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Last year, there were doubts about early commercial batches of the Pfizer-BioNTech mRNA vaccine. Marcos del Mazo/Getty Images
  • Recent studies confirm that mRNA vaccines are safe and provide a high degree of protection against COVID-19.
  • However, leaked emails show that there were doubts last year about early commercial batches of the Pfizer-BioNTech mRNA vaccine.
  • The emails reveal that the European Medicines Agency (EMA) raised concerns with Pfizer that the vaccine contained lower levels of intact mRNA molecules than expected.
  • The company resolved the issue to the satisfaction of the EMA and regulatory agencies in the United States and Canada.

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There is growing evidence that vaccination programs are already protecting some of the most vulnerable individuals from COVID-19, reducing the number of severe infections and preventing deaths.

While clinical trials in 2020 found mRNA vaccines to be safe and effective, several recent studies suggest that they also provide a high degree of protection in the “real world.”

For instance, a study by researchers in the United Kingdom, one that has not yet been peer-reviewed, found that a single dose of the Pfizer-BioNTech vaccine is up to 79.3% effective at reducing the risk of hospital admission with COVID-19 in adults over 80 years of age.

Another study in the U.K. estimates the vaccine’s effectiveness at 89% from 14 days after the second shot. This research has also not undergone peer review yet.

In the U.S., a 2021 study, which has not yet been peer-reviewed, found that two doses of either the Pfizer vaccine or another mRNA vaccine made by Moderna was 88.7% effective at preventing a SARS-CoV-2 infection in adults.

It therefore comes as a surprise to learn that in November 2020, the EMA raised concerns that proposed commercial batches of the Pfizer vaccine did not contain as many intact mRNA molecules as expected.

Each mRNA molecule in a vaccine is a genetic template that provides instructions for making a single viral protein.

When human cells take up the mRNA, they use it to manufacture millions of copies of the protein. These are harmless fragments of the virus, but they provoke an immune response that protects a person against future infection by the whole virus.

However, RNA molecules break down easily, which is why mRNA must be stored at very low temperatures. To further stabilize the mRNA in vaccines, manufacturers encapsulate the molecules in tiny blobs of fat called lipid nanoparticles.

“[T]he complete, intact mRNA molecule is essential to its potency as a vaccine,” wrote Daan J. A. Crommelin, professor of biopharmaceutics at Utrecht University in the Netherlands, and his colleagues in the Journal of Pharmaceutical Sciences in December 2020.

They noted that even minor degradation anywhere along the length of the mRNA strand can slow down or prevent the cell from properly making the viral protein.

Internal emails reveal that in November 2020, the EMA had concerns that batches of the Pfizer vaccine that were proposed for commercial use contained less intact mRNA than previous batches made for clinical trials.

Only around 55% of the mRNA molecules in those early commercial batches remained intact.

The doubts the EMA had have come to light only as a result of a cyberattack on the agency’s computer system in December 2020.

Unknown persons sent the leaked emails to several journalists, including at The BMJ, and the journal have now published an investigation into the agency’s concerns.

Pfizer do appear to have addressed all the questions raised by the EMA, which authorized the vaccine on December 21, 2020.

According to one of the leaked emails, dated November 25, 2020, an undisclosed source in the U.S. had given the agency positive news: “The latest lots indicate that % intact RNA are back at around 70–75%, which leaves us cautiously optimistic that additional data could address the issue.”

The BMJ report that the EMA, the Food and Drug Administration (FDA), and Health Canada worked together during the approval process and applied common criteria.

Health Canada told The BMJ that Pfizer had investigated the “root cause” of the problem with the commercial batches.

“[C]hanges were made in their processes to ensure that the integrity was improved and brought in line with what was seen for clinical trial batches,” said the EMA.

Health Canada further revealed that all three medical agencies subsequently concluded that “there was no concern with the RNA integrity or any other product specifications.”

While regulators are confident of the safety and efficacy of all the mRNA vaccines currently in use, questions remain about what criteria they use during the approval process for this relatively new technology.

When The BMJ approached manufacturers and several national regulators for comment, none would disclose what percentage of intact mRNA molecules they consider to be acceptable.

The FDA, the EMA, and Health Canada all told the journal that specific details about the acceptability criteria are confidential.

The EMA emphasized that the amounts of protein that a shortened mRNA strand could potentially produce “would be too low to constitute a safety risk.”

The agency also underlined that Pfizer had addressed their concerns about the amount of intact mRNA in the vaccine.

The article notes: “Each batch of vaccines is tested by the official medicinal control laboratory — the [Paul-Ehrlich-Institut] in Germany — before final product release. As a result, the quality of all vaccine doses that are placed on the market in Europe has been double-tested to ensure compliance with the specifications agreed upon with the regulatory authorities.”

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