Pfizer CEO Albert boura made a bold commitment in June. Just before the G7 summit, at a press conference in St Ives, Britain, bourla stood next to US President Joe Biden and said that if it is necessary to develop a new covid-19 vaccine, his company can prepare a vaccine within 100 days.
He was referring to the need for the possible emergence of a “escape variant” – a major strain of sars-cov-2 that evades the primary immunity established through vaccines and previous infections. No such strain has yet been found, but Pfizer and other leading COVID-19 -19 vaccine manufacturers are preparing for this situation.
What flexibility is needed to design and test an updated vaccine against unknown virus strains in a record time? Nature magazine interviewed three COVID-19 -19 vaccine manufacturers, Pfizer, Modena and AstraZeneca, to find out how they were prepared.
In the past few months, all three companies have been rehearsing to practice the known sars-cov-2 variant. This includes updating the vaccine to match variants such as β and δ， Test it in clinical research, adjust its internal workflow and coordinate with regulatory agencies. Their goal is to learn from these warm-up experiments and straighten out the tangles in the process so that they can act quickly in the event of a real escape variant.
“To some extent, it is inevitable that we will have to make a variant vaccine – if the vaccine is the way to maintain people’s immunity – but we have not reached the level where we can confidently predict the evolution of the virus,” said Paul binias, a virologist at Rockefeller University in New York City. “It seems a reasonable way to practice with existing variants.”
The first generation of COVID-19 -19 vaccine seems to be resistant to Delta and other known variants, at least in the prevention of serious diseases and hospitalization. Pfizer, Modena and AstraZeneca said their vaccine was based on the sars-cov-2 strain initially detected in Wuhan, China, and still provided the best protection for all known variants. Catherine Edwards, scientific director of the Vanderbilt vaccine research project at Vanderbilt University Medical Center in Nashville, Tennessee, said: “there is really no need to make a more effective new vaccine now, because it seems that the old vaccine is very effective for the delta variant.”.
If escape mutation occurs, RNA vaccine manufacturers such as Pfizer and Moderna may design and synthesize an initial prototype vaccine against it within a few days. Viral vector vaccines, such as AstraZeneca, may follow. Making RNA vaccines usually requires generating a new gene sequence and encapsulating it in fatty substances such as lipids. Viral vector vaccine is produced by inserting key gene sequences into harmless vector viruses, cultivating a large number of viruses in bioreactor and purifying them.
But before deploying these vaccines, they must be tested in humans, which takes time. Therefore, pharmaceutical companies are carrying out trial operation. Pfizer and its partner, biontech of Mainz, Germany, are testing one in a randomized, placebo-controlled clinical trial β- Specific RNA vaccine, with 930 subjects. In August, the two companies began a multivalent vaccine trial against Delta and alpha variants.
“We didn’t do this because we actually thought we needed a new vaccine against these strains,” said Philip Dormitzer, vice president and chief scientific officer of virus vaccine and mRNA at Pfizer in New York. “We want to practice all aspects of implementing strain change – including preclinical research, production, clinical trials and regulatory submissions – so that if we do see a variant that really escapes vaccine immunization, we are ready to act quickly,” domitzer said. Pfizer currently has no plans to deploy its vaccine in the public β or δ vaccines
Modena, based in Cambridge, Massachusetts, is recruiting 300-500 participants to test against β、δ as well as β A new RNA vaccine combined with the original strain. The company also plans to test one β-δ Multivalent vaccine. Jacqueline Miller, senior vice president and head of infectious disease research of Moderna, said that the purpose is to submit test cases to the U.S. Food and Drug Administration and “establish a process to achieve this goal faster in the future”.
β Is a particular focus of attention because it carries mutations that make it more resistant to antibody neutralization in humans after vaccination than any other known variant. “If another strain evolves these mutations in the future, we can use what we have learned from studying beta mutations,” Miller said.
AstraZeneca, headquartered in Cambridge, UK, has begun a project on β- Large scale study of specific virus vector vaccine. The study was launched in June with more than 2800 participants, many of whom have been vaccinated with messenger RNA vaccine or AstraZeneca’s first generation viral vector vaccine. Mene Pangalos, executive vice president of AstraZeneca biopharmaceutical R & D, said: “we are certainly practicing this, but we are also developing it. If it succeeds, we will be ready to use it.”.
Real world effectiveness
Determining the true efficacy of the mutant vaccine will be difficult. In areas where COVID-19 -19 vaccine tests are well established, it may be difficult to find volunteers who have not yet been vaccinated but are willing to participate in the new vaccine trial. Considering the availability of effective vaccines, the recruitment of placebo group for randomized controlled trials may also have ethical problems.
Matthew Hepburn (Matthew Hepburn) said: “if we do not plan to conduct randomized controlled trials of curative effects, the other option is to carry out immunogenicity study, plus a truly robust, well designed and effective study.” he was the director of COVID-19 -19 vaccine development of the United States government’s anti acceleration team before August (formerly the “twist speed action”). He is now a special adviser to the White House Office of science and technology policy.
Immunogenicity studies will measure the immune response triggered by the variant vaccine – such as an increase in antibody or B cell levels – and compare it with the effect of the first generation vaccine. This seems to be the direction of some vaccine manufacturers: AstraZeneca will use it according to the guidance of European regulators β A method of vaccine testing.
Moderna also focuses on immunogenicity data and works with a hospital system in Southern California to collect real data on vaccine effectiveness. In these observational studies, participants can choose whether to be vaccinated or not, and the researchers monitor the two groups to understand their situation. These studies admit that “they are not perfect” because the two groups may have different behavior and risk factors.
How public health authorities will determine that a mutant virus has escaped – so the world needs a new, new, new, new, new, new, new vaccine – is unclear. Pangalos provides a way to measure this: “if we start to see a lot of people getting vaccinated in hospitals, then we have a problem,” he said. “But now, we are far from here.”
The World Health Organization has a strict procedure to decide when and how to change influenza vaccines to adapt to emerging strains. These decisions are based in part on the long history of monitoring virus evolution and immunization. Hepburn said, “there is no such thing as COVID-19.”
Miller hopes that the process of updating the new COVID-19 -19 vaccine will eventually be as simple as replacing the flu vaccine, and flu vaccines usually do not require much clinical research. She added that because RNA vaccines are produced faster than traditional vaccines, “our idea is to make this transformation faster than we can deal with influenza”.