--- title: COVID-19 Vaccine Development Process tags: live-v0.1, facts, misinformation, debunking permalink: https://c19vax.scibeh.org/pages/vaxprocess --- <!---{%hackmd FnZFg00yRhuCcufU_HBc1w %}---> {%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 (months instead of years, which are normally needed for the development of a vaccine) and the fact that the main COVID-19 vaccines use relatively novel mRNA technology. **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 explain the standard development process of any vaccine and the pragmatic obstacles that are faced in this process under normal circumstances. We then explain why this process could be accelerated for the development of the COVID-19 vaccines. --- ## The current state of COVID-19 vaccines in the world <span style = 'color:green'>As of early mid-May 2021: * **In the USA**, vaccines from two companies have been approved by the CDC as safe and effective for vaccination against COVID-19 in the USA: * [Pfizer-BioNTech](https://www.cdc.gov/vaccines/covid-19/info-by-product/pfizer/index.html) * [Moderna](https://www.cdc.gov/vaccines/covid-19/info-by-product/moderna/index.html) * [Johnson & Johnson](https://www.cdc.gov/vaccines/covid-19/info-by-product/jansen/index.html) Details on these products can be found [on the CDC website](https://www.cdc.gov/vaccines/covid-19/info-by-product/index.html). * **In the UK**, <span style = 'color:green'>there are four Covid-19 vaccines currently approved for vacination:</span> Pfizer-BioNTech's mRNA vaccine and [Oxford-AstraZeneca's](https://www.bbc.com/news/health-55280671) vaccine are the two products first approved for vaccinations. The Oxford-AstraZeneca product is [a different type of vaccine to that of Pfizer](https://www.nytimes.com/interactive/2020/health/oxford-astrazeneca-covid-19-vaccine.html): it is a genetically modified virus from chimpanzees, infused with the mRNA for producing the COVID-19 spike protein. <span style = 'color:green'>In January 2021, [Moderna](https://www.gov.uk/government/news/moderna-vaccine-becomes-third-covid-19-vaccine-approved-by-uk-regulator) was the third Covid-19 vaccine to be approved for use by the MHRA and was the second mRNA vaccine. On the 28th May 2021, [MHRA approved a one-dose Janssen Covid-19 vaccine](https://www.gov.uk/government/news/janssen-coronavirus-covid-19-vaccine-authorised-by-uk-medicines-regulator); this is the only single dose cCovid-19 vaccine that meets the expected standards of saftey, quality and effectiveness * **In [China](https://www.bbc.com/news/world-asia-china-55212787)**, <span style = 'color:green'>the following five vaccines have been approved for use: * <span style = 'color:green'>Coronavac (inactivated virus), BBIBP-CorV (inactivated vaccine), Convidicea (recombinant, adenovirus type 5 vector vaccine), WIBP-CorV (inactivated vaccine), ZF2001 (recombinant vaccine). The vaccines have also been [approved in a number of other countries](https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker). The inactivated vaccines are of the traditional inactivated virus type, similar to the ones used for flu and measles vaccinations. * **In Russia** * <span style = 'color:green'>[Sputnik V](https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30402-1/fulltext?ref=brianlovin.com) (recombinant adenovirus r Ad26 and rAd5 vaccine and Sputnik light (reconbinant adenovirus rAd26)) has been approved and administered to more than 800,000 people. Russia has started sending the vaccine to dozens of other [countries](https://www.aljazeera.com/news/2020/12/31/bolivia-algeria-sign-vaccine-deals-for-russias-sputnik-v). Sputnik is [different from the other COVID-19 vaccines](https://www.precisionvaccinations.com/vaccines/sputnik-v-vaccine): other vaccines are given as two shots of the same product. Sputnik V relies on two injections using different inactive viruses, known as vectors. Each dose is based on different viral vectors that normally cause the common cold. * <span style = 'color:green'>EpiVacCorona (peptide). Russia has granted [regulatory approval](https://www.cnbc.com/2020/10/14/russia-approves-second-covid-19-vaccine-after-preliminary-trials-.html) to this despite it not yet entering Phase 3 trials. * <span style = 'color:green'>CoviVac (inactivated vaccine) approved in Russia however, late-stage trials of the vaccine have yet to begin. * **In India**, two vaccines are currently cleared for emergency use: Oxford-AstraZeneca's and [Covaxin](https://www.bharatbiotech.com/covaxin.html) (produced by Bharat Biotech). However, Covaxin has still not proceeded with its phase III clinical trials, thus [efficacy questions are currently unanswered](https://www.ndtv.com/india-news/covaxin-government-clears-two-covid-vaccines-no-efficacy-data-for-one-so-far-2347168). </span> <span style = 'color:green'>Here is a summary list of vaccines developed and approved thus far in various countries of the world. More regularly-updated information about each of these vaccines can also be found on the [RAPS vaccine tracker](https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker). <sub>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).</sub> | Vaccine name | Type| Clinical trial III | price per dose | effectiveness | minimum age | | --------------- | ------------------------- | ----------- | ----- | ------------- | ----------- | | Pfizer/ BioNTech | mRNA | 44,000 | $20 | 95% | 16 | | Oxford-AstraZeneca | single adenovirus vector | >23,000 | $4 | 70-90% (?) | 18 | | Moderna | mRNA | 30,000 | $33 | 94% | 18 | | Sputnik V | double adenovirus vectors | 16,000 (?)| $10 | 91-95% | ? | | Coronavac | inactivated virus | 29,000 (?)| $14 | 50-91% (?) | 18? | | Sinopharm | inactivated virus | 15,000 | $19-$36 | 79-86% (?) | 18 | | <span style = 'color:green'>Johnson & Johnson | <span style = 'color:green'>adenovirus viral vaccine | 40,000 | $10 | <span style = 'color:green'>67-85% | <span style = 'color:green'>18 | <sub>**Note:** The companies that develop the Oxford-AstraZeneca and the Sputnik V vaccines have announced that [they will collaborate](https://www.cnbc.com/2020/12/11/coronavirus-astrazeneca-to-work-on-vaccine-with-russias-gamaleya.html) to investigate whether they can increase the effectiveness of vaccination by combining the two approaches which use the same adenovirus.</sub> --- ## 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 (I, II and III) and a set of beaureucratic procedures with a specific order. All of these steps usually experience severe delays, which are not inherent to the research itself but more owed to pragmatic limitations. ### Development steps * **Preclinical studies**: Scientists test the vaccine in cells and then to animals to check if it produces an immune response. * **Clinical trial, Phase I**: vaccine is tested on a small number of healthy people to check its safety. * **Clinical trial, Phase II**: 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**: vaccine is tested to 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 relatively rare side-effects to be found. In order for this phase to be considered concluded, it is necessary that a large number of the participants are exposed naturally to the virus and the vaccine-vs-placebo groups are compared (how many from each group get infected?). This stage may take time to conclude if the disease investigated has a low prevalence. ### Pragmatic 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 trial is concluded and approval is granted to the company by the responsible bodies, the vaccine is produced, allocated and provided to people around the world. As the vaccine is given to million of people, the responsible company keeps track of potential rare 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 for pragmatic reasons 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. The following articles illustrate the normal development process for a vaccine: * [BBC: Covid vaccine update: When will others be ready?](https://www.bbc.com/news/health-51665497) * [BBC: Is the Covid vaccine safe?](https://www.bbc.com/news/health-55056016) * [BBC: Oxford vaccine: How did they make it so quickly?](https://www.bbc.com/news/health-55041371) * [Vaccine FAQs from London School of Hygiene and Tropical Medicine ](https://www.lshtm.ac.uk/research/centres/vaccine-centre/vaccine-faqs) ## 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 since February. As a result: * Scientists from all over the world contributed in the effort to find a vaccine. In fact, more than 60 vaccines are developed simultaneously by different research teams. This increased the chances that some vaccines would be developed fast. * Volunteers were abundant, reducing the time needed for clinical trials to begin from years to weeks. Actually, 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. * Money flowed from all directions (WHO, national foundations, NGOs, private companies) and every major pharmaceutical company poured resources into this global competition. In fact, governments reassured companies that they would buy large numbers of their vaccines, inducing pharmaceutical companies to take financial risks and start manufacturing before the official approval, so that there was no delay between completion of testing, approval and rollout. * Bureaucratic obstacles were fast-tracked as COVID-19 was labeled a global pandemic by the WHO and any vaccine received priority over other drugs waiting for approval. The following image illustrates the differences between the normal process and the COVID-19 vaccine development. ![](https://i.imgur.com/67nnXWK.jpg) <sub>Source: [BBC](https://www.bbc.com/news/health-55056016).</sub> Furthermore, the medical community has made strides in recent years in accelerating the vaccine development process in general, with Ebola being the trigger for this situation: 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 that the medical community was better prepared than ever to deal with such a threat. Indeed, as [Adam Finn discusses in a piece in _The Guardian_, there are 10 reasons for the fast development](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. **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).** ---- <sub>Page contributors: Konstantinos Armaos, Stephan Lewandowsky</sub> {%hackmd GHtBRFZdTV-X1g8ex-NMQg %} {%hackmd TLvrFXK3QuCTATgnMJ2rng %} {%hackmd oTcI4lFnS12N2biKAaBP6w %}