Rapid development map for the ChAdOx1 nCoV vaccine (AZD 1222)
This rapid human vaccine development map illustrates how the timeframe for the development and licencing of a new human vaccine can be expedited in the face of a pandemic threat and capture the lessons learnt from the UK COVID-19 vaccine development programme.
- Pre-clinical Discovery and Vaccine Platform Development.
- Pre-clinical Discovery - Sequence of new pathogen. Available 10th Jan 20. Day 0.
- Vector vaccine design. 27th Jan 20. Day 17.
- Manufacturing - Vaccine Seed production. 28th Jan 20.
- Manufacturing - Production of GMP vaccine. 17th Mar 20 to 22nd April.
- Pre-clinical development, including safety in small animals, livestock and primates.
- Phase 1 clinical trials. Start 23rd April 20. 104 days. Completed by 21st May 20. 18th Jul 20 immune response data available.
- Phase 2 clinical trials. 22nd May 20 recruitment begins.
- Phase 3 clinical trials. 22nd May 20 recruitment begins. Result 23rd Nov 20. 312 days.
- Manufacturing scale-up. AstraZeneca 30th April 20. Starts 111 days.
- Large scale GMP batch production.
- Regulatory review.
- Regulatory approval. Emergency approval 30th Dec 20. 349 days.
- First dose of approved vaccine administered. 4th Jan 21. 359 days.
In order to respond to pandemic disease threats, we must recognise that there is now a growing need for new and improved vaccine technology platforms offering the opportunity for rapid product development, convenience of manufacture and ease of administration. In the case of COVID-19, we knew the vaccine target from previous work on coronaviruses, we had the genetic sequence available within a few months of the first reported case of disease and we had vaccine delivery platforms ready to go as a result of years of scientific research. Indeed, the UK Vaccine Network established in 2015 had foreseen the risk posed by such zoonotic infections and had invested in the understanding of mutually relevant diseases and expanding the translational control.
The COVID-19 vaccine developed by the Jenner Institute in Oxford, UK was based on a Platform Technology that had been in development for over 8 years. Starting from a sample of a virus known as ‘Y25’ provided by Wadell, a Jenner graduate student (Matthew Dicks, working with senior virologist Matthew Cottingham) created and performed early testing of the ‘ChAdOx1’ vector in 2012 (Dicks et al. (2012) PLoS One;7(7): e40385.). ChAdOx1 differed from Y25 in that key genes needed for the virus to multiply in human cells were completely deleted, and in that Dicks exchanged one of the Y25 virus’ ‘non-structural’ genes for one from a human adenovirus, which would make the virus easier to manufacture. Most importantly for SARS-CoV-2, this vector had also been used to develop another Coronavirus vaccine against Middle East Respiratory Syndrome (MERS) since 2017 (Alharbi et al (2017) Vaccine;35, 3780-3788)
COrona VIrus Disease 2019 (COVID-19) first appeared on a small scale in November 2019 with the first large cluster appearing in Wuhan, China, in December 2019. The World Health Organization (WHO) announced on March 11th 2020, that the outbreak of COVID-19, which initially started in Asia, had become a pandemic (Asselah el al 2021, Journal of Hepatology, 74, 168-174). The causative agent of COVID-19 is a novel coronavirus officially named SARS-CoV-2. It was named after SARS-CoV, because of their genomic homology. Coronaviruses are enveloped, large, positive-sense single-stranded RNA viruses (+ssRNA) of the Coronaviridae family. On the 12th January 2020 China publicly shared the genetic sequence of COVID-19. Chan, J. F. et al. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg. Microbes Infect. 9, 221–236 (2020). This was an essential pre-requisite for the development on novel vaccine approaches based on the delivery of the immunogenic ‘spike’ protein of the virus.
Using a previously well characterised vaccine vector, promoter and terminator sequences, the final design of the vaccine to express the selected antigen includes the choice of whether to add an N-terminal leader sequence, whether to express the complete antigen or only part of it, and selection of an optimised DNA sequence to express the desired protein sequence.
Using a research grade vaccine preparation, confirm immunogenicity in animal models, and ideally demonstrate absence of vaccine associated pathology on exposure of vaccinated animals to the pathogen, plus evidence of vaccine efficacy.
Phase I trials test vaccine reactogenicity and immunogenicity in young healthy adults. Phase II expands the population tested to larger numbers and a wider range of ages, again determining vaccine reactogenicity and immunogenicity. In phase III trials a much larger number of individuals is included with a 1:1 randomisation of vaccine to control, and vaccine efficacy is determined once the number of confirmed infections in the trial reaches a pre-defined limit.
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