A COVID-19 vaccine made by BioNet-Asia in Ayutthaya, Thailand, should be cheaper than the two messenger RNA vaccines used in richer countries.ADAM DEAN
From: Science/ By Jon Cohen
The two COVID-19 vaccines based on messenger RNA (mRNA) have been the breakout stars of the pandemic. Both trigger impressive immune responses with minimal side effects, and both did exceptionally well in efficacy trials. But the vaccines, produced by the Pfizer-BioNTech partnership and Moderna, have also split the world. Because of their high prices and their need to be stored at extremely low temperatures, few people in lower and middle-income countries have had access to them.
That might soon change. More than a dozen new mRNA vaccines from 10 countries are now advancing in clinical studies, including one from China that’s already in a phase 3 trial. Some are easier to store, and many would be cheaper. Showing they work won’t be easy: The number of people who don’t already have some immunity to COVID-19 because of vaccination or infection is dwindling. But if one or more of the candidates gets the green light, the mRNA revolution could reach many more people.
The Pfizer-BioNTech and Moderna shots rely on mRNA to direct cells to produce spike, a protein on SARS-CoV-2’s surface. Although 23 COVID-19 vaccines are in use around the world, based on technologies including inactivated SARS-CoV-2 and cold viruses engineered to carry the spike gene, the two mRNA vaccines account for about 30% of the 13.2 billion doses produced so far, according to health care data company Airfinity. But the companies have been reluctant to share their intellectual property (IP) and know-how, which would allow manufacturers in poorer countries to produce the shots.
Instead, BioNTech and Moderna each recently announced plans to build their own plants in African countries. In a separate effort, the World Health Organization has created a training hub for mRNA vaccines that will teach scientists from low- and middle-income countries how to build and run their own plants. But it may take years before these efforts bear fruit.
The candidates already under development could reach the marketplace much faster. IP protections are still a challenge, says Melanie Saville, who heads vaccine R&D at the Coalition for Epidemic Preparedness Innovations: “Who can do what and where is going to be a critical question.” But the new mRNA developers have managed to dodge some of the showstoppers.
Furthest along is a vaccine made by Walvax Biotechnology in Kunming, China, together with Suzhou Abogen Biosciences and the Chinese Academy of Military Science. Details are hard to come by and Walvax did not respond to detailed questions from Science, but a paper about a phase 1 trial, published in The Lancet Microbe in January, offers some information. Instead of using mRNA that encodes the entire spike protein, the Walvax team only included the sequence of a key portion known as the receptor binding domain. In July 2021, the company launched a placebo-controlled phase 3 trial in 28,000 people in Mexico, Indonesia, Nepal, and China.
A key advantage is that Walvax’s product can be kept in a standard refrigerator, says Víctor Bohórquez López, a clinician who leads trials at five sites in Mexico for Red OSMO, a network based in Oaxaca. A company official told Reuters in January that Walvax can produce 400 million doses a year.
In Thailand, a team lead by Kiat Ruxrungtham at Chulalongkorn University has developed an mRNA vaccine, produced by the French-Thai company BioNet-Asia, that has completed phase 1/2 studies. The team followed a key step in the playbook used by the Pfizer-BioNTech collaboration and Moderna: replacing uridine—one of the four basic building blocks of RNA—with methylpseudouridine, a substitution that reduces the toxicity of mRNA and increases the amount of spike protein cells produce. The substitution is “the most important thing that people have done with mRNA vaccines,” says Philip Krause, a former top vaccine official at the U.S. Food and Drug Administration (FDA). BioNet-Asia can use the replacement for free because the company that licensed the technology from the University of Pennsylvania, where it was invented, has not sought protection in Southeast Asia.
A new wave of mRNA COVID-19 vaccines
A bevy of messenger RNA (mRNA) vaccines against COVID-19 are currently in clinical trials around the world. Because placebo-controlled efficacy trials are increasingly seen as unethical, some trials compare a new vaccine with a proven one (comparator). Others give the vaccine to people who are already fully vaccinated and measure the immune response (booster).
| MAIN MANUFACTURER | Country | mRNA type | Clinical phase |
|---|---|---|---|
| Walvax Biotechnology | China | Conventional | 3 (booster) |
| Gennova Bio* | India | Self-amplifying | 2/3 (comparator) |
| Vinbiocare Biotechnology** | Vietnam | Self-amplifying | 1/2/3 (comparator) |
| Daiichi Sankyo | Japan | Conventional | 1/2/3 (booster) |
| BioNet-Asia | Thailand | Conventional | 2 |
| Providence Therapeutics | Canada | Conventional | 2 |
| Arcturus Therapeutics** | United States | Self-amplifying | 2 |
| Elixirgen Therapeutics | United States | Self-amplifying | 1/2 |
| EyeGene | South Korea | Conventional | 1/2 |
| Stemirna Therapeutics | China | Conventional | 1/2 |
| AIM Vaccine Group | China | Unknown | 1/2 |
| HDT Bio* | United States | Self-amplifying | 1 |
| GlaxoSmithKline (GSK) | United States | Self-amplifying | 1 |
| VLP Therapeutics | Japan | Self-amplifying | 1 |
| Imperial College London | England | Self-amplifying | 1 |
| Gritstone Bio | England | Self-amplifying | 1 (booster) |
| University of Melbourne | Australia | Conventional | 1 (booster) |
| CureVac/GSK | Germany | Conventional | 1 |
*/** denote shared technologyDATA: WORLD HEALTH ORGANIZATION; COVID-19 VACCINE TRACKER
The vaccine differs from the marketed ones in other ways, however. Kiat’s team did not introduce two mutations in spike that stabilize the protein, which would have required an expensive IP license. They avoided another licensing issue by having the code direct cells to secrete the spike protein, rather than leaving it bound to the membrane. Some comparative studies have found this leads to a weaker immune response, but Kiat’s mouse studies saw no difference, and human data show the vaccine triggers robust levels of antibodies that can neutralize the virus, he says.
BioNet-Asia can make up to 100 million doses a year, Kiat says, at a lower price than the Pfizer-BioNTech collaboration and Moderna. Japan’s Daiichi Sankyo and Canada’s Providence Therapeutics have mRNA vaccines at similar stages of development.
About half of the new candidates are “self-amplifying”: They include harmless genes from an alphavirus that code for an enzyme used in RNA replication, enabling the spike mRNA to make additional copies of itself. Each dose can get by with less mRNA, which could make it easier to vaccinate more people. A downside is that self-amplifying mRNA vaccines can’t use the methylpseudouridine substitution—they need the natural uridine to replicate.
A phase 1 study of a self-amplifying vaccine developed at Imperial College London triggered such mediocre immune responses that the researchers went back to the drawing board. But a similar candidate from GlaxoSmithKline solidly protected hamsters against SARS-CoV-2 infection, a January paper in Molecular Therapy showed. That vaccine is now being tested in a 10-person phase 1 trial.
Showing that the new vaccines work in humans presents formidable challenges. “I’m in trouble because I can’t find the population right now for the phase 3 trial,” Kiat says. Not only is it becoming more difficult to find people who have no immunity at all against SARS-CoV-2, but enrolling participants in a placebo-controlled study is increasingly ethically fraught, because proven COVID-19 vaccines are now widely available. Producers of self-amplifying vaccines in India and Vietnam instead plan to compare the vaccines with others already in use.
Kiat hopes to judge his candidate based on a proxy measure: how well it boosts antibody levels in people who are fully vaccinated. Past studies of the marketed mRNA vaccines have shown that specific levels of neutralizing antibodies are correlated with protection from disease, and BioNet-Asia and other manufacturers hope regulators will accept similar data to authorize use of their vaccines. The European Medicines Agency and regulators from several countries have indicated they will accept such “immunobridging” data in some circumstances, Krause says. FDA has yet to issue guidelines. “I know from talking to people at FDA that they are reluctant” to rely on antibody data, says Stanley Plotkin, a veteran vaccine researcher who consults with Moderna and many other companies.
One problem is that antibodies are only part of the immune response triggered by mRNA vaccines. T cells—which are more difficult to measure—play a role in preventing severe disease by eliminating infected cells. They also offer better protection against new virus variants than antibodies and help ensure the durability of immunity. Still, Plotkin and others say, antibody levels are good enough surrogates to issue emergency use authorizations. For full approval, they say, vaccines will have to prove effective in real-world studies.
“We know that there are a lot of hurdles ahead,” Kiat says. But even if their COVID-19 vaccine fails, his team is building capacity for the future, he says. “We can now manufacture new mRNA vaccines very quickly, so that’s a way to solve the next pandemic—and we can make the price lower than the Big Pharmas.”
