TROUBLE IN PARADISE: A PRIMER IN ADENOVIRUS VACCINES

Blood clotting problems with J&J and AstraZeneca Vaccines Leads to Temporary Pause in Vaccinations

On April 8, the CDC recommended that the J&J vaccine, the most commonly used single-dose vaccine available in the US, be put on hold as they examined the risk of rare types of blood clots. By April 23, the CDC lifted the pause, noting that the risk of dying from blood clots was much lower than the risk of dying from Covid-19. Several countries in Europe carried out similar breaks for blood clots for the AstraZeneca vaccine. It is important to note that both J&J and AstraZeneca used related technologies to produce their vaccines, which differed significantly from the Moderna and Pfizer vaccines.

Both J&J and AstraZeneca use a generally harmless virus called adenovirus to deliver the critical spike protein into our cells. The spike protein is what allows the Coronavirus to enter into our cells, ultimately causing Covid-19. For the adenovirus to work, it requires a change in its genetic code. A gene (called E1) is removed from the virus, making room for a laboratory-produced gene resulting in our cells making the coronavirus spike protein. The spike protein, common to all coronaviruses, stimulates our immune system to produce antibodies to ward off the infection. Before the J&J and AstraZeneca vaccines, the only commercially available adenovirus vaccine in use today is a rabies vaccine used to innoculate wild animals.

The adenoviruses produced in the lab for J&J and AstraZeneca cannot divide and are called replicant deficient. Both replicant deficient and other subunit vaccines (both Moderna and Pfizer vaccines are subunit since they represent only a tiny part of the spike protein gene) result in disease protection of more limited duration. Patients receiving these vaccines will likely require a “booster” sometime in the future. Other replicant deficient adenovirus vaccines undergoing human trials include vaccines against HIV, Ebola virus, influenza virus, tuberculosis, and malaria. Viruses used in vaccines that can reproduce are called replicant competent. Replicant competent viruses are used to produce live-attenuated vaccines (vaccines produced with a live, though weakened, virus) and usually elicit life-long protection from disease. Examples of live-attenuated vaccines include measles, mumps, rubella, polio, and yellow fever.

The clotting disorder noted in both vaccines strongly resembles a rare side effect seen in heparin therapy called heparin-induced thrombocytopenia (HIT). Heparin is a blood thinner used to treat patients who have developed blood clots. The syndrome is called vaccine-induced immune thrombotic thrombocytopenia (VITT). VITT is triggered when heparin binds to a protein called platelet factor 4, which ultimately results in platelet destruction and the release of clot-promoting material. Platelets are tiny cells in our blood that initiate the clotting mechanism. In VITT, patients form blood clots in unusual areas such as the brain and abdomen. This unique reaction to heparin is also associated with a drop in platelet count called thrombocytopenia.
Interestingly, the small number of patients receiving the J&J or AstraZeneca vaccine who developed these unusual blood clots were similarly found to have low platelet counts as well as an immune response to platelet factor 4. Researchers are unsure what component of these vaccines could be causing this deleterious response against platelet factor 4. “It could be caused by the adenovirus vectors, 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. Although most cases have occurred in females, ages 18-48, the European Medicines Agency reported last week but 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 stressed 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 been reported out of 7 million vaccinated. Most importantly, it is yet unknown what impact this will have on the public’s interest in seeking vaccination.