COVID Vaccine Makers Prepare for a Variant Worse than Delta

Albert Bourla, chief executive of Pfizers, made a bold pledge in June. Bourla, who was speaking alongside Joe Biden, the US President, at a press conference held in St Ives (UK) just before the G7 summit meeting made a bold promise that his company would be able to produce a new COVID-19 vaccination if necessary.
He was talking about the possibility of an escape strain of SARS-CoV-2, which could evade the fledgling immunity that has been established through vaccinations and other infections. Pfizer and other COVID-19 vaccine manufacturers have begun to prepare for this scenario. However, no such strain has been found.

How do you design and test a vaccine against a new virus strain in record time? Nature interviewed three COVID-19 vaccine manufacturers Pfizer, Moderna, and AstraZeneca about their preparations.

Dress rehearsal

All three companies have been practicing on known SARS variants over the past months in dress rehearsals. These include updating their vaccines to match variants like Beta and Delta, as well as testing them in clinical trials, fine-tuning their internal workflows, and communicating with regulators. They want to learn from these trials and fix any kinks in the process so they can be ready for an escape variant.

We will have to create variant vaccines at some point. If vaccines are to maintain population immunity, we need to do so. However, we don't know enough to predict the evolution of the virus. Paul Bieniasz is a virologist at Rockefeller University in New York City. It seems reasonable to practice with the existing variants.

The first generation COVID-19 vaccine seems to have been able to protect against Delta and other variants. This is at least when it comes to preventing severe illness and hospitalization. Moderna, Pfizer and AstraZeneca claim that their vaccines are still the most effective against all known variants. They are based on the original SARS CoV-2 strain, first discovered in Wuhan, China. Kathryn Edwards is the scientific director of Vanderbilt Vaccine Research Program, Vanderbilt University Medical Center, Nashville, Tennessee. She says that there really isn't a need to create a better vaccine at the moment. It looks like the existing ones are very effective against the Delta variant.

Moderna and Pfizer could design and produce a prototype jab against an escape variant in just a few days if there is a new variant. AstraZenecas could be closely following. An RNA vaccine is typically made by creating a new genetic sequence, and then encapsulating it with a fatty substance like a fat. Viral-vector vaccines can be created by inserting the key sequence into a harmless carrier viral, growing large numbers of the virus in bioreactors, and then purifying them.

These shots will need to be tested on humans before they can be used. This will take some time. Pharma companies are conducting dry runs. Pfizer and its partner BioNTech, located in Mainz in Germany, are testing a Beta-specific vaccine in a randomized, placebo-controlled clinical study with as many as 930 participants. The companies started a multivalent vaccine trial that targets both the Alpha and Delta variants in August.

We are not doing that because, in fact, we think we need a vaccine for those strains. Philip Dormitzer is vice-president, chief scientific officer of viral vaccinations and mRNA at Pfizer. He is based out of New York City. We want to practice all aspects of the execution of a strain change, including the preclinical research and manufacturing as well as the clinical testing. This will allow us to be ready for any variant that escapes vaccine immunity.

Moderna is based in Cambridge, Massachusetts and recruiting cohorts of 300500 people to test new RNA vaccines for Beta, Delta, and a combination Beta and the original strain. A BetaDelta multivalent vaccine is also being tested by the company. Moderna's senior vice-president and head for infectious-disease research Jacqueline Miller says that the purpose of the test cases is to be submitted to the US Food and Drug Administration.

Beta is an important focus because it has mutations that make it more resilient than any other variant to neutralization of antibodies after vaccination. Miller said that if there is a future strain with these mutations, Miller believes we can draw on the knowledge we have already gained from studying the Beta variant.

AstraZeneca is a UK-based company that has started a large study on a Beta-specific virus-vector vaccine. The study, which began in June, has more than 2,800 participants. Many of these people have been vaccinated either with a messenger-RNA vaccine or AstraZenecas' first-generation virus-vector vaccine. We are already practicing with this vaccine, but we are also working on it. If it succeeds, we will be able to offer it for use," Mene Pangalos (executive vice-president of AstraZeneca's biopharmaceuticals research & development) says.

Real-world effectiveness

It will be difficult to determine the effectiveness of variant vaccines. It can be difficult to find volunteers willing to participate in an experimental trial of a novel vaccine in regions with established COVID-19 vaccine trials. Given the availability of effective vaccines, there might be ethical concerns about recruiting placebo groups to randomized controlled trials.

Matthew Hepburn says that if we don't want to conduct randomized controlled trials of efficacy, there are other options. Hepburn was, until August, the director of COVID-19 vaccine design at the US Countermeasures Acceleration Group (formerly Operation Warp Speed), and now is a special advisor at the White House Office of Science and Technology Policy.

Immunogenicity studies could measure immune responses to variant vaccines, such as an increase in antibody levels or B-cell counts, and compare them with the effects of the original-generation vaccine. This seems to be the direction that vaccine manufacturers are going: AstraZeneca, based on guidance from European regulators will employ this approach in its Betavaccine trial.

Moderna also studies immunogenicity data and collaborates with a southern California hospital system to gather real-world data about vaccine effectiveness. Participants can decide whether to get a vaccine, and researchers track the results of both groups. Miller admits that such studies can be imperfect because different risk factors and behaviours might exist in the two groups.

It is not yet clear how public-health authorities will decide that a variant of the virus has escaped, and therefore the world requires a new COVID-19 vaccination. Pangalos suggests one way to determine that. If there are a lot of people coming into the hospital who have been vaccinated then it is a sign that we have a problem. Right now, we are not even close to that.

The World Health Organization follows a structured process to determine when and how to modify an influenza vaccine to match a new strain. These decisions are partly based on a long history in monitoring the evolution of the virus and immunizing against it. Hepburn says that COVID does not have such a history.

Miller hopes that updating a COVID-19 vaccination will be as simple as changing a flu shot. This is because it doesn't usually require clinical trials. She also notes that RNA vaccines are more easily manufactured than traditional jabs. This would allow for a faster switch to flu.

This article was originally published in October 2021.

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