The rare, deadly blood clots triggered by an autoimmune response to the COVID-19 vaccines from Johnson & Johnson and AstraZeneca seem to be caused by a gene that’s also responsible for an unusual but almost identical reaction to the virus that causes the common cold. The findings could have implications for future vaccines.
In a letter published May 15 in The New England Journal of Medicine, an international team of scientists explained that people who carry certain variants of a gene called IGLV3-21*02 are predisposed to developing both vaccine-induced immune thrombocytopenia and thrombosis (VITT) and the same type of reaction after infection with the adenovirus. Both the J&J and AstraZeneca vaccines are delivered to the body in adenovirus vectors, which explains why the etiology of the conditions is the same.
“Our findings have the important clinical implication that lessons learned from VITT are applicable to rare cases of blood clotting after adenovirus infections, as well as having implications for vaccine development," Tom Gordon, M.D., Ph.D., of Flinders University, who led the co-study, said in a press release. Theodore Warkentin, M.D. from McMaster University in Canada and Andreas Greinacher, M.D., from Greifswald University in Germany also led the work.
AstraZeneca’s vaccine, Vaxzevria, was dogged by reports of VITT not long after the shot rolled out in Europe. Soon after, news of VITT in six U.S. patients who took the J&J vaccine emerged as well, prompting officials to pause it to investigate and later restrict its use. It was removed from the market entirely two years later. AstraZeneca’s shot remained available in some parts of Europe until May 2024, when the company requested its marketing approval be revoked due to a decline in demand.
As of May 2023, the same month J&J’s vaccine was pulled, there had been 60 cases of VITT reported in the U.S., including nine deaths. The last count for VITT cases related to AstraZeneca’s vaccine in the U.K. before it was taken off the market was 455, with 81 deaths, according to the U.K.'s healthcare watchdog the Medicines and Healthcare products Regulatory Agency.
The reactions are caused by antibodies against the protein platelet factor 4, or PF4, a protein involved in blood clotting. In 2022, Gordon and his colleagues used a screening method called antibody proteomics to show that antibodies expressed by a variant of IGLV3-21*02 targeted PF4. Genetic analysis of five patients who developed VITT after getting the AstraZeneca vaccine showed that all of them had this gene variant.
Then, in 2023, another research team reported that adenovirus infection led to the same anti-PF4 antibodies and immune thrombocytopenia and thrombosis. The pathogenesis was identical to VITT; this was the first signal of an “anti-PF4 disorder,” as the researchers called it, that might share its etiology.
The two groups teamed up to validate their hypotheses. When they analyzed the structure of the anti-PF4 antibodies from patients in each group and superimposed them, they found they were “extremely similar,” as they wrote in the NEJM letter.
“Such an extraordinary level of autoantibody fingerprint identity between two disorders—at the level of patient-derived antibodies—strongly indicates that VITT and the anti-PF4 disorder that is associated with adenoviral infection are a distinct class of adverse immune responses associated with viral (presumably, adenoviral) structures,” the researchers wrote.
With regards to the AstraZeneca and J&J vaccines, the findings concretely implicate the adenovirus as the cause of VITT rather than other ingredients. But while the researchers know that the immune response to the virus triggers the creation of antibodies to PF4, they still need to identify the antigen, or the proteins or sugars on the virus, that stimulates their creation. This would potentially enable them to genetically engineer the adenovirus vector so it doesn’t have the antigen and, thus, makes adenovirus-based vaccines safer. The team behind the new NEJM paper is currently investigating the antigenic epitope, or the part of the antigen the immune system recognizes, Gordon confirmed to Fierce Biotech Research in an email.
Previously, the Flinders scientists said it may be possible to create a genetic test that can identify patients at risk of VITT as well as to come up with a therapy that neutralizes the anti-PF4 antibodies.
In a statement to Bloomberg earlier this week, an AstraZeneca spokesperson said the company “welcomes any further examination of the possible underlying mechanism of thrombosis with thrombocytopenia syndrome.” J&J told the outlet in an email that it supports the research as well and that “more data are needed to fully understand potential factors that may be associated with this rare event.”