January 19, 2021
The European Agency’s “Major Objections”
“We thus discover that in November the European agency was formulating three ‘major objections’ to this vaccine:
certain production sites had not yet been inspected
data were lacking on the vaccine batches that are to be marketed
the available data showed qualitative differences between the commercial batches and those which had served during the clinical trials. It was on this point that the assessors seemed most concerned.
In order to move from a clinical to a commercial stage, the manufacturers had to change the manufacturing process; they invested in new production lines and in new factories.
Modifications which may explain the differences in the exact composition of the vaccine, in particular a decrease in the degree of integrity of the RNA. This being the crucial element of this vaccine, which allows, once injected into the cells, the manufacture of the virus’s Spike protein and thus teaches the immune system to recognise the pathogen and to neutralise it.
The messenger RNA in the vaccine is a copy of a small part of the RNA of the SARS-CoV-2 virus. This molecule has the role of giving our cells the instructions needed to produce the Spike protein, a protein to which the immune system will react by producing specific antibodies.
The Ministry of Health of Romania:
Low RNA concentration
The vaccines used during the clinical trials contained between 69% and 89% ‘integral’ RNA. By contrast, data concerning the batches manufactured on the new production lines showed a lower percentage, on average 59%.
Certain batches went as low as 51% and 52%. A ‘blocking point’, the EMA notes on 23 November.
Two questions arose:
Is it less effective?
Is it less safe, because less integral RNA means more impurities, in particular truncated RNA.
These truncated RNAs cannot be turned into Spike protein.
‘We frequently have RNA that is a little shorter or a little longer in these products. We filter according to the size of the molecule, but this filtering is difficult on a large scale’, says Steve Pascolo, a researcher at the university hospital of Zurich, who has worked for 20 years in the field of RNA vaccines (a co-founder of CureVac in 2000, he left the company and today has joint projects with BioNTech).
Nevertheless, the data supplied by Pfizer/BioNTech show that at a percentage of 62% complete RNA the protein is produced in comparable quantities.
‘In BioNTech’s first trials they had immune responses with a single microgram of RNA’, Steve Pascolo points out. ‘Now the vaccine is calculated to have 30 micrograms, so they have a margin.’
This is also the view of the American governmental agency for public health (FDA), with which the EMA was in contact. ‘The question of the quantity of messenger RNA is not considered to be major’ for the FDA, an EMA official explains in an e-mail dated 23 November.
Pfizer answers the objections raised by the EMA
What the documents stolen from the European Medicines Agency say about the anti-COVID-19 vaccines. The checks made by the experts before approval
The Pfizer factory in Puurs, near Antwerp, Belgium, was modernised in order to increase the production capacity for the anti-COVID-19 vaccines | Photo: EPA
On 26 November, BioNTech and Pfizer answer the EMA’s objections. Inspections of the various production sites are under way, one may read in their presentation.
They also propose to raise the percentage of minimum RNA integrity to 60% in the first stages of manufacture, so that it should not fall below 50% in the final product, which appears as an acceptance criterion in all the documents consulted.
In the presentation, the manufacturers of the vaccine officially named Comirnaty state that the differences in the quantity of RNA ‘should not affect’ either the efficacy or the safety of the product. Some of these batches were used in the clinical trials, the company further states.
The European agency asks for new guarantees
The European agency does not seem definitively convinced, since the last documents or exchanges to which the journalists had access do not allow this ‘major objection’ to be lifted.
A screenshot of an e-mail exchanged on 30 November between the EMA and Pfizer/BioNTech confirms this idea: ‘These issues are considered critical, especially in the context of the novelty of this type of product and of the limited experience; a stricter control strategy is desired.’
In one of the last accessible reports we learn, however, that an adjustment of the manufacturing processes allows integrity levels of around 75% to be recovered, comparable with the clinical-trial batch.
Pfizer settles the problem
Three days later, the Wall Street Journal published an article announcing that there had been a production problem with the Pfizer vaccine. ‘Certain batches of raw materials did not meet the standards. We solved the problem, but we lost time in meeting the shipments planned for this year’, explained ‘a person directly involved in the development of the Pfizer vaccine’.
Is there any connection with the problem signalled by the EMA? Pfizer did not wish to comment.
The European authority confirmed to Le Monde that the quality problem was subsequently settled: ‘The company was in a position to solve these problems and to supply the information and the data necessary to allow the EMA to move towards a positive recommendation for the vaccine.’
The agency assures that the current specifications concerning the level of RNA ‘are considered to be scientifically justified and acceptable’.
It is unlikely, the agency stresses, that these truncated RNA molecules could be turned into proteins or peptides and thus cause undesirable effects.”
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