Scientists worldwide are searching for potential COVID-19 vaccines, but they’re far from easy to make, and would normally take years to become available. Professor Colin Pouton unravels the challenges of finding a swift answer.

As COVID-19 restrictions ease, medical scientists across the globe are searching for potential vaccines against the deadly virus. Experts agree that dangerous respiratory illnesses – and, potentially, future pandemics – are likely. Vaccines are complex to make, with most taking 10 to 15 years and three phases of testing to enter the market.

Here, we ask Professor Colin Pouton from Monash University’s Faculty of Pharmacy and Pharmaceutical Sciences about the virus itself, and the challenges of quickly finding a vaccine.

A serious global pandemic of a new virus – while deadly serious – must be fascinating for research pharmacists. What’s captured your attention most about COVID-19?

COVID-19 illustrates how viral infections caused by closely related viruses can have very different characteristics.  The COVID-19 virus (SARS-CoV-2) has a similar structure to the SARS coronavirus, but COVID-19 presents very different problems.  SARS-CoV-2  is much more contagious, but isn’t as life-threatening. SARS was contained because it was easy to identify infected patients, and the risk of catching SARS was low.

Many people experience mild symptoms when they catch COVID-19, so we have very little idea how many people have been exposed to the virus. Until we start testing large numbers of people, irrespective of whether they’ve experienced COVID-19 symptoms, we will not know the scale of the problem we’re facing. Some reports suggest the actual number of infections may be 20 times higher than the published figures. That would be good – we would be further down the path to “herd immunity”.

Human trials have already started on some potential vaccines. Can you talk us through what’s been happening since March? 

There’ll be several different approaches to vaccination in human safety trials by the end of June. The announcements are coming thick and fast.  The consensus is that all approaches are worthy of investigation at this stage. Most programs will probably progress to small efficacy studies if they have sufficient funding.

What’s not clear at present is how large a phase III efficacy study will be required. This is why there are so many conflicting opinions on how long it will take. The desire to find a vaccine quickly will encourage some fast-track approaches with the agreement of regulatory agencies

What’s your faculty doing, specifically, around developing a vaccine?

We think mRNA vaccination is the most promising way to respond quickly to an outbreak such as COVID-19. Over the past few years, we’ve been working on mRNA delivery for both vaccination and therapeutic applications, so it was natural for us to make some candidate COVID-19 vaccines.

There are three or four well-funded international programs making use of mRNA technology, one of which was the first vaccine to enter clinical trials, a US program involving Moderna Inc and NIAID (part of NIH).

These programs are unlikely to publish the details of what they’re doing. So, our immediate interests are to investigate how to optimise the design of the mRNA molecule and the design of the delivery systems.  We’re testing our vaccine candidates at present.  We’d be very interested to take an Australian mRNA vaccine forward into the clinic, but this will depend on funding.

What is mRNA technology? Is it a new class of drug? What’s new about it?

Yes – mRNA is effectively a new class of drug, and as yet there are no products approved for human use.  It’s likely that a COVID-19 vaccine will be the first mRNA product.  Messenger RNA (mRNA) molecules encode for production of proteins.  They’re produced from DNA in the cell nucleus, and are exported into the cell cytoplasm, where they take part in the process called “translation” – that is, the code is used to guide production of a specific protein.

One of the interesting aspects of COVID-19 is that it’s so contagious that it should be much quicker to set up test and control groups and establish efficacy.

When we inject an mRNA vaccine, the mRNA gains access to cells, and is then translated to produce a viral protein, or part of a viral protein. In the case of COVID-19, we’ll deliver an mRNA molecule that encodes for production of the SARS-CoV-2 spike protein, or a fragment of the spike protein.  The hope is that this will allow our immune systems to raise antibodies against the spike protein that will neutralise the virus and prevent infection.

There’s already been reports the virus has mutated. Does using this mRNA technology mean you respond to changes quickly – and swifter than other research teams?

The mutations we’re hearing about are small changes that aren’t causing significant changes to the activity of the virus.  RNA viruses typically mutate regularly, but the COVID-19 virus, as with other coronaviruses, is relatively stable – which is a good thing in relation to developing a vaccine.

Large changes that occur and change the properties of the virus – such as SARS to SARS-CoV-2 – are much rarer events and usually involve substantial change in the viral genome, such as acquisition of a piece of RNA from another virus. When a large change occurs, it usually implies the need for a completely new vaccine and – yes – mRNA technology would be a great way to respond quickly.

We think it’s important that Australia develops capability and capacity in mRNA technology.  This would allow us to respond rapidly to the next viral challenge.  This would be particularly important if it happens to be a local event in our region of the world.

What’s the story with the big American study funded by the pharmaceutical company Moderna?

Moderna is a specialist mRNA company with several vaccine and therapeutic programs in clinical development. Moderna was approached by an NIAID team led by Barney Graham, who’s a well-known virologist and vaccine scientist. Their collaboration led to the first test of a candidate COVID-19 vaccine in a volunteer just 63 days after the virus genome was published in China – extraordinary speed.

The Moderna/NIAID vaccine has recently been awarded substantial funding to develop the vaccine – up to US$483 million – by the US agency BARDA. Moderna is effectively the frontrunner, but there are at least two other big mRNA vaccine programs underway from companies based in Germany, and a fourth program supported by the UK government.

This week Moderna announced that they’ve established, during the phase I safety studies, that their vaccine is capable of inducing an antibody response. However, some vaccine experts have already expressed scepticism at the Moderna results, which they say have not been published in scientific journals, and were released only in part.

What about pre-clinical trials – are they advancing? Are there issues with testing on pre-clinical models?

Pre-clinical challenge testing (against an infection) is difficult, because most animals are not susceptible to infection by SARS-CoV-2. CSIRO has a ferret model that was used for testing SARS vaccines, and it’s carrying out experiments with the challenge model for at least two international vaccine programs.

The alternative pre-clinical approach, which all programs will be using, is to test for the induction of antibodies after vaccinating mice. Then a cell culture model can be used to test whether the antisera are able to neutralise the virus. This strategy has been accepted as enough information to progress into the clinic.

What are the issues around getting large-scale clinical trials going for potential vaccines like this?

One of the interesting aspects of COVID-19 is that it’s so contagious that it should be much quicker to set up test and control groups and establish efficacy. A vaccine efficacy trial requires enough people to catch the infection in the control group – which should not be a limiting step in a population that is experiencing large numbers of infections.

Given the urgency, it may be possible to test the vaccine using specific groups of frontline medical staff, or aged care facilities.  It will be interesting to see how the efficacy studies are designed over the next few months.

Does a pandemic speed up or slow the development of new vaccines for new viruses? Equally, does an easing of restrictions globally speed up or slow down vaccine development?

COVID-19 will probably have a significant effect on the future of vaccine design. Several of the approaches being used to develop COVID-19 vaccines have been widely recognised as potential new ways to vaccinate. If a successful vaccine is developed using mRNA technology, for example, it’s likely that this approach will become a standard technology for future vaccine development.

Were vaccines made for SARS version one, or MERS? How similar are these viruses to COVID-19?

Both SARS and MERS were contained before a vaccine had been developed and approved. These two viruses are closely related to SARS-CoV-2, but COVID-19 is so rapidly spread that a vaccine is likely to be necessary to contain the disease. It’s been estimated that herd immunity requires at least 60 per cent of the population to become infected and raise immunity.  We’re a long way from that – even in those countries that have had many more cases than Australia.

Why are acute respiratory syndromes the ones mutating and finding humans as a good host?

Viruses are mutating constantly. We’re vulnerable to lung infections primarily because transmission by droplet inhalation is so likely.  Think about HIV – that is a very serious infection, but much more difficult to catch.

When do you think a COVID-19 vaccine will be available in Australia?

I think that’s quite uncertain. If one of the Australian vaccines is developed and approved by the TGA, then we’ll be in control of our destiny. If we’re required to wait for a vaccine to be manufactured overseas, there’s no guarantee that there will be a ready supply.  Many other countries will be keen to secure a supply. Also, as yet it’s not clear how much we’ll have to pay for the vaccine.

This article was originally published in Lens by Monash University.