The world is hungry for mRNA COVID vaccines like Pfizer’s. But we’re short of vital components

Archa Fox, The University of Western Australia and Pall Thordarson, UNSWGiven the AstraZeneca COVID-19 vaccine is no longer recommended for under-50s following news of very rare blood clots, Australia is looking to other vaccines to plug the gap.

Pfizer’s mRNA vaccine will become the mainstay of the rollout, with 40 million doses expected to arrive before year’s end.

But Australia isn’t the only country eager to get its hand on this vaccine.

Skyrocketing demand coupled with shortages of vital components is leading to bottlenecks in the supply chain of this and other mRNA vaccines, delaying vaccine supplies.

The Victorian government also announced last week it would provide A$50 million to set up local manufacturing of mRNA vaccines in Australia. It’s feasible supply chain issues could also impact local manufacturing of mRNA vaccines.

So what are the missing supplies for making mRNA vaccines?

Read more:
What is mRNA? The messenger molecule that’s been in every living cell for billions of years is the key ingredient in some COVID-19 vaccines

The shortages slowing mRNA vaccine production

1. mRNA manufacturing and capping

Manufacturing mRNA vaccines is kind of like making a car, with an assembly line and many steps. Each step needs to lead to the next and flow smoothly to make the final product.

COVID mRNA vaccine manufacturing starts with making the “messenger RNA”, the instructions that tell our cells to make the coronavirus’ spike proteins. The mRNA is produced in reactor vessels, where protein enzymes track along a DNA template and copy that DNA sequence into RNA form.

The first shortage is in sterile, single-use plastic bags which sit inside the metal reactor vessels used for making the mRNA, almost like a bin liner. Several suppliers of these plastic liners are ramping up production so it’s anticipated this shortage won’t last too long.

The second main shortage relates to “capping” the mRNA at one end. Capping involves adding a chemical molecule to the mRNA which stops the mRNA breaking down too quickly and helps our cells use the mRNA to make protein. Early on during the worldwide upscaling of mRNA manufacturing, rumours abounded that the enzymes and raw materials to make the mRNA cap were running short, given related enzymes used for COVID tests were also in short supply.

However, while only a few players dominate the field, this doesn’t seem to be a bottleneck now. But it does still remain one of the most costly parts of the mRNA production process.

2. Lipids in nanoparticles

The main bottleneck right now is the supply of some of the lipids making the nanoparticles that protect the mRNA and deliver it into our cells.

One lipid in particular, a so-called “cationic lipid”, wraps around the mRNA and then releases it inside the cell. Several chemical synthesis steps are required to make these cationic lipids, and prior to COVID only a handful of manufacturers worldwide were making these, and only on a fairly small scale.

Upscaling this production of cationic lipids has been even harder than setting up the mRNA production. Currently, four companies — Croda/Avanti, CordenPharma, Evonik and Merck — are the main manufacturers of these lipids.

As an indication of how serious this shortfall in lipids is, in December 2020 former US President Donald Trump invoked the Defense Production Act to assist Pfizer in accessing more lipids.

Why do we have these shortages?

The reasons for these shortages are complex. In most cases, demand has outstripped supply. In some cases, some countries or companies have been stockpiling some of these components. “Operation Warp Speed”, initiated by the Trump administration to speed up COVID vaccine development, used its financial clout throughout 2020 to buy up and secure many vaccine components including vials and lipids. This has put the vaccine manufacturers based in the United States in a good position, including Moderna and several Pfizer sites.

For some materials, the reason for the shortfall is simply that they’re hard to make. The bespoke cationic lipids are chemically synthesised in ten steps that all have to performed under strict quality control. Even if the equipment is ready, setting up such a manufacturing process takes months.

How could these shortages impact future mRNA manufacturing in Australia?

When Victoria’s new mRNA manufacturing facility comes online, hopefully in the next 12-24 months, some of these global shortages may still be plaguing the worldwide supply chains. This shouldn’t stop our efforts on that front as raw material supplies are rapidly increasing.

Australia should also do more manufacturing of small molecule active pharmaceutical ingredients, that is, the biologically active component in each drug, including lipids and other building blocks of mRNA. Australia imports over 90% of its drugs from overseas. Making active pharmaceutical ingredients is important, not just for COVID vaccines but more generally.

Australia nearly ran out of some essential drugs, like ventolin, in the early days of the COVID-19 crisis. This was due to both Australians’ panic buying, as well as COVID-hit Chinese factories slowing down their manufacturing, leading to a lack of access to these ingredients for our most commonly used drugs. The added benefits of locally based manufacturing of active pharmaceutical ingredients is we’d be part of the solution when components are in short supply in future.

Australia also has a very strong research community in mRNA and nanomedicine. There are several world-leading groups working on creating better lipid nanoparticles for the delivery of mRNA and other medical products.

Having access to local manufacturing capability of active pharmaceutical ingredients would therefore transform the ability of Australian researchers to lead the way in developing the next blockbuster medical technology based on mRNA or nanoparticle delivery.

Read more:
3 mRNA vaccines researchers are working on (that aren’t COVID)

The Conversation

Archa Fox, Associate Professor and ARC Future Fellow, The University of Western Australia and Pall Thordarson, Professor, Chemistry, UNSW

This article is republished from The Conversation under a Creative Commons license. Read the original article.

3 mRNA vaccines researchers are working on (that aren’t COVID)


Archa Fox, The University of Western Australia and Damian Purcell, The Peter Doherty Institute for Infection and ImmunityThe world’s first mRNA vaccines — the COVID-19 vaccines from Pfizer/BioNTech and Moderna — have made it in record time from the laboratory, through successful clinical trials, regulatory approval and into people’s arms.

The high efficiency of protection against severe disease, the safety seen in clinical trials and the speed with which the vaccines were designed are set to transform how we develop vaccines in the future.

Once researchers have set up the mRNA manufacturing technology, they can potentially produce mRNA against any target. Manufacturing mRNA vaccines also does not need living cells, making them easier to produce than some other vaccines.

So mRNA vaccines could potentially be used to prevent a range of diseases, not just COVID-19.

Remind me again, what’s mRNA?

Messenger ribonucleic acid (or mRNA for short) is a type of genetic material that tells your body how to make proteins. The two mRNA vaccines for SARS-CoV-2, the coronavirus that causes COVID-19, deliver fragments of this mRNA into your cells.

Once inside, your body uses instructions in the mRNA to make SARS-CoV-2 spike proteins. So when you encounter the virus’ spike proteins again, your body’s immune system will already have a head start in how to handle it.

So after COVID-19, which mRNA vaccines are researchers working on next? Here are three worth knowing about.

1. Flu vaccine

Currently, we need to formulate new versions of the flu vaccine each year to protect us from the strains the World Health Organization (WHO) predicts will be circulating in flu season. This is a constant race to monitor how the virus evolves and how it spreads in real time.

Moderna is already turning its attention to an mRNA vaccine against seasonal influenza. This would target the four seasonal strains of the virus the WHO predicts will be circulating.

But the holy grail is a universal flu vaccine. This would protect against all strains of the virus (not just what the WHO predicts) and so wouldn’t need to be updated each year. The same researchers who pioneered mRNA vaccines are also working on a universal flu vaccine.

The researchers used the vast amounts of data on the influenza genome to find the mRNA code for the most “highly conserved” structures of the virus. This is the mRNA least likely to mutate and lead to structural or functional changes in viral proteins.

They then prepared a mixture of mRNAs to express four different viral proteins. These included one on the stalk-like structure on the outside of the flu virus, two on the surface, and one hidden inside the virus particle.

Studies in mice show this experimental vaccine is remarkably potent against diverse and difficult-to-target strains of influenza. This is a strong contender as a universal flu vaccine.

Read more:
A single vaccine to beat all coronaviruses sounds impossible. But scientists are already working on one

2. Malaria vaccine

Malaria arises through infection with the single-celled parasite Plasmodium falciparum, delivered when mosquitoes bite. There is no vaccine for it.

However, US researchers working with pharmaceutical company GSK have filed a patent for an mRNA vaccine against malaria.

The mRNA in the vaccine codes for a parasite protein called PMIF. By teaching our bodies to target this protein, the aim is to train the immune system to eradicate the parasite.

There have been promising results of the experimental vaccine in mice and early-stage human trials are being planned in the UK.

This malaria mRNA vaccine is an example of a self-amplifying mRNA vaccine. This means very small amounts of mRNA need to be made, packaged and delivered, as the mRNA will make more copies of itself once inside our cells. This is the next generation of mRNA vaccines after the “standard” mRNA vaccines seen so far against COVID-19.

Read more:
COVID-19 isn’t the only infectious disease scientists are trying to find a vaccine for. Here are 3 others

3. Cancer vaccines

We already have vaccines that prevent infection with viruses that cause cancer. For example, hepatitis B vaccine prevents some types of liver cancer and the human papillomavirus (HPV) vaccine prevents cervical cancer.

But the flexibility of mRNA vaccines lets us think more broadly about tackling cancers not caused by viruses.

Some types of tumours have antigens or proteins not found in normal cells. If we could train our immune systems to identify these tumour-associated antigens then our immune cells could kill the cancer.

Cancer vaccines can be targeted to specific combinations of these antigens. BioNTech is developing one such mRNA vaccine that shows promise for people with advanced melanoma. CureVac has developed one for a specific type of lung cancer, with results from early clinical trials.

Then there’s the promise of personalised anti-cancer mRNA vaccines. If we could design an individualised vaccine specific to each patient’s tumour then we could train their immune system to fight their own individual cancer. Several research groups and companies are working on this.

Yes, there are challenges ahead

However, there are several hurdles to overcome before mRNA vaccines against other medical conditions are used more widely.

Current mRNA vaccines need to be kept frozen, limiting their use in developing countries or in remote areas. But Moderna is working on developing an mRNA vaccine that can be kept in a fridge.

Researchers also need to look at how these vaccines are delivered into the body. While injecting into the muscle works for mRNA COVID-19 vaccines, delivery into a vein may be better for cancer vaccines.

Read more:
4 things about mRNA COVID vaccines researchers still want to find out

The vaccines need to be shown to be safe and effective in large-scale human clinical trials, ahead of regulatory approval. However, as regulatory bodies around the world have already approved mRNA COVID-19 vaccines, there are far fewer regulatory hurdles than a year ago.

The high cost of personalised mRNA cancer vaccines may also be an issue.

Finally, not all countries have the facilities to make mRNA vaccines on a large scale, including Australia.

Regardless of these hurdles, mRNA vaccine technology has been described as disruptive and revolutionary. If we can overcome these challenges, we can potentially change how we make vaccines now and into the future.The Conversation

Archa Fox, Associate Professor and ARC Future Fellow, The University of Western Australia and Damian Purcell, Professor of virology and theme leader for viral infectious diseases, The Peter Doherty Institute for Infection and Immunity

This article is republished from The Conversation under a Creative Commons license. Read the original article.