Vaccines contain “active ingredients”. This usually refers to either “killed” (inactivated) whole virus, or components of a target virus (known as “attenuated” vaccine). There’s a new vaccine type, called mRNA vaccines. But they have the same objective: give them through a shot in the arm (intramuscular) and trigger our body’s immune response to antigens — viruses, bacteria and other pathogens, or parts of them.
To manufacture vaccines in a safe and effective way, and in order for them to work well, it’s important that they also contain other key ingredients. These are also known as "excipients". With the current pandemic, the role of vaccines has come to the fore. We explore some numbers:
Q: How many COVID-19 vaccines does the world need?
Vaccine makers are struggling to keep up with an unprecedented demand — experts estimate the world needs at least 10 billion COVID-19 vials as soon as possible. There are supply chain and raw material constraints that have posed global challenges.
But let's not ignore man's capacity to fight back, when rowing in the same direction. Just barely 14 months after the SARS-CoV-2 genome was sequenced, 1 billion vaccine doses had already been produced/administered in 177 countries (actually in just 4 months after the vaccines were approved). That ramp is a huge milestone by any standard. Yet there's still not enough to go around for everyone. But for now, let’s focus on what goes into vaccines:
Q: What do vaccines contain?
Linda Geddes, writing for Gavi, the global vaccine alliance, looked at the active ingredients that go into a vaccine and the roles they play. In general, vaccines contain the following:
- Sterile water
- Antiseptic liquids
- Antiviral agents/Antigen (genetic material of a target virus) to stimulate immune reaction in the body
- Preservatives to prevent contamination
- Other ingredients
Q: What are the “other” ingredients?
Aside from the active ingredient (antigens), vaccines contain many other stuff. They are technically known as “excipients”. Excipients include preservatives and stabilisers, traces of things that were used to produce the vaccine, and adjuvants. These “other” ingredients are often a source of concern for wary parents and patients. Below is a list of common ingredients in many vaccines, along with information on their purpose and safety, according to the CDC and publichealth.org:
Use: This ingredient has been used as a preservative in vaccines since the 1930s. Today, it is only found in vaccines for influenza. Preservatives are necessary for preventing dangerous bacterial or fungal contamination.
Health concerns: Mercury-containing thimerosal has become a major source of vaccine safety concerns. While mercury is a naturally-occurring element found in soil, water, and food, large amounts of it can be harmful, especially for children. Back in 1997, children were receiving three vaccines that together contained more mercury than the EPA recommended limit (though not more than the FDA limit). This led to speculation that thimerosal in vaccines could be linked to autism or other conditions.
Safety: Years of research have reduced concerns. This is because the type of mercury found in thimerosal — ethylmercury — differs from methylmercury, the type commonly found in fish and known to be harmful in large amounts. Ethylmercury is broken down and excreted from the body much more quickly than methylmercury, and no scientific study has found a link between ethylmercury and autism or any other harmful effects.
Amount: In 1999, public health agencies and vaccine manufacturers agreed to cease using thimerosal as a precautionary measure. Today, no vaccine contains Thimerosal except the influenza vaccine, and Thimerosal-free alternatives are available.
Use: Formaldehyde has been used for decades in vaccines to inactivate viruses and detoxify bacterial toxins, ensuring they don't result in sickness when injected.
Health issues: Both the EPA, the International Agency for Cancer Research (IACR) and the US National Toxicology Program classify formaldehyde as a carcinogen. Additionally, several studies have since linked strong, long-term formaldehyde exposure to certain types of cancer.
Safety: The potential for harm depends on the amount. Formaldehyde is always present in the human body as part of our natural metabolic process, but long-term exposure to high amounts can overwhelm our system and be harmful. The amount of formaldehyde found in vaccines is very small, most of it being diluted down to residual amounts during the manufacturing process. The FDA reports there is 50 to 70 times more formaldehyde present in an average newborn's body than in a single dose of vaccine. In brief, current science shows formaldehyde in vaccines to be harmless.
Amount: The highest amount of formaldehyde present in any vaccine is .02 mg per dose. An average two-month-old baby would have around 1.1 mg of formaldehyde circulating in their body, with higher naturally-occurring amounts for older children.
Use: Aluminum is used as an “adjuvant” in vaccines. That is, it makes them more effective by strengthening the immune system response. The use of adjuvants allow people need fewer doses of vaccine to build immunity.
Health issues: Sometimes the mention of aluminum in vaccines makes parents uneasy; that's because there has been some evidence that long-term exposure to high amounts of aluminum can contribute to brain and bone disease. However, aluminum is naturally present in water, foods, even breast milk. Aluminum has only been shown to harm people if absorbed in very high amounts and when a person's kidneys aren't working properly. In contrast, the amount of aluminum in vaccines is negligible.
Safety: Aluminum is the third most-common naturally-occurring element, after oxygen and silicon. It is found in plants, soil, air, and water. Aluminum has been used safely for over 6 decades in vaccines, with no scientific evidence indicating otherwise.
Amount: Babies always have a small naturally occurring amount of aluminum in their bloodstreams, about 5 nanograms. A breast-fed infant will naturally ingest around 7 milligrams of aluminum in her diet throughout the first six months of her life. In contrast, the standard vaccines administered over the first six months of an infant's life contain an average of just 4.4 milligrams of aluminum. The quantity of aluminum in a vaccine is so small it doesn't cause any noticeable raise in this base amount found in the blood, even immediately after an injection.
Use: During the production process of some vaccines, antibiotics may be used to counter the risk of dangerous bacterial infection.
Health issues: Concern occasionally arises about antibiotics in vaccines because of the risk of allergic reactions in some children.
Safety: These fears are greatly exaggerated. Vaccine manufacturers only use antibiotics that are far less likely to provoke a reaction, and because antibiotics are only used during production, they are reduced to trace or undetectable amounts in the final product. In fact, no allergic reaction to a vaccine has ever been traced back to antibiotics. The overall odds a child will suffer from a severe allergic reaction from an MMR or Hepatitis B vaccine, from any ingredient, is 1 in 1,000,000, one hundred times less than the 1 in 10,000 chance a child will be struck by lightning.
Amount: During the purification steps of the production process, antibiotics are removed, resulting in miniscule or undetectable amounts in the final vaccine.
Use: Gelatin is used as a preservative and stabiliser, keeping vaccines effective under heat or cold and for the duration of their shelf life.
Health concerns: For a very small number of children, gelatin can cause an allergic reaction.
Safety: While gelatin is the single largest identifiable source of severe allergic reactions from vaccines, the incidence rate is still incredibly small. There is about one case of anaphylaxis caused by gelatin in vaccines for every two million injections.
Amount: The amount of gelatin varies by vaccine, with the MMR vaccine on the high end, containing 14.5 mg per dose, and the DTaP on the low end, with only 0.0015 mg. Children with a history of gelatin allergies can seek alternatives or exemptions.
Monosodium Glutamate (MSG)
Use: Like gelatin, MSG is used as a preservative and stabilizer in some vaccines, keeping them effective through heat, cold, and shelf life.
Health concerns: MSG gained a bad reputation starting in the 1960s after anecdotal reports surfaced of nausea, headaches, flushing, or sweating due to food with MSG. As a result, concern has spread about its use in vaccines. However, these concerns are not supported by scientific research.
Safety: While the scientific community acknowledges that a very small minority of people may suffer from short-term reactions to MSG, decades of research have not found the element to be harmful. As a result, the Food and Drug Administration, the WHO, and the UN all declare MSG to be safe. It has been used for decades and continues to be used in foods as a flavour-enhancer.
Amount: While some websites have trumped up MSG-based alarm, it is only present in two scheduled vaccines, adenovirus and influenza.
Source: CDC https://www.cdc.gov/vaccines/vac-gen/additives.htm
Q: What are adjuvants?
The science behind vaccines has gone through 220 years of development. Today, many vaccines contain active ingredients robust enough to kick our immune system into action, but some need a little bit of extra help to be effective.
Adjuvants make vaccines stronger. They are compounds that elicit a strong immune response, improving how well a vaccine works. Examples of adjuvants include:
- Biological molecules (i.e. components isolated from bacteria, synthetic DNA
Aluminum in the form of aluminum salt, is used in a number of vaccines, including several routine childhood vaccines. Adjuvants help boost the production of antibodies. It use as an “adjuvant" goes back to the 1930s. While some scientists believe that the metal can cause damage to the nervous system and promote autoimmunity, many experts disagree with this assessment, pointing out that some of the research implicating aluminum has been retracted.
The US Food and Drug Administration (FDA) published a study in 2011 in the journal Vaccine, which concluded that “episodic exposures to vaccines that contain aluminum adjuvant continue to be extremely low risk to infants and that the benefits of using vaccines containing aluminum adjuvant outweigh any theoretical concerns.”
What's squalene used for?
Squalene, a naturally-occurring oil, is another example of an adjuvant. The Fluad vaccine, a flu vaccine licensed for adults aged 65 years and older, contains an adjuvant called MF59, which is an oil-in-water emulsion containing squalene. The squalene used in MF59 is purified from shark liver oil.
In 2000, a research team pointed to a link between squalene and Gulf War Syndrome, prompting fears about the safety of this adjuvant. However, subsequent research did not back up the findings, and the WHO concluded in 2006 that these fears were “unfounded.”
What about human cell lines?
There are two human cell lines that pharmaceutical companies use. These are called WI-38 and MRC-5. Both of these cell lines were established from cells taken from the lungs of aborted foetuses.
After “expansion”, viruses are harvested from these cell lines and purified. The chance of any human cell material being present in the vaccine is very small.
Other viruses are grown in animal cells before being incorporated into vaccines. Animal cells used for this purpose include kidney cells from African green monkeys (Vero cells) and chick embryo cells. Some recombinant vaccines may contain small trace amounts of yeast proteins or yeast DNA.
Flavouring, colouring syrups
Flavouring and colouring syrups may also be used. They are known as “excipients” —which are inactive substances — but feature heavily in all medicines. Sugars and flavouring in syrups help dull the potentially unpleasant taste of the formulation. Colours help people avoid mistaking one drug for another. Some excipients improve how well a drug can penetrate the skin or determine where in the gastrointestinal tract its breakdown occurs.
Q: Why did the US block exports of the critical vaccine material?
Today, every country wants to vaccinate its people against COVID-19 — and as soon as possible. But there aren’t enough shots to go around (or are least not yet). Production bottlenecks have been reported due to the sheer, unprecedented demand. And it doesn’t help that the US has blocked exports of important vaccine ingredients, until it made a dramatic policy U-turn only on Monday, April 26.
To accelerate vaccine production for the US population, the Biden administration invoked the Defence Production Act (DPA), which effectively curbed vaccine raw materials exports.
As it turns out, the US vaccine makers also source from India some of their key ingredients, especially for mRNA shots, used by both Moderna and Pfizer. US vaccine makers have ramped up production, but also reported bottlenecks in terms of raw materials and logistics.
Q: What’s been the reaction to the ban?
As India reels from a massive spike in COVID caseloads in key states, there was a sense of exasperation as US refused, initially, to lift the ban on badly-needed vaccine raw materials.
The US move vis-a-vis India was seen a one-way street. As the world watched in shock amidst India’s COVID catastrophe, Bollywood stars like Priyanka Chopra chimed in with appeals for the lifting of the export ban.
It’s a shockingly one-sided, unjust unconscionable stance. For example India’s VAV Lifesciences and its subsidiary VAV Lipids, “nutraceutical” specialty ingredient maker based in Mumbai, has not stopped the supply of highly purified “synthetic phospholipids” required for vaccine manufacturing in the US.
As such, the US boosted supplies of key raw materials like bags, filters, vials, glass, cell culture media, plastic tubings, stoppers and some reagents. A ban on these items directly impacted Indian vaccine makers.
Q: What are phospholipids?
Phospholipids are synthetic lipids — fat — used in the formulation of lipid nanoparticles (LNPs). They are crucial “biomolecules” used in manufacture of mRNA-based COVID-19 vaccines. VAV Lifesciences and VAV Lipids have a deal with a US-based multinational contract development and manufacturing organisations (CDMO), to supply high-purity “synthetic phospholipids” required for vaccine manufacturing. The White House has since lifted the export ban to India.
Q: What are phospholipids used for?
The CDMOs use lipids made by India’s VAV to produce gene-based LNPs for exclusive use in the COVID-19 vaccines of Pfizer-BioNTech and Moderna, two of the leading US vaccine makers. The tiny fat particles enclose submicroscopic mRNA strands which is then administered into the arms of people.
For the mRNA vaccines — being used in humans for the first time — LNPs effectively deliver the mRNA to the target cells and help bind the active vaccine ingredients to the relevant cells.
By nature, mRNA is extremely sensitive to degradation and rapid breakdowns. LNPs function to ensure the protection of the mRNA until its uptake in cells. The technique was pioneered by the power research duo Dr Katalin Kariko and Dr Drew Weissman, both known as the intellectual “parents” of mRNA vaccines. The result: better cellular response and efficacy against virus replication, significantly enhancing the overall immunogenic response of vaccines.
Q: How many manufacturers of phospholipids are there in the world?
One report states there are only up to four manufacturers of this highly specialised material. India's VAV Lifesciences is the only manufacturer in India.
Q: Why is there a COVID-19 vaccine shortage?
Because of the sheer demand. The COVID-19 crisis is unprecedented, and governments are facing challenges in vaccinating their people. As part of his campaign, US President Joe Biden promised to administer 100 million vaccination shots in his first 100 days in office (by April 30, 2021). The government aims to buy 600 million vaccines for its 300 million population. This has put stress on the US raw material companies — given the demand from all across the world.
The US recently decided to buy an additional 100 million doses of each of the two — Pfizer and Moderna. This has increased the total vaccine order for the US by 50 per cent, from 400 million to 600 million.
Q: Will removing intellectual property (IP) protections speed up vaccine production?
Given the sheer volume of demand, estimated at 10 billion doses at least, proponents of doing away with IP rights say more companies in more countries could produce the vaccines. This, they said, would provide broader access in poorer nations that so far have seen few doses. However, removing IP protections from COVID-19 vaccines or pressuring companies into technology sharing, will not necessarily speed up production of the shot, and could even slow it down, say industry experts.
275number of COVI-19 vaccine manufacturing deals — including on technology transfer among staunch competitors.
An IP waiver "wouldn't give us the tools to produce more doses of vaccines", Thomas Cueni, head of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), said.
Already, around 275 manufacturing deals — including on technology transfer among staunch competitors — had helped the industry go from zero to one billion COVID-19 vaccine doses produced within 12 months after the virus started spreading from China. The world’s vaccine makers have set a collective goal of 10 billion doses by the end of the 2021.
Q: How do vaccines help global public health?
The WHO estimates that vaccinations prevent between 2 and 3 million deaths every year across the globe. Severe side effects are very rare, making vaccines one of the safest healthcare interventions in the history of modern medicine.