German researchers say they hope theory could help adapt adenovirus vector vaccines to increase safety
A German research team has put forward a potential solution to prevent the rare, serious blood clots caused by two leading COVID-19 vaccines, but other scientists warn it’s too early to draw conclusions about the mechanism behind the potentially deadly condition.
Even so, the researchers behind the new preprint study say they hope their theory could eventually help laboratories adapt the AstraZeneca-Oxford and Johnson & Johnson vaccines to increase safety and potentially boost global vaccination efforts.
Though uncommon, vaccine-induced immune thrombotic thrombocytopenia (VITT) is much more severe than a typical blood clot because it can cause cerebral venous sinus thrombosis (CVST), where veins that drain blood from the brain are obstructed and can potentially cause fatal bleeding.
The German researchers suggest the problem lies within the delivery system of these two similar vaccines, both of which use adenovirus vector technology to send genetic instructions into cells to produce the spike protein of the coronavirus.
The findings, which were published online on Wednesday and have not yet been peer reviewed, note this type of vaccine sends the DNA gene sequence of the spike protein directly into the nucleus of the cell, at which point certain parts of the spike protein DNA may become spliced, or broken apart.
The study, based on the team’s own lab work involving experiments with the commonly-used HeLa human cell line, suggests these “undesirable” breakdowns can cause mutations to occur within the spike protein DNA, which could make it tougher for those proteins to bond to the cell, allowing them to secrete into the body and potentially trigger “inflammatory reactions” that can result in the rare blood clots.
The researchers suspect three steps are at play: The rogue spike proteins flowing through the bloodstream, combined with the newly built antibodies designed to attack them, plus the highly specific blood flow conditions in veins that drain from the brain, “may result in the rare but severe events after vaccination,” the team wrote.
The Public Health Agency of Canada (PHAC) now estimates the rate of VITT in Canadians who have received the AstraZeneca vaccine is between 1 in 83,000 and 1 in 55,000, with a fatality rate of between 20 and 50 per cent, but that is subject to change as more data emerges.
PHAC said in a statement to CBC News Thursday there have been 27 confirmed cases of VITT to date in Canada out of two million doses administered, with five deaths among those cases.
Problem ‘absent’ in mRNA vaccines
The researchers say their study offers the “first molecular evidence” that adenovirus vector-based vaccines that encode the spike protein “exhibit a problem that is completely absent in mRNA-based vaccines,” such as Pfizer-BioNTech and Moderna.
“The adenoviral vaccines are delivering their complete DNA (including the gene for the antigen) to the nucleus, where transcription is taking place,” Prof. Rolf Marschalek, a professor of pharmaceutical biology at Goethe University in Frankfurt and lead author of the study, said in an email to CBC News. “Transcription means to make RNA copies from the DNA.”
Marschalek says the RNA is then spliced into pieces that encode smaller protein variants when derived outside of the nucleus to the cytosol of the cell. He says his team has identified the “splice products” in experiments in “relevant amounts,” so they are significant.
If proven to be accurate, the finding could potentially lead to reformulations of the AstraZeneca-Oxford and Johnson & Johnson vaccines in the future in order to prevent the rare blood clots.
The researchers say they strongly suggest the adenovirus vector vaccines should be “re-optimized” to avoid “unintended splice reactions” and “increase the safety” of the shots.
“When we know exactly where all these splice reactions occur, we can modify the gene appropriately to make it ‘splice safe,'” Marschalek told CBC News.
The researchers say the reason mRNA vaccines such as Pfizer-BioNTech and Moderna don’t have similar issues with splicing and blood clots is because the spike protein mRNA instructions they deliver aren’t able to enter the cell’s nucleus.
Data ‘thin,’ more research needed, experts say
But outside experts are urging caution due to a lack of concrete causal data. They say it’s too early to draw firm conclusions on the theory.
“The authors convincingly showed that there might be some differences in the way that the spike protein is processed when delivered through these viral-vectored vaccines, relative to mRNA vaccines, but they don’t show directly — or definitively — that that difference is responsible for these thrombotic events,” said Matthew Miller, an associate professor of infectious diseases and immunology at McMaster University in Hamilton.
Prof. Alyson Kelvin, an assistant professor at Dalhousie University and virologist at the Canadian Center for Vaccinology and the Vaccine and Infectious Disease Organization in Saskatoon, was also cautious when assessing the finding. She says the data in support of it is “thin.”
“I am not seeing much mechanistic data showing a causal relationship between the splice variants and blood clots,” she said in an email to CBC News.
“I think it is an interesting observation that should be explored, but at this time, nothing to hang my hat on.”
Dr. Zain Chagla, an infectious diseases specialist at St. Joseph’s Health Centre in Hamilton, agreed more research is needed, and noted the theory doesn’t explain a key characteristic of VITT: low levels of platelets, the small blood cell fragments that help form clots to stop bleeding.
“It might be a red herring altogether … or at least isn’t the smoking gun,” Chagla told CBC News.
Both the researchers themselves and other outside experts stressed the findings don’t answer multiple crucial questions about how this rare clotting condition is occurring, including why the clots appear to be happening in the channels that drain blood from the area in and around the brain, and why it impacts only certain people, but not most others.
Shots were paused over clot concerns
The study follows earlier research out of Norway in March, which identified the mechanism behind VITT, saying it was due to a “powerful immune response” following a shot of the AstraZeneca vaccine.
That finding had massive implications on the rollout of the vaccine in Canada and around the world, leading to the use of the shot being paused in parts of Europe.
Canada’s vaccine advisory committee recommended the AstraZeneca vaccine for Canadians over 65 on March 16, then advised immediately suspending the use of it in Canadians under 55 in late March following reports of VITT in Europe.
The AstraZeneca vaccine is currently approved by Health Canada for Canadians 18 years of age and older, although most provinces have stopped giving first doses of the shot and are reserving future supply for second doses.
The Johnson & Johnson vaccine is recommended for all Canadians 30 years of age and older, but Canada’s vaccination advisers also say to weigh the risk of VITT against COVID-19 levels in the community when deciding whether to hold out for another vaccine.
Health Canada is holding off on distributing the first shipment of that vaccine after it became clear the doses that arrived last month were processed in the same U.S. plant that’s been mired in quality-control problems.
According to Miller, if the latest theory behind VITT is confirmed and these vaccines can eventually be adapted to prevent rare but potentially deadly blood clotting, it would be good news for Canada and the global community.
“We’re already living through and observing the massive global inequities in vaccine distribution that are a result of the limited supply and massive global demand,” he said.
“And so, ideally, we want as many vaccines as possible — that are safe — to be available to administer to the global population that needs them.”
Article From: CBC
Author:Lauren Pelley, Adam Miller
