Researchers in Germany report significant levels of human and viral proteins in AstraZeneca’s coronavirus vaccine. Although the study has not yet been peer-reviewed, it suggests that these contaminants may be related to the strong reaction seen in many people two to three days after being vaccinated. The preprint also states that it is conceivable, albeit doubtful, that these proteins could be associated with rare blood clotting events.

AstraZeneca’s vaccine contains a chimpanzee adenovirus that has been genetically engineered to prevent its replication and instead creates Covid-Spike protein in people who receive the vaccine. The human protein contaminants – mainly heat shock and cell scaffolding proteins – come from the human kidney cell line used to produce the chimpanzee adenovirus. Viral proteins, which are important for the virus to replicate in producer cells, were also present.

The lead researcher of the study, Stefan Kochanek from the University of Ulm, was surprised by the amounts of proteins that were detected by mass spectrometry in three vaccine batches. “At least half of the proteins in the vaccine are of human origin,” says Kochanek. One batch of vaccine contained approximately 12.5 µg of virus in one dose and approximately 22 µg of non-virus proteins.

The adenovirus vector is obtained by destroying cultured mammalian cells infected with the virus, and the viruses are then purified. “If this process is not super perfect, then what we see here comes in the end: the presence of proteins from the production cells, which is why we call them process-related impurities,” explains Kochanek.

Heat shock proteins can stimulate the immune system by attaching to other immune cells and releasing proteins to them. “In principle, they could strengthen the immune response against everything to which they bind,” says Kochanek. Although he doubts they caused the rare blood clotting events, he says it is a possibility.

“There is evidence that the proteins left in the AstraZeneca vaccine have safe levels that are similar or lower than levels seen in other similarly manufactured vaccines,” said a statement by AstraZeneca Chemistry world. “There is no evidence of this [the proteins] are immunogenic. The relationship between proteins and the occurrence of thrombosis and thrombocytopenia syndrome is suspected, but there is no experimental evidence. ‘

The experts are divided on the significance of the study results. “The fact that there are fragments of virus fragments and some parts of the cells that are used to grow the virus is no surprise,” says Daniel Bracewell of University College London, UK, who has studied host cell proteins in the production of monoclonal antibodies. He is skeptical about a connection with the thrombosis syndrome and describes this as speculative.

What surprised Bracewell was the variation between the lots. “It could reflect a consistency problem that is worrying when it is outside the boundaries of the material for clinical trials,” he notes. Nonetheless, he says AstraZeneca and the regulatory agency discussed such protein contaminants and agreed on acceptable levels.

An image showing the distribution of proteins in three batches of vaccine as a pie chart.

Immunologist Hildegund Ertl of the Wistar Institute in Philadelphia, USA, says that the Food and Drug Administration will allow the presence of such proteins normally in the nanogram per dose range. But “the AstraZeneca vaccine is in the microgram range, so it’s pretty high,” she says.

Whether the impurities cause the rare thrombosis syndrome has yet to be proven, says Ertl and describes this as a working hypothesis. “This is still a very good vaccine,” adds Ertl. “I’m not saying people shouldn’t take it.” She criticizes some negative press reports that the vaccine received in her home country, Germany.

Ertl notes that Johnson & Johnson’s adenovirus vaccine is associated with fewer thrombotic side effects, while the other adenovirus vaccine, Sputnik V, appears to be absent. She wonders if this could be due to the cleaning processes. “If there are cleaning problems, they are not difficult to solve,” says Ertl, who worked on adenovirus vaccines against HIV and is now an unpaid consultant at Sputnik V.

However, Bracewell warns that AstraZeneca cannot noticeably alter their cleaning processes, at least not in ways that alter the vaccine. “Whatever you’ve approved, you have to do it. There is nothing you can do to make it more pure [from what was used in the clinical trial] ,’ he says. In addition, some of the contaminants in mammalian cells could have immune-boosting adjuvant effects, he notes.

Andreas Greinacher, doctor and expert on platelet dysfunction at the University of Greifswald in Germany, rejects the designation of cell and virus proteins as “impurities” and prefers the term “vaccine components”. Still, Bracewell says that the official terminology describes them as contaminants that are controlled by purification technologies to a level acceptable to the regulator. He admits that the word “impurities” has a negative connotation, but this is different from impurities, which must be completely absent from a vaccine.

“The company has developed and validated quality control tests to measure proteins in accordance with industry standards,” AstraZeneca said in a statement. “Every batch is tested before a batch that has conditional or emergency approval is released.”

Rare blood coagulation events became known when young health workers, mainly women, were vaccinated in Europe, Greinacher notes. “Thrombosis is extremely rare in healthy women between the ages of 20 and 30, which made the treating physicians very suspicious when it first appeared,” he says.

But Greinacher also emphasizes that this side effect is extremely rare and says that one should not do without the AstraZeneca vaccination due to the advantages of the vaccination. He plans to analyze the Johnson & Johnson vaccine and compare the results with the AstraZeneca vaccine.


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