How was the COVID-19 vaccine developed so fast?

Race for the vaccine

The development of vaccines for the treatment of infectious diseases typically takes 10-15 years, starting with drug discovery up until it is distributed to the public. Prior to the pandemic, the fastest vaccine developed had been the mumps vaccine, which took 4 years to develop^1,2. The COVID-19 vaccine was developed in record time, with the first vaccine distribution to the public starting less than 1 year after COVID-19 was declared a pandemic. The natural question that follows – and a big driver of vaccine hesitancy – is whether vaccine safety was compromised during clinical trials and if not, how exactly were the vaccines developed in less than a year? 

Typical vaccine development process

The standard vaccine development process has 6 stages:

(i) pharmaceutical studies of candidate vaccines

(ii) non-clinical research (including animal studies)

(iii) clinical trials in human subjects (phase I, II and III trials)

(iv) submission to federal regulatory agencies for authorisation (i.e approval for distribution to the public)

(v) large-scale vaccine manufacturing

(vi) post-licensing safety studies (phase IV trials).

Image from the European Medicines Agency ³

Clinical trials and vaccine safety

Normally, a clinical trial stage (phases I-III) lasts between 6 months and 2 years for the evaluation of vaccine safety and effectiveness. Historically, side effects occur in the first 6 weeks of receiving the vaccine, after which they become extremely unlikely. Thus, the duration of clinical trials does not reflect an expectation that side effects might occur in those 6 months to 2 years, but rather reflects the time it takes to study the effectiveness of the vaccine (did the vaccine elicit an immune response? Did the response protect the individual? What were their antibody titres?)⁴.

Accelerated COVID-19 vaccine development process 

Image from the European Medicines Agency ³

Ø  Prior knowledge: The vaccine discovery (i) and pre-clinical studies (ii) stages were accelerated due to prior knowledge on coronaviruses; 

Ø  Parallel clinical trials: Phase II trials ran in parallel to phases I and III trials; 

Ø  Widespread infection: COVID-19 infections were so prevalent that it was possible to see the vaccination effectiveness results from the trials in a very short period of time amongst those vaccinated versus those that received the placebo; 

Ø  Rolling review: Phase I-III clinical trials (iii) and scientific evaluation by regulatory agencies (iv) were conducted in a way that enabled protocols and results from the clinical trials to be reviewed by regulatory agencies (e.g. FDA in the USA and MHRA in the UK) as the trials progressed, rather than waiting until the trials had ended; 

Ø  At-risk vaccine manufacturing: Large-scale manufacturing (v) started prior to regulatory authorisation for vaccine distribution (iv), at a high financial risk for the manufacturers. 

Ø  Worldwide collaboration and large financial contributions were key to speed up the vaccine development process (e.g. the USA government contributed > $10 billion as part of Operation Warp Speed for the development of 6 vaccines)⁴.

Not a completely novel virus

The development of the COVID-19 vaccine started long before COVID-19 was declared a pandemic. Based on previous knowledge of coronaviruses, scientists already had an understanding of COVID-19 – namely, that the vaccine was going to target the virus’ spike protein (the proteins that give the COVID-19 virus its familiar crown appearance)⁴.

Speeding up regulatory authorisation

The duration of the regulatory review stage from the time clinical data is submitted until authorisation is issued can normally take up to 2 years^4,7. For COVID-19 vaccines, this stage was drastically reduced, taking as little as 2 months⁸. This was possible due the submission of draft versions of the studies to regulatory agencies as the trials progressed (known as “rolling review”). Regulatory agencies also agreed to review safety data up to 8 weeks post vaccination (on the basis that side effects are expected to occur only in the first 6 weeks) and continue to review new safety data for those vaccines, as part of the terms of the temporary authorisation granted⁴. Information on vaccine authorization can be accessed from regulatory agency websites, such as the MHRA, FDA or EMA websites.

As of the 25^th May 2021, there were 115 COVID-19 vaccines undergoing phase I-III clinical trials and a total of 8 vaccines fully approved for use (data from The New York Times COVID-19 Tracker ⁹).

What about the mRNA vaccine – wasn’t that one rushed?

Different vaccine technologies have been developed since the first vaccine was invented in the 18^th century, many of which are still used today¹⁰. A new vaccine technology – the mRNA vaccine – had been in the works since 2011¹¹. The prioritisation and subsequent increase in funding for the development of a COVID-19 vaccine simply accelerated the release of the mRNA vaccine. In addition, the mRNA vaccine technology has a much shorter production time compared to traditional technologies (which can take between 12 and 24 months)⁴, hence why mRNA vaccines were one of the first to hit the shelves. These vaccines were held to the same safety and effectiveness standards as any other vaccine during all stages of development, including clinical research and regulatory review³.

What clinical trials have showed us

The first COVID-19 vaccine trials tested effectiveness against mild and severe COVID, with licensed vaccines achieving protection rates of 85-100% against severe COVID. Even though these vaccines were based on the traditional virus strain (Wuhan strain), they have shown similar rates of protection against the UK strain. For the South African and Brazilian strains, the vaccines still offer good protection against severe COVID-19, but lower efficacy against mild COVID-19⁴. For the Indian strain, the first vaccine dose may be less effective; however, the second dose was shown to protect against this strain at a similar level as other strains – thus supporting the need to prioritize uptake of the booster dose among at-risk individuals¹².

Despite the vaccines showing an acceptable safety profile, a risk of blood clotting events (1 in 100,000 vaccinated people) was picked up in two vaccines after their authorisation for distribution¹³. This is because these side effects are too rare to be picked up in phase I-III clinical trials (before authorisation). For more information on the role of clinical trials in the development of the COVID-19 vaccine, you can watch the ECCRT’s webinar by Professor Isabel Leroux-Roels.

What we still don’t know

As part of their conditional or emergency authorisations issues by federal regulatory agencies, all currently authorised vaccines are undergoing clinical trials to address many questions that remain, including the following:^{4,12,14,15,16} 

It is safe to say that the pandemic forced researchers and pharmaceutical companies to re-evaluate traditional vaccine development frameworks in record time and maximise the efficiency of existing processes. This process has already saved thousands of lives¹⁶ and has undoubtedly made us better prepared in the event of a future pandemic.

Written by Dr Carolina Duarte, Scientific Advisor at medDigital

Glossary

Antibody titre: quantity of antibodies

mRNA vaccine: messenger RNA vaccine that encodes a protein (e.g. the COVID-19 spike protein). Human cells read the code and produce the COVID-19 spike proteins, which trigger the production of COVID-19-specific antibodies by the immune system.

Regulatory authorisation (or marketing authorisation): licensing of a medicine or vaccine following the review of clinical trial data by a federal regulatory agency, such as the FDA in the USA, the MHRA in the UK, and the EMA in the European Union. Authorisation is legally required before distribution of vaccines to the general public.

Temporary or conditional authorisation: temporary license valid for one year issued by a federal regulatory agency, provided that specific requirements are met, such as ongoing or new studies.

Spike protein: a type of protein that coats coronaviruses, which enable attachment to the host’s cells. Spike proteins give COVID-19 its familiar “crown” appearance.

References

1. How did scientists manage to develop safe COVID-19 vaccines in just ten months?, GAVI The Vaccine Alliance, https://www.gavi.org/vaccineswork/how-did-scientists-manage-develop-safe-covid-19-vaccines-just-ten-months, accessed 25 May 2021

2. How a New Vaccine Was Developed in Record Time in the 1960s, History.com, https://www.history.com/news/mumps-vaccine-world-war-ii#:~:text=AFP%2FGetty%20Images-,It%20took%20just%20four%20years%20to%20get%20the%20mumps%20vaccine,stuff%20of%20medical%20textbook%20legend, accessed 25 May 2021

3. COVID-19 vaccines: development, evaluation, approval and monitoring, European Medicines Agency (EMA), https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines/vaccines-covid-19/covid-19-vaccines-development-evaluation-approval-monitoring, accessed 25 May 2021

4. The importance of clinical research in developing new vaccines webinar by Professor Isabel Leroux-Roels, ECCRT, https://www.youtube.com/watch?v=zCqpX4DnE98 The importance of clinical research in developing new vaccines, accessed 25 May 2021

5. ClinicalTrials.org Identifier NCT04313127, Phase I Clinical Trial of a COVID-19 Vaccine in 18-60 Healthy Adults (CTCOVID-19), US National Library of Medicine, https://clinicaltrials.gov/ct2/show/NCT04313127, accessed 25 May 2021

6. ClinicalTrials.org Identifier NCT04283461, Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19), US National Library of Medicine, https://clinicaltrials.gov/ct2/show/NCT04283461, accessed 25 May 2021

7. Priority Review, US Food and Drug Administration (FDA), https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review, accessed 25 May 2021

8. Vaccine BNT162b2 – CONDITIONS OF AUTHORISATION UNDER REGULATION 174, UK Medicines and Healthcare products Regulatory Agency (MHRA), https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/988296/Pfizier_Conditions.pdf, accessed 25 May 2021

9. The New York Times COVID-19 Tracker, data from Johns Hopkins University, https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html, accessed 25 May 2021

10. Plotkin S. A. (2009). Vaccines: the fourth century. Clinical and vaccine immunology: CVI, 16(12), 1709–1719. https://doi.org/10.1128/CVI.00290-09  

11. Pardi N., Hogan M., Porter F. et al. (2018) mRNA vaccines — a new era in vaccinology. Nat Rev Drug Discov, 17, 261–279. https://doi.org/10.1038/nrd.2017.243

12. Lopez Bernal J et al. (2021) Effectiveness of COVID-19 vaccines against the B.1.617.2 variant [preprint], https://doi.org/10.1101/2021.05.22.21257658

13. AstraZeneca’s COVID-19 vaccine: benefits and risks in context, European Medicines Agency (EMA), https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-benefits-risks-context, accessed 25 May 2021

14. A Timeline of COVID-19 Vaccine Developments in 2021, The American Journal of Managed Care (AJMC), https://www.ajmc.com/view/a-timeline-of-covid-19-vaccine-developments-in-2021, accessed 25 May 2021

15. COM-COV Study, University of Oxford, https://comcovstudy.org.uk/home, accessed 25 May 2021

16. COVID-19 vaccines have prevented 10,400 deaths in older adults, GOV.UK, https://www.gov.uk/government/news/covid-19-vaccines-have-prevented-10-400-deaths-in-older-adults, accessed 25 May 2021