As it conducted its analysis of the Pfizer-BioNTech COVID-19 vaccine in December, the European Medicines Agency (EMA) was the victim of a cyberattack. More than 40 megabytes of classified information from the agency’s review were published on the dark web, and several journalists — including from The BMJ — and academics worldwide were sent copies of the leaks. They came from anonymous email accounts and most efforts to interact with the senders were unsuccessful. None of the senders revealed their identity, and the EMA says it is pursuing a criminal investigation.
The BMJ has reviewed the documents, which show that regulators had major concerns over unexpectedly low quantities of intact mRNA in batches of the vaccine developed for commercial production.
EMA scientists tasked with ensuring manufacturing quality — the chemistry, manufacturing and control aspects of Pfizer’s submission to the EMA — worried about “truncated and modified mRNA species present in the finished product.” Among the many files leaked to The BMJ, an email dated Nov. 23 by a high ranking EMA official outlined a raft of issues. In short, commercial manufacturing was not producing vaccines to the specifications expected, and regulators were unsure of the implications. EMA responded by filing two “major objections” with Pfizer, along with a host of other questions it wanted addressed.
The email identified “a significant difference in % RNA integrity/truncated species” between the clinical batches and proposed commercial batches — from around 78% to 55%. The root cause was unknown and the impact of this loss of RNA integrity on safety and efficacy of the vaccine was “yet to be defined,” the email said.
Ultimately, on Dec. 21, EMA authorized Pfizer-BioNTech’s vaccine. The agency’s public assessment report, a technical document published on its website, noted, “the quality of this medicinal product, submitted in the emergency context of the current (COVID-19) pandemic, is considered to be sufficiently consistent and acceptable.
It’s unclear how the agency’s concerns were satisfied. According to one of the leaked emails dated Nov. 25, positive news had come from an undisclosed source in the US: “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 email said.
A near miss?
It’s also unclear whether the events in November constitute a near miss in the commercial manufacturing of mRNA vaccines.
EMA says the leaked information was partially doctored, explaining in a statement that “whilst individual emails are authentic, data from different users were selected and aggregated, screenshots from multiple folders and mailboxes have been created, and additional titles were added by the perpetrators.”
But the documents offer the broader medical community a chance to reflect on the complexities of quality assurance for novel mRNA vaccines, which include everything from the quantification and integrity of mRNA and carrier lipids to measuring the distribution of particle sizes and encapsulation efficiency. Of particular concern is RNA instability, one of the most important variables relevant to all mRNA vaccines that has thus far received scant attention in the clinical community. It is an issue relevant not just to Pfizer-BioNTech’s vaccine but also to those produced by Moderna, CureVac, and others as well as a “second generation” mRNA vaccine being pursued by Imperial College London. Read Full Article >