The article is about vaccine development – not particularly covid-19 vaccines but vaccines in general. Various processes occur behind the scenes that a few people understand about the vaccine and drug development. We describe the process of how scientists develop vaccines. In the process, we shall summarise the systems that ensure their safety before and after they are licensed. We also describe how vaccine efficacy differs from effectiveness.
Worldwide, the World Health Organisation (WHO) monitors the vaccine development process. In the US, the Food and Drug Administration (FDA) solely regulates their development. Before a vaccine undergoes testing in humans, any new vaccine undergoes multiple preclinical studies and investigations. In such studies, investigators identify the antigen and develop a manufacturing process. Afterwards, they submit relevant data to the regulatory bodies – say FDA. They also present an investigational new drug (IND) application. Once this succeeds, investigators can then proceed with the human (clinical) trials. Clinical trials occur in phases – one, two, three, and four.
In phase 1 trials, investigators usually recruit about 20 to 100 volunteers. They participate in the studies to principally discern how safe the new vaccine is. Investigators ascertain the incidence of any adverse events. They also gather preliminary data about the vaccine efficacy. They also establish the dose and the optimal scheduling.
When phase 1 trials succeed, investigators recruit more volunteers – normally in hundreds to further elucidate the vaccine safety and the immune response it creates. We term this clinical phase trial 2.
In clinical phase trial 3, through controlled randomisation, investigators recruit hundreds to thousands of volunteers. The participants either receive the new vaccine or a placebo, or current standard therapy. Investigators follow them up, and they calculate the vaccine efficacy. They also continue monitoring for any adverse events, as well as vaccine safety.
When this phase succeeds, the vaccine sponsor can submit a Biologics License Application (BLA) to the FDA – which will only approve it if the new vaccine has proven safe for use and its benefits outweigh its disadvantages. After licensing, the regulatory bodies – say the FDA – routinely inspect the vaccine manufacturing units, including the vaccine lots, to assess purity and potency.
After licensure, clinical trial phase 4 commences. It entails post-marketing surveillance, large-scale trials to monitor safety and efficacy, and safety reporting. Different regions have different bodies through which the public reports any adverse events – say National Drug Authority (NDA) in Uganda. They gather information and convey it to the vaccine manufacturers.
In a few instances, some events occur, and post-marketing surveillance reports them. But investigators never detected them during the prelicensure clinical trials due to their infrequency. Such events usually happen in less than one for every 1000 individuals. We term them rare adverse events. Examples are anaphylaxis, Bell palsy, Guillain-Barré Syndrome, and intussusception.
How well a vaccine works in an ideal, controlled environment like a clinical trial constitutes its efficacy. How well it works under the usual circumstances at a population level using real-world data is the effectiveness. Vaccine effectiveness is often lower than its efficacy- due to the heterogeneity in the population receiving the vaccine, variability in both dosings and among providers in how they administer the vaccine.
In a nutshell, no vaccine hits the market for global utilisation before investigators have and provide efficacy and safety data to the regulatory bodies. In some circumstances like the Covid-19 pandemic, the regulatory bodies can authorise emergency use of the said vaccine using the best evidence available – they can revoke or revise this authorisation at any time. Throughout the clinical trials, people volunteer to use the vaccine as investigators ascertain its efficacy and safety. Vaccine efficacy and effectiveness often differ. This article uses information from an ongoing Covid-19 vaccines training at the NEJM Knowledge+.