Scientists had already researched the platforms for delivering vaccines in preclinical studies. So, all scientists needed was a SARS-CoV-2 genome to substitute for whatever viral genome they had before the pandemic. It is the sole reason why scientists developed the vaccines so rapidly when compared to conventional vaccine development.
Currently, there about sixty Covid-19 vaccines in clinical development – classified based on their delivery platform. SARS-Cov-2 is not the first coronavirus to pose a human threat. We had experienced a prequel of SARS-CoV in 2009. In today’s article, we discuss the basics that you should know about vaccine development such that you lead informed discussions about Covid-19 vaccines.
Before the volunteers try it out, developing a novel vaccine involves a series of preclinical studies and investigations. The scientists first identify the antigen to will elicit the required immune response. Scientists develop a manufacturing process and carry out both animal and in vitro studies, followed by submitting the crucial data to the relevant authority – say FDA in the USA. They then file in an investigational new drug (IND). If it is a success, they proceed to conduct human trials. Human (clinical) trials begin with phase 1 through phase 4.
Phase 1 clinical trials comprise a small number of participants – about 20 to 100 volunteers. Such studies aim to establish the safety of a new vaccine. They measure the incidence of adverse events and also garner early efficacy data. In many instances, they may include finding the optimal dose and when to schedule investigations.
Phase 2 clinical trials involve a large number of participants, usually in hundreds. During the process, scientists further evaluate the safety of the vaccine and the immune response it generates.
Phase 3 clinical trials recruit hundreds to thousands of volunteers. They usually take the form of randomised controlled trials, whereby some participants get the novel vaccine whilst others get a placebo or current standard therapy. (to define placebo). Scientists then follow up on the participants and calculate the efficacy of the vaccine. They continue monitoring any adverse events, as well as other safety parameters.
When these 3 phases are complete, the vaccine sponsor submits a Biologics License Application (BLA) to the FDA. If the novel vaccine has proven safe for use and the benefits it confers outweigh the risks associated with its use, the FDA can then approve the BLA. Following licensure, the FDA routinely inspects the vaccine manufacturing facilities and vaccine lots for purity and potency.
The vaccine is now ready for use among humans. However, large-scale clinical trials commence intertwined with post-marketing surveillance to monitor and report vaccine safety and efficacy. We term this phase 4 of vaccine development. Many Covid-19 vaccines are under emergency use authorisation – an interim approval that the relevant bodies use in an emergency. The FDA bases it on the best available evidence, only effective until the emergency declaration ends, during which the licensure can either be revoked or revised.
Rare adverse events are any untoward medical occurrences that occur in less than 1 for every 1000 individuals that have received an investigational new drug – a vaccine in this context. They are usually unsolicited adverse events that may be too infrequent for scientists to detect in prelicensure clinical trials. They often recognise them in post-marketing surveillance studies. Examples are anaphylaxis, Bell’s palsy, intussusception, and Guillain-Barre syndrome.
How well a vaccine works in ideal, controlled environments – say clinical trials, defines its efficacy. How it works in real-world settings on a population level entails its effectiveness.
The effectiveness of any vaccine is usually lower than its efficacy because of the population diversity, dosing variability, and variation among providers in administering the vaccine.
Throughout vaccine development and after licensure, researchers evaluate the incidence of AEFI (adverse events following immunisation). An AEFI is any untoward medical occurrence that follows vaccination. It does not necessarily have a causal relationship with the use of the vaccine. They are either solicited or unsolicited.
Reactogenicity describes the signs and symptoms of the inflammatory response elicited after vaccination. We measure it up to seven days after vaccination. It can be local, for example, pain and swelling at the injection site, or systemic, for example, fever, arthralgia, myalgia, nausea, and headache.
Covid-19 vaccines have had a rapid manufacturing process because scientists had already researched the new vaccine delivery platforms in preclinical studies. They rapidly sequenced the viral genome allowing them to identify and develop the necessary antigens to include in the vaccine. Also, in contrast to the usual step-by-step vaccine development process, scientists executed the steps in parallel. The high disease prevalence allowed clinical trials to show a beneficial effect rapidly. Lastly, there was a high participant enrolment. Vaccine production occurred in parallel with on-going clinical trials, enabling the achievement of such an extraordinary feat.
In a nutshell, we all astonishingly understand that the Covid-19 vaccines have undergone rapid production and licensure. However, we aren’t still in the nineteenth century when technology was still at an infancy stage. And the circumstances through which scientists developed the previous vaccines were different from the prevailing ones today. We are in a revolution where the next big thing is the CRISPR/Cas9 gene-editing technology. Vaccines will never delay if we have enough volunteers. The world cannot wait for a conventional way of vaccine production. The income inequality gap widened further due to Covid-19.
Note: We have partly got the information entailed in this article from the on-going NEJM Knowledge+ training about Covid-19 vaccines. Enrol for free. The images belong to the respective owners.