Covid vaccine: How do trials actually work?

With the race for a coronavirus vaccine reaching its final stages, the finer details of the development process have fallen under even greater scrutiny.

Almost 70 different types of vaccine are currently being tested on tens of thousands of volunteers across the world, though only a handful have entered the final large-scale phase 3 trial.

Following the news that the Pfizer/BioNTech candidate appears to be 90 per cent effective in preventing disease, we take a closer look at how vaccine trials work.

Pre-clinical and early-stage trials

In the pre-clinical stage of testing, researchers give the vaccine to animals to see if it triggers an immune response. After this, it is then administered to humans to establish whether it is safe and to ascertain what type of immune response it provokes. This is the phase 1 trial.

If this returns encouraging results, the vaccine progresses to phase 2 in which hundreds of volunteers are given doses. This allows scientists to further check for any safety concerns while allowing them to tweak the dosage, depending on the response recorded among participants.

Phase 3 trial

In the third and final phase, thousands of healthy people who haven’t been previously infected with Covid are inoculated with the vaccine. This includes all ages and ethnicities to give an indication of what sort of immunological response is triggered among different groups of the population.

Importantly, this study confirms the jab’s safety – any rare side effects often come to light at this stage given the number of volunteers involved – as well as its effectiveness. These trials involve a control group that is given a placebo.

A number of phase 3 trials will be conducted simultaneously in various countries across the world. Researchers are precise about which parts of a country they choose to set up their research clinical sites. Public health data and incidence trajectory modelling will be used to identify sustained high-incidence areas and hotspots where transmission rates are rising.

This makes it more likely that trial participants will be exposed to coronavirus out in the wider community. Those who have been inoculated will possess some degree of immunity against the virus, depending on the type of vaccine, while volunteers in the control group will be susceptible to infection.

As the trial progresses, statisticians will count up the number of participants who have tested positive for Covid-19. Once the researchers believe they have enough cases, it will be revealed which of these individuals were injected with the vaccine and which were given the placebo. This is called “unblinding the trial” and it confirms how effective the vaccine is.

If the group of infected volunteers is predominantly made up of those individuals who were given the placebo, this indicates there is a high statistical likelihood that the vaccine is effective.

In the case of the Pfizer/BioNTrech vaccine, the companies opted to take a look at the interim data after 94 infections had been reported among 44,000 trial participants. Analysis showed that their candidate was 90 per cent effective in preventing disease. Although the data hasn’t been published or peer-reviewed yet, we can assume that the majority of cases came from the trial group.

Pfizer and BioNTech will keep running the study until researchers have recorded 164 positive cases – a figure that will provide greater accuracy in determining their candidate’s effectiveness. Other vaccine developers have indicated that they won’t “unblind” their phase 3 study until they’ve amassed at least 150 infections among their volunteers.

As in previous phases, adverse events can potentially occur and are not uncommon, particularly in large-scale studies. If an unexpected serious adverse event (SAE) occurs, recruitment or medication dosing may be paused so all pertinent medical information can be reviewed before deciding whether to restart the clinical trial – as happened with the Oxford University vaccine.

Phase 3 trials can sometimes take years, though this stage of development has been condensed into a matter of months during the pandemic.

What next?

If the phase 3 trial delivers positives results, vaccine manufacturers will then submit an application to regulatory bodies such as the UK’s Medicines and Healthcare products Regulatory Agency or the US Food and Drug Administration. At this stage, clinical trial data is reviewed to make sure the vaccine is safe and effective.

Manufacturing will be scaled up in the meantime in anticipation of approval. A rapid rollout will follow, though the logistical challenges involved in distribution pose an entirely different set of challenges.

Of all the Covid-19 vaccines in development, the Pfizer candidate will be one of the most difficult to store and transport. Doses need to be maintained at temperatures as low as -80C.

“Nowhere on the planet does the logistical capacity exist to distribute vaccines at this temperature and volume without massive investment,” says Toby Peters, a professor of energy storage at the University of Birmingham.

“The problem is particularly acute in the Global South where many rural villages don’t even have a working vaccine fridge.  We must take this once-in-a lifetime opportunity to create sustainable solutions for Covid-19 vaccine deployment that also can deliver resilient and sustainable health cold-chain systems, including ultra-low temperature.”