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Vaccines have long been celebrated as one of the most significant achievements in public health. They are designed to protect us from infections caused by both viral and bacterial organisms. For instance, measles and smallpox are viral diseases, while Streptococcus pneumoniae is a bacterium responsible for illnesses like pneumonia, ear and sinus infections, and meningitis. Vaccines have saved hundreds of millions of lives by eradicating smallpox and drastically reducing polio and measles cases. Yet, some confusion persists about how vaccines are made and why certain seemingly frightening ingredients [PDF] are included in the manufacturing process.
Vaccine production has advanced considerably since its early days when vaccination carried potential risks. Initially, inoculating a person with crushed smallpox scabs often resulted in a mild infection (known as 'variolation') that provided immunity from the disease, but there was always the possibility of a severe infection. When Edward Jenner introduced the first real vaccine using cowpox, the risk of smallpox became much lower, but challenges remained: The cowpox material could be contaminated with other germs, and occasionally, it was transmitted from one vaccinated person to another, inadvertently spreading blood-borne pathogens. In the past 200 years, we have made remarkable progress.
There are various types of vaccines, and each requires a unique process to go from the laboratory to your doctor's office. The central element in all of them is the creation of one or more antigens—the part of the microbe that prompts the immune system to respond.
Live Attenuated and Inactivated Vaccines
Antigens can be produced through various methods, with one common approach being the cultivation of a virus in a cell culture. These cultures are typically grown in large containers known as bioreactors, where living cells are infected with the virus. The virus is placed in a nutrient-rich liquid growth medium that provides proteins, amino acids, carbohydrates, and essential minerals to facilitate viral growth. In the process, the virus also receives protection in the form of antibiotics like neomycin or polymyxin B, which help prevent bacterial or fungal contamination that could harm the host cells.
After the virus completes its life cycle within the host cell, it is purified by separating it from the host cells and the growth medium, both of which are discarded. This separation is typically done using filters of various types. The small size of the viruses allows them to pass through these filters, which trap larger host cells and cellular debris.
This process is how 'live attenuated vaccines' are made. These vaccines contain viruses that have been altered to be harmless to humans. Some viruses are grown in non-human cells, such as chicken cells, over many generations, leading to mutations that prevent them from causing harm. Others, like the influenza nasal mist, are cultured at low temperatures to inhibit replication at the warmer body temperatures found in the lungs. Many childhood vaccines, including those for measles, mumps, rubella, and chickenpox, are live attenuated vaccines.
Live attenuated vaccines replicate for a short period in the body, provoking a strong and long-lasting immune response. Since the immune system reacts intensely to what it perceives as a serious threat, fewer doses are needed to protect against these diseases. Unlike the harmful virus, these vaccines replicate only minimally and are extremely unlikely to cause the disease or transmit it to others. One exception was the live polio vaccine, which could spread to others and, in rare cases, cause polio (about one case per 3 million doses). As a result, the live polio vaccine was phased out in the United States in 2000.
Scientists apply the same growth method for 'killed' or 'inactivated' vaccines, but with an additional step: viral destruction. The viruses in these vaccines are killed, typically through heat treatment or exposure to chemicals like formaldehyde, which alter the virus's proteins and nucleic acids, rendering it unable to replicate. Inactivated vaccines include Hepatitis A, the injected polio vaccine, and the flu shot.
A dead virus cannot replicate in the body, which means the immune response to inactivated vaccines is not as intense as the one generated by live attenuated vaccines. While the live virus replicates and triggers various immune cells to respond, killed viruses mainly stimulate one part of the immune system—your B cells, responsible for producing antibodies. This is why inactivated vaccines require more doses to build and maintain immunity.
While live attenuated vaccines were the standard method for creating vaccines until the 1960s, concerns about safety and the complexity of manufacturing them have led to fewer attempts at developing new live attenuated vaccines today.
Combination, Bacterial, and Genetically Engineered Vaccines
Some vaccines are made not from entire organisms but from parts of microbes. An example is the combination vaccine that protects against diphtheria, pertussis, and tetanus all in one shot. Known as DTaP for children and Tdap for adults, this vaccine includes toxins (the proteins that cause disease) from the bacteria responsible for diphtheria, pertussis, and tetanus. These toxins are inactivated by chemicals and referred to as 'toxoids' once neutralized. This ensures protection against diseases like diphtheria and tetanus, even if exposed to the bacteria. (Though some viruses, like Ebola, have toxins, they are not used as the key antigens in current vaccines.)
Just like with live attenuated or inactivated vaccines, the scientists creating bacterial vaccines first need a target bacterium to cultivate. However, unlike viruses, bacteria do not require host cells for growth. Therefore, vaccine manufacturers can produce them in simple nutrient broths. After growing the bacteria, the toxins are separated from the rest of the bacteria and growth medium, then inactivated for use in vaccines.
Similarly, some vaccines only use specific antigens from certain bacterial species. Vaccines for *Streptococcus pneumoniae*, *Haemophilus influenzae* type B, and *Neisseria meningitidis* all utilize sugars found on the bacterial outer surface as antigens. These sugars are extracted and then attached to a protein, which boosts the immune response. The added protein helps to recruit T cells alongside B cells, leading to a stronger immune reaction.
Genetic engineering also plays a role in vaccine production. For example, the vaccine for Hepatitis B, which causes severe liver disease and liver cancer, contains a single antigen: the hepatitis B surface antigen, a protein found on the virus's surface. The gene responsible for producing this antigen is inserted into yeast cells. These cells are then grown in a medium similar to bacterial culture, and the hepatitis B surface antigen is extracted from the yeast to form the primary component of the vaccine.
Other Ingredients in Vaccines (and Why They're There)
In some cases, once live or killed viruses or purified antigens are obtained, additional chemicals are necessary to preserve the vaccine or improve its effectiveness. Adjuvants, such as aluminum salts, are common additives. They enhance the immune response by keeping the antigen in contact with immune cells for longer periods. Vaccines like DTaP/Tdap, meningitis, pneumococcus, and hepatitis B all use aluminum salts as adjuvants.
Some additional chemicals may be included as stabilizers to ensure the vaccine remains effective even under challenging conditions, such as extreme heat. Stabilizers may include sugars or monosodium glutamate (MSG). Preservatives might also be added to prevent the growth of microbes in the final vaccine product.
For many years, thimerosal, a compound that is 50 percent ethylmercury by weight, was the most common preservative used. Ethylmercury is rapidly eliminated by the body through the digestive system, in contrast to methylmercury, which can accumulate in fish and cause long-term harm in humans at high doses. Due to consumer concerns, thimerosal was phased out of childhood vaccines in 2001, but numerous studies have confirmed its safety.
The vaccine is then packaged into vials for distribution to physicians, hospitals, public health agencies, and some pharmacies. These vials may be single-dose or multi-dose, with multi-dose vials being suitable for multiple patients as long as they are handled and stored away from patient areas. Preservatives are especially important for multi-dose vials, as repeated use increases the risk of contamination from bacteria and fungi. This is why thimerosal is still used in certain multi-dose influenza vaccines.
Although some of the ingredients in vaccines may sound concerning, most are eliminated during the extensive purification process. The chemicals that remain, such as adjuvants, are crucial for the vaccine's effectiveness. These substances are present in extremely low quantities and have a strong safety record.
