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Alan Stolier, MD/

TROUBLE IN PARADISE  A Primer on Adenovirus Vaccines

TROUBLE IN PARADISE

One might have to be on Mars not to have noticed that both the J&J and the AstraZeneca vaccines have been tentatively linked with blood clots in a small number of patients. Moreover, the clots occur in unusual parts of the body such as the brain or abdomen and are associated with low platelet levels. Both the J&J and AstraZeneca vaccines are based on the use of an adenovirus. The J&J vaccine usage has been placed on hold in the US, and the AstraZeneca vaccine has been held in several European countries. The editors felt it appropriate to add to our general medical knowledge and review some of what we know about adenovirus-based vaccines.

 

Adenoviruses are double-stranded DNA viruses measuring 34-43 kilobases. They are thought to be excellent vectors for delivering antigens to hosts because they can elicit both an innate (non-specific) and an adaptive (specific) immune response. Furthermore, because of its relatively large size and well-known genome, adenoviruses are easy to manipulate genetically. The only adenovirus vaccine used commercially today is a rabies vaccine used to inoculate wild animals. 

 

The adenoviruses generated in the lab are classified as replication-deficient or replication-competent. When a replication gene (called E1) is removed, the viral vector can no longer replicate. Removal of this gene makes room for the genetic material that the investigator wants to be inserted into the target cells. However, replication-deficient or subunit vaccines generally result in protection of more limited duration. Replication competent viruses are used to produce live attenuated vaccines that usually elicit life-long protection against viral disease. Examples of live-attenuated vaccines include measles, mumps, rubella, polio, and yellow fever. 

 

Both the J&J and the AstraZeneca vaccines are replication-deficient adenoviruses. They benefit from high thermostability and the ability to grow to high titers with the easy application through systemic or mucosal routes. They both induce both CD4 and CD8 cell-mediated immune responses. Examples of replication-deficient adenovirus vaccines undergoing human trials include those developed against HIV, Ebola virus, influenza virus, Mycobacterium tuberculosis, and Plasmodium falciparum. 

 

The clotting disorder noted in both vaccines strongly resembles a rare side effect seen in heparin therapy called heparin-induced thrombocytopenia (HIT). The syndrome is called vaccine-induced immune thrombotic thrombocytopenia (VITT). It is thought to be triggered when heparin binds to a protein called platelet factor 4, which ultimately results in platelet destruction and the release of clot-promoting material. Presently, researchers are unsure of what component of these vaccines could be causing this deleterious immune response against platelet factor 4. “It could be caused by the vector, it could be caused by the spike protein, it could be caused by a contaminant present in the vector,” said viral immunologist Hildegund Ertl at the Wistar Institute in Philadelphia, Pennsylvania. At Erasmus University Medical Center in Rotterdam, the Netherlands, Virologist Eric van Gorp is co-chairing a consortium that will look at the effect of different vaccines on vascular cells grown in the laboratory. The group will also look for antibodies against platelet factor 4 in recipients of various COVID vaccines. Although most cases have occurred in females, ages 18-48, the European Medicines Agency reported last week that it could not identify a particularly high-risk group from its data on the AstraZeneca vaccine.

 

Douglas Cines and James Bussel from the Perelman School of Medicine at the University of Pennsylvania noted that the very low prevalence of this complication, however severe, relative to the benefits of preventing COVID-19 with its 1-2% mortality and possible long-term sequelae, must be emphasized. It should also be emphasized that the risk of developing VITT is extremely low. As of March 22, 2021 only 86 potential cases have been reported out of 25 million vaccinated with the AstraZeneca vaccine. Of those receiving the J&J vaccine only 6 cases have thus far been reported out of 7 million vaccinated. It is yet unknown what impact this will have on the public’s interest in seeking vaccination.

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