The Univeristy of Melbourne The Royal Melbourne Hopspital

A joint venture between The University of Melbourne and The Royal Melbourne Hospital

Issue #59: The scientific defence that brings us to Phase III, the penultimate trial

31 May 2021

Issue #59: The scientific defence that brings us to Phase III, the penultimate trial

The power of modern molecular science is such that, adapting technology developed for other pathogens, making the candidate mRNA (Pfizer BioNTech and Moderna) and adenovirus-vectored (AstraZeneca, Johnson and Johnson and Sputnik) vaccines (#49, #50) to counter SARS-CoV-2 infection was reasonably straightforward. And, once naturally occurring (in people) SARS-CoV-2 variants that also infect laboratory mice emerged – the initial strains only infected hamsters, mustelids (ferrets and mink) and monkeys – vaccine protection studies in animals became much more feasible.

Early on, the CSIRO ultra-high security ACDP (Australian Centre for Disease Preparedness) laboratory at Geelong was – for Australia – uniquely equal to the task, with ferrets being used for the preclinical evaluation of the AstraZeneca vaccine. Once the mouse model was available, we were able to test some of our own vaccine candidates in an established BSL3 (Bio Safety Level 3) facility at the Walter and Eliza Hall Institute. And, working with Agriculture Victoria, we now have access to a further substantial ‘small animal’ BSL3 operation.

Why am I making this point? The present high technology effort based in sophisticated science, vaccine R&D, production and roll-out required substantial, long-term investment of both dollars and time. As with vaccine production, we are vulnerable and ‘out of the loop’ if such human and physical resources are not ‘in-country’. Any work with dangerous pathogens has to be done in high security facilities that are appropriately credentialed and staffed. Central to all this is the necessity to support a committed, smart, trained workforce at every level, both to do the work and to enable the essential evaluation processes. This national defence strategy based in innovation and highly skilled people must be fed by a reliably ‘flowing stream’, not a tap that is turned on and off! That’s true for all science. It takes time, dollars and hard work to build capacity. That can be destroyed overnight with the withdrawal of funding.  

Returning to the subject of human trials, we’ve discussed what happens (#53-#58) as a vaccine candidate moves from pre-clinical (animal), through Phase I and Phase II human trials to the penultimate analysis, the Phase III trials that involve tens of thousands of people. The ultimate test is, of course, when the vaccine later goes into millions of people after, in this pandemic situation, Emergency Use Approval (EUA) has been granted. Our regulatory agency the TGA (Therapeutic Goods Administration) does not have an EUA category, though working largely from information provided also to the US FDA (Food and Drug Administration) and the EMA (European Medicines Agency), their deliberative process can move fast to give rapid approvals.

In general, Australia doesn’t have the infrastructure or population size to conduct Phase III vaccine trials. And, of course, any trial of a vaccine to prevent, or ameliorate, SARS-CoV-2 infection has to be done in places where the virus is circulating. What does such a double blind, randomized Phase III trial look like? As an example, the following is abstracted from the FDA Briefing Document submitted (by the manufacturers on 20/11/2020) for the Pfizer BioNTech (PB) vaccine. This summarised the situation for more than 40,000 individuals from the US and other sites of active infection across the planet – assigned in equal numbers to the vaccine and placebo (saline) groups – who had no evidence of prior SARS-CoV-2 infection and were given two identical injections three weeks apart.

After reading and signing the informed consent form, participants were aware that they were required to report any side effects and, of course, any indication that they were infected with COVID-19. They were also aware that the diagnosis would be confirmed by nasal swab and PCR as a definitive proof of SARS-CoV-2 involvement.

Typical of the initial round of Phase III trials for the different vaccine candidates, the basic endpoint was to determine the extent of protection from mild to severe clinical disease over an interval of seven days to two months after the second injection. Though desirable, stopping virus replication in the nose and limiting transmission was never a requirement.  Initially, there were two ethnically diverse cohorts of people aged 18-55 and 65 through 85. Later, the analysis was extended to test for safety and efficacy in the young, with no red flags being raised.

Built into this initial trial was a series of ‘primary efficacy endpoints’ where, once 62, then 92, then 120 cases were confirmed, the independent Data Safety Monitoring Board (DSMB) could ‘break-in’ and see what was happening. At the time of this report, there had been eight cases of COVID-19 in the vaccine group compared with 162 in the placebo controls, a 95% vaccine efficacy. Many reported a transient ‘reactogenic response’ at the injection site. For those who are reasonably aware, this must have been a welcome experience as such symptoms (headache, muscle pains, fatigue, joint pains, fever) were a clear indication that they had indeed received the vaccine and not saline!

Similar FDA submissions are available for the other mRNA vaccine (Moderna) that is currently in use, and for the Johnson and Johnson adenovirus-vectored (human Ad-5) vaccine. Both proved to be highly efficacious and generally safe. They have, under EUA licensing, now been given to much larger numbers of people. Next week we’ll look at the ultimate trial, vaccine roll-out to the broader community.

Setting it Straight by Laureate Professor Peter Doherty Archive