Two breakthrough vaccines using the same revolutionary technology have proven to be very effective in preventing Covid-19, but differences in the way shots are designed affect how quickly production can increase and how they are distributed.
The vaccines – one manufactured by the American company Moderna and the other through a partnership between Pfizer and the German BioNTech – both recorded an efficiency of over 94% in clinical trials, raising global hopes that they could provide a way out of the pandemic.
At the heart of both shots is the direction of ribonucleic acid, or mRNA, a sequence of about 2,000 biochemical letters of the genetic code that carry instructions from the recipient̵
Moderna’s vaccine uses 100 micrograms of RNA per dose, while the Pfizer-BioNTech shot uses only 30 micrograms, which makes production easier and cheaper, explained Zoltan Keys, a researcher at the future vaccine production center at Imperial College London.
This should allow Pfizer-BioNTech to increase vaccine production faster than its US competitor. Immunologists added that it was not yet clear why the Moderna shot needed a higher dose of RNA.
“It’s hard for outsiders to know exactly what’s in the vaccine,” said Alexander Edwards, an associate professor of biomedical technology at the University of Reading. “But the way it’s made can have a big effect on how it works.” Although the RNA in each is essentially the same, there may be small differences in the genetic sequence that make Pfizer-BioNTech more effective in smaller doses.
“RNA for mRNA vaccines is produced by a chemical process, not by biological processes used to make other vaccines that involve growing cell cultures,” said Prof. Edwards. It is slightly altered by “wild-type” RNA naturally present in the virus to make it more stable and easier to read by human cells, he said.
In both Moderna and Pfizer-BioNTech vaccines, RNA is encapsulated in “lipid nanoparticles”. These microscopic droplets of oily fluid – about 0.1 microns in diameter – enclose and protect fragile genetic instructions as they are produced, transported, and finally injected into humans. The composition of lipid nanoparticles is slightly different in the two vaccines, the researchers said, with a number of consequences.
“These nanoparticles can give a magical blow to the formulation,” said Prof. Edwards. “You may have a list of ingredients, but you don’t know how to combine them to get the best-sized and shaped particles. There are strong parallels with food production – you may know the ingredients of Heinz ketchup, but you can’t. “
Pfizer and BioNTech received their nanoparticles from the specialized Canadian company Acuitas, while Moderna developed its own lipid technology.
“The art and challenge of developing nanoparticles is to combine lipids with different physical characteristics in a way that stabilizes RNA as effectively as possible,” said Mike Watson, former head of vaccines at Modern.
In both cases, cold storage is required to keep the nanoparticles in good shape and to stop mRNA degradation. But while Moderna’s vaccine is stable enough to survive six months of storage at -20C, the temperature of a standard household or medical freezer, the Pfizer / BioNTech vaccine must be stored and transported at -70C.
As a result, once approved by regulators, Moderna’s vaccine can be distributed “more easily and at a lower cost,” said Dr. Keys of Imperial.
Pfizer and BioNTech had to design special “thermopeders” that could keep the product at this temperature for up to 15 days when regularly filled with dry ice. Each package has a GPS-connected thermometer that tracks its temperature and location in Pfizer’s distribution network. However, the temperature requirement will make it difficult to spread the vaccine in countries without sufficient cold chain storage capacity, as many in Africa and Asia.
In contrast, adenoviral vaccines under development, such as those produced by Oxford University and AstraZeneca, can be stored for many months without freezing. Instead of using mRNA, the Oxford vaccine attaches the protein genes to coronavirus proteins used to provoke an immune response to a harmless adenovirus that transmits them to human cells. Sarah Gilbert, head of the Oxford team, said her vaccine was stable at normal refrigerator temperatures between 2C-8C.
Differences in the way Pfizer-BioNTech and Moderna formulate lipids are also likely to affect the way each shot works. “Lipid nanoparticles have some adjuvant activity, providing little inflammation with vaccination, which helps the immune system produce antibodies and T cells targeting the Sars-Cov-2 virus,” said Brian Ferguson, an immunology researcher at the University of Cambridge.
Another approach developed by Imperial College in early clinical trials is a self-amplifying RNA vaccine that makes more copies of itself after injection into human cells. This approach could ultimately reduce the amount of RNA needed by just 1 microgram per dose, Dr. Keys said.