--- title: COVID-19 Vaccine Development Process tags: live-v0.1, facts, misinformation, debunking permalink: https://c19vax.scibeh.org/pages/vaxprocess --- <!---{%hackmd FnZFg00yRhuCcufU_HBc1w %}---> {%hackmd 5iAEFZ5HRMGXP0SGHjFm-g %} {%hackmd GHtBRFZdTV-X1g8ex-NMQg %} # The COVID-19 Vaccine Development Process ## ..and why you should not worry about it Many people understand the need for a COVID-19 vaccine but have [concerns about its safety and effectiveness](https://apnorc.org/projects/many-remain-doubtful-about-getting-covid-19-vaccine/) due to the rapid development of the vaccine and the use of relatively novel [mRNA technology](https://www.nature.com/articles/d41586-021-02483-w). ::: info **You can read more about mRNA technology and why it is safe on our [dedicated COVID-19 vaccine fact page](https://c19vax.scibeh.org/pages/c19vaxfacts).** ::: Here we summarise the current state of vaccines, explain the standard vaccine development process and the obstacles that are faced under normal circumstances. We then explain how and why it was possible to accelerate this process for the development of the COVID-19 vaccines. --- ## The current state of COVID-19 vaccines across the world There are a number of different COVID-19 vaccines under development and approved for clinical use. :::info The approval processes for COVID-19 vaccines vary by country/regions. **To find out which vaccines are approved in your country/region, see [this vaccine tracker provided by the VIPER Group of the McGill University](https://covid19.trackvaccines.org/vaccines/approved/).** ::: * Regularly updated information about each of these vaccines can also be found on the [Regulatory Affairs Professionals Society vaccine tracker](https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker). The vaccine development process continues with researchers working on [new vaccine candidates](https://covid19.trackvaccines.org/vaccines/). The [WHO](https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines) provides a detailed spreadsheet of information about vaccines in development, with twice-weekly updates. Since the beginning of the pandemic, [researchers have been prepared](https://www.nature.com/articles/d41586-021-02854-3) for the possibility that new vaccines will be needed to tackle future COVID-19 variants. In fact, [bivalent COVID-19 vaccines](https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-bivalent-vaccine-boosters) include both the original strain virus and the omicron variant to offer broader protection. There is also some [interesting research](https://www.scientificamerican.com/article/to-beat-covid-we-may-need-a-good-shot-in-the-nose/) regarding the administration of vaccines through nasal inhalation rather than needles, which may increase vaccine uptake among those with trypanophobia (fear of needles). :::spoiler Click this arrow (on the left) to view a table of data about the earlier and more well-known vaccines. _{Note: The numbers in the _Clinical trial III_ column refer to the number of participants in the test (our [COVID-19 facts page](https://c19vax.scibeh.org/pages/c19vaxfacts) explains those trials in more detail).} | Vaccine name | Type | effectiveness | | --------------- | ------------------------- | ----------- | | Pfizer/ BioNTech | mRNA | 95% | | Oxford-AstraZeneca | single adenovirus vector | 70-90% | | Moderna | mRNA | 94% | | Sputnik V | double adenovirus vectors | 91-95% | | Coronavac | inactivated virus | 50-91% | | Sinopharm | inactivated virus | 79-86% | | Johnson & Johnson | adenovirus viral vaccine | 67-85% | ::: <br> :::info For more detailed information on vaccine effectiveness, visit our [Vaccine Success Page](https://c19vax.scibeh.org/pages/vaxsuccess) ::: ## The standard vaccine development process (and its obstacles) The [vaccine development process](https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html) consists of a series of clinical trials (Phases I, II and III) and a set of bureaucratic procedures for phases to be undertaken in a specific order. All of these steps usually experience severe delays, which are not inherent to the research itself but due to external limitations. ### The steps of vaccine development * **Preclinical studies**: Scientists test the vaccine in cells a laboratory setting and then in animals to check if it produces an immune response. * **Clinical trial, Phase I**: the vaccine is tested on a small number of healthy people to check its safety. * **Clinical trial, Phase II**: the vaccine is given to hundreds of people to investigate its safety, explore different dosages and see if the vaccine is producing the required response. * **Clinical trial, Phase III**: the vaccine is tested on thousands of people in order to gain a deeper understanding and a higher degree of certainty regarding the safety and effectiveness of the vaccine. The large number of participants allows for any rare side-effects to be found. In order for this phase to be completed, it is necessary that a large number of the participants are exposed naturally to the virus and the vaccine-vs-placebo groups are compared. This stage may take time to conclude if the disease under investigation has a low prevalence. ### Obstacles in the standard process * **Funding**: All three of the clinical trial phases require funding. This can cause long delays for most vaccines. Furthermore, not all pharmaceutical companies are interested in investing money, equipment and personnel for every vaccine. * **Vaccine approval procedure**: All drugs have to be approved by one or more national health associations in order for production to begin. In many cases, this process can take months, and companies do not risk beginning production before the procedure is finished. * **Volunteers**: Phases II and especially III need a large number of volunteers. When a virus is rarely mentioned in the news and has low prevalence, the difficulty of finding volunteers may cause serious delays. * **Production, distribution & vaccination ("Phase IV")** Once Phase III clinical trials are concluded and approval is granted to the company by the responsible regulators, the vaccine is produced, allocated and provided to people around the world. As the vaccine is given to millions of people, the responsible company keeps track of potential side-effects. This is sometimes called Phase IV. Again, distribution and vaccination may take a long time in cases were the situation does not seem to be extremely urgent. Therefore, the process of vaccine development is long and arduous and not due to inherent scientific obstacles. As Mark Toshner (who has been involved in the trials at sites in Cambridge) [said](https://www.bbc.com/news/health-55041371): > "Most of the time, it's a lot of nothing, writing grant applications, having them rejected, writing them again, getting approval to do the trial, negotiating with manufacturers, and trying to recruit enough people to take part. It can take years to get from one phase to the next. The process is long, not because it needs to be and not because it's safe, but because of the real world." To learn more about the standard vaccination development process, visit the [Vaccine FAQs from London School of Hygiene and Tropical Medicine](https://www.lshtm.ac.uk/research/centres/vaccine-centre/vaccine-faqs) FAQ resource page. ## The special case of COVID-19 vaccines In the case of COVID-19, none of the above usual problems posed an issue. The virus was everywhere, taking a huge toll in lives and destroying economies. It disrupted life and forced people into social distancing, wearing masks and avoiding any kind of unnecessary contact. Coronavirus has also been the major news topic worldwide. As a result: * Scientists from all over the world contributed in the effort to find a vaccine. In fact, more than 60 vaccines were initially developed simultaneously by different research teams. This increased the chances that an effective vaccine would be developed quickly. * Volunteers were abundant, reducing the time needed for clinical trials to begin from years to weeks. In fact, there were so many volunteers that the clinical trials included tens of thousands of participants, much more than normal, leading to a greater certainty about the safety and effectiveness of the vaccines. * The virus has been spreading everywhere, allowing for naturally-occurring infections to take place more rapidly than it would be with other, rarer diseases. This reduced the time needed for clinical trials drastically. * Funding was not an issue. Money flowed from all directions (WHO, national foundations, NGOs, private companies) and major pharmaceutical companies poured resources into this global effort. Governments reassured companies that they would buy large numbers of their vaccines, encouraging pharmaceutical companies to take financial risks and start manufacturing before official approvals. As a result, there was no delay between completion of testing, approval, manufacture and rollout. * Bureaucratic obstacles were fast-tracked as COVID-19 was labelled a global pandemic by the WHO and any vaccine approval request received priority over other drugs. The following image illustrates the differences between the normal process and the COVID-19 vaccine development. To read more about the COVID-19 vaccines development, evaluation, approval and monitoring process, The [EMA has a great resource page](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#Figure2).  _{Source: [BBC](https://www.bbc.com/news/health-55056016).} What has not been widely publicised is that this is not the first time that a vaccine has been developed so rapidly. For example, the Ebola vaccine took [10 months from development to clinical trials](https://www.who.int/news-room/feature-stories/detail/the-vaccines-success-story-gives-us-hope-for-the-future), setting a new benchmark. Therefore, COVID-19 appeared in a period when the medical community was better prepared than ever to deal with such a threat. In an interview with [The Guaridan Adam Finn discusses the 10 aspects behind the fast development of the COVID-19 vaccines](https://www.theguardian.com/commentisfree/2020/dec/26/ten-reasons-we-got-covid-19-vaccines-so-quickly-without-cutting-corners?CMP=Share_iOSApp_Other): > 1. Long before the Covid-19 crisis, there was an awareness that a pandemic of some sort was likely in the coming years and plans had already been made to tackle it. Governments, international agencies and foundations had been pooling resources. The international Coalition for Epidemic Preparedness Innovations (CEPI) was launched in 2017 and when Covid-19 arrived they were ready. In addition several companies and academic institutions, notably including BioNTech, Moderna and University of Oxford, had also been working on new technologies capable of generating vaccines from the genetic codes of infectious pathogens and cancers and testing them for several years. > > 2. Professor Yong-Zhen Zhang at Fudan University, Shanghai, and colleagues in China quickly obtained material from an early case of Covid-19 and [identified a novel coronavirus](https://virological.org/t/novel-2019-coronavirus-genome/319). They elucidated the genetic sequence of the RNA in the virus very quickly and made the information public. That fired the starting gun for vaccine production. The fact that the RNA and viral vector vaccine platforms only needed the nucleotide sequence of the virus – the genetic code used by all living things from viruses to whales to reproduce themselves – in effect a series of letters you could send as a text message – and not a sample of the actual virus, allowed design and manufacture to happen very fast. > > 3. The vaccine developers had access to immediate and substantial funding. Normally getting money to develop new vaccines takes time. Either you have to persuade grant funding agencies or charities and their advisers – who are often your competitors – that your ideas are sound or, if you are a company, you have to persuade your own directors or external funders to invest. With the health and economic costs of the pandemic so great, funders enabled all plausible options, while CEPI was also ready to support the most promising proposals immediately. > > 4. The processes of writing clinical trial protocols and getting the necessary approvals to carry them out was speeded up. This usually evolves very slowly – ethics committees and regulators have to fit them into long queues of proposals. But now researchers were working and meeting at all hours and extra personnel were drafted in. Committees received applications, prioritised them and made decisions usually within 24 hours. Everyone redoubled their efforts to put these studies first. > > 5. Experienced vaccine teams were swiftly able to run Covid-19 vaccine trials. In the UK, there were already four very experienced centres ready to start the Oxford vaccine study immediately and through the National Institute for Health Research, which coordinates all clinical trials done by the NHS, an additional 14 sites were identified and set up for the larger phase 2/3 studies which followed. > > 6. Information technology was readily available and used. Clinical trials have been slow to embrace electronic methods of data recording and collection for fear of glitches. Paper records are familiar solid objects that everyone can see and believe in but they are slow and error prone. Where other sectors have led, research has now finally followed. When you buy an airline ticket, you do it online and the form does not allow you to make mistakes or omit important pieces of information before you complete a purchase. Such characteristics are also vital for data collection and during the 3 to 5 years prior to this pandemic, research trials have been switching to this approach, with data collected straight into computers and tablets in the clinic. Mistakes and omissions are rare. Information is immediately available for analysis even as it is being collected. > > 7. There is massive public support for and engagement with these studies. Many people wanted to take part and help out. Typically vaccine trials take weeks or months to recruit, but for these studies – assisted by the speed of media information, social media and the ability of subjects to register interest instantly online – it was possible to identify willing volunteers within just a few hours. Without the participants the studies could not happen. > > 8. For results, there need to be cases of disease. Even with all this speed, large scale trials got going only towards the end or after the first wave of Covid-19 cases in most countries. While low rates of disease during the summer in many places was great news for our health, sanity and the economy, it actually made the trials more difficult. If you have large numbers of people who have had vaccine or control injections, in order to find out whether the vaccine works you need cases of Covid-19 to occur. You hope the cases will mostly be among the controls. But if no one gets sick you are none the wiser. The arrival of the second wave is a massive public health challenge, but it has enabled these trials to yield results rapidly. > > 9. It’s much quicker to get a result on a vaccine that works well than one that only works feebly. Even a vaccine that only prevents a small proportion of cases could be useful in the context of a pandemic, but it takes longer to find out whether a weaker effect is really there. If a vaccine were 100% effective (no such vaccine exists but just for the sake of argument) then you might only need about 20 cases of disease in your study – which would all occur among the controls – to be almost certain that the vaccine caused the imbalance of 20 sick controls and 0 sick vaccinated people. But if the vaccine was only moderately effective, 20 cases would not be nearly enough. 7 cases in vaccine recipients and 13 in controls could be due to vaccine induced protection, but could also easily be chance and a vaccine with no effect at all. You would want many more cases, for example 70 to 130 to be more sure of your result. But getting 10 times more cases would take much longer. The fact that the early vaccines have worked well has made it quicker to be much more certain about the strength of their protective effects. > > 10. Using “rolling review”, a completely different approach was taken to regulatory approval this time. Normally all the trial results and data are prepared in a massive package once the studies are finished, a process taking months. The whole lot is then presented to the regulators, who are the agencies that issue licences for drugs and vaccines, and they then begin their review, another process taking months. This time the data were provided to the regulatory agencies as they were being generated and were being reviewed while the studies were on-going. When the final results came in, those were the only results left to be reviewed. The whole process took months, but the last steps only days. > Authorisation is not the end of this “fast vaccines” story. Roll out and administration of vaccines began almost immediately. That isn’t normal either. No sensible company would start manufacturing vaccine until it knew it would definitely be allowed to sell it but this time the manufacturing was done at risk and in advance. If the vaccines had failed, all of the doses already made would have had to have been scrapped. Fortunately that has not happened. > > There are more vaccines in the pipeline and we have more to learn about the ones that have arrived – much more information about safety and side-effects will accumulate as they are given to far larger numbers. But the fact we are already in a position to start protecting the vulnerable and the highly-exposed by immunisation is the result of foresight, hard work and some lucky breaks. In conclusion, the fast development of COVID-19 vaccines was the result of thousands of researchers, lots of money, tens of thousands of volunteers, global attention (that allowed for facilitation of procedures) and the high virus prevalence, which made it easy to measure the safety and effectiveness of the vaccines. :::info **For more information regarding the COVID-19 vaccines, their safety, effectiveness, and relevant links and sources, see our dedicated page on [facts about COVID-19 vaccines](https://hackmd.io/@scibehC19vax/c19vaxfacts).** ::: ---- _{Page contributors: Konstantinos Armaos, Stephan Lewandowsky, Dawn Holford, Michelle Barden} {%hackmd GHtBRFZdTV-X1g8ex-NMQg %} {%hackmd TLvrFXK3QuCTATgnMJ2rng %} {%hackmd oTcI4lFnS12N2biKAaBP6w %}