How to run a vaccine trial in Australia

With its low rate of COVID-19 vaccinations, Australia is in the rare position of being able to continue vaccine trials on unvaccinated people.

This is especially necessary because even vaccines with high efficacy, such as Pfizer and AstraZeneca, have no guarantee of remaining effective as the virus mutates.

“There’s a desperate need for as many vaccines as possible,” says Chris Rook, fellow of the Royal College of General Practitioners. “And it definitely is a race, contrary to some of the some of the political comments we’ve had.

“We’ve been really lucky so far, in that all the vaccines that have been made have been very effective. And that’s actually quite remarkable.”

The clinical trial platform Evrima will run one such COVID-19 vaccine trial. As principal investigator, Rook will be conducting a phase III clinical trial of a protein vaccine. But even though vaccine trials are necessary, it’s still a long process from conception to approval. So how do you run a vaccine trial in Australia?

What are the stages of a vaccine trial?

Every clinical trial must go through the same steps to assess safety and efficacy. The trial will not continue if it looks like the drug or vaccine is unsafe at any point.

Preclinical

First, researchers identify a particular antigen during preclinical experiments. For example, the vaccine might contain a molecule, such as a protein or mRNA sequence, that has the same, or similar, shape as the virus. It must look enough like the target virus that the body will learn to recognise that shape again in the future, if the person ever becomes infected.

This is based on many different fields of study, such as genomics, proteomics and immunology. Animal studies provide the first information about the safety of the vaccine. If the animals show severe side effects, the trial will not continue to humans.

Phase I

After this, researchers will recruit a small cohort to test the vaccine. Each participant will recieve a very small dose, and researchers document any side effects. With such a small cohort, the triallists will receive constant monitoring to assess all the health outcomes and they may stay in a medical facility for a few days so they can receive help around the clock.

“At that stage, you’re looking at dose levels and safety,” says Rook. “That’s your main priority.”

People in this trial divide into two groups. Some people receive a placebo vaccine and others receive the real vaccine. This establishes whether symptoms are exclusively linked to the vaccine.

The trials are split into further groups to test vaccine dosage. The first group will start with a very low dose, and if the trial is successful the next group will receive a higher dosage. These incremental stages help to alleviate the severity of symptoms if a vaccine does show bad side effects.

Phase II

Phase II involves hundreds of people, expanding on safety and immune response with a larger dataset.

This stage is very similar to phase I. Like the previous phase, there is still a placebo group, and dosage gradually increases as researchers establish safety.

This part of the trial collects more data. This is because a large sample of people is necessary to know how the vaccine affects different people. For example, does the vaccine affect men and women, or age groups, differently?

The triallists may also stay in a facility during this portion of a trial, and they will often have follow-up visits to see if there are any long-term side effects.

Clinical vaccine trials primarily test safety and usefulness in the early stages, so development can stop if there are any major safety concerns. For example, one Australian trial was stopped last year because it seemed to interfere with HIV diagnosis.

During phase II, the sample size is too small to really test vaccine efficacy.

Phase III

The final stage of human trials has the largest group of people, to make the experiment statistically robust.

“Phase III, which is basically the end, involves thousands of people,” says Rook. “Again, safety is always an important part, but you’re now also looking at efficacy – does it actually work?

“The problem with this stage is that the virus has to actually be circulating (to test whether the vaccine works). That’s why it can take quite a long time.”

In these trials, thousands of participants can receive the full recommended doses. Some people will also receive a placebo. They will then go on with their daily lives, and researchers will follow up with them over the length of the trial to see whether they get sick.

---

Read more: How well do COVID vaccines work in the real world?

---

The reason this can only work when the virus is already circulating is because triallists need to actually be exposed to the virus to test whether the body can fight it off.

“In an ideal world, you’d make a vaccine, give the vaccine and then you’d actually infect people with the virus,” explains Rook. “You can’t do that ethically, of course. So, the only way you can know for sure that a vaccine is working is when you actually get it out there.”

Approval

Finally, when a vaccine has completed all stages of trials, the Therapeutic Goods Administration (TGA) reviews it for approval. It will assess all the safety, quality and effectiveness data from the trial to determine whether it is acceptable for use in Australia.

The TGA reviews every vaccine, even after another country approves it, because the Australian standard may be different to international standards. This takes time and is the reason why Moderna was approved for use in other countries before Australia.

Sometimes a vaccine completes all three phases but doesn’t pass TGA approval, and so can’t be used.

The TGA also continuously monitors vaccine side effects after approval, to make sure they remain safe.

Why are these trials happening now?

There are several ongoing COVID-19 vaccine trials in Australia right now, which range from phase I to phase III, because the virus is always evolving and our vaccines need to evolve, too.

Australia can conduct preclinical, phase I and phase II trials at any time. However, you an only conduct a phase III trial if the virus is circulating within the community, and Australia was relatively COVID-free for much of the pandemic. Now, with the recent outbreaks, trials can begin.

One of the major benefits of trialing a vaccine in Australia is that relatively few people have received a vaccine. Because of this, many more people are eligible to take part. Currently, Australia ranks 35th out of 38 among OECD countries, with around 27% of people fully vaccinated. For this reason, some other countries with a more highly vaccinated population don’t have enough unvaccinated people to trial.

“France and Spain, for instance, were due to be doing some of what we’re doing and they’ve had to pull out because they don’t have enough people who haven’t had COVID or the vaccine,” says Rook.

“That’s one of the reasons why Australia was recruited.

“And for somewhere like Adelaide, where we are, we’ve been very lucky, but I’m sure it’s going to change soon.  So, it’s actually been incredibly easy to recruit people.”

Why are the vaccine trials so fast?

Vaccine trials usually take a long time, but coronavirus research has been prioritised for approval. However, this doesn’t mean they get fewer approvals. Instead, their studies will go to the top of the list and be examined more quickly.

“There’s been an enormous amount of international collaboration and emergency-use authorisation,” says Rook. “The full registration could take years.

“But despite the shortened timescale, no shortcuts have been taken. It’s all been done properly.

“The only issue that we’ve had is that we have to explain that, really, you should probably strongly consider getting an authorised vaccine, rather than coming to us to have the trial vaccine, even though the evidence we have so far suggests that it’s going to work very well.”

What kind of vaccine will be tested in the trial?

There are five types of vaccine that use different components to stimulate the immune system: inactivated virus, attenuated virus, live virus, mRNA/DNA and protein subunits.

---

Read more: What’s in a COVID vaccine?

---

The vaccine under trial from Evrima doesn’t have a name yet but is a type of protein vaccine. Likewise, this is the same technology that the Novavax vaccine uses.

It will contain a modified spike protein that is specifically based on mutations in the Delta variant in order to make sure it can fight that particular strain.

“There is a small modification to the spike protein that stops it sort of falling apart,” says Rook.

“They initially tried injecting the spike protein on its own into the arm, but the immune response wasn’t good enough. So, it’s now given with an adjuvant.

“That’s something that enhances the immune system. It’s not actually really understood why, but it’s a tried-and-tested adjuvant that’s been used for a long time, most recently in a flu vaccine in Europe and in the US called Flu Block.

“You literally just shake the protein and adjuvant together and it’s injected. It’s working very well.”

Potentially, we may use the vaccine as a booster vaccine in the future. However, right now the trial is testing efficacy on unvaccinated people

Who can participate in the vaccine trial?

Fusion Clinical Research clinics will conduct the trial. Eligible South Australians between 18 to 55 years of age who have not had a COVID jab and have never had COVID-19 can participate. All eligible participants will be paid for their time.

Participants can expect the trial to last up to 55 weeks. This includes: 

• First vaccination at the clinic 
• Second vaccination at the clinic, 21 days later 
• Six follow-up visits at the clinic 
• Regular phone calls

“So far, we’re actually full, but we may take on more people soon because countries like France and Spain may not be able to take their quota,” says Rook.

Interested participants can sign up at http://adelaidecovidstudy.com.