Adenovirus vaccine blood clots were caused by a rare misdirected immune response called vaccine-induced immune thrombotic thrombocytopenia, or VITT. New research in the New England Journal of Medicine shows that in people with specific immunoglobulin light-chain gene variants, IGLV3-21*02 or *03, antibodies first raised against an adenoviral core protein, pVII, can acquire a somatic mutation that shifts binding to the human protein PF4, activating platelets and triggering clots. This explains why the reaction occurred after AstraZeneca and Johnson & Johnson COVID-19 shots that used adenoviral vector vaccines, and why it was extraordinarily rare.
What is VITT?
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is an autoimmune reaction in which antibodies target platelet factor 4 (PF4), activating platelets and causing unusual blood clots together with low platelet counts. It was identified in 2021 in a small number of recipients of adenovirus-based COVID-19 vaccines. VITT is mechanistically distinct from common clotting disorders and from the myocarditis signal linked to mRNA vaccines.
VITT is mediated by platelet-activating anti-PF4 antibodies, which can very rarely emerge after adenoviral vector exposure, including vaccination and, in rare cases, natural adenovirus infection.
How do adenovirus vaccine blood clots happen?
The new study mapped a chain of events. First, vaccination introduces an adenoviral vector, which carries DNA instructions for the SARS-CoV-2 spike but also contains its own structural proteins. In some people, B cells generate antibodies that recognize a basic linear epitope on the adenoviral core protein pVII. In those who carry the light-chain allele IGLV3-21*02 or *03, a specific somatic hypermutation in the antibody light chain, designated K31E, can arise.
That single-letter change shifts the antibody’s preferred target from pVII to PF4, a positively charged human protein released by platelets. The resulting PF4 antibodies cross-link and activate platelets, launching the VITT cascade. The evidence comes from antibody sequencing in 21 VITT patients and light-chain genotyping in 100 patients, epitope mapping to pVII, and functional tests showing that reversing the K31E mutation removed the antibody’s prothrombotic activity and restored binding to pVII instead of PF4 (NEJM, 2026). A separate NEJM correspondence documents similar VITT-like reactions after natural adenovirus infection, reinforcing the adenoviral trigger hypothesis (NEJM, 2023).
The study’s conclusion: VITT arises when a susceptible light-chain allele, IGLV3-21*02 or *03, combines with a specific K31E hypermutation in an anti-pVII antibody, redirecting it toward PF4 and activating platelets.
How rare is VITT and who is at risk?
VITT was exceedingly uncommon with the COVID-19 adenoviral vaccines. Early surveillance identified about 60 cases among nearly 19 million Johnson & Johnson doses in the United States and 455 cases among almost 50 million AstraZeneca doses in the United Kingdom, as summarized by reporting in The Atlantic that cites national tallies (The Atlantic, 2026). That is on the order of a few cases per million doses. Fatal outcomes, while tragic, were rarer still.
Approximate reporting rates: about 3 per million J&J doses in the U.S. and about 9 per million AstraZeneca doses in the U.K., with smaller fatality rates within those cases.
The new genetics explain the rarity. Carrying IGLV3-21*02 or *03 appears necessary but not sufficient. The pathogenic K31E mutation must also occur in the right B-cell clone, and additional immune context likely matters. This multilayer requirement makes the event statistically very unlikely. Regulators also noted variation by age and sex in early signals, which guided temporary use preferences while the risk was characterized (CDC MMWR), (UK Government guidance).
Do mRNA vaccines cause this problem?
No. VITT has been linked to adenoviral vector vaccines, not to the mRNA COVID-19 vaccines from Pfizer-BioNTech and Moderna. mRNA vaccines do not contain adenovirus components like pVII, the epitope implicated in the new study. Safety monitoring did identify other rare events with mRNA vaccines, for example myocarditis in young males, which is mechanistically distinct and managed differently.
Can you be tested for VITT risk?
In principle, the light-chain alleles IGLV3-21*02 or *03 can be genotyped, but routine clinical screening is not currently recommended. A positive result would not mean a person will develop VITT, because the critical K31E somatic mutation arises randomly in individual B cells during an immune response. Conversely, people without these alleles would be at extremely low risk through this mechanism, but no test eliminates all risk.
Public health guidance remains that vaccination choices should follow current regulatory recommendations and individualized clinical advice. The new findings primarily inform safer vaccine design rather than immediate patient-level screening decisions (The Atlantic).
What does this mean for future vaccines?
Identifying pVII as the inciting antigen region and the light-chain mutation that drives PF4 cross-reactivity gives developers specific levers to reduce risk. Adenoviral vectors could be engineered to remove or alter the pVII epitope that mimics PF4, lowering the chance of cross-reactive antibodies. This preserves the advantages of adenoviral platforms, including cost, stability, and rapid manufacturing for future outbreaks.
- Refine adenoviral components, for example modifying or masking the pVII epitope.
- Screen candidate vectors preclinically for PF4 cross-reactivity.
- Continue pharmacovigilance to detect ultra-rare events across platforms.
Other research has proposed additional biophysical pathways that could contribute to clotting independently of VITT, for example direct platelet aggregation by certain vaccine components, so multifactor risk reduction is prudent (summary).