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By Roger Highfield on

Coronavirus: The Moth Vaccine

Roger Highfield, Science Director, discusses two new COVID-19 vaccines under development, one of which is manufactured by cells from the fall armyworm moth, with Dr Ian Gray, Medical Director of Sanofi UK and Ireland.

A technology that is used to manufacture a seasonal influenza vaccine is being adapted to create another kind of COVID-19 vaccine, one based on virus protein.

All vaccines work the same basic way, using some of the SARS-CoV-2 virus, or a harmless version of the virus, to train the body’s protective immune system to detect and fight the real thing.

There are many ways to spur immunity against COVID-19: inject messenger RNA, mRNA, genetic code which persuades cells in the body to make the spike protein of the virus, or inject a weakened cold virus to carry the code for the spike protein into the body, where it is turned into spike protein.

An alternative approach is to inject the virus spike protein itself. The protein can be manufactured in insect cells, using ‘Baculovirus Expression System Technology’, BEST, then purified and used in a vaccine with a booster, an ingredient called an adjuvant.

Since 2013, the French pharmaceutical company Sanofi has manufactured an influenza vaccine this way using insect cells. Trials are now underway of a COVID-19 vaccine based on BEST.

I talked to Dr Ian Gray, Medical Director of Sanofi UK and Ireland. His edited responses are in italics.


We have two vaccines in development. One is based on messenger RNA, which I will discuss later, and one is based on our Baculovirus Expression System Technology (BEST) which uses a baculovirus, which is a virus that infects insect cell lines, in our case one called SF9  (Spodoptera frugiperda, which is the fall armyworm moth).

The idea is that we take the DNA of the spike protein of the SARS CoV-2 virus and insert that into the DNA of the baculovirus. The baculovirus transports this DNA instruction into the cell of the insect cell line, which begins to produce the spike protein (this is also called the antigen, the term used for any substance that provokes the immune system).

In this way, we grow the antigen in the insect cells and then extract and purify for formulation and packaging of the spike protein which, because of the way it is manufactured, is called a recombinant protein.

We use the same insect cell lines as we do for our seasonal influenza vaccine and have worked on this technology with the support of the US Biomedical Advanced Research and Development Authority, BARDA, to try and utilise it for a pandemic influenza vaccine. Now we are working on a pandemic COVID-19 vaccine using the same technology with the exception of the actual final antigen that’s used in the vaccine.

Generating the spike protein in insect cells and purifying the protein is step one. We are in partnership with the company GSK and combine the spike protein with a GSK adjuvant that they’ve used in previous vaccines. They call it the AS03 adjuvant.


AS03 is based on an oil called squalene, which is made in the body, and a type of vitamin E (α-tocopherol), in water.

An adjuvant is an ingredient used in some vaccines that helps create a stronger immune response in people receiving the vaccine. Adjuvants help the body to produce an immune response strong enough to protect the person from the disease he or she is being vaccinated against.


Yes.  There is a genetic identical match, from the actual source virus to the final antigen which is in the vaccine.


It is just SARS-CoV-2 spike protein antigen and adjuvant. This platform will allow us to develop a vaccine that can be stored and administered at a temperature that does not require the same extreme storage conditions as other vaccines based on messenger RNA.

So, we’re looking at between 2 to 8 degrees of storage, which helps meet some of the World Health Organisation’s reference criteria around temperature stability, so it is easier to manage, transport and store.

An Australian vaccine, developed by the University of Queensland and the biotech company CSL, had to be abandoned because it stabilized the virus spike protein with a molecular ‘clamp’ consisting of two fragments of a protein found in H.I.V., the Aids virus. The H.I.V. protein posed no risk, but generated antibodies recognized by H.I.V. tests at higher levels than the scientists had expected.


In December 2020, our Phase 1/2 study results showed an immune response comparable to patients who had recovered from COVID-19 in adults aged 18 to 49 years, but a lower immune response in older adults, likely due to an insufficient concentration of the antigen.

However, instead of stopping the actual development, we looked at the root cause and preclinical data on review, and then restarted a new phase two trial last month with a slightly higher antigen concentration that we expect will give us the results we need in older adults to bring it into phase three.


Variations in the SARS-CoV-2  are something that every vaccine manufacturer is taking stock of (many mutant viruses have evolved over the course of the pandemic). We like other manufactures are processing and reviewing the changing variations in circulation to try and mitigate any impact it may have as we develop our vaccines.

At present, we are still assessing our current recombinant spike protein approach to assess how it deals with the different variants as we see today and predict in the future, though as trials continue and more information becomes available we will adjust as needed.  

Of course, there are other proteins on the virus that could be of interest in future (some proteins make up the virus itself, such as the spike, while others help the virus to reproduce, such as NSP7, NSP8 and NSP12, where NSP refers to ‘non-structural protein’).

This approach of trying to develop a vaccine that incorporates variations in the circulating virus is not uncommon in that it is something we do each year with the seasonal influenza vaccine.  Every February, the World Health Organisation, WHO, releases to all manufacturers what they predict as being the dominant influenza strains – a lot of strains are in circulation at one time. The WHO assessment is based on their predictions and knowledge of the circulating strains in the Southern Hemisphere, so manufacturers take those virus variants as the basis of their next flu vaccines.

The same approach could in essence be used for the COVID-19 vaccine. However, it might take a few more years to understand patterns in outbreaks and seasonality, that is, the way COVID-19 cases rise in the winter, but it’s still too early to say because so many are living in lockdown. Once measures are relaxed, we will be able to see the full impact of the vaccine, how long protection lasts beyond six months and so on. It is still very unknown territory, but we’ll learn more as the years progress.


If data from the new Phase 2 trial are positive, a global Phase 3 study is planned for the second quarter of 2021. Positive results from the Phase 3 study would lead to regulatory submissions in the second half of 2021, with the vaccine expected to be available in the final quarter of 2021, if approved.  

Our recombinant protein-based COVID-19 vaccine candidate is using a licensed technology that has been approved in the US, by the Food and Drug Administration, and in Europe by the European Medicines Agency and the UK by the Medicine and Healthcare products Regulatory Agency, MHRA, for the manufacture of our seasonal influenza vaccine.

Our insect cell-based Baculovirus Expression System Technology (BEST) has been validated as a platform for the manufacture of our seasonal influenza vaccine since 2017.

When it comes to the UK, engagement with the MHRA as a sovereign regulator is very important to ensure that the vaccines we do develop answer questions about quality, safety and efficacy. So, conversations with the MHRA and other UK stakeholders on clinical trial design and our vaccine development progress is crucial.

Sanofi, being a world leader in vaccine development and manufacturing, means that we have the infrastructure and expertise in house to produce and deliver to the scale that is needed. We have manufacturing and logistics sites throughout many countries worldwide that can be used to focus on COVID-19 vaccine production.

Having a fantastic vaccine technology and being able to make a vaccine – even with 100% efficacy – comes to nothing if you cannot scale up and you can’t manufacture in a way that is able to vaccinate the world. Sanofi, with its manufacturing infrastructure across the globe, could go on to distribute and potentially vaccinate countries worldwide.


At Sanofi, not only are we are pushing through with our two COVID-19 vaccine candidates we also wanted to ensure that while we are progressing those that we try to find other ways to help in the interim.  

To this end, we are working with  Janssen/Johnson and Johnson and Pfizer so that they can use our facilities for the manufacture of their COVID-19 vaccines. Once authorized, we will provide Johnson & Johnson access to our established infrastructure and expertise at the vaccine manufacturing plant in Marcy l’Etoile, France, to formulate and fill vials of Janssen’s COVID-19 vaccine candidate in 2021, at a rate of approximately 12 million doses per month.

When it comes to Pfizer-BioNTech we will support the manufacturing and supply of more than 125 million doses of their COVID-19 vaccine. Once again, we take the bulk vaccine from them and then we do the formulation and fill so they are able to have the doses they need to meet the demand for their vaccine.


On average, it typically takes between 12-36 months to manufacture a vaccine. To provide an example when it comes to a hexavalent – six antigens combined into one vaccine, it can up to three years to manufacture, so if you put in your order today you can’t really get your delivery for years – the more antigens you add, the longer it takes due to added complexity.

Vaccines are complex biological products with lengthy manufacturing and control processes. Quality controls are applied all along the manufacturing process and represent up to 70% of the manufacturing time.

Quality assurance ensures that vaccines are produced following the highest standards. All components, manufacturing steps, controls tests including reagents and standards, distribution steps comply with good practices such as Good Manufacturing Practices (GMPs), Good Laboratories Practices (GLPs) and Good Distribution Practices (GDPs).


That’s something that many groups are also working towards for COVID-19 and influenza. We’ve identified the spike protein as the target for now, but that isn’t to say that when we get more information, and we have more time, and we can start looking at other protein structures in the virus that are less prone to mutate and change and that are important for stimulating antibodies that the body uses to defend against a broad range of variants.


We are using similar technology platforms to the other mRNA vaccines developed by other manufactures like Moderna and Pfizer/BioNTech. This technology delivers the mRNA packaged in lipid nanoparticles (LPN) – fatty droplets – to encase the RNA and protect it so it can get inside human cells. Once inside the cell’s own machinery is used to translate the mRNA into the virus spike protein.

This is at an earlier stage than our recombinant vaccine approach. However, on March 12th we announced that we have moved into phase 1/2 of our clinical trials with the intention of having us moving into phase three and hopefully approval for the end of the year. If the wind is blowing the right way, we could end up having our vaccine candidates – the coronavirus recombinant vaccine and the mRNA vaccine – approved by the end of the year.


We are not involved in the challenge trials yet, where volunteers are deliberately infected to see in detail how well the vaccine works.  


That’s a very interesting question because if you give someone vaccine A and they show an immune response, will the response be improved if the booster comes from a different platform, vaccine B?

That is something that is a real interest to me and perhaps there will be some value in the fact that you are basically boosting the individual with another vaccine type to give them – probably – broader protection. But I must stress we don’t know this yet for sure and needs more analysis and review.


I don’t see it as a race for a vaccine but a race to get ahead of the virus to try and end this pandemic, I keep having to pinch myself.

This time last year I was thinking that to develop a COVID-19 vaccine in a year is a pipe dream. The fact we have several is a testament to science, a testament to everything that a scientist believes, and shows how science works in a transparent way. Everyone and their dog now understand what a vaccine is, about viruses and the importance of protecting yourself.

Like many others, I get alerts from the WHO and other stakeholders regarding new potential vaccine candidates under development. As of yesterday, there were 250 candidate vaccines, 180 in preclinical development and then about 76 in clinical trials, using lots of different platforms. It is amazing to see the activity that’s going on. Not all these vaccines will make it, but the information and insights we will gather will help us develop vaccines in the future, and not just for COVID-19.

But one note of caution. We can’t be complacent because of the huge roll out in the UK. We have to look at how other countries are doing it too because if they lag behind, it means we can’t travel and there will be an economic impact. When you look at countries like France, for example, vaccination has been off to a very slow start. If we do not work as a global community to help address ways to reduce the impact of the pandemic and speed up the vaccination roll out we may need to stay as an island for a little bit longer.   


The latest picture of how far the pandemic has spread can be seen on the Johns Hopkins Coronavirus Resource Center or Robert Koch-Institute.

You can check the number of UK COVID-19 lab-confirmed cases and deaths along with figures from the Office of National Statistics.

There is more information in my earlier blog posts (including in German by focusTerra, ETH Zürich, with additional information on Switzerland), from the UK Research and Innovation, UKRI, the EUUS Centers for Disease ControlWHO, on this COVID-19 portal and Our World in Data.