Vaccine Knowledge Ingredients https://vk.ovg.ox.ac.uk/vk/vaccine-ingredients#activeingredients

Vaccine ingredients

Quicklinks

• Active ingredients • Added ingredients: o Aluminium, an adjuvant o MF59 (squalene oil), an adjuvant o Thiomersal, also called Thimerosal o Gelatine o Sorbitol and other stabilisers o Emulsifiers o Taste improvers • Products used in vaccine manufacture: o Antibiotics o Egg proteins (ovalbumin) o Yeast proteins o Latex (in packaging) o Formaldehyde o Acidity regulators • Growing the active ingredients: o Human cell strains, animal cell strains and GMOs o Recombinant DNA technology o Bovine products o Other growing media • Further information

General information

The key ingredient in all is one or more active ingredients (see below). Apart from this, the main ingredient in vaccines is water. Most injected vaccines contain 0.5 millilitres of liquid, in other words a few drops. All other ingredients weigh a few milligrams (thousandths of a gram) or even less. Unlike food products, the list of may include products used during the manufacturing process, even if they do not remain in the finished product. Added ingredients are present in very small quantities (usually a few milligrams). Products used in making vaccines or growing the active ingredients may not remain in the final vaccine at all. If they do, they are present only in trace amounts.

Vaccine ingredients can look unfamiliar. However, it is important to remember that many of the substances used in vaccines are found naturally in the body. For example, many vaccines contain salts based on and potassium (see the section on 'Acidity regulators'), which are essential for life. People may think of formaldehyde as a man-made chemical, but in small quantities it is also found naturally in the bloodstream.

All vaccine ingredients are present in very small quantities, and there is no evidence that they cause harm in these amounts. The exception to this is the small number of people who may be severely allergic to a vaccine ingredient, even if it is present only in trace amounts (for example, egg proteins or antibiotics used in vaccine manufacture). If you look up some vaccine ingredients on the internet you may read that they could be harmful, but most of them are present in vaccines in amounts that are completely normal for our bodies. Even common salt (), which is essential for normal functioning of the body, is harmful in large quantities.

A list of vaccine ingredients can be found on the Patient Information Leaflet (PIL) and Summary of Product Characteristics (SPC) sheet for each vaccine. See the list of PILs and SPCs on our links page. For further information about vaccine ingredients, contact the manufacturer of the vaccine.

Active ingredients

These are the parts of the vaccine made from viruses or bacteria (also called ‘antigens’). They challenge the immune system so that it makes to fight the disease (see our animation on 'How do vaccines work?'). Vaccines contain tiny quantities of active ingredients – just a few micrograms (millionths of a gram) per vaccine. To give some idea of how small these quantities are, one paracetamol tablet contains 500 milligrams of the drug. This is several thousand times more than the quantity of the active ingredient you would find in most vaccines. Hundreds of thousands of individual vaccines could be made from a single teaspoon of active ingredient.

Some vaccines contain whole bacteria or viruses. In these cases the bacteria or viruses will either be severely weakened (attenuated) so that they cannot cause disease in healthy people, or killed altogether (inactivated). Many vaccines contain only parts of viruses or bacteria, usually proteins or sugars from the surface. These stimulate the immune system but cannot cause disease. See our page on 'Types of vaccine'.

Compared to the number of viruses and bacteria in the environment that our bodies have to deal with every day, the amount of active ingredient in a vaccine is very small indeed. Most bacterial vaccines contain just a few proteins or sugars from the relevant bacterium. By contrast it is estimated that 100 trillion bacteria live on the skin of the average human being, each of them containing many thousands of proteins which constantly challenge our immune systems.

A few vaccines in the UK schedule are made using recombinant DNA technology. Only one vaccine used in the UK contains genetically modified organisms (GMOs).

Added ingredients

These are products such as aluminium salts that help to improve the immune response to vaccines, or products that act as and stabilisers (for example, gelatine or human serum albumin). These are listed on vaccine information leaflets as ‘excipients’ (inactive ingredients). Like vaccines, most of the medicines we use also contain excipients.

Aluminium, an adjuvant

Many vaccines contain aluminium salts such as aluminium hydroxide, aluminium phosphate or potassium aluminium sulphate. They act as adjuvants, strengthening and lengthening the immune response to the vaccine. Aluminium salts appear to slow down the release of the active ingredient from the vaccine once it is injected, and stimulate the immune system to respond to the vaccine. They also absorb protein well, and stop the proteins in the vaccine sticking to the walls of a container during storage.

Aluminium is the most common metal in the earth’s crust and we are exposed to it all the time. It reacts with other elements to form aluminium salts, and small amounts of these are found naturally in almost all foods and drinking water, as well as in breast milk and in formula milk for babies. Aluminium salts are used as food additives (for example in bread and cakes) and in drugs such as antacids, and aluminium is widely used in food packaging.

Aluminium is not used by the body. Any aluminium absorbed from food or other sources is gradually eliminated through the kidneys. Babies are born with aluminium already present in their bodies, probably from the mother’s blood. Over time, small amounts of the aluminium from food, drink and other sources do accumulate in the body, but this is not believed to pose a significant risk to health (see for example this UK research from 2004 ). The view of most experts is that there is currently no convincing evidence that exposure to everyday levels of aluminium in any form increases the risks of Alzheimer’s disease, genetic damage or cancer.

The amount of aluminium present in vaccines is small - less than 2 milligrams of the salts, and less than a milligram of actual aluminium. In the UK, the highest dose of aluminium that babies receive in one go from vaccines is just under 1.5 milligrams (from the 6-in-1, PCV and MenB vaccines at 8 weeks and 16 weeks). A study from 2011 modelled the impact of aluminium from diet and vaccines in infants, and concluded that the total amount of aluminium absorbed from both sources was likely to be less than the weekly safe intake level. A study from 2002

drew similar conclusions. A study published in March 2018 took samples of blood and hair from 85 babies and measured their levels of aluminium. These levels varied considerably, but researchers did not find any correlation between aluminium levels in blood or hair and the estimated amount of aluminium that the babies had received from vaccines.

Vaccines that contain aluminium are associated with more redness and hardness at the injection site than other vaccines. Rarely, aluminium adjuvants may cause small itchy lumps (granulomas) to form at the injection site. A 2014 Swedish study found that this happened in a small number of children (fewer than 1 in 100) after with the 5-in-1 vaccine (Infanrix) and (Prevenar). Granulomas are not dangerous but can be irritating and last for months or even years. The study found that children with granulomas often developed an aluminium contact . However, most children recovered from their symptoms.

Aluminium salts are found in these vaccines used routinely in the UK. The exact amounts of aluminium per dose are listed for each vaccine:

• 6-in-1 vaccine: Infanrix Hexa (0.82 milligrams) • PCV (pneumococcal ): Prevenar 13 (0.125 milligrams) • MenB vaccine: Bexsero (0.5 milligrams) • Pre-school Booster vaccines: Repevax (0.33 milligrams), Infanrix IPV (0.5 milligrams) and Boostrix-IPV (0.5 milligrams) • HPV vaccine: (0.225 milligrams) • Teenage Booster vaccine: Revaxis (0.35 milligrams) • HepB vaccine: HBVaxPro (0.25 to 0.5 milligrams, depending on which version of HBVaxPro is given)

MF59 (squalene oil), an adjuvant

MF59 is used in only one vaccine licensed in the UK: Fluad, a flu vaccine introduced in the 2018- 19 flu season for adults aged 65 and older (see the page on the Inactivated Flu Vaccine). Fluad is not a new vaccine; it was first licensed in 1997 and millions of doses have been given worldwide. MF59 is added to the vaccine to make it more effective. It is an adjuvant which helps to strengthen and lengthen the immune response to the vaccine. It may also lead to an increase in common side effects such as pain, swelling or redness at the injection site, slightly high temperature, headache, feeling generally unwell, shivering, or tiredness. However, there is no evidence that MF59 causes more serious adverse effects.

The main ingredient in MF59 is squalene oil, a naturally-occurring oil found in humans, plants and animals. The squalene oil in MF59 comes from fish oil and is highly purified before it is used. Fluad contains less than 10mg of squalene (1mg is one thousandth of a gram).

MF59 also contains very small amounts of these ingredients (around 1mg or less):

• polysorbate 80, sorbitan trioleate and sodium citrate. These are all emulsifiers which stop the squalene oil separating out from the water in the vaccine. Polysorbate 80 and sodium citrate are commonly used in food and drink. Sorbitan trioleate is a compound made from oleic acid (a natural fatty acid) and sorbitol, also found naturally in fruits and other foods. • citric acid, used extensively in foods and drinks.

Thiomersal, also called thimerosal in the US (a )

Thiomersal is a -based preservative used in tiny quantities in some vaccines to prevent the growth of bacteria and fungi which can contaminate from the environment when the vaccine is opened.

Most single-dose vaccines do not contain thiomersal because they are used only once and so there is very little risk of contamination. However, some vaccines are produced in multi-dose vials. There are two reasons for this: they are cheaper, and they are easier to produce quickly in large quantities in the event of an epidemic. Tiny quantities of thiomersal are often used in multi-dose vaccines to stop them becoming contaminated once they are opened.

Thiomersal was removed from UK vaccines between 2003 and 2005, and is no longer found in any of the childhood or adult vaccines routinely used in the UK. Before 2005, thiomersal was present in - and -containing vaccines, as well as and some flu vaccines. It was not used in the MMR vaccine, the , the MenC vaccine, the oral or the BCG vaccine. Thiomersal was present in the Swine Flu (H1N1) vaccine , used in the 2009-10 and 2010-11 flu seasons in the UK. However, it is not present in any of the annual flu vaccines currently in use in the UK.

In the US, UK and Europe, thiomersal was removed from vaccines as a precaution. This was in line with the global goal of reducing environmental exposure to mercury from all sources. However, there was no evidence that thiomersal in vaccines caused harm. Thiomersal contains a compound called ethyl mercury, but concern about mercury in the environment has centred on a different compound called methyl mercury, which accumulates in the food chain and in the human body. More detailed information can be found on the US National Institute of Allergy and Infectious Disease website. A study from 2008 showed that the ethyl mercury in thiomersal does not appear to accumulate in the bodies of even very small babies. It is cleared from the blood in 30 days, and the evidence suggests that it is passed out in the baby’s stool (poo).

The World Health Organization (WHO) and the European Medicines Agency (EMA, previously EMEA) have both stated that there is no evidence of risk from thiomersal in vaccines. Read the

WHO statement and the EMA statement . There is also detailed information about the safety of thiomersal on the US Food and Drug Administration's pages . A 2014 Australian study of over a million children found no evidence of a link between thiomersal in development.

Gelatine (a stabiliser)

Gelatine derived from pigs is used in some live vaccines as a stabiliser to protect live viruses against the effects of temperature. Gelatine in vaccines is highly purified and hydrolysed (broken down by water), so it is different from the natural gelatine used in foods. For example, very sensitive scientific tests have shown that no DNA from pigs can be detected in the nasal flu vaccine (Fluenz).

There have been a tiny number of cases of allergic reaction to vaccines containing gelatine (about one case for every 2 million doses of vaccine). People with a known allergy to gelatine should seek expert advice before receiving vaccines containing gelatine.

Members of Muslim or Jewish religious communities may be concerned about using vaccines that contain gelatine from pigs (porcine gelatine). According to Jewish laws, there is no problem with gelatine or any other animal substance if it is used in a product that does not go into the mouth. Some Muslim leaders have also ruled that the use of gelatine in vaccines does not break religious dietary laws, because it is highly purified and it is also injected or inhaled rather than ingested (eaten).

Gelatine is found in these vaccines used in the UK:

• the Nasal Flu vaccine (Fluenz). However, very sensitive scientific tests have shown that no DNA from pigs can be detected in Fluenz. These tests show that the gelatine is broken down so much that the original source cannot be identified. • one of the MMR vaccines (MMRVaxPro). (Priorix, the other MMR vaccine used in the UK, does not contain gelatine.) • the shingles vaccine (Zostavax) • one of the chickenpox vaccines (Varivax). (Varilrix, the other chickenpox vaccine used in the UK, does not contain gelatine.)

More information can be found in the NHS leaflet 'Vaccines and porcine gelatine' . This information is also available in Arabic , Bengali and Urdu .

Sorbitol and other stabilisers

Sorbitol is produced naturally in the human body and also found in fruit and berries. It is commonly used as a sweetener in foods and drinks. In vaccines it is used in small quantities as a stabiliser. There may be up to 15 milligrams of sorbitol in the MMR vaccines used in the UK (MMR VaxPro and Priorix). Sorbitol may also be present in one of the chickenpox vaccines (Varilrix). Sorbitol is usually harmless, but people with an allergy to sorbitol, or with rare inherited problems of fructose intolerance, should not receive vaccines containing sorbitol.

Other products used in very small quantities as stabilisers in vaccines include:

• Sugar (sucrose) • Lactose (milk sugar) • Mannitol, similar to sorbitol – see above • Glycerol, a common non-toxic substance often used as a food additive • Medium 199, a solution which contains amino acids (the building blocks of proteins), mineral salts and vitamins • Arginine hydrochloride, another common amino acid • Monosodium glutamate, a salt made from the common amino acid glutamine • Urea, a harmless organic compound found in the human body

Emulsifiers

Polysorbate 80 is a common food additive used in several vaccines as an emulsifier (to hold other ingredients together). Compared to its use in foods, there is very little polysorbate 80 in vaccines.

Taste improvers

The oral (Rotarix) contains about a gram of sugar (sucrose) to give it a pleasant taste. This is about a quarter of a teaspoon of sugar.

Products used in the manufacture of the vaccine

Unlike food products or other drug product listings, substances used in the production of a vaccine may also be listed under ‘excipients’, even though they are not added to the vaccine. However, many of the items listed do not actually remain in the finished vaccine. If they do, they will often be present in trace amounts.

Antibiotics

Antibiotics are used during the manufacturing process of some vaccines to stop bacteria growing and contaminating the vaccine. However, antibiotics which commonly cause allergic reactions (such as penicillins, cephalosporins and sulphonamides) are not used in vaccines. Traces of five antibiotics may be found in some of the vaccines used in the UK. These are neomycin, streptomycin, polymyxin b, gentamicin and kanamycin. People with a known allergy to any of these antibiotics should ask for expert advice before receiving these vaccines.

Antibiotics are used in the manufacture of the following vaccines used in the UK:

• The 6-in-1 vaccine (Infanrix Hexa) may contain traces of neomycin and polymyxin b • The MenB vaccine may contain a trace of kanamycin. • Both MMR vaccines (MMRVaxPro and Priorix) may contain a trace of neomycin • The Nasal Flu vaccine (Fluenz) may contain a trace of gentamicin • Inactivated Flu Vaccines may contain traces of neomycin, streptomycin, polymyxin b, gentamicin or kanamycin. Check the Patient Information Leaflet for the vaccine you are offered. • One of the Pre-school Booster vaccines (Repevax) may contain traces of neomycin, streptomycin and polymyxin b • The shingles vaccine (Zostavax) may contain a trace of neomycin • Both chickenpox vaccines (Varivax and Varilrix) may contain a trace of neomycin • Some of the hepatitis A vaccines may contain a trace of neomycin. Check the Patient Information Leaflet for the vaccine you are offered. Egg Proteins (Ovalbumin) Egg allergy is quite common in children under 5, and much more common in children than in adults. Around 60,000 children in the UK have egg . In the UK schedule, both the Nasal Flu Vaccine (Fluenz Tetra) and two of the Inactivated Flu Vaccines may contain traces of egg proteins. This is because the flu virus is grown on fertilised hens' eggs. The Joint Committee on

Vaccination and Immunisation has advised that most children with an egg allergy can be safely vaccinated with the nasal flu vaccine (Fluenz Tetra). This is because the ovalbumin content is very low. The only exception is children who have a history of severe anaphylaxis to eggs which has previously needed treatment in intensive care. These children should be referred to specialists for immunisation in hospital. This advice is based on a recent study called SNIFFLE which tested Fluenza Tetra on several hundred children with egg allergy. See more information about the SNIFFLE study and an information sheet from Public Health England showing the ovalbumin content of flu vaccines in the current flu season. Other non-routine vaccines, such as , may also contain egg proteins. Those with egg allergy should always ask about egg protein content before receiving a vaccine.

In the past, people with an egg allergy were advised not to receive the MMR vaccine. Advice on this changed more than ten years ago. The measles and mumps viruses are grown on a culture which contains chick embryo cells (not on eggs). This means that there is not enough egg protein in the MMR vaccine to cause allergic reactions, so children with severe egg allergies can safely receive the MMR. Doctors have carefully studied this issue and confirmed that there is no increased risk of reactions to the MMR vaccine in children who are allergic to eggs. See the video about this on the MMR vaccine page under 'Ingredients'. Yeast Proteins

Yeast is used in the production of the HPV vaccine (Gardasil) used in the UK. Department of Health advice is that the HPV vaccine can be given to yeast allergy sufferers because the final product does not contain any yeast. A tiny quantity of yeast protein may remain in the 6-in-1 vaccine (Infanrix Hexa) and the Hepatitis B vaccines used in the UK, but there is no evidence that this can cause allergic reactions. Latex Latex (natural rubber) is used in the packaging of some vaccines. For example, the needle tip of the syringe may be protected with a latex bung. This is a risk for people who have a severe allergy to latex (one that causes an anaphylactic reaction), and they should talk to a doctor before receiving a vaccine. People who have less severe latex allergies (for example, a history of contact allergy to latex gloves) are not at risk from latex in vaccine packaging.

In the UK the product information leaflets of the following vaccines state that latex is used in the packaging: • Hepatitis B vaccines (HBVaxPro and Engerix B) • MenB vaccine (Bexsero) Formaldehyde and Formaldehyde is an organic compound found naturally in many living things. It is used in the production of some vaccines to inactivate toxins from bacteria and viruses (for example, poliovirus, Hepatitis B antigen, and diphtheria and tetanus toxins). It is possible that tiny traces may remain in the 6-in-1 vaccine (Infanrix Hexa), Hepatitis B vaccine (HBVaxPro), one of the Pre- school Booster vaccines (Repevax), and the Teenage Booster vaccine (Revaxis). However, formaldehyde breaks down quickly in water (and most of the vaccine is water). The human body produces and uses formaldehyde as part of the process of metabolism. The amount of natural formaldehyde in a 2-month-old infant’s blood (around 1.1 milligrams in total) is ten times greater than the amount found in any vaccine (less than 0.1 milligrams). A pear contains around 50 times more formaldehyde than is found in any vaccine.

Glutaraldehyde is a similar kind of organic compound which is also used to inactivate toxins from bacteria used in vaccines. A trace may remain in one of the Pre-school Booster vaccines (Repevax). Acidity Regulators Like all other living things, viruses and bacteria need to be kept at the right pH (acid/alkaline level). A number of different products are used in very small quantities to help keep the pH balance right while vaccines are being manufactured. These products include:

• Salts based on potassium phosphate and sodium phosphate. These are common and harmless. As well as keeping the pH balance, they also help to keep the fragments of active ingredient suspended in the water, so that they do not settle out. A product called Hanks’ Salts, which contains these salts and others, is sometimes used. • Disodium adipate, also commonly used as a food additive. • Succinic acid, which is involved in several chemical processes in the body. • and hydrochloric acid: when these are used they react together to form water and harmless salts, and so do not appear in the final vaccine in their original form. • Histidine, an amino acid found in almost every protein in the human body. • Sodium borate (borax): a few micrograms (millionths of a gram) may remain in the Hepatitis B vaccine (HBVaxPro) and the HPV vaccine (Gardasil). This amount is too small to cause any harm. • Trometamol, also used in the manufacture of other medicines. Growing the active ingredients Human Cell Strains For some vaccines, the active ingredient is grown in laboratories on cultures that contain human cells. Some viruses, such as chickenpox (varicella), grow much better in human cells. After they are grown, the viruses are purified several times to remove the cell culture material. This makes it unlikely that any human material remains in the final vaccine. For vaccines used in the UK, human cell strains are used to grow viruses for these vaccines: • the rubella part of both MMR vaccines (MMRVaxPro and Priorix) • the shingles vaccine (Zostavax) • both chickenpox vaccines (Varivax and Varilrix) The cell strains currently used (called WI-38 and MRC-5) were started in the 1960s using lung cells taken from two aborted foetuses. The abortions were legal and agreed to by the mothers, but they were not performed for the purpose of vaccine development.

Some people may have moral concerns about using a vaccine produced in this way. In 2005 the Vatican’s Pontifical Academy for Life issued a statement (20-6-5 Pontificia Academia Vaccine Safety Concerns) called ‘Moral reflections on vaccines prepared from cells derived from aborted human foetuses’. This statement says that they believe it is wrong to make vaccines using human cell strains derived from foetuses, and that there is a ‘moral duty to continue to fight’ against the use of such vaccines and to campaign for alternatives. However, it also states that if the population is exposed to ‘considerable dangers to their health’ through diseases such as rubella (German measles), then ‘vaccines with moral problems pertaining to them may also be used on a temporary basis’. Animal Cell Strains Viruses for some vaccines are grown in laboratories on animal cell strains. This is because viruses will only grow in human or animal cells. In the UK schedule this applies to these vaccines: • The polio part of the 6-in-1 vaccine (Infanrix Hexa), the pre-school booster vaccines (Repevax, Infanrix IPV and Boostrix-IPV) and the teenage booster vaccine (Revaxis) • The Rotavirus vaccine (Rotarix) • One of the Inactivated flu vaccines (QIVc) Viruses for these vaccines are grown on Vero cells. This is a cell strain started in the 1960s using kidney cells from an African green monkey.

The measles and mumps parts of the MMR vaccines (MMRVaxPro and Priorix) are grown on a culture which began with cells taken from a chick embryo. There is no evidence of any risk that animal diseases can be transmitted by vaccines grown on animal cell strains. Genetically Modified Organisms (GMOs)

The only vaccine in the UK schedule which contains GMOs is the Nasal Flu vaccine (Fluenz). The viruses for flu vaccines are usually made by injecting two flu virus strains into an egg and letting them recombine naturally to make new strains. Researchers then look through all the new viruses to see which one has the features they are looking for to make this year’s vaccine. The viruses used to make Fluenz are custom-made by putting together individual genes that will give the right features. This is a quicker and more accurate process. Recombinant DNA Technology Recombinant vaccines are made using bacterial or yeast cells to manufacture the vaccine. A small piece of DNA is taken from the virus or bacterium that we want to protect against. This is inserted into other cells to make them produce large quantities of active ingredient for the vaccine (usually just a single protein or sugar). For example, to make the hepatitis B vaccine, part of the DNA from the hepatitis B virus is inserted into the DNA of yeast cells. These yeast cells are then able to produce one of the surface proteins from the hepatitis B virus, and this is purified and used as the active ingredient in the vaccine. Proteins for the HPV vaccine, part of the MenB vaccine and the hepatitis B part of the 6-in-1 vaccine are produced using a similar technique. Bovine products ‘Bovine products’ refers to any product that is derived from a cow or calf (such as bovine serum, which comes from cow's blood). Some sources state that bovine products may be present in the media that are used to grow the viruses or bacteria that are used to make the components of some vaccines. The Vaccine Knowledge Project has only been able to find one vaccine currently used in the UK which states that bovine products are used in its manufacture. This is Repevax, one of the Pre-school Booster vaccines available in the UK. The Summary of Product Characteristics sheets (SPC) for Repevax states that bovine serum albumin is used in the manufacture of the vaccine and that trace amounts may remain in the vaccine. This is potentially a risk for people who are severely allergic to bovine products. Other vaccines in use in the UK may use bovine products in their manufacture, but this is not stated on their SPCs.

The European Medicines Agency (EMA) has issued a series of statements and Q&A sheets on the risk posed by bovine products used in vaccine manufacture . These have been prepared in response to the recognition of BSE in the 1980s and are regularly updated. Other growing media

Some bacteria do not need to be grown on human or animal cells. Instead they can be grown on cultures that are rich in proteins, vitamins and salts. Cultures that are often used in the production of vaccines are Medium 199, Eagle Medium and Minimum Essential Medium. Further information If you have questions about any of the other ingredients or excipients used in vaccines, ask your GP for advice, or contact the vaccine manufacturer named on the vaccine's Patient Information Leaflet (PIL) or Summary of Product Characteristics (SPC) sheet. See the list of PILs and SPCs on our links page. In the UK you can also contact the Medicines and Healthcare products Regulatory

Agency (MHRA) which regulates medicines, including vaccines, in the UK. See their

Customer Service contact list . An article from 2003 giving further detailed information on vaccine ingredients can be found here . The information on this page is based on the best information that we can find from the available literature.

COVID-19 vaccines (Update – older info below) COVID-19 is a disease caused by a new type of coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus was first detected in Wuhan, China, in December 2019 and has led to a Pandemic, announced by the World Health Organization on 11thMarch 2020. This page provides the following information: • Key facts about COVID-19 vaccines • Pfizer BioNTech vaccine • Oxford AstraZeneca vaccine • Who should have the vaccines? • Safety and side effects • Vaccine ingredients • Nucleic acid and viral vector vaccines explained Key vaccine facts COVID-19 (coronavirus disease) is an emerging disease caused by a newly discovered coronavirus. It can result in severe illness and death, particularly for people in risk groups. COVID-19 presents with a range of symptoms of varying severity. Asymptomatic also occurs, and it is predicted that between 20–30% of people who have the virus do not show symptoms. For around 40% of people who have symptomatic COVID- 19, symptoms are mild andwithout hypoxia (low level of in the blood) or pneumonia. 40% have moderate symptoms and non-severe pneumonia, 15% have significant disease including severe pneumonia, and 5% experience critical disease with life-threatening complications. Critical disease includes acute respiratory distress syndrome (ARDS), sepsis, septic shock, cardiac disease, thromboembolic events, such as pulmonary embolism and multi- organ failure. There is growing evidence that in those who develop critical COVID-19 disease, there can be longer-term consequences such as rare neurological and psychiatric complications. These may include stroke, delirium, anxiety, depression, damage or inflammation of the brain, and sleep disturbances. Refer to the long-term health effects guidance for further information on commonly reported symptoms and services available for recovering COVID-19 patients. Some risk factors are associated with a higher chance of developing severe or critical COVID-19 disease. These are: • Increasing age • Male sex • Underlying health conditions (clinically vulnerable) • Clinically extremely vulnerable • Being from a black, ethnic or minority group • Working in health and social care More information about COVID-19 disease, including the global impact of the pandemic see: Coronavirus (COVID-19) It is recognised that a vaccine is urgently needed to prevent people from becoming severely ill and dying from COVID-19. The aim of the UK COVID-19 vaccination programme is to protect those who are most at risk. In response to the COVID-19 pandemic, scientists around the world have come together to focus their efforts on developing vaccines to prevent people from becoming infected with the coronavirus. Over 270 vaccines are in various stages of development, and some of these utilise similar technologies to existing vaccines in use, whilst others involve newer approaches. Although clinical trials have been completed more rapidly during the pandemic, this has been achieved by overlapping the different stages (phase 1, 2 and 3) of clinical testing rather than completing them sequentially. Assessment of safety has not been compromised and the trials have been subject to the same strict regulatory requirements as any other vaccine studies. Each of the vaccines that has received or is under review for temporary licensing have been tested in trials with over 20,000 people, collecting many months of safety follow-up data. In many cases, these trials are larger than trials for other drugs and vaccines which have been licensed. See below for information about how vaccines are developed and how some of the administrative processes were speeded up during the COVID-19 pandemic. With thanks to Nature https://www.nature.com/ for permission to use this video How New Vaccines Are Developed https://youtu.be/2t_mQwTY4WQ. “How and why do we create a vaccine and why does it take so long? First you have to identify the virus or bacterium that causes the disease…” In the UK, two vaccines are currently in use, following regulatory approval. These are the BNT162b2 vaccine, developed by Pfizer and BioNTech and the ChAdOx1 nCoV-19 (AZD1222), developed by the University of Oxford and AstraZeneca. Both of these vaccines have been authorised for emergency use by the Medicines and Healthcare products Regulatory Agency (MHRA), as well as a vaccine developed by Moderna, which is expected to be available from Spring 2021. For more information about how vaccines are licensed, see How vaccines are tested, licensed and monitored.

Pfizer-BioNTech BNT162b2 vaccine

The BNT162b2 vaccine is a COVID-19 mRNA vaccine developed by Pfizer and BioNTech. It contains the genetic code (mRNA) of the spike protein, which is found on the surface of the SARS-CoV-2 virus. Once inside the body, the spike protein is produced, causing the immune system to recognise it and initiate an immune response.

This means that if the body later encounters the spike protein of the coronavirus, the immune system will recognise it and destroy it before causing infection. As there is no whole or live virus involved, the vaccine cannot cause COVID-19 disease. The mRNA is naturally degraded after a few days. More information about mRNA vaccines is below.

The safety and efficacy of the BNT162b2 vaccine have been assessed in clinical trials of over 44,000 people in six countries: USA, Germany, Brazil, Argentina, South Africa and Turkey. The trial reported that the vaccine can prevent 95% of COVID-19 cases. This means that in a group of 20 people who are vaccinated, if all are exposed to the coronavirus, 19 people will be prevented from getting COVID-19. The trial also showed that the vaccine provides similar protection in people of all ages, races and ethnicities. The BNT162b2 vaccine is a two-dose course, which is given as an injection into the upper arm. The second dose can be given 3-12 weeks after the first dose.

Oxford-AstraZeneca ChAdOx1 nCoV-19 (AZD1222)

The ChAdOx1 nCoV-19 vaccine was developed by the University of Oxford and AstraZeneca. The vaccine works by delivering the genetic code of the SARS-CoV-2 spike protein to the body’s cells, similarly to the BNT162b2 vaccine. Once inside the body, the spike protein is produced, causing the immune system to recognise it and initiate an immune response. This means that if the body later encounters the spike protein of the coronavirus, the immune system will recognise it and destroy it before causing infection.

This Oxford-AstraZeneca vaccine uses the ChAdOx1 technology, which has been developed and optimised by the Jenner Institute over the last 10 years. This type of vaccine technology has been tested for many other diseases such as influenza (flu) and middle east respiratory syndrome (MERS), another type of coronavirus. More information about viral vectored vaccines is below.

The ChAdOx1 nCoV-19 vaccine has been tested by the University of Oxford in clinical trials of over 23,000 people in the UK, Brazil and South Africa. AstraZeneca are also running a further trial with 40,000 people in the USA, Argentina, Chile, Columbia and Peru.

Interim results from the UK and Brazil trials showed that the vaccine can prevent 70.4% of COVID-19 cases. This was calculated across two different groups of people, who received two different dose regimens. The vaccine was shown to prevent 73% of cases in individuals with at least one underlying health condition. The vaccine has also been shown to produce similar immune responses in older adults when compared with young, healthy individuals, although the efficacy data for this group is not yet available.

The ChAdOx1 nCoV-19 vaccine is given as a two-dose course, which is given as an injection into the upper arm. The second dose is given 4-12 weeks after the first dose.

Safety and side effects

The COVID-19 vaccines currently approved have been thoroughly reviewed by the Medicines and Healthcare products Regulatory Agency in the UK (the MHRA). The regulatory team have completed a full review of the safety information reported from the trials, which includes several months follow-up data from 23,000 people for the Oxford-AstraZeneca vaccine and 44,000 people for the Pfizer-BioNTech vaccine.

This means that the MHRA has reviewed all the information from the clinical trials of these vaccines, which includes assessing all the side effects and medical conditions that people in the trials experienced.

The number of illnesses reported in the vaccinated group is compared with the control group, to see whether the vaccine could be associated with an increase in any medical conditions. The rates of illness are also compared with the rate of those illnesses in the general population. For any severe illnesses reported, a specialist doctor involved in treating the person and an independent safety committee consider whether the illness could be associated to the vaccine.

All the information about adverse events (unexpected illnesses) reported during the trial has been provided to the regulators, and the safety profile of both the Oxford-AstraZeneca and the Pfizer BioNTech vaccines is similar to that of other vaccines.

Expected side effects

Because vaccines work by triggering your immune system to produce a reaction, you can however have side effects after you receive the vaccine that feel similar to having a real infection. Things like having a fever, or feeling achey, or getting a headache (often described as “flu-like” symptoms) are common after receiving many vaccines and this is the same for the approved COVID-19 vaccines. Having these symptoms means that your immune system is working as it should be. Usually, these symptoms last a much shorter time than a real infection would (most are gone within the first 1-2 days).

The common side effects associated with the currently approved vaccines are below. These symptoms generally last 1-2 days following vaccination.

For more information on side effects, ask for the Patient Information Leaflet for the vaccine you are offered. Full information about side effects is available here:

Oxford-AstraZeneca ChAdOx1 nCoV-19

Pfizer-BioNTech BNT162b2

None of the currently approved vaccines are using a live SARS-CoV-2 virus in them; so you cannot get COVID-19 from them.

Who should have the vaccines? The aim of the COVID-19 vaccination programme is to protect those who are most at risk of becoming seriously ill with COVID-19.

Following advice from the UK Joint Committee on Vaccination and Immunisation, the programme will vaccinate people in the order of highest risk of severe COVID-19 disease, due to occupation, age or other risk factors. The categories are outlined below:

At-risk groups included in priority group 6 are:

• Chronic respiratory disease (including severe asthma) • Chronic heart disease and vascular disease • Chronic kidney disease • Chronic liver disease • Chronic neurological disease • Diabetes • Immunosuppression • Dysfunction of the spleen • Morbid obesity • Severe mental illness • Adult carers • Younger adults in long-stay care homes Immunosuppression

People whose immune systems do not work normally, either because of a medical condition or treatment, are being recommended to have the COVID-19 vaccines at present. There is no concern that these vaccines will cause harm in people with immunosuppression, but there is a chance that they may not get as much protection from any vaccine received. This is because for a vaccine to work well, your immune system needs to make a strong response to it. Any condition or treatment that reduces the function of the immune system can reduce the response to a vaccine.

Who can’t have the vaccines? (Contraindications)

Pregnancy and breastfeeding

None of the trials conducted on the currently available vaccines have included pregnant or breastfeeding women. There have, however, been people who became pregnant during the trials, and they and their babies are being monitored closely. At the moment, there isn’t any sign that these vaccines cause harm to pregnant women or the unborn baby. However, there isn’t yet enough data to say that they should be given in pregnancy. It is expected that there will be more trials and data on this in future.

For cases where a pregnant woman is at high risk of exposure to the virus or they are at very high risk of having serious complications from COVID-19, they should discuss the risks and benefits of being vaccinated with their clinician.

The JCVI recommended that women who are breastfeeding may be offered both the Pfizer- BioNTech and Oxford-AstraZeneca vaccines. There is no known risk associated with receiving non-live vaccines whilst breastfeeding.

Children

Children and young people have a very low risk of becoming seriously ill from COVID-19 disease compared to adults. At the moment, children under the age of 16 have not been included in the vaccination recommendations. Some children with complex medical conditions may be advised to receive a COVID-19 vaccine, but this assessment will be made on an individual basis. Clinical trials are being planned or already underway to provide evidence for use in this age group.

Allergies

There were no serious allergic reactions during any of the trials of these vaccines. None of these trials included participants who were known to have severe allergies. After the Pfizer-BioNTech vaccine was rolled out in the UK, two people had severe reactions (anaphylaxis) caused by an ingredient in the vaccine. Both individuals already had severe allergies and carried emergency adrenaline pens.

The Pfizer-BioNTech and Oxford-AstraZeneca vaccines should not be given to those who have had a previous severe allergic reaction to: • A previous dose of the same COVID-19 vaccine • An ingredient in of the COVID-19 vaccine

The Pfizer-BioNTech vaccine contains (PEG) which is in a group of known allergens commonly found in medicines. The Oxford-AstraZeneca vaccine does not contain PEG, so those with allergies to this ingredient can receive the alternative vaccine.

Additional information about anaphylaxis and adverse reactions to vaccines can be found here.

Vaccine ingredients

For full information on ingredients, ask for the Patient Information Leaflet for the vaccine you are offered. Common ingredients used in vaccines, and present in both the Pfizer-BioNTech and Oxford-AstraZeneca vaccines are:

• Sucrose (sugar) • Acidity regulators such as Histidine, and sodium and potassium salts

The active ingredient of the Pfizer-BioNTech vaccine is BNT162b2, which contains the genetic code for the coronavirus spike protein, inside a lipid (fat) capsule. The vaccine also contains other inactive ingredients such as cholesterol.

The active ingredient of the Oxford-AstraZeneca ChAdOx1 nCoV-19 vaccine is made from a modified adenovirus which causes the common cold in chimpanzees. This virus has been modified so that it cannot cause an infection. It is used to deliver the genetic code for the coronavirus spike protein. The vaccine also contains inactive ingredients such as polysorbate 80, an emulsifier, and a very small amount of alcohol (0.003mg per dose). The vaccine also contains traces of magnesium (3 to 20 parts per million).

All vaccine ingredients are present in very small amounts and there is no evidence that they can cause harm in these amounts. The Pfizer-BioNTech and Oxford-AstraZeneca vaccines do not contain:

• Human or animal products • Common allergens such as latex, milk, lactose, gluten, egg, maize/corn, or peanuts

Both the Pfizer-BioNTech and Oxford-AstraZeneca vaccines use genetic technologies to generate an immune response. More information about these technologies is below.

The manufacturing process for the Oxford-AstraZeneca vaccine involves the production of a virus, the adenovirus, which carries the genetic material to the cells inside the body. To produce this virus in the laboratory, a “host” cell line is needed. For some vaccines, chicken cells are used for this process, and for other human cell lines are used to produce the virus. The Oxford- AstraZeneca vaccine uses a cell line called HEK-293 cells. HEK-293 is the name given to a specific line of cells used in various scientific applications. The original cells were taken from the kidney of a legally aborted foetus in 1973. HEK-293 cells used nowadays are clones of those original cells, but are not themselves the cells of the aborted foetus.

Other therapeutic products which use HEK-293 cells as a producer cell line include Ad5 based vaccines, such as Cansino’s COVID-19 vaccine, Adeno associated viruses (AAV) and lentiviruses as gene therapy vectors for various diseases. Many of these products are in clinical trials.

See also, information about the use of human cell lines in the production of vaccines.

Nucleic acid and viral vectored vaccines explained

Newer vaccines such as mRNA vaccines and viral vectored vaccines, including the Oxford ChAdOx1 nCoV-19 vaccine differ from many traditional vaccines in the way they activate the immune system. Most traditional vaccines inject the antigen (part of the disease that stimulates an immune response) directly into the body. See types of vaccine for information about how different types of vaccines work.

In contrast, these two newer approaches deliver the genetic instructions for the antigen to the body’s cells. The cells then manufacture the antigen which goes on to stimulate the immune response. Injecting genetic material has raised questions about the use of these vaccines, such as whether they can modify the DNA of those receiving them. Here, we will explain why this is not possible.

Firstly, we will look at how cells normally manufacture proteins. Our DNA (DeoxyRibonucleic Acid) is safely packaged inside the nucleus of a cell and cannot leave. Within this DNA are gene sequences, and each gene encodes the blueprints for making one of the proteins the body needs. To make a protein the first step is to transcribe DNA into mRNA (messenger Ribonucleic Acid) using a special enzyme (or “tool”) called RNA polymerase. This step is a one-way process as cells are unable to transcribe RNA back into DNA. Unlike DNA, mRNA is free to leave the nucleus as it has a pass that allows it to exit. However, this pass is one way and once it leaves, the mRNA cannot return. Once it has left the nucleus the mRNA links up with the special cellular machinery in the cytoplasm. This machinery uses the information coded in the mRNA to make new proteins. As with the process of going from DNA to mRNA this process is also one-way, and it’s not possible to go backwards from protein to mRNA. These proteins may be used inside the cell or transported out of the cell for use elsewhere in the body. The COVID-19 mRNA vaccines take advantage of this internal process to make copies of the spike protein, which usually appears on the surface of the coronavirus. There are two types of vaccine which use this process: mRNA vaccines In this type of vaccine, mRNA is delivered to the cell inside a lipid membrane. Once the mRNA is inside the cell, the same machinery that is used to make our own proteins can make the spike protein. This mRNA has no way of getting into the nucleus where our DNA is. Even if it could, mRNA cannot fuse with DNA and as with our own mRNA, has no way of getting translated back to DNA. As such, there is no way for human DNA to be altered by an mRNA vaccine. This mRNA lasts a few days before the cell removes it, but in that time we have produced a lot of spike protein to stimulate the immune response. Viral vectored vaccines Viral vectored vaccines work in a different way. The genetic information inside a viral vectored vaccine like ChAdOx1 is DNA rather than RNA. This DNA is a short linear piece of double stranded DNA which contains the viral genes along with the gene for the spike protein. The viral vector first infects the cell and then delivers this DNA to the cell nucleus. The cell can then translate the viral genes (DNA) into mRNA using the same RNA polymerase it uses for our own genes. After translation, the mRNA gets tagged so it can leave the nucleus and be made into spike protein by the cell machinery. In the Oxford vaccine, the viral gene that is required to replicate viral DNA has been removed. As viruses use a different process to human cells to replicate their DNA, the cell itself cannot replicate viral DNA either. This means the viral vector cannot replicate (make more viruses) or cause disease. Both the original viral DNA and the spike protein mRNA only last a few days before the cell removes them. Such design features alongside a cell’s natural DNA protection measures, prevents any possibility of viral DNA integrating with human DNA. For more information about the new types of COVID-19 vaccines, see The Race for Coronavirus Vaccines.

Coronavirus COVID-19 (Older Information) COVID-19 is a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). This virus was first detected in Wuhan, China, in December 2019 and has led to a Pandemic, announced by the World Health Organization on 11thMarch 2020. This page provides the following information:

• Key facts about COVID-19 • What is a coronavirus? • How can you protect yourself? • Ongoing scientific research

Key facts Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in the city of Wuhan, China, in December 2019, after a cluster of patients with pneumonia of unknown cause were reported to the World Health Organization (WHO). The outbreak was declared a public health emergency of international concern on 30thJanuary 2020, and the disease caused by SARS-CoV-2 was officially named COVID-19 on 11thFebruary 2020. After assessing the outbreak and following transmission of the virus in many other countries worldwide, on 11thMarch 2020 the WHO declared COVID-19 a pandemic. This means that the disease has spread worldwide, and it is the first time that a coronavirus has led to a pandemic. Scientists are still trying to identify when and how the virus was initially transmitted to humans. Other coronaviruses are known to be transmitted via respiratory droplets, from coughing and sneezing, and COVID-19 is also thought to be transmitted this way. COVID-19 symptoms are similar to that of seasonal influenza (flu), and include:

• Dry Cough – constant and becoming more severe over time • Fever – a high temperature • Shortness of breath • Fatigue

You can prevent the spread of COVID-19 using similar methods as you would for the seasonal flu, such as washing your hands regularly, coughing into your elbow, and sneezing into tissues which are immediately thrown away. The control of a respiratory disease like COVID-19 is dependent on everyone in the country taking preventative measures to protect themselves and each other. If you feel unwell, with any of the symptoms above, please follow the NHS guidance.

What is coronavirus? Coronaviruses are a group of viruses that infect animals or humans. Animal coronaviruses mostly don’t infect humans, but can sometimes be transmitted from animals to humans. Most human coronaviruses cause a mild illness, such as the common cold, but there have been recent outbreaks by new coronaviruses that can cause more severe diseases, like middle east respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS). So far, scientists have not been able to identify the animal which led to human infection with the 2019 coronavirus but there are reports that the genome of SARS-CoV-2 is most similar to that of bat coronaviruses. There are still many uncertainties around the COVID-19 pandemic, but scientists are using all the data available to identify the severity of the disease. It is not yet clear what proportion of people will have no symptoms when infected with the virus. So far, it appears that 80% of people with proven infection experience a mild or moderate illness, with 20% requiring hospitalisation, and 6% needing intensive care. The disease is more severe in older people, particularly those over the age of 80, with 22% of this age group dying from the disease. Those with underlying medical conditions are also at a higher risk of dying from the disease, with the mortality rates as follows: 10.5% for those with cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6% for hypertension and 5.6% for cancer. In people without an underlying health condition, the risk of mortality is 0.9%. These data are from the China Center for Disease Control and Prevention, and can be viewed on the Our World in Data website. We do not yet have enough information to identify exactly how COVID-19 spreads. However, we know that other respiratory diseases caused by coronaviruses such as MERS and SARS, are spread by respiratory droplets, through coughing and sneezing. These droplets can either be inhaled by people nearby or can spread to other individuals via hands or surfaces. It is for this reason that the advice to protect yourself is to regularly wash your hands, and to cough or sneeze into your elbow instead of your hands. If you do touch surfaces in public places, it is also best to try not to touch your mouth or face afterwards, until you have washed your hands or applied hand sanitiser. COVID-19 has been compared with seasonal influenza, and while both may cause similar symptoms, the European Centre for Disease Control estimates that 1 in 1000 people die prematurely when infected with influenza, and the current estimates for COVID-19 suggest that 15-30 people in every 1000 infected will die from the disease. See the ECDC website for more information.

How can I protect myself? The practical measures being introduced, and the NHS advice is changing rapidly. To stay up to date, visit this UK government website. People are being advised to stay at home if they experience any of the common COVID-19 symptoms, to restrict unnecessary travel to some countries, and to increase respiratory hygiene practices like hand washing and binning tissues. All government advice is based on the most up-to-date scientific information, and our researchers, politicians, doctors and nurses are working hard to protect the UK from the most severe public health crisis in a generation. But they need the support of everyone else across the country to fight this epidemic. We must all work together to protect ourselves and each other from this disease. Many of the measures being introduced will be unfamiliar and may appear harsh. The everyday lives we are used to will be heavily disrupted and normal daily tasks will become difficult. These decisions are not being made lightly. In the UK, we have many leading experts in infectious diseases and public health, and these researchers are providing information to the government to support policy decisions. All guidance has been developed to protect our communities as best we can, and we must support each other during this time of uncertainty.

Scientific Research The main reason that COVID-19 poses more of a threat than seasonal influenza is because we have no immunity to the virus. As part of the UK immunisation programme, we vaccinate children against flu with the nasal flu vaccine, and older people and those with health conditions with the inactivated flu vaccine. Since SARS-CoV-2 is a new virus, we do not currently have a vaccine to protect against it. Many scientists around the world are working hard to develop a vaccine to prevent COVID-19, but there is a lot to be done. A team in Oxford led by Professor Adrian Hill, Professor Sarah Gilbert and Professor Andrew Pollard are working as fast as possible on the development of a vaccine to prevent infection from the virus.

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