The process starts with a so-called ‘candidate’ vaccine – something that a team of scientists think has the potential to work well as a vaccine. This is the quickest part of the process taking weeks at most.
Vaccines must be safe
Vaccine safety is first assessed in studies with mice or rabbits. If the animals do not develop signs of illness after being given the vaccine, then tests begin with humans in a series of trials which involve steadily increasing numbers. In Phase I, also called first-in-human trials, the vaccine is given to a small group (10–100) of healthy volunteers. The purpose here is not to test whether the vaccine protects against the disease, but whether it is safe to give – for instance, does it cause a severe reaction? In Phase II, it is given to a larger group (100–1,000), and in Phase III, a larger group still (1,000–100,000). Separate studies may be needed in adults, children and the elderly. Sometimes vaccines that appear to be safe when given to a few people are revealed to have adverse effects when given to thousands. This is because rarer complications are less likely to be seen when only few people are vaccinated. Continued follow up is important in case of delayed complications. In a pandemic, these sequential studies can be shortened and partially overlapped but it is important to follow thousands of vaccinated people for several months before clearing the vaccine for general use.
Vaccines stimulate immunity to the virus but they can also stimulate inflammation in the body. People notice this as pain or swelling at an injection site, or as general symptoms like fever or fatigue – symptoms similar to mild COVID-19 disease. For most vaccines these reactions are mild and affect only a minority of people. If there are more serious signs of inflammation, or if the vaccine causes the immune system to malfunction in other ways, then it might not be suitable for wide use. When such adverse effects are identified, they inevitably lead to delay.
Vaccines must be effective
If a vaccine produces an antibody response in a mouse or a human, it does not necessarily mean that the vaccine will protect against disease. Ideally, before moving to human studies, scientists should be able to show that the vaccine will protect animals from developing disease if they are experimentally infected with the virus. For previous coronavirus diseases (SARS and MERS) it was difficult to find an animal species that was affected by the disease in the same way as humans. However, this past research may help scientists speed up the process of animal testing for COVID-19.
The protective effect of a vaccine in humans is evaluated using the same series of studies undertaken for safety. If the vaccine stimulates an immune response, for instance if antibodies can be detected in the small Phase I study, then the larger Phase II and Phase III studies can be designed to look at whether it protects against infection or disease. Although COVID-19 is a new disease, research on SARS and MERS has helped us to understand how the human body responds to coronaviruses and how immune changes relate to protection. Smaller human studies can also be used to work out the correct dose and schedule for the vaccine. Some vaccines elicit a strong immune response after a single dose but others require a ‘booster’ dose a month or more later and this increases the length of the trials.
To assess whether a vaccine prevents COVID-19 among those exposed to infection, it must be tested in Phase III trials, in a setting where infection is actively taking place. In response to the West African Ebola outbreak in 2014/15 the rVSV Ebola vaccine was put through all three phases of clinical development in just 12 months with focused coordination by the WHO, MSF (Doctors Without Borders) and the manufacturer. This meant that cases of Ebola were still occurring in Guinea and protection was demonstrated by vaccinating contacts of residual cases as they occurred.
Vaccines must be manufactured
For pandemic vaccines, tens or hundreds of millions of vaccine doses are required almost immediately. It takes existing manufacturing facilities at least six months between the time that a new pandemic flu strain is announced and being able to produce such large volumes of the new vaccine. For any new vaccine, more manufacturing checks will be required for what will be a new process. Scientists need to ensure that the quality of the vaccine is consistent throughout manufacturing and this requires repeated testing. And, since vaccine manufacture is a biological process, inevitably some vaccine batches will fail for reasons that are not always clear, potentially further delaying production. There are relatively few facilities in the world that can produce vaccines at the scale needed to respond to a pandemic.
There are many different types of vaccine currently being investigated for COVID-19. Each type will require a slightly different sort of facility and they are unlikely to be built or adapted until a much later stage in clinical trials, when it is clear which ones are likely to be successful. Distribution, allocation and deployment of vaccines on the required scale takes months. The vaccine might need refrigeration to keep it stable, in which case tests would be required for vaccine stability as it is stored and distributed.
Vaccines must be regulated
Before initiating each stage of the human testing process, the developer needs to provide evidence that the vaccine has early indications of protection and is safe among those who have been tested so far. Research ethics committees undertake the review of clinical trial plans and vaccine regulators such as The European Medicines Agency oversee the whole vaccine development process before licensing the vaccine for general use. These reviews usually take weeks or months. Whilst they will be shortened in the face of a pandemic, many COVID-19 vaccines in development use novel technologies. This means regulators will not be able to rely upon experience of similar vaccines to speed up the process.
COVID-19 vaccine developers have been given a target of producing a vaccine within 12–18 months whilst historically vaccines have taken 15–20 years to develop. Some diseases still do not have vaccines despite decades of work. For example, over 100,000 children die each year from respiratory disease caused by another RNA virus, RSV (respiratory syncytial virus, a cause of wheeze and pneumonia). Despite 50 years of research and 18 products in development, no RSV vaccine is currently available.
Over 30 different scientific groups are developing a COVID-19 vaccine, using a range of different approaches. Having many groups in the race is important because most vaccines that enter clinical trials will fail on grounds of safety or effectiveness. But if a vaccine can be tested for safety and effectiveness in one year, as with the Ebola vaccine; and if capacity can be developed quickly to manufacture the successful vaccine, ideally in parallel with trials, it may be possible to distribute a COVID-19 vaccine sooner rather than later, perhaps within 18 months.