COVID-19, vaccines and pandemic preparedness: lessons learnt

With Australia officially in its eighth wave of COVID-19 at the time of writing, the time is ripe to look back at the challenges faced and lessons learnt from vaccine development during the early days of the pandemic. The Peter Doherty Institute for Infection and Immunity recently covered this very topic in a discussion with three pre-eminent vaccinologists.

Professor Sarah Gilbert was made a Dame Commander of the British Empire in 2021, in recognition of her work initiating and leading the production and development of the Oxford–AstraZeneca vaccine (trade name Vaxzevria). The first Vaxzevria vaccine was administered less than a year after the pandemic was officially declared, on 4 January 2021 — so how did Gilbert’s team at the University of Oxford manage to develop it so rapidly?

“With outbreak pathogens, we’d been following the usual academic funding model of doing a little bit of work and then publishing results and then trying to get money for the next stage,” Gilbert said. “It was very, very slow. So in 2019 I’d started thinking how would we do all this if we needed to do it quickly; how would we move from the idea through to actually having a vaccine in clinical trials in a really short space of time?

“I wasn’t successful in getting that project funded, but at least it had meant that we’d done a lot of thinking about what would we need to do to respond fast if there was an outbreak of an unknown virus, and that’s then what happened at the beginning of 2020.

“We’d done 12 clinical trials with ChAdOx1 [adenoviral] vector vaccines prior to April 2020 when we started the COVID vaccine trials; so we had all the teams in place, we had the expertise, we had the experience of working with the regulatory and ethical authorities, we’d done all of this before in terms of at least getting to a phase 1 trial.

“It was a question of doing what the team knew how to do but working out the fastest way we could do it, what had to be done before the next thing could be done, looking many steps ahead, and just getting everything off the ground as quickly as possible.”

The big challenge, Gilbert said, was actually not to do with speed but funding — she said she had “a little bit of research funding” available to kickstart the process in the lab, but she was unsure how she would be able to afford to manufacture the vaccine for clinical trials. Luckily, this issue was soon resolved.

“We got to the point, later on in April, where the UK Vaccines Taskforce was formed, and that was set up to assess all the different technologies that were being used to create vaccines and to test them, and to provide whatever funding was necessary for multiple different technologies owned by different people, with the aim of getting at least one of them through to licensure in the shortest possible time,” she said.

Following that first clinical trial, AstraZeneca agreed to take on the manufacture of the vaccine for full clinical development and then for commercial supply. Gilbert explained, “What they did was set up a fantastic manufacturing network, they took our vaccine technology, they understood how to make it, they then transferred it to 25 different manufacturing sites worldwide — one of them in Australia, CSL — and got all of these manufacturing sites up and running and making essentially the same product, so that the regulators would recognise it as the same product.

“They also ran some clinical trials themselves … and they really were a great partner to work with in this crisis situation where we had to get things moving really quickly. They not only used their own expertise, but they allowed us to use our expertise, which is really important in a partnership.”

Meanwhile, here in Australia, Professor Paul Young’s team at The University of Queensland (UQ) were developing their own vaccine based on so-called ‘molecular clamp’ technology, which works by ‘locking’ viral proteins involved with infection and cell entry into a shape that allows for an optimal immune response. Young explained that the team had already been working on the technology for about eight years, but in 2019 they received a grant from the Coalition for Epidemic Preparedness Innovations (CEPI) to develop the platform, and spent a year targeting MERS before CEPI asked them to pivot to COVID-19.

“We’d had significant funding to do it, and that meant we were also able to reach out and support a wider team, and that included people at the Doherty and other academic organisations, and also into some NGOs, and ultimately CSL agreed to partner with us early in 2020,” Young said.

“That was probably the biggest component of 2020 that I took out of the experience, and that was the power of partnerships. That broader national perspective — everybody keen to be working with each other with a single directive was really empowering.”

Clinical testing of UQ’s vaccine candidate was underway by July 2020, which provided positive safety and immunogenicity data. But disaster struck when the scientists discovered that a constituent of the vaccine candidate resulted in diagnostic interference with some HIV tests, leading to false positive HIV results in study volunteers.

The team revealed in December 2020 that they would not progress the COVID-19 vaccine candidate into phase 2/3 clinical trials, with Young saying at the time that re-engineering the vaccine would set development back by around 12 months. CEPI did however support the team to resolve the diagnostic interference issue, and announced in November 2022 that it would help fund phase 1 testing for potential use in the global response to future disease outbreaks.

“It was a big call to say we’re just going to pick ourselves off the floor and re-engineer and move forward, but that’s exactly what we did,” Young said. “I think we took a week off after [working] 24/7 for a full year… and came back and redesigned, and we were back fairly quickly.

“The structural motif that we use that underlies the platform is seen across a wide array of different proteins, and we were able to choose one from many that works really well. And we were able to take that COVID vaccine back into clinical trial just earlier this year, and that was with CEPI-funded support.”

That trial compared the second-generation clamp (Clamp2) vaccine head-to-head with the TGA-approved Novavax vaccine, finding that the two produced highly comparable results; indeed, while there have been no new COVID infections recorded among the Clamp2 volunteers, there have been three such cases detected among the Novavax recipients. UQ’s commercialisation company, UniQuest, has since licensed the molecular clamp technology to startup company Vicebio, which is looking to progress its use against respiratory pathogens such as respiratory syncytial virus, human metapneumovirus and parainfluenza viruses.

Young said his team has been able to sort out a number of the issues that they faced during 2020, such as with downstream processing and manufacturing, but he has also become aware of significant gaps in the translational development pipeline here in Australia — one of the biggest being the ability to get a product into phase 1 clinical trials in the first place.

“It’s an extraordinarily complex process; you need a lot of expertise around the regulatory environment, the GMP manufacturing of products and so on, but you also need to be able to make that product in the early stages, and that’s a very expensive prospect, and often too big a hurdle to cross,” he said. “So I think what we could be doing in Australia is really focusing to some degree on developing that early-phase, small-scale manufacture that can go into phase 1 clinical trials.”

Young is not the only one who’s been trialling a new COVID vaccine, with Professor Terry Nolan last year leading a phase 1 trial of two different vaccines — one made by the Doherty Institute and one by the Monash Institute of Pharmaceutical Sciences (MIPS).

“In fact we started early in 2020 in preparing one of those two vaccines … a recombinant protein vaccine based on not the whole of the spike protein but on the tip of the spike, which is called the receptor binding domain of the spike protein,” Nolan said.

“At that time we didn’t know whether any vaccine was going to work … [and] that pipeline was being filled with potential candidates, and some proceeded very, very rapidly, including the AstraZeneca vaccine.

“The mRNA candidate, which was the second of the two vaccines, from our Monash colleagues, was also similarly targeted at just the tip of the spike protein, and we had planned from the very beginning to actually have a head-to-head comparison of these two quite different candidates. Again, at the time this all started no one knew that an mRNA vaccine was actually going to work for sure, and certainly whether it would be better or different to a more conventional approach … So that was the set-up for doing this, and we actually started enrolling last year and finished the follow-up of those enrolled subjects for our phase 1 study in April of this year.”

The phase 1 study of 76 subjects confirmed that the two vaccines were safe, with no evidence of any issues in terms of reaction to the vaccines. Both candidates were also found to work very well against the target receptor binding domain of the variant that was studied, as well as a high level of cross-protection against Omicron and subvariants of Omicron that have subsequently evolved.

“To start with a candidate early in 2020 and get it to phase 1 now completed itself is a remarkable feat — nothing of course in comparison to what Sarah was able to achieve in Oxford,” Nolan said. He said his team is now seeking the support of a major manufacturer to help take the vaccines into phase 2/3 studies, and is currently floating the idea of the recombinant protein candidate going into a combination vaccine that would protect against multiple respiratory viruses.

So with all they have learnt from COVID-19, how do the scientists think we can prepare for the next pandemic? Young noted that many scientists are focusing on respiratory pathogens, since they tend to spread out in a pandemic environment, and that many countries are looking to develop a local manufacturing capacity.

“We’re getting more and broader engagement by industry in focus on potential pandemic-type agents, and the development of both vaccines and therapeutics to combat those — as a toolkit or even as a stockpile for future potential emergent — but also locally developing in each country the infrastructure that will be able to move swiftly in developing some of those,” he said.

Nolan said that influenza remains one of the most likely pandemics to arise in the future, with the last such flu pandemic occurring back in 2009, and that groups such as Gilbert’s are now trying to develop a type of vaccine that could be adapted very quickly to an unexpected virus that might come from a group of similar or related viruses.

“So rather than having to start from scratch, [to] very quickly adapt as Sarah did with her coronavirus, because they were already studying a different type of coronavirus; this MERS one that Paul also had mentioned, that was readily adaptable to the platform and also it was the same family of viruses,” he said. “So that so-called pandemic preparedness, and having those sort of platforms available, is really the most important insurance that we can do in the research sector to be prepared for whatever might unexpectedly turn up in the future.”

“The more that we can do before a new pandemic starts, the better placed we are,” Gilbert agreed. “So we shouldn’t just be thinking about getting ready to move quickly from a standing start. We should be thinking about how much of the work can be done in advance of a new outbreak starting, or a new pandemic starting, because then we actually have a much better chance of achieving it. And there’s many, many different factors to that.

“It’s not just about the vaccines — it’s about diagnostics, about therapeutics, it’s about the non-pharmaceutical interventions, and it’s about the social science studies of how people respond to these interventions, because I think people have maybe changed their views since the pandemic as to what they will be prepared to do another time.

“We’ve learnt a lot in the last pandemic, but unfortunately this has probably moved out of the public eye, but we need to keep it there, because there’s a lot more that we need to do to keep countries protected for the future.”

Image credit: iStock.com/Bertrand Blay