While COVID-19 vaccines currently available today are considered safe and effective and have demonstratively shown a reduction in rates of mortality and morbidity; this does not suggest that we cease pharmacovigilance of these new products. Of the several type of vaccines that are on the market or are in development, two are genetically engineered viruses, otherwise known as adenoviral vectors. As a point of reference, this is nearly 30-year-old technology. These adenoviral vectors are designed to transport a particular gene from SARS-CoV-2 into the body where the cells will read it, synthesize coronavirus spike proteins, and in turn induce an immune response that would protect the body should the person be exposed to the actual virus. However, the latest generation of vaccines involving the use of adenoviruses may pose new challenges to their safety profile as there is speculation that patients with a history of blood disorders and immunological conditions who are vaccinated with this type of vaccine may trigger blood clot formation. The UK based Oxford–AstraZeneca vaccine (AZ vaccine) and Johnson & Johnson’s vaccine (JNJ vaccine) both use adenoviral vectors to elicit an immune response after entering the body. The JNJ vaccine and AZ vaccine differ from Pfizer and Moderna COVID-19 vaccines in that the latter two companies use mRNA technology to mimic a portion of the genetic material associated with SARS-CoV-2 virus. When the mRNA is introduced into the body, it enters the cell, which then generates a protein on its surface (essentially the same protein or a portion thereof that is found on the SARS-CoV-2 virus) which the body recognizes as an antigen and the immune system generates antibodies to protect the body. However, the advantage of both the AZ and JNJ vaccines is that they can be stored under more “normal” conditions compared with the unstable mRNA vaccine which must be stored cryogenically. Notwithstanding the foregoing, it was thought that the adenoviral vector would elicit spike protein specific antibodies, but as well may increase the likelihood of immune cross reactivity and inflammations.
On March 18, 2021, the European Medicines Agency (EMA) stated that less than one in one million cases are showing associative symptoms of thrombotic events post vaccination with AZ vaccine [1]. As of March 22, 2021, AstraZeneca cited, based on a US Phase III clinical trial, 79% vaccine efficacy at preventing symptomatic COVID-19 and 100% efficacy against severe or critical disease and hospitalization.[2]
For clarity, thrombotic events include thrombosis in the brain, lungs, and stomach along with symptoms of thrombocytopenia or deficiency in blood platelets. In general, thromboembolism can cause blockage in the veins. Notwithstanding the observation that no causal link between the AZ vaccine and rare or uncommon thrombolytic events are observed, there needs to be continuous pharmacovigilance and monitoring of the use of any of these vaccines. In addition, there needs to be a strict vigilance of any side effects three to four days after vaccination as stated by EMA. If there are symptoms of headache, shortness of breath or breathlessness, chest or stomach pain, swelling in arm or leg, persistent bleeding, multiple small bruises and/ or blood blisters under the skin after the foregoing time frame, a patient should seek medical attention immediately [1].
Probable Risk factor groups
After concern was raised regarding blood clots possibly being caused by the AZ vaccine, clinicians began to consider other potential risk factors. A small-scale study demonstrated that women were more likely to acquire clots after vaccination than men. The data raised a concern for patients with haemolytic disorders, low platelet counts, and other co-morbid diseases which affect both circulatory and immune systems [3].
Possible mechanisms
In March 2021, there was speculation that there might be intracellular production of spike proteins within megakaryocytes and platelets after mRNA translation following vaccination. There might be reticuloendothelial phagocytosis and CD8+ T cell lysis following an autoimmune type mechanism of the major sentinels like thrombocytes and megakaryocytes, resulting in blood leakage and platelet deficiency [4]. Subsequently, Oslo et al, 2021 reported that antibody driven attacking platelets with concomitant thrombotic events are likely mechanisms for blood clots and thrombocytopenia. Both theories lead to internal bleeding and spontaneous blood clots and haemorrhage [4, 5].
The Current Knowhow and US scenario
More than 20 million individuals are vaccinated with AZ vaccine in the UK alone, out of which 79 individuals were reported with rare blood clots with thrombocytopenia according to the Medicine and Healthcare Regulatory Authority, UK (MHRA). Moreover, 19 deaths were reported with no direct connection with the side effects from the vaccine. Thus, the thrombotic events accounts for one in 250,000 individuals vaccinated which is 0.0004% and one death in 1,000,000 individuals, which is 0.0001%. Therefore, a direct connection of the AZ vaccine with blood thrombotic events seems highly unlikely. In fact, on March 18, 2021, MHRA gave a statement as ‘evidence does not suggest that blood clots are caused by COVID-19 Vaccine AstraZeneca and assured that the benefits of the vaccine in preventing COVID-19 far outweigh the thrombotic risks and people should continue taking the vaccine when offered’ [6].
For clarity, according to interim data from Phase III trials carried out in US, Chile and Peru on March 22, 2021, the vaccine was shown to be efficacious across all ethnic groups of whom 22% were Hispanic, 8% were African American, 4% were native American and 4% were Asian. The vaccine also showed efficacy in elderly people over 65 years. Furthermore, according to an independent neurologist and the study’s independent data safety monitoring board, no increased risk of thrombosis or thrombotic events was observed among the participants who received at least one dose of vaccine [7]. A vaccine scientist, Ann Falsey in New York at the University of Rochester, stated “Overall it’s a win for the world”. She also is an investigator on the trial who developed the protocol for the vaccine. AstraZeneca confirms that it plans to file the vaccine for emergency-use authorization by taking the approval from the FDA. In addition, they will also submit the analysis of the full trial in a peer reviewed publication. The FDA as of this writing has not approved the AZ vaccine for use in the United States.
Additionally, an interim report on Phase I and Phase II trials in January 2021 showed that the JNJ vaccine, on all age groups in cohort studies induced neutralizing antibody titers along with T cell responses thereby indicating proper immunogenicity and safety. Common systemic adverse effects included myalgia, headache and injection site pain [8]. On February 26, 2021, the FDA voted unanimously to grant emergency use authorization to JNJ while trials continued. By March 2021 reports confirmed that one dose of vaccine was 66% effective in preventing moderate to severe COVID-19 and 100% effective in preventing hospitalisation related severity and death [9]. However, during the first week of April 2021 blood clots were reported after vaccination. According to a joint statement released by FDA and the Centers for Disease Control (CDC) on April 12, 2021, out of more than 6.8 million doses given in US, six individuals reported a rare and severe type of blood clot in combination with thrombocytopenia after receiving the vaccine. Therefore, vaccinations using the JNJ vaccine were paused on April 13, 2021 in the US. [10].
Conclusion
Considering the foregoing information, pharmacovigilance and review of all new vaccines should be made public immediately regarding potential side effects. We must remember we knew there were risks in developing vaccines so quickly, but in hindsight, the risk is worth it considering the lives that have been saved. Clearly more research must be done regarding these novel vaccines, the relevant agencies need to be vigilant in following up on reported adverse events and reevaluating the risk/reward benefit. Additional research needs to be conducted in order to ascertain the effect these antiviral vectors have on the human immune system, and in particular with those people who have a history of thrombocytopenia. Large scale clinical trials across all ethnicities and races should continue. The data would continue to be updated in order to draw robust conclusions regarding these particular vaccines. Of course, as blot clots and thrombotic events are associated with COVID-19 side effects, a more than causal relationship between these types of vaccines and SARS-CoV-2 virus may not exist. It is essentially too early to tell.
Interestingly, on March 14, 2021, the EU Commission decided not to renew COVID-19 vaccine contracts next year with AstraZeneca and Johnson & Johnson according to the Italian daily La Stampa, citing a source from the Italian health ministry. “The European Commission, in agreement with the leaders of many (EU) countries, has decided that the contracts with the companies that produce (viral vector) vaccines that are valid for the current year will not be renewed at their expiry,” the newspaper reported. It added that Brussels would rather focus on COVID-19 vaccines using messenger RNA (mRNA) technology, such as Pfizer’s and Moderna’s.
Written by: Souvik Datta, Ph.D., Lawrence D. Jones, Ph.D.
Keywords: COVID-19, SARS-CoV-2, thrombocytopenia, blood clots
References:
1. Merchant, H.A. CoViD vaccines and thrombotic events: EMA issued warning to patients and healthcare professionals. J of Pharm Policy and Pract 14, 32 (2021). https://doi.org/10.1186/s40545-021-00315-w.
2. https://www.astrazeneca.com/media-centre/press-releases/2021/astrazeneca-us-vaccine-trial-met-primary-endpoint.html
3. The BMJ. AstraZeneca vaccine: Blood clots are “extremely rare” and benefits outweigh risks, regulators conclude. News. BMJ 2021;373:n931. Doi: https://doi.org/10.1136/bmj.n931 (Published 08 April 2021)
4. Merchant HA. CoViD Vaccines and thrombotic events: Possibility of mRNA translation and spike protein synthesis by platelets? BMJ 2021;372:n699/rr-6, https:// www. bmj. com/ content/ 372/ bmj. n699/ rr-6.
5. WSJ. Scientists say they found cause of rare blood clotting linked to Astra-Zeneca vaccine. https:// www. wsj. com/ artic les/ scientists- say- they- found cause-of- blood- clotting- linked- to- astrazeneca- vaccine- 11616 169108.Accessed 19 March 2021.
6. Gov.UK. UK regulator confirms that people should continue to receive the COVID-19 vaccine AstraZeneca. https:// www. gov. uk/ government/news/ uk-regulator- confirms- that- people- should- continue- to- receive the-covid- 19-vaccine-astrazeneca. Accessed 19 March 2021
7. The BMJ. Covid-19: AstraZeneca vaccine prevents 79% of symptomatic disease and 100% of severe disease, US study finds. News. BMJ 2021;372: n793. doi: https://doi.org/10.1136/bmj.n793 (Published 22 March 2021)
8. Sadoff J, Le Gars M, Shukarev G, Heerwegh D, Truyers C, de Groot AM, Stoop J, Tete S, Van Damme W, Leroux-Roels I, Berghmans PJ. Interim Results of a Phase 1–2a Trial of Ad26. COV2. S Covid-19 Vaccine. New England Journal of Medicine. 2021 Jan 13.
9. Livingston EH, Malani PN, Creech CB. The Johnson & Johnson Vaccine for COVID-19. JAMA. 2021 Mar 1.
10. https://www.cdc.gov/media/releases/2021/s0413-JJ-vaccine.html
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