Two COVID-19 vaccines based on Messenger RNA (mRNA) have broken the epidemic breakout star. Both trigger impressive immune responses with minimal side effects and both performed exceptionally well on efficacy tests. But the Pfizer-Biotech partnership and the vaccines produced by Modern have also divided the world. Due to their high cost and the need to store them at extremely low temperatures, very few people in low- and middle-income countries have access to them.
That may change soon. More than a dozen new mRNA vaccines from nine countries are now advancing clinical studies, including one from China, which is already in the third phase of testing. Some will be easier to save, and many will be cheaper. It will not be easy to show their work: the number of people who are already immune to COVID-19 due to vaccination or infection is declining. But if one or more candidates get the green light, the mRNA revolution could reach many more people.
Pfizer-BioNTech and Moderna shots rely on mRNA to direct cells to form a protein spike on the surface of SARS-CoV-2. Although 23 COVID-19 vaccines are being used worldwide, based on technologies including inactivated SARS-CoV-2 and cold viruses to carry the spike gene, the two mRNA vaccines are still responsible for approximately 30% of the 13.2 billion doses produced, the healthcare information company said. According to Airfinity. But companies are reluctant to share their intellectual property (IP) and know-how, which allows manufacturers in poorer countries to make 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 center for mRNA vaccines that will teach scientists in low- and middle-income countries how to create and operate their own plants. But it may take years for these efforts to bear fruit.
Already developing candidates can reach the market very fast. IP protection is still a challenge, says Melanie Savile, head of Vaccine R&D at the Initiative for Epidemic Preparedness: “Who can do what and where is going to be an important question.” But new mRNA developers have been able to dodge some shostopers.
Suzhou Abogen Biosciences and the Chinese Academy of Military Sciences in Kunming, China. Details are hard to come by and did not answer detailed questions from Walvax ScienceBut a paper about a Phase 1 trial, has been published The Lancet Microbe In January, provided some information. Instead of using mRNA that encodes the entire spike protein, the Valvax team includes only a sequence of key components known as receptor binding domains. In July 2021, the company launched a placebo-controlled Phase 3 trial of 28,000 people in Mexico, Indonesia, Nepal and China.
One key advantage is that Valvax products can be stored in a standard refrigerator, says Victor Bohrkez Lopez, a physician who conducts trials on five sites for the Red OSMO in Mexico, an Oxaca-based network. A company official told Reuters in January that Walvax could produce 400 million doses a year.
In Thailand, a team led by Kiat Ruxrungtham of Chulalankorn University developed an mRNA vaccine, produced by the French-Thai company Bayonet-Asia, which completed a phase 1/2 study. The team followed a key step in the playbook used by Pfizer-BioNTech collaboration and Moderna: ureidin replacement – one of the four basic building blocks of RNA – with methylpisudoridine, a replacement that reduces mRNA toxicity and increases the amount of spike protein produced by cells. Philip Krauss, a former top vaccine official at the US Food and Drug Administration (FDA), said: “The most important thing is what people have done with the mRNA vaccine.” BioNet-Asia could use the free replacement because the company that licensed the technology from the University of Pennsylvania, where it was invented, did not seek protection in Southeast Asia.
A new wave of the mRNA COVID-19 vaccine
A baby of the Messenger RNA (mRNA) vaccine against COVID-19 is currently in clinical trials around the world. Since placebo-controlled efficacy trials are increasingly seen as unethical, some trials compare a new vaccine to a proven (comparative) one. Others give the vaccine to people who are already fully vaccinated and have measured immunity (booster).
|Main manufacturer||Country||mRNA type||Clinical phase|
|Valvax Biotechnology||China||Conventional||3 (booster)|
|Genoa Bio *||India||Self-enhancing||2/3 (comparator)|
|Vinbiocare Biotechnology **||Vietnam||Self-enhancing||1/2/3 (comparator)|
|Daiichi Sankio||Japan||Conventional||1/2/3 (booster)|
|Arcturus Therapeutics **||United States||Self-enhancing||2|
|Elixirgen Therapeutics||United States||Self-enhancing||1/2|
|AIM Vaccine Group||China||Unknown||1/2|
|HDT Bio *||United States||Self-enhancing||1|
|At Imperial College London||England||Self-enhancing||1|
|Greetstone Bio||England||Self-enhancing||1 (booster)|
|University of Melbourne||Australia||Conventional||1 (booster)|
However, vaccines differ from those marketed in other ways. Kiat’s team did not introduce two mutations to Spike that stabilized the protein, which would have required an expensive IP license. They avoid the licensing problem by not binding the code directly to the cell membrane to secrete spike proteins. Some comparative studies have shown that this leads to a weakened immune system, but no differences were found in Kiat’s mouse study, and human data show that the vaccine produces strong antibody levels that can neutralize the virus, he said.
Bayonet-Asia could produce 100 million doses a year, Kyat says, at a lower cost than Pfizer-Bioentech collaboration and Modern. The mRNA vaccine is at the same stage of development as Daiichi Sankio in Japan and Providence Therapeutics in Canada.
About half of the newcomers are “self-propagating”: they incorporate an alpha-virus-free gene that codes for an enzyme used in RNA replication, enabling spike mRNA to replicate itself. Each dose can be obtained with less mRNA, which may make it easier for more people to be vaccinated. One downside is that self-amplifying mRNA vaccines cannot use methylpoxyudoridine substitutes – they need natural uredine to replicate them.
A Phase 1 study of a self-enhancing vaccine developed at Imperial College London has elicited a moderate immune response that led researchers to return to the drawing board. But a candidate similar to GlaxoSmithKline strongly protected hamsters against SARS-CoV-2 infection, according to a study published in January. Molecular therapy The vaccine is now being tested in a Phase 1 trial of 10 people.
Demonstrating that new vaccines work in humans presents daunting challenges. “I’m in trouble because I can’t find the population for the Phase 3 trial right now,” Kyat said. Finding people who have absolutely no immunity against SARS-CoV-2 is becoming increasingly difficult, but enrolling participants in a placebo-controlled study is increasingly ethically complex, as proven COVID-19 vaccines are now widely available. Producers of self-enhancing vaccines in India and Vietnam are planning to compare the vaccine with others already in use.
Kyat hopes to judge his candidate based on a proxy measurement: how well it improves antibody levels in fully vaccinated people. Past studies of marketed mRNA vaccines have shown that certain levels of neutral antibodies are related to disease protection, and BioNet-Asia and other manufacturers expect regulators to accept similar data to approve their vaccine use. The European Medicines Agency and regulators in several countries have indicated that they will accept such “immunobridging” data in certain circumstances, Krause said. The FDA has not yet issued guidelines. “I know people at the FDA are reluctant to rely on antibody data,” said Stanley Plotkin, an experienced vaccine researcher who has consulted with Moderna and many other companies.
One problem is that antibodies are only part of the immune response caused by the mRNA vaccine. T cells – which are more difficult to measure – play a role in preventing serious disease by eliminating infected cells. These provide better protection against new virus forms than antibodies and help ensure immunity stability. Nevertheless, Plotkin and others say the antibody level is good enough to allow for emergency use. For full approval, they say, vaccines need to be proven effective in real-world research.
“We know there are a lot of obstacles ahead,” Kyat said. But while their COVID-19 vaccine failed, his team is building capacity for the future, he said. “We can now develop a new mRNA vaccine very quickly, so that it is a way to solve the next epidemic – and we can lower prices from Big Pharma.”