Gelsinger's death an "ice age" for gene therapy.
However, those dark years eventually yielded to a thaw. And while there have been some recent stumbles, they are considered part of the trial-and-error that has often accompanied medical research as opposed to an ominous "stop" sign.
The deaths of three patients last year receiving gene therapy for myotubular myopathy – a degenerative disease that causes severe muscle weakness – promptly ended the clinical trial in which they were enrolled. However, the incident caused few ripples beyond that. Researchers linked the deaths to dosage sizes that caused liver toxicity, as opposed to the gene therapy itself being an automatic death sentence; younger patients who received lower doses due to a less advanced disease state experienced improvements.
The gene sequencing and editing that helped create vaccines for COVID-19 in record time also bolstered the argument for more investment in research and development. Cheruvu notes that the field has usually been the domain of investors with significant expertise in the field; these days, more money is flowing in from generalists.
The Challenges Ahead
What will be the next step in gene therapy's evolution? Many of Samulski's earliest innovations came in the laboratory, for example. Then that led to him forming a company called AskBio in collaboration with the Muscular Dystrophy Association. AskBio sold its gene therapy to Pfizer five years ago to assure that enough could be manufactured for stage 3 clinical trials and eventually reach the market.
Cheruvu suggests that many future gene therapy innovations will be the result of what he calls "congruent innovation." That means publicly funded laboratories and privately funded companies might develop treatments separately or in collaboration. Or, university scientists may depend on private ventures to solve one of gene therapy's most vexing issues: producing enough finished material to test and treat on a large scale. "Manufacturing is a real bottleneck right now," Brunn says.
The alternative is referred to in the sector as the "valley of death": a lab has found a promising treatment, but is not far enough along in development to submit an investigational new drug application with the FDA. The promise withers away as a result. But the new abundance of venture capital for gene therapy has made this scenario less of an issue for private firms, some of which have received hundreds of millions of dollars in funding.
There are also numerous clinical challenges. Many gene therapies use what are known as adeno-associated virus vectors (AAVs) to deliver treatments. They are hollowed-out husks of viruses that can cause a variety of mostly mild maladies ranging from colds to pink eye. They are modified to deliver the genetic material used in the therapy. Most of these vectors trigger an antibody reaction that limits treatments to a single does or a handful of smaller ones. That can limit the potential progress for patients – an issue referred to as treatment "durability."
Although vectors from animals such as horses trigger far less of an antibody reaction in patients -- and there has been significant work done on using artificial vectors -- both are likely years away from being used on a large scale. "For the foreseeable future, AAV is the delivery system of choice," Brunn says.
Also, there will likely be demand for concurrent gene therapies that can lead to a complete cure – not only halting the progress of Duchenne's in kids like Conner Curran, but regenerating their lost muscle cells, perhaps through some form of stem cell therapy or another treatment that has yet to be devised.
Nevertheless, Samulski believes demand for imperfect treatments will be high – particularly with a disease such as muscular dystrophy, where many patients are mere months from spending the remainder of their lives in wheelchairs. But Samulski believes those therapies will also inevitably evolve into something far more effective.
"We are watching something of a conditional evolution, like a dot-com, or cellphones that were sizes of shoeboxes that have now matured to the size of wafers," he says. "Our space will follow along very similarly."
Jessica Curran will remain forever grateful for what her son has received: "Jude gave us new hope. He gave us something that is priceless – a chance to watch Conner grow up and live out his own dreams."