COVID-19 vaccine makers are figuring out how to fine tune their recipes against disturbing viral mutations – and regulators are looking to influenza as a model if and when vaccines need to be updated.
“It’s not really something that you can sort of flip a switch, do overnight,” warned Richard Webby, who runs a World Health Organization flu center from from St. Jude Children’s Research Hospital.
Viruses are constantly mutating and all it takes is the right combination of specific mutations to escape vaccination. But studies raise concerns that first-generation COVID-19 vaccines may not work as well against a mutant that first appeared in South Africa as against other versions circulating around the world.
The good news: Many of the new COVID-19 vaccines are made with new technology that is flexible and easy to upgrade. What’s more difficult: deciding whether the virus has mutated enough that it’s time to change the vaccines – and what changes to make.
“When do you pull the trigger?” asked Norman Baylor, a former head of vaccines for the Food and Drug Administration. “He’s a moving target right now.”
WHO and FDA look to the global influenza vaccination system to decide how to handle similar decisions regarding COVID-19 vaccines.
The flu mutates much faster than the coronavirus, and flu shots need to be adjusted roughly every year. National centers around the world collect circulating influenza viruses and monitor their progress. They send samples to laboratories designated by the WHO for more sophisticated “antigenic” testing to determine the strength of the vaccine. The WHO and regulators then agree on the recipe for the vaccine of the year, and manufacturers get to work.
For COVID-19 vaccines, Webby said a critical step is to establish a similar surveillance and testing network to report important mutations. Today, there is great geographic variability in the tracking and testing of mutated versions. Britain, for example, performs more testing of the evolving viral genome than the United States
Three variants first discovered in Britain, South Africa and Brazil are worrying due to combinations of mutations that make them more contagious.
U.S. researchers on Sunday reported an even different mutation found in seven variants that have arisen in several states. No one yet knows if this mutation makes the virus easier to spread, but the report, which has yet to be approved by other scientists, calls for further research to find out.
Just because a variant is more contagious does not mean that it will also be immune to vaccination. But the variant first identified in South Africa raises concerns. David Ho of Columbia University put blood samples from people who received Pfizer or Moderna vaccines in laboratory dishes with the mutated virus. The antibodies produced by the vaccine still provided protection, but they were much less potent.
Preliminary testing results from two other candidate vaccines – from Novavax and Johnson & Johnson – quickly confirmed these results. Both are still protected but were weaker when tested in South Africa, where this variant dominates, than when tested elsewhere. A much smaller test of the AstraZeneca vaccine in South Africa has raised questions about its effect.
“If the virus was able to make one or two more mutations, it could escape even more,” Ho warned.
If fully immune people begin to be hospitalized with a mutated virus, “that’s when the line is crossed,” said Dr. Paul Offit, a vaccine expert at Children’s Hospital of Philadelphia who advises the FDA.
It hasn’t happened yet, but “we have to prepare,” he added.
Moderna is about to explore an option: Could a third dose of the original vaccine boost immunity enough to fend off some variants even if it’s not an exact match?
The Ho of Columbia said it was a good idea to test because people can “still have a lot of cushion” if their overall antibody levels are very high.
Major manufacturers are also developing experimental vaccine variants, just in case.
COVID-19 vaccines produce antibodies that recognize the spike protein that covers the coronavirus. When the virus mutates, the spike protein is sometimes changed in key areas, making it more difficult for the antibodies produced by the vaccine to recognize it.
Pfizer and Moderna vaccines are made with a piece of genetic code called messenger RNA that tells the body how to make harmless copies of the spike protein that trains immune cells. To update the vaccine, they can simply change the payload: replace the original genetic code with mRNA for the mutated spike protein.
The AstraZeneca vaccine and the soon-to-be rolled out Johnson & Johnson vaccine are made with cold viruses designed to bring a spike protein gene into the body. Adjusting their vaccines requires growing the common cold virus with the mutated gene, a little more complex than the mRNA approach but not as laborious as reformulating the old-fashioned influenza vaccines.
The Novavax vaccine, also in final stages of testing, is made with a lab-grown copy of the spike protein that could also be altered to match mutations.
The first generation COVID-19 vaccines have been tested on tens of thousands of people to make sure they work and are safe – research that took several months.
Just changing the recipe to better target mutations in the virus won’t require repeating these studies on thousands of people, Dr. Peter Marks, FDA chief vaccine officer, recently told the American Medical Association.
The FDA is still in the process of finalizing the requirements, but Marks said the agency intends “to be pretty nimble.” If an updated vaccine is needed, testing a few hundred people would probably be enough to tell if it triggers a good immune response, he said.
But an even bigger question: If only certain places are faced with vaccine-resistant virus mutants, would authorities want injections only of the variants or vaccines that protect against two types in one fell swoop? After all, influenza vaccines protect against three or four different types in one shot.
Companies should do some basic research first to make sure that a version containing only variants properly stimulates the immune system, said John Grabenstein of the Immunization Action Coalition, a former vaccine official. from Merck. Then a combined plan would require more testing to be sure that there is an equal response to both types.