- Research and development usually take a number of years before a vaccine can be approved and given to millions of people.
- But due to decade-long preclinical research, as well as massive amounts of funding, Covid vaccines could be developed in under a year.
- Rigorous studies were done and no corners were cut.
Vaccine development is a complex process. The clinical trial process generally takes seven to 10 years before a vaccine can be approved and rolled out to a population. How then, were the Covid-19 vaccine studies completed in just 10.5 months?
Thanks to over a decade of research that centred on vaccine technology and other coronaviruses, and enormous funding, this was made possible, Shabir Madhi, Professor in Vaccinology at the University of the Witwatersrand (Wits) explained in a webinar hosted by CENSCOM in conjunction with GroundUp on 20 August.
The Covid vaccine clinical trial studies, he said, were done in such a manner that the vaccines can stand up to scientific scrutiny. “And by that, I mean that it [addressed] all of the potential pitfalls that might exist that could bias results in one way or another.”
The purpose of clinical trials
Without these rigorous trials, there simply wouldn’t be any advance in science, Madhi added.
“We do clinical trials largely to increase and improve medical knowledge. The purpose is solely that we can advance when it comes to preventing diseases and improving patient care. It is about prolonging life; it’s about making people lead a healthier life; and it’s about reducing suffering … there’s absolutely no other reason to do clinical trials,” he said.
Understanding the different phases
Clinical development of vaccines involves the following distinct phases:
- Preclinical testing: Takes several years. Involves animals such as mice or monkeys to see if the vaccine produces an immune response.
- Phase 1 safety trials: Take 6–12 months. Involve a small number of people to test the safety and dosage of the vaccine, as well as to confirm that the vaccine stimulates the immune system.
- Phase 2 expanded trials: Take 12–24 months. Involve hundreds of people split into groups, such as children and the elderly, to see if the vaccine acts differently in them. They further test the vaccine’s safety and ability to stimulate the immune system.
- Phase 3 efficacy trials: Take 3–4 years. Involve thousands of people and compare volunteers who receive either the vaccine or a placebo, and determine if the vaccine protects against the virus and is safe.
- Phase 4: Looks at the real-world experience with the vaccine after it has been introduced to populations.
When scientists speak about the preclinical phase taking years to complete, they mean that they have to design the technology and develop the proper animal models. When this is done, they have to produce the product (in this case, a vaccine) and test it on animals.
Fortunately, in the context of Covid vaccine development, all that preclinical development and actual preparation had already taken place, said Madhi. The purpose of that past work was to use new technologies as an intervention against other illnesses, or to develop vaccines against other diseases.
“As an example, the messenger RNA (mRNA) is not a technology that has been developed specifically for Covid vaccines,” said Madhi. “In fact, it has been around for almost a decade and it’s been used in cancer research to customise approaches at the individual level. Messenger RNA technology has always been there,” he added.
This type of technology, used in the Covid vaccines by Pfizer-BioNTech and Moderna, is a very adaptable technology that allows scientists to add on a new target very rapidly, said Madhi. This is why, instead of scientists needing to spend a few years on preclinical studies, they were able to move into phase 1 studies in a matter of months, rather than years.
MERS and SARS-CoV
“Ten years ago, we had the SARS-CoV virus and then we had the Middle East respiratory syndrome (MERS) virus, which is another coronavirus, so vaccine research around coronaviruses didn’t start just 10 months ago,” Madhi said.
The vaccines for SARS-CoV and MERS didn’t materialise because those epidemics fortunately died down. “But all of the tremendous time it takes to do this preclinical work has pretty much taken place over the past 10 years."
Generally, most of the risks in clinical trials are taken on by a single company, Madhi said.
“Companies need to account to their shareholders and they need to be risk-averse, so they need to have a high level of certainty that a product is going to work before they start investing hundreds of millions of dollars – which is when you reach your phase 3 [studies].”
A phase 2 study, such as the one in South Africa that tested the efficacy of the Oxford-AstraZeneca vaccine against the Covid-19 virus, and enrolled around 5 000 participants, cost in the region of about $35 million to $40 million, said Madhi.
He went on to say that the average phase 3 trial which involves around 30 000 to 40 000 volunteers costs between $700 million and $1 billion.
“As you can imagine, if a company plans to spend half a billion dollars on its product, it needs to have a certain guarantee that what they’re seeing in phase 1 and 2 is actually promising enough to allow them to go to phase 3,” he said.
These phases are usually done in series, rather than in parallel. But with the Covid pandemic, there was a shift in the paradigm, “simply because governments came forward and said, 'We don’t want you to do things in series, we want you to do things in accordance with regulations … You need to do as much as you can in parallel and you need to mobilise resources, and you don’t have to worry about money,’” Madhi further explained.
Covid trials scrutinised
Despite these phases running in parallel, it doesn’t mean any safety corners were cut, said Madhi. “The intensity of scrutiny of the Covid vaccine trials is something that has been completely unprecedented,” he said.
There are a number of regulations that govern the ability of countries to conduct studies and the ability of any investigator and company to conduct studies, said Madhi, and this is governed by independent institutions.
In South Africa, we would need to get approval at the level of the ethics committee; regulatory authority (the South African Health Products Regulatory Authority – Sahpra); and the National Department of Health. And additionally, for genetically modified products (the vaccines in this case), the Department of Agriculture, Land Reform and Rural Development also needs to be involved.
“It is a lengthy process … [and] it’s not just about getting approval. Sahpra, as an example, requires you to provide written feedback about a clinical trial and any safety concerns every six months, usually, but with Covid vaccines it changed to feedback being requested every two weeks. And they send through reminders if it’s overdue,” he said.
Madhi further added: “We’ve had audits within a few weeks of the [South African] study starting, whereas those audits by Sahpra usually take place after the clinical trial is coming close to its end. So Covid vaccine trials have neither been short-circuited from a regulatory perspective, nor in terms of the regulatory oversight, nor in terms of the phases we go through. But … a lot of them have been going in parallel.”
Understanding phase 4 studies
With Phase 4 studies, scientists aim to address the issue of the prevalence of extremely rare side effects.
“And when I talk about rare side effects, that’s the equivalent of someone being struck by lightning in Johannesburg. The chances of that are in the region of 1 in 300 000,” said Madhi.
One example of these very rare side effects is unusual blood clots with low blood platelets, as seen in a small number of people who received the AstraZeneca or J&J vaccines.
But since the clinical studies don’t involve such large numbers of people, this aspect cannot be addressed until it’s given to hundreds and thousands, and millions, of people in the "real world".
Sahpra confirmed in a statement on Friday that so far, investigations for 32 death cases have been completed, and it was assessed that 28 were coincidental to vaccination.
"This means that these deaths were not related/linked to the vaccination. Four cases are unfortunately unclassifiable because there was either no information available about the case or the information was completely inadequate.
"Hence, causality assessment could not be conducted or concluded," Sahpra said.
Getting full approval
The current Covid vaccines are rolled out under Emergency Use Authorisation (EUA): “That is done as an exception rather than the rule – it’s done to address an immediate public crisis,” said Madhi.
Pfizer, Moderna, and J&J, in parallel to having EUA, are now in the process of applying for full approval, said Madhi.
While this process generally takes two to three years, it will be happening in just a few months. “And if people want to wait the full timeline of two to three years, then we would’ve introduced Covid vaccines after the virus would have … [infected] everyone, where some would die, and the rest would become immune through natural infection,” said Madhi.