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By Kashmi Ranasinghe Cass Erbs 27 May 2020 6 min read

The Australian Centre for Disease Preparedness (ACDP) in Geelong is a high containment biosecurity facility. Previously called the Australian Animal Health Laboratory, it operates to allow scientific research into the most dangerous infectious agents in the world. ACDP also works at the highest biosecurity level, which is Physical Containment level four. There are very few like it in the world.

This is where we’re testing two vaccine candidates for COVID-19 for their efficacy. The Coalition for Epidemic Preparedness Innovations (CEPI) has selected these candidates in consultation with the World Health Organization (WHO) based on their readiness. It’s part of the global response to the current COVID-19 pandemic.

Professor Trevor Drew, Director of ACDP where the testing is taking place, says these candidates were amongst the first three CEPI-funded vaccines to enter Phase 1 clinical trials.

“These two were quick because these particular types of vaccines didn’t need the SARS-CoV-2 virus. All the scientists needed was its genetic code. They also have two different approaches to how we might vaccinate,” he says.

With the help of Prof Drew, we’ll take you through each vaccine candidate in detail. We’ll also explain how they provide your immune system with the tools needed to fight the virus.

University of Oxford

The first vaccine is from the University of Oxford (Oxford) in the UK.

This vaccine, known as ChAdOx1 nCoV-19, is a replication-deficient simian adenoviral vaccine vector. Despite its complicated name, this vaccine is made from a weakened version of one of the common cold viruses, which is an adenovirus.

“This adenovirus is defective so it can begin an infection in human cells, but it can’t replicate itself to grow the infection in the human body,” Prof Drew says.

Now here’s the cool part. Oxford’s scientists have inserted the SARS-CoV-2 genome into the defective adenovirus genome. The key coronavirus proteins become expressed when the adenovirus starts to replicate. The immune system recognises the virus and develops immunity to the SARS CoV-2 virus. It can now kill SARS-CoV-2 if it ever encounters the real virus.

“Because it goes through the initial stages of replication, vaccines of this type are very stimulating to all parts of the immune system, compared to killed vaccines or those which only contain proteins of SARS-CoV-2,” Prof Drew says.

“As well as antibodies, which most people will have heard of, we have two other types of immunity – primitive innate immunity and what we call T cell immunity. These are very important to our early response to viruses. If we can stimulate these with a vaccine, it will do a better job.”

CEPI and WHO chose Oxford’s vaccine candidate as it can generate this strong immune response from one dose. On top of this, this particular vector is not a replicating virus. That means it cannot infect a vaccinated individual – it starts to replicate but cannot complete the cycle. In addition, adenoviral vectors like Oxford’s vaccine candidate are extremely well studied and used safely. They are extensively used in gene therapy and hundreds of people have already received vaccines of this type in trials for other diseases, such as Ebola and influenza.

INOVIO Pharmaceuticals

The second vaccine candidate is from INOVIO Pharmaceuticals (Inovio) in the US. This vaccine is a DNA vaccine, which is a new technology.

"It is a very different type of vaccine and an entirely new approach," Prof Drew says.

DNA vaccines like Inovio's candidate are made up of reprogrammed DNA plasmids. Plasmids are small circles of double-stranded DNA. Computer sequencing technology reads or reorganises these plasmids into something similar, but different. With Inovio's vaccine candidate, a computer designs how to reorganise the DNA. They're reorganised to produce a specific immune response in the body. Our immune system then kills the virus if it encounters your healthy cells.

"It actually inserts a piece of the genome of the virus but in a way our bodies can recognise. Our body then starts producing the viral proteins, or antigens, encoded by this DNA," Prof Drew says.

"The vaccine actually commands our cells to make some of the viral protein but it's only the protein – not the whole virus. This creates a more effective immune response as your body develops antibodies that bind to the antigen. These antibodies will help to prevent the real virus from infecting our cells and help our immune system to eliminate the infection."

Pre-clinical trials at ACDP

Prof Drew said scientists at the ACDP are evaluating these vaccines to see how they defend against the progression of the infection.

“The studies will allow us to clearly define the level of protection afforded by the vaccine. We’re not just testing their efficacy. Our pre-clinical trials are also trying to figure out the best way to administer the vaccines,” Prof Drew says.

“Researchers at ACDP are determining if an intramuscular injection works best. Otherwise, it may be through less invasive routes, like through the nose. These findings could have a huge impact on future vaccinations. We may ultimately find that a combination of different types of vaccine, given at different times, may be required for best protection,” he says.

Our work is still underway and won’t conclude until late-June. The pre-clinical trials take three months to complete. Once the vaccines have passed their pre-clinical trials in animals, they’ll go through a series of clinical trials in humans. There are three phases of clinical trials.

Phase I: testing for safety

Testing in a small number of humans. This phase is about making sure the vaccine is safe. So it’s usually carried out in people who are at low risk. These are people who are healthy with no underlying health conditions. Once we know it is safe, we can see if it actually works.

Phase II: testing for efficacy

Testing on more humans. Does the vaccine actually work?  For this, we need to test in healthy people who have never met the disease but have a risk of becoming infected.

Phase III: testing for effectiveness

Testing on a larger number of humans to confirm its effectiveness. This will involve more people, diverse in age, with different medical backgrounds and perhaps even some who have already recovered from the disease. This will make sure it is safe for everyone.

When can we find out if the trials are successful?

These phases progressively allow us to determine that the vaccine is safe, if it leads to a strong immune response, and gives the best levels of protection against the virus in everyone. The COVID-19 vaccine process has been streamlined to try to make it available as soon as possible. Various stages of its development have been undertaken at the same time, while still ensuring it is both safe and effective.

Results are likely to be announced by the vaccine developers – Oxford and Inovio. However, they have both released some preliminary pre-clinical results from work being undertaken elsewhere. Oxford has reported that monkeys in Montana given the vaccine did not fall ill, despite heavy subsequent exposure to the virus. Inovio has several animal challenge studies currently ongoing. Inovio’s pre-clinical research data has been accepted for a peer-reviewed publication in Nature Communications. The paper shows a strong antibody and T cell response in several animal models with the INO-4800 vaccination. This means it could translate effectively to a human immune response.

What's next?

Both Oxford and Inovio started their Phase I clinical trials at the same time as our pre-clinical trials. Oxford started Phase 1 trials in healthy young volunteers in the UK in late-April. Inovio announced their Phase 1 clinical trial is looking at interim immune responses and safety, with results expected in late-June.

Researchers warn developing an effective COVID-19 vaccine will be no easy task. There are no guarantees of success. Vaccine development can be a long and uncertain process.

“No single institution or organisation can do this by themselves. We will only succeed through collaborative science,” Prof Drew says.

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