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Examining Risk–Benefit Profiles for Vaccines

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Article

Examining Risk–Benefit Profiles for Vaccines

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The following article is an opinion piece written by David Elder. The views and opinions expressed in this article are those of the author and do not necessarily reflect the official position of Technology Networks.

During the early stages of the COVID-19 pandemic, researchers around the globe began a frantic race against time to develop an effective vaccine. By the middle of 2020 there were 17 candidates in clinical development1 and by the start of 2021, three vaccines were approved: Pfizer–BioNTech (mRNA), Moderna (mRNA) and Oxford–AstraZeneca (DNA, modified chimpanzee adenovirus), now trademarked as Vaxzevria. As many of the severe symptoms of COVID-19; “including acute respiratory distress syndrome, pulmonary oedema, acute lung injury and pulmonary fibrosis”; are also related to the normal immune processes; the challenge was to protect the patient – without also inducing immune-mediated lung damage.1

Initially, most attention was focused on the mRNA vaccines and the potential for severe allergic reactions – this was subsequently linked with the use of PEG (polyethylene glycol) in the nano-particle formulation.2 However, during the early part of 2021, researchers also became aware of a rare but concerning occurrence of unusual blood clots related with low blood platelets, in some patients taking the Oxford–AstraZeneca vaccine. One potential explanation was an exaggerated immune response, leading to a condition similar to heparin induced thrombocytopenia (HIT).3

Nonetheless, the European Medicines Agency (EMA) indicated that “COVID-19 is associated with a risk of hospitalization and death. The reported combination of blood clots and low blood platelets is very rare, and the overall benefits of the vaccine in preventing COVID-19 outweigh the risks of side effects”.3 The response to this balanced prognosis from the EMA, was markedly different in many European countries. Denmark totally banned the vaccine,4 prompting many requests from other EU countries for their stocks of the vaccine. France having initially branded the vaccine as “quasi-ineffective” and restricting use to individuals under 65 years performed a complete volte face and restricted use to the over 55s.5 The UK initially restricted use of this vaccine to those over 30 years6 based on a 1 in 1,000,000 risk profile; which as the BBC explained is “roughly the same risk as being murdered in the next month or – if you get in a car and drive for 250 miles – the risk of you dying in a road accident on that journey”.7

Subsequently, based on additional data, the UK restricted the Oxford–AstraZeneca vaccine use for the over 40s.8 The UK health agency reported that in the UK about 1 in a 1000 people are affected by venous thrombosis each year, many linked with the contraceptive pill.9 This compares with 242 reported cases of thrombosis reports with low platelets (as of April 28, 2021), out of a total of 22.6 million first doses of Oxford–AstraZeneca vaccine,8 i.e., ca. 1 in 100,000 risk. In addition, there is a 10-fold greater risk of blood clots from COVID-19 infection compared to the Oxford–AstraZeneca vaccine.10 So, if all medicines regulatory agencies had access to the same clinical data, why did the “experts” not arrive at the same conclusions?

To answer that question, we need to better understand what risk is. Risk can be defined as, “The combination of the probability of harmful events and the severity of that harm”.11 However, much of what we think and do about risk makes little or no sense. Why do we fear relatively minor threats, whilst tolerating significantly greater threats?12 One of the reasons why some countries were intolerant of this small risk is that they had access to alternative supplies of mRNA COVID-19 vaccines. Vaccine hesitancy and the need to reassure patients of the absolute safety of the vaccines may be another reason – not helped by politicians making wildly inaccurate claims about vaccine efficacy.5 Although the various COVID-19 vaccines appear to have similar efficacy based on real-life data, cost may have been another factor. Psychologists have long been aware that people often equate cost with quality, even though there may be no difference in the efficacy of the products.13 AstraZeneca was extremely philanthropic and provided their vaccine “at cost”; whereas, both Pfizer and Moderna will make significant profits from their products. This lower cost may have fueled vaccine hesitancy in the minds of many patients. Historical incidences of rare side effects from vaccines can also lead to poor public confidence in some vaccines. An extensive study of the background rates of narcolepsy in six European countries before and after 2009 H1N1 pandemic vaccine campaigns confirmed increases in Finland, Sweden and Denmark;14 which probably resulted in Denmark’s decision to ban the Oxford–AstraZeneca vaccine. As the old adage goes, risk is in the eye of the beholder!

References

1. Thames AH, Wolniak KL, Stupp SI, Jewett MC. Principles learned from the international race to develop a safe and effective COVID-19 vaccine. ACS Cent. Sci. 2020;6:1341−1347. doi: 10.1021/acscentsci.0c00644

2. 
De Vrieze J. Suspicions grow that nanoparticles in Pfizer’s COVID-19 vaccine trigger rare allergic reactions. AAAS. https://www.sciencemag.org/news/2020/12/suspicions-grow-nanoparticles-pfizer-s-covid-19-vaccine-trigger-rare-allergic-reactions. Published December 21, 2020. Accessed May 18, 2021.

3. 
AstraZeneca’s COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. European Medicines Agency. https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood#:~:text=symptoms%20of%20blood%20clots%20such,vaccination%20after%20a%20few%20days. Published April 7, 2021. Accessed May 18, 2021.

4. 
Skysdgaard N. In a world first, Denmark ditches AZ covid 19 shot. Reuters. https://www.reuters.com/world/europe/world-first-denmark-ditches-astrazenecas-covid-19-shot-2021-04-14/. Published April 14, 2021. Accessed May 18, 2021.

5. 
Mishra S. France reverses stance on Oxford covid jab which Macron labelled ‘quasi-ineffective’. Independent.  https://www.independent.co.uk/news/world/europe/covid-vaccine-france-astrazeneca-macron-b1810072.html. Published March 2, 2021. Accessed May 18, 2021.

6. 
MHRA and JCVI announcement regarding AstraZeneca vaccine and next steps. NHS. https://www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2021/04/c1245-mhra-jcvi-announcement-astrazeneca-vaccine-next-steps.pdf. Published April 7, 2021. Accessed May 18, 2021.

7. 
Cuffe R. AstraZeneca vaccine: How do you weigh up the risks and benefits? BBC. https://www.bbc.co.uk/news/explainers-56665396. Published April 7, 2021. Accessed May 18, 2021.

8. 
Blood clotting following COVID-19 vaccination. Information for health professionals. Public Health England. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/984404/PHE_COVID-19_AZ_vaccine_and_blood_clots_factsheet_7May2021.pdf. . Published April 28, 2021. Accessed May 18, 2021.

9. 
Combined pill-Your contraception guide. Advantages and disadvantages. NHS. https://www.nhs.uk/conditions/contraception/combined-contraceptive-pill/. Published July 1, 2020. Accessed May 18, 2021.

10. 
Smout A. Blood clots from COVID-19 up to 10 times more likely than vaccines: researchers. Global News. https://globalnews.ca/news/7759372/blood-clots-covid-more-likely-vaccines/. Published April 15, 2021. Accessed May 18, 2021.

11. 
Speer J. The definitive guide to ISO 14971 Risk management for medical devices. Greenlight Guru. https://www.greenlight.guru/blog/iso-14971-risk-management#:~:text=Risk%20per%20ISO%2014971%20is,total%20product%20life%20cycle%20process. Published February 25, 2020. Accessed May 18, 2021.

12. 
Gardner D. Risk: The Science and Politics of Fear. Great Britain: Virgin Books; 2009:11,15.

13. 
A study of price and perceived quality. The University of Texas at Arlington.   https://www.uta.edu/news/news-releases/2019/09/05/price-and-perceived-quality.  Published September 5, 2019. Accessed 18 May 18, 2021.

14. 
Schnirring L. Study finds post-H1N1-vaccination rise in narcolepsy in 3 nations. Center for Infectious Disease Research and Policy. https://www.cidrap.umn.edu/news-perspective/2013/01/study-finds-post-h1n1-vaccination-rise-narcolepsy-3-nations. Published January 30, 2013. Accessed May 18, 2021.

About the author

Dr Elder studied chemistry at Newcastle upon Tyne (BSc, MSc), before moving to Edinburgh to study for a PhD in crystallography. He is a visiting professor (King’s College, London). Dr Elder has 44 years of experience at a variety of different pharmaceutical companies (Sterling, Syntex and GSK). He is currently a CMC consultant.

Dr Elder is a member of the British Pharmacapoeia (Expert Advisory Group PCY: Pharmacy), a Fellow of the Royal Society of Chemistry (RSC), UK and the immediate past chairman of the Joint Pharmaceutical Analysis Group, UK. 
He has presented regularly on drug development and drug delivery. He has over 160 publications and given 178 external presentations at scientific symposia. He has co-edited two books: the Analytical Characterisation and Separation of Oligonucleotides and their Impurities and ICH Quality Guidelines: An Implementational Guide

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