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The UK is the first country in the world to give temporary authorisation to the Pfizer/BioNTech coronavirus vaccine for emergency pandemic use. This is a new kind of vaccine, based on RNA, and the first approved for use in humans. Roger Highfield, Science Director, talks to Dr Berkeley Phillips, UK Medical Director of Pfizer.

The urgent need for mass vaccination against COVID-19 has been underlined by the emergence of a new strain of SARS-CoV-2, which goes by the name B.1.1.7 and appears to be faster at spreading between people. Expert reaction has ranged from calls for more research to accusations that the strain is a ‘political football.’

The virus was detected by the UK’s huge effort to read SARS-CoV-2 genetic codes and, of the new strain’s 17 mutations, eight are in the spike protein that the virus uses to invade human cells. The Pfizer/BioNTech vaccine depends on making the spike protein in the body.

The edited responses of Dr Berkeley Phillips, UK Medical Director of Pfizer, are shown in italics.

WHEN DID COVID-19 VACCINATION START?

On 8 December – dubbed ‘V Day’ – Margaret Keenan, then 90, became the first person in the world to receive the Pfizer-BioNTech COVID-19 vaccine outside of a trial following its emergency authorisation after trials on more than 40,000 people in the US, Brazil, Argentina, South Africa, Germany and Turkey.

It has been such an emotional rollercoaster ever since March when the pandemic broke in the UK and it has been so much work to try and develop the vaccine in time, but we did it!

The moment we saw Margaret get vaccinated was incredibly emotional. I had tears in my eyes, just like Health Secretary Matt Hancock, and the Deputy Chief Medical Officer for England, Jonathan Van-Tam.

The empty vial and syringe from Margaret’s historic immunisation is now part of the Science Museum Group Collection, a highlight of our COVID-19 Collecting project.

The first vial of COVID vaccine used in a mass immunisation programme
The first vial of COVID vaccine used in a mass immunisation programme.

HOW MUCH HAS PFIZER INVESTED?

The financial investment has been huge, and it could have so easily failed but we didn’t have any choice because of the pandemic.

Pfizer took the decision that we weren’t going to take any outside funding for the programme. So, we self-funded the entire Phase 2 and Phase 3 clinical development programme and scale-up of manufacturing. 

Today we have invested about $2.5 billion and that was essentially all at risk because we had no idea whether the vaccine would be successful but, because we were in a crisis situation, we couldn’t wait. 

Normally what would happen is we would do the research, see the outcome and only then would we invest more into full clinical development and start to scale up manufacturing. That’s why normally the end-to-end vaccine development process takes several years.

It is important to emphasise however that at no point has the rigorous testing of quality, efficacy and safety been compromised and this has been independently assessed by the UK Medicines Regulator, the Medicines and Healthcare products Regulatory Agency (MHRA).

HOW DID THE UK BECOME THE FIRST TO USE AN RNA VACCINE?

In every aspect of dealing with the COVID-19 pandemic, the MHRA has been rigorous but flexible. For our vaccine development programme, the MHRA offered a “rolling review” in which we were able to submit data throughout the programme rather than waiting until the end. 

For example, in the summer, we had early safety data and early data on the immune response to the vaccine, such as the effect on antibodies and T cells. Rather than waiting we sent that to the MHRA.  Then in the autumn when the Phase 3 trial provided key efficacy and safety information we sent that to the MHRA. 

In this way the MHRA were able to build a picture of the profile of our vaccine over a number of months and this enabled faster decision making in the final stages of the process.

WHO CREATED THE VACCINE?

The vaccine RNA technology was developed by the German biotech firm BioNTech, founded by Turkish-born Ugur Sahin, with his wife and fellow board member Özlem Türeci, along with his former teacher, Prof Christoph Huber, an Austrian cancer expert. BioNTech, which had already been working with Pfizer on a flu vaccine, agreed in March to co-develop and distribute a potential vaccine for Covid-19.

Pfizer had been working with BioNTech for a few years prior to the COVID pandemic on RNA vaccines, notably an RNA vaccine for flu. And so, when the COVID pandemic broke, although the world of RNA vaccines was new for a lot of people, for us and for BioNTech we already had the platform, if you like the nuts and bolts of what was needed for the foundation of developing the COVID vaccine. 

We weren’t starting from scratch. That of course saved a huge amount of time. The Pfizer/BioNTech partnership took the vaccine into full clinical development and in parallel scaled up the manufacturing process, initially to supply vaccines to the clinical trial sites and then to enable distribution to millions of people around the world. 
We aim to produce up to 1.3 billion doses by the end of 2021.

HOW WELL DOES THE VACCINE WORK?

BioNTech and Pfizer announced on November 18 that their vaccine is 95 per cent effective against COVID-19. Britain’s medicines regulator, the MHRA, said on 2 December that the jab is safe to be rolled out.

On December 10, the results were published in the New England Journal of Medicine. Pfizer and BioNTech reported that among 36,523 trial participants with no prior history of SARS CoV-2 infection, there were 170 cases of COVID-19. With 8 cases in vaccine recipients, and 162 COVID-19 cases in placebo recipients, that corresponds to 95.0% vaccine efficacy.

Our trial included almost 44,000 people in six countries: US, Brazil, Argentina, South Africa, Germany and Turkey. 

There is now no upper age limit in the clinical trial so about 41% of the population were aged 56 – 85. We also have some 90-year olds in the trial. It is very important to study the vaccine in older people because sometimes vaccines don’t work quite so well in the older age group. 

However, we were able to show in our studies that the vaccine was 95% effective overall and also 95% effective in the older population. This is an important result given that age has been shown to be the strongest risk factor for developing more severe COVID disease. It is also important to note that our trial targeted racially and ethnically diverse populations around the world, with 42% of our study population from these diverse backgrounds.

We haven’t got enough young children in the trials to authorise the vaccine for those aged under 16. We are looking to do a specific paediatric trial in the future so we can generate more data relevant to children. 

On December 14 they released an analysis of participants immunized with the vaccine that showed a broad immune response with SARS-CoV-2-specific neutralizing antibodies, and two kinds of white blood cells:TH1 type CD4+ T cells, and CD8+ T cells, directed against multiple regions of the spike protein.

Ugur Sahin, CEO and Co-Founder of BioNTech, said: “While there is a broad consensus that vaccines should induce antibody responses against the virus, experiences from the prior SARS pandemic indicate that CD8+ T cell responses may be of critical importance to achieve long-term protection.”

WHAT ARE THE SIDE EFFECTS?

The Phase 3 trial had a safety monitoring committee, independent of Pfizer, independent of BioNTech, independent of the regulator and they were monitoring safety data on all 43,448 patients in real time to make sure there were no significant safety concerns. If they saw any, they would have raised their hands and said we need to stop.

They didn’t see any significant safety concerns which is very reassuring. The trial will also continue for a further 2 years to monitor efficacy and safety.

The side effects you do see are typical of many vaccines so some people may get pain at the injection site or flu-like symptoms in the first 24-48 hours so things like a mild temperature, headache, tiredness or some muscle aches. They tend to be mild to moderate in nature and then quickly disappear.

On day one of the vaccination programme, you may have seen on the news that two people had an allergy reaction known as anaphylaxis, which we did not see in the earlier trial.  This can be a rare side effect of any vaccine. The two people had a history of severe allergies, with previous reactions to certain foods, or to a number of other medicines. They were given the appropriate treatment and they made a good recovery.

Now guidance on the vaccine label says that if anyone has a history of severe allergy, anaphylaxis, they shouldn’t have the vaccine.

This is an indication that the yellow card reporting system, which is the mechanism in the UK for highlighting adverse events quickly, is working because within 24 hours we had identified the issue, we acted upon it and we have the recommendation on the product label.

ARE YOU CONCERNED BY VACCINE HESITANCY?

Vaccination prevents 2-3 million deaths a year. Even before this pandemic, a further 1.5 million deaths annually could be avoided if global coverage of vaccinations improved and the World Health Organisation has identified vaccine hesitancy – the reluctance or refusal to vaccinate– as one of the top global health threats.

White child's cotton bib with printed message: "MMR is safe, tell your friends"
White child’s cotton bib with printed message: “MMR is safe, tell your friends”, sold by The Guardian’s newspaper Bad Science columnist Ben Goldacre, 2007. Image credit: Science Museum Group Collection

Claims of anti-vaccination campaigners have been debunked many times over and psychologists are investigating the psychology of science denial even when confronted with irrefutable evidence.

However, opposition to vaccination dates back centuries. When the Vaccination Act of 1853 introduced mandatory smallpox vaccination for infants in England and Wales it was opposed by people who demanded the right to control their bodies and those of their children.

There is also evidence anti vaccination sentiment is on the rise, despite the pandemic, and will dominate in the coming decade.

Vaccine hesitancy is understandable but the amount of false information circulating on the internet is worrying and this can influence public opinion.

The only way to deal with this issue is to make sure that we are constantly communicating the accurate facts to counterbalance the misinformation.

HOW DOES THIS RNA VACCINE WORK?

Many traditional vaccines are based on a weakened or modified form of virus, or parts of it, but the Pfizer/BioNTech vaccine, like those developed by Imperial College London and Moderna, is based on synthetic strands of genetic code (RNA).

RNA, closely related to DNA, is present in all living cells. The genetic material, known as messenger RNA, is encased in a tiny protective particle of fat which enables it to enter human cells and this forms the main components of the vaccine.

Now in the form of an RNA vaccine, it turns human muscle cells into vaccine factories, making a COVID-19 protein – called the spike – which the immune system recognises as foreign.

The body’s immune system reacts and produces antibodies and activates T-cells that recognise these spike proteins. If the person later becomes infected with coronavirus, the antibodies and T-cells are primed and ready to fight the virus and protect the individual from becoming ill.

We explored four different variants of the messenger RNA to see which gave the best balance of efficacy and safety.

One of them was the RNA code for the spike protein, and one for the receptor binding domain or RBD, a little piece of the spike protein that latches on to human cells. We also tested what were either modified or unmodified RNA, where the modification is to give the RNA a bit more stability because natural RNA is quite fragile and gets broken down pretty quickly in the body. And we tested a self-amplifying messenger RNA to see if a similar response could be produced with a smaller dose.

Of all these options, the RNA coding for the spike protein won in the end. It just seemed to have the best balance of a good safety profile with good efficacy in terms of immune response. If you just used the receptor binding domain, it didn’t quite stimulate the same degree of immune response. The spike, which is bigger than the RBD, seems to be a better antigen, a better target to stimulate the immune system.

HOW DO YOU PROTECT DELICATE RNA FROM THE BODY?

If you just inject the natural RNA it disintegrates in the body and will be broken down too quickly to stimulate an immune response. So, we house it in a lipid nanoparticle, a fat particle. This fuses with the membrane of muscle cells in the body, so the RNA then goes into the cytoplasm – the thick solution in cells – and that’s when the virus spike protein is made. The spike protein goes on the surface of the muscle cell and that stimulates the body’s immune system to make antibodies and T-cells.

WHY DOES THE VACCINE HAVE TO BE KEPT SO COLD?

RNA itself likes to be cold but the lipid particle that carries it particularly likes to be cold to stay stable, so our storage requirements are minus 70°C (+/- 10°C) for up to six months.

Once you then want to use the vaccine in the health service it can be thawed and stored in a normal fridge for up to five days, at 2 – 8°C. It is a challenge but, so far, the implementation is going well across the NHS.

HOW DO YOU KEEP THE VACCINE SO COLD?

As much innovation has gone into the manufacturing process and what we call the ‘cold chain’ as into the actual clinical research and clinical trials.
We have a number of manufacturing sites around the world and normally we produce about 200 million doses of all sorts of vaccines.

But what we didn’t have is widespread minus 70 °C freezers at all our manufacturing sites.

We rapidly had to develop what we call freezer farms, so huge spaces with lots of minus 70°C freezers to store the vaccine.

Then we had to think about how we were going to transport the RNA vaccine because we obviously can’t transport it in freezers. We developed what we call thermal shipping containers, or shippers, containing dry ice (frozen carbon dioxide) to maintain the minus 70 °C temperatures for transport.

We put the vaccine vials into what we call “pizza boxes”, each of which contain 195 vials of vaccine which equates to 975 doses (as one vial contains 5 doses). They go into the shippers and then the dry ice goes in to maintain the temperature of minus 70°C.

We had to be sure those temperatures were maintained during transportation, so we built into the shippers GPS-enabled thermal sensors to monitor the temperature and the location. These sensors are able to detect in real time what the temperature is for the whole transportation of the vaccine.

We saw pictures on the TV news of the lorries coming out of our Belgium manufacturing site. They travelled from there to the Channel Tunnel and into the UK. Every part of that journey, we were receiving temperature readings back in our central control room. There is an allowable range of -60 to -90°C in the thermal shippers and this temperature was maintained throughout the transportation.

CAN YOU AVOID THE ‘COLD CHAIN’?

We are exploring what we can do in the manufacturing process and other potential formulations (for example lyophilised or freeze-dried) which might not require ultra-low temperatures. This is the subject of further research.

We are also conducting ongoing stability testing at 2-8 °C fridge temperatures to see if in the future the vaccine could be stored for longer than 5 days.

WHAT IS THE ADVANTAGE OF USING AN RNA VACCINE?

Once the SARS-CoV-2 genetic sequence came through from China in January we had to then turn it into DNA and the DNA into RNA, and then we essentially made the vaccine. This RNA technology lends itself well to a pandemic situation because it is so fast.

RNA vaccines offer a way to make a vaccine at pandemic speed – all that is required is the genetic sequence of the responsible virus.

These vaccines can be made with fewer components and fewer steps than alternatives. For example, a viral vector which would have to be grown in the lab (often in animal cells) is not required for RNA vaccines.

A manufacturing plant could, in theory, produce several kinds of vaccines using this approach, whereas other kinds of vaccines, such as MMR (measles, mumps, and rubella) and Ervebo (an Ebola vaccine), each require their own dedicated manufacturing plant.

WILL THE VACCINE WORK AGAINST MUTANT STRAINS?

Mutations in viruses are common and often have no impact on vaccine efficacy such that vaccines are able to protect individuals against a range of different strains. In addition, the RNA technology provides a platform for rapid development of new vaccines should they be required for future pandemics.

WHO WILL GET THE RNA VACCINE?

The Joint Committee on Vaccination and Immunisation (JCVI) is the committee that determines the priority risk groups for receiving the vaccine based on the scientific evidence and advises the government.

Nine at-risk groups will be the first to benefit, with the highest priority groups being residents in care homes, people aged > 80 and frontline healthcare workers.

Overall, the UK has ordered 40 million doses of the Pfizer/BioNTech vaccine over 2020 and 2021 – enough to vaccinate 20 million people.

HOW IS THE VACCINE ADMINISTERED?

Full information about the vaccine and how to administer it can be found in the information for healthcare professionals and recipients on the MHRA website.

The vaccine has to be stored in an ultra-low temperature freezer at -80°C to -60°C where its shelf life is 6 months.

The undiluted vaccine can be thawed and stored for up to 5 days at 2-8°C in the fridge, or up to 2 hours at temperatures up to 25°C, prior to use.
One vial contains five doses each of 30 micrograms – millionths of a gram – of the RNA vaccine.

To administer the vaccine, it must be diluted with 1.8ml of sodium chloride solution and given as soon as practically possible and within 6 hours. Any unused vaccine after 6 hours must be discarded.

The vaccine is injected into the deltoid muscle in the upper arm. A second dose is required 21 days later, and maximum protection occurs from 7 days after the second dose.

There is some immune response after the first dose, but it is important to receive the second dose for maximum protection.

WHAT ELSE IS PFIZER DOING TO COMBAT THE PANDEMIC?

Pfizer has begun Phase 1 trials of a small molecule that disables the 3CL protease, an enzyme that coronaviruses use to assemble themselves so they can multiply in human cells.

Pfizer chemists first discovered the drug during the 2002–2003 outbreak of severe acute respiratory syndrome (SARS). But this earlier coronavirus epidemic petered out and the antiviral was archived in the research library.

Fortunately, the 3CL protease of SARS-CoV is very similar to that of SARS-CoV-2 – they look very similar at the molecular level. Test tube studies showed the small molecule (in fact PF-0083523, which is the active form found in the body) had activity against two strains of SARS-CoV-2. If approved, this would be the first antiviral drug to target this protein in SARS-CoV-2.

A vaccine is obviously incredibly important to prevent the disease, but we still need very good treatments if people get COVID and sadly, huge numbers are still getting it and many in at risk categories (e.g., the elderly and those with underlying health conditions) are having to go into hospital and sadly some do not survive or suffer ongoing ill health.

We are busy researching this anti-viral treatment, which is in Phase 1 at the moment; we are hoping for it to go into Phase 2 in the first few months of next year.

This approach is already used in HIV treatment. Now we hope this same technology, the inhibition of the protease enzyme, can be effective in coronavirus as well. We have seen it is very effective against the virus in the lab, but the real test is whether it will be effective in patients.

HOW CAN I FIND OUT MORE?

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

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

More information can be found about the vaccine on the MHRA website.

There is even more information in our Coronavirus blog series (including some in German by focusTerra, ETH Zürich, with additional information on Switzerland), from the UKRI, the EU, US Centers for Disease Control, WHO, on this COVID-19 portal and Our World in Data.

The Science Museum Group is also collecting objects and ephemera to document this health emergency for future generations.