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All adenoviral vector vaccine platforms are not the same, and the Johnson & Johnson COVID-19 vaccine may have different biologic characteristics and biologic effects than the AstraZeneca vaccine, researchers from Johnson & Johnson's Janssen unit argued.

In a letter to the published Friday, Macaya Douoguih, MD, of Janssen Vaccines and Prevention in the Netherlands, and colleagues responded to a case report on of cerebral venous sinus thrombosis (CVST) with thrombocytopenia associated with the vaccine, published in NEJM on Wednesday.

Not surprisingly, Douoguih's group asserted the cases were "insufficient evidence" of a causal relationship between the J&J vaccine and CVST with thrombocytopenia, claiming the rate occurs within the expected background rate for this "extremely rare" event. However, they went further, attempting to distance their adverse events from those associated with AstraZeneca's vaccine.

Douoguih and colleagues rejected the theory of a class effect, noting that the vectors and spike protein inserts in the two vaccines are "substantially different. The Johnson & Johnson vaccine uses a human Ad.26-based vector, whereas AstraZeneca uses a chimpanzee adenovirus-based vector, ChAdOx1."

Because they use different species of adenovirus, "these two vectors use different host cell receptors and are likely to have different phylogenetic and biologic characteristics." They also "may have quite different biologic effects," Douoguih and colleagues argued.

They noted that the one case of CVST with thrombocytopenia in a vaccine recipient during a phase III trial was judged to be unrelated to the vaccine, though they added that the recipient was found to have antibodies against platelet factor 4. The authors acknowledged the pause on the vaccine instituted by the FDA and CDC on April 13, and continued by the CDC's Advisory Committee on Immunization Practices (ACIP) on April 14. (Another ACIP meeting to discuss the issue is set for April 23.)

However, many more cases of thrombosis and thrombocytopenia were linked to the AstraZeneca vaccine. Data presented by CDC at ACIP indicated 79 cases of thrombosis with thrombocytopenia, with 19 fatalities, including 44 cases of CVST with 14 fatalities in the U.K. There were also 62 cases of CVST and 24 cases of splanchnic vein thrombosis with thrombocytopenia, and 18 fatalities in the European Union.

During a call with clinicians on Thursday, CDC staff acknowledged they are "still learning the extent to which those cases [after the Johnson & Johnson vaccine] represent the same syndrome" as cases associated with the AstraZeneca vaccine.

More AstraZeneca Vaccine-Linked Cases of Thrombosis Accrue

Adding to cases already reported from Germany, Austria, and Norway, Marie Scully, MD, of University College London Hospital's NHS Foundation Trust, and colleagues, about 23 patients presenting with thrombosis and thrombocytopenia 6-24 days after receiving the AstraZeneca COVID-19 vaccine.

Similar to in prior research, 21 of 23 patients tested positive for antibodies to platelet factor 4 unrelated to use of heparin therapy.

Median age was 46, though patients ranged from ages 21 to 77. Sixteen patients were younger than 50, and 14 were women. One patient had a history of deep venous thrombosis and one was taking oral contraceptives.

Thirteen patients had clinical features consistent with cerebral venous thrombosis, four had pulmonary embolism, two had an ischemic stroke affecting the middle cerebral artery territory, and two had portal vein thrombosis.

Interestingly, the authors reported all patients had D-dimer levels much higher than patients with acute venous thromboembolism -- levels "typically seen in patients with cancer." All patients had low or normal fibrinogen levels.

The authors cautioned that these patients should not be treated with transfusions, "because such treatment would provide a substrate for further antibody-mediated platelet activation and coagulopathy."

Seven patients died, and available postmortem results revealed evidence of thrombosis in the lungs, intestines, cerebral veins, and venous sinuses, and evidence of extensive intracerebral hemorrhage.

An by Douglas Cines, MD, of the University of Pennsylvania in Philadelphia, and James Bussel, MD, of Weill Cornell Medicine in New York City, raises a number of questions, including, "what components or components of the vaccine ... elicit a new (or recall) response to a seemingly unrelated host protein, PF4?"

Cines and Bussel also posed a chicken-or-the-egg question: "Is PF4 a bystander component within an immune complex that activates platelets or does it contribute directly to clot propagation?"

"Detailed study of anti-PF4 antibodies after natural infection and in recipients of each of the SARS-CoV-2 vaccines may provide insight into the risk of [vaccine-induced thrombotic thrombocytopenia] and into the pathophysiological mechanisms underlying the condition," the editorialists wrote. "The next step should be a direct demonstration that the anti-PF4 antibodies described here cause thrombosis and thrombocytopenia in an in vivo model."

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