1 What is a Vaccine and How do Vaccines Work?
- Kristen A. Feemster
A vaccine is a substance that is given to a person or animal to protect it from a particular pathogen—a bacterium, virus, or other microorganism that can cause disease. The vaccine prompts an immune response in the body that produces antibodies, which are proteins that fight specific pathogens. The goal of giving a vaccine is to prompt the body to create antibodies specific to the particular pathogen, which in turn will prevent infection or disease; it mimics infection on a small scale that does not induce actual illness. A similar process does occur when the body confronts actual pathogens, but vaccines spare individuals from the dangers of disease.
A vaccine can be made from any one of a variety of sources: a killed or weakened bacteria or virus, a protein or sugar from the pathogen, or a synthetic substitute. For a vaccine to do its job, the following need to happen: (1) The vaccine needs to stimulate antibody production, and (2) the antibodies need to have avidity (attraction to the specific pathogen). Antibodies will not work if they do not bind to the invading pathogen. Vaccine protection also requires that the body recognize the pathogen and keep making antibodies when they are needed, which is called immune memory. When this happens, the vaccinated body is ready to produce more of these antibodies right away, whenever the body is exposed to the bacteria or virus.
Antigens are proteins on the surface of a pathogen that prompt the production of antibodies by the immune system. Bacteria and viruses are both covered in antigens, and during the process of natural infection, these antigens are what the body recognizes. Depending on the pathogen, its antigen coating can be made up of several proteins or several thousand.
Vaccines, on the other hand, are often made using just a few antigens from a bacteria or virus. This is because some antigens are better than others at sparking the immune system. This is also because it is important to separate the parts of a pathogen that cause disease and make one sick from those that induce an antibody response. The ability to cause disease is called virulence, whereas the ability to induce a protective immune response is called immunogenicity.
The number of antigens in vaccines is actually quite small compared to the number of antigens that confront the immune system during an actual infection (or just from the environment on a daily basis). For example, the pathogen that causes whooping cough contains more than 3,000 antigens; the vaccine that is used to protect against whooping cough contains only 3–5 different antigens. Our immune systems are stimulated all the time, but all stimulation is not the same.
What happens when the immune system is confronted by an antigen?
When one’s body encounters an antigen (from either a vaccine or a natural exposure), it sparks a cascade of events that constitute an immune response. This response requires communication between several different types of cells and ends in the creation of memory cells that are equipped to respond to future invasions by the same antigen. When antigens are introduced as part of a vaccine, the steps essentially are as follows:
Helper T cells activate B cells (these make antibodies) or killer T cells (needed to attack pathogens such as viruses that live inside of cells).
The activated B cells and killer T cells become memory immune cells that will reactivate during actual infection and keep the pathogen from invading.
How do cells signal each other in the process of creating antibodies?
Immune cells emit signals through the secretion of cytokines. Cytokines are crucial to our immune response in that they recruit all the cells we need to attack antigens and create memory cells. Some cytokines are also responsible for the symptoms that are generally associated with infection, such as fever. This is why we may experience a low fever after vaccination: It means our immune system is in the process of making memory cells, and cytokines are being employed as part of the communication between cells that contributes to this process.
Which is better, natural immunity or immunity after vaccination?
In general, natural infection results in a more robust, durable immune response. This is because an actual infection usually results in a stronger immune response (not to mention an actual illness), whereas we may need more than one dose of a vaccine to achieve full protective immunity. After infection, we make a greater number and greater diversity of antibodies—ones that may recognize different parts of a pathogen (i.e., its antigens). In the case of some pathogens, such as chickenpox and measles, infection results in lifelong immunity.
However, this is not the case for all pathogens. For example, immunity decreases over time after a pertussis (whooping p. 4↵cough) infection. Children younger than age 2 years who are infected with a certain family of bacteria are not able to mount an immune response that makes memory cells, so even after infection, they have no long-lasting immunity. If a virus or bacteria has multiple strains, infection with one strain may not provide immunity against other strains.
Some vaccines induce a stronger immune response than natural infection. One example is the human papillomavirus (HPV) vaccines, which are made from a purified capsid protein that induces higher antibody levels than are seen in individuals who have had actual HPV infection. The same is true of tetanus vaccines: Those who receive the vaccine have more antibodies than those who survive infection.
However natural immunity may compare to vaccine immunity for a given disease, it is important to remember that natural immunity comes with the cost of having to endure a disease or infection, which depending on the illness can result in disability or death.
What is the real risk of vaccine-preventable diseases?
Since the advent of vaccines, the incidence of vaccine-preventable diseases has decreased dramatically. The risk of being exposed to many of these diseases is therefore quite low, and some diseases (including polio and diphtheria) have been eliminated from the United States. For other vaccine-preventable disease, overall incidence has decreased but cases still occur because available vaccines do not cover all of the different types of the bacteria or virus. For example, the bacterium Pneumococcus, for which a vaccine has existed since the 1980s, continues to cause tens of thousands of cases of pneumonia, bloodstream infections, and meningitis every year.
On the other hand, the incidence of some vaccine-preventable diseases has persisted and even increased in recent years. Pertussis (whooping cough) cases have increased steadily since the 1980s, with nearly 50,000 cases reported p. 5↵in the United States in 2012. Pertussis affects all age groups, although infants have the highest risk of severe disease and typically require hospitalization. There are also regular outbreaks of vaccine-preventable diseases such as mumps, varicella, measles, and Meningococcus (which causes bloodstream infections and meningitis) in the United States and internationally. In places where there is reliable access to a developed medical system, the risk of death due to infection with any of these pathogens is low, but severe disease can and does still occur. The global risk of death due to pertussis among infected infants is approximately 1 in 100; for measles it is 1 in 1,000; and for Meningococcus across all age groups, the fatality rate for infected individuals is 1 in 10.
Thus, the actual risk of contracting a vaccine-preventable disease is difficult to project. Outbreaks of vaccine-preventable diseases generally occur when there are clusters of susceptible individuals or people who do not have immunity. When this happens, there is nothing to stop the virus or bacteria from moving between people. This is a larger issue for pathogens that are easily spread from person to person, such as pertussis or measles. Vaccination works by reducing the number of susceptible individuals, thereby stopping transmission; the bacteria or virus simply runs out of places to go. This is called herd immunity.
What is herd immunity?
Vaccines work by protecting the individual who is vaccinated. A vaccinated individual is less likely to become infected, and if the individual is not infected, he or she cannot spread the infection to others. When there are many vaccinated people in a community, there is nowhere for the bacteria or virus to go—the group, or herd, becomes immune. So even if there are a few individuals who are not vaccinated in the group, they are protected because there is no one around to expose them to the infection. This works better for some infections p. 6↵compared to others. Viruses or bacteria that are easily transmitted, including measles and pertussis (whooping cough), require that almost everyone in a given group be vaccinated in order to achieve herd immunity. Other infections require close contact for longer periods of time in order for exposure to result in infection. In these cases, a lower immunization rate can achieve herd immunity. In this manner, vaccines have had greater impact on disease rates than they would if every disease required uniform vaccination rates.
What happens when immunization rates are not high enough to achieve herd immunity?
When immunization rates are low, more individuals are susceptible to infection and are at risk of becoming infected. If anyone does become infected, the lower the immunization rate, the more opportunities there will be to spread the infection to other susceptible individuals in their group. When several cases such as this cluster together, an outbreak occurs. Outbreaks grow as long as there are more susceptible people in a given community to become infected and expose others. Outbreaks slow and eventually end when enough people are immune—either because of infection or because of vaccination.
How large are most outbreaks?
The size of an outbreak depends on the number of susceptible people, the infectivity (or contagiousness) of the pathogen, and the severity of disease caused by infection. For example, if a pathogen causes people to become very sick very quickly, there may be less opportunity for those individuals to go out and infect others. However, some pathogens, such as pertussis, can be transmitted before people even know they are infected, making these infections more difficult to control once they have started spreading in a community. This is why vaccines p. 7↵are used as a response to outbreaks: They prevent people from becoming infected in the first place.
What is the difference between immunization and vaccination?
Immunization refers to any exposure that provides immunity, which means that it encompasses both vaccination and natural infection. Immunization is often referred to as active or passive. Active immunization occurs when an individual is exposed to an antigen and then has an immune response that produces antibodies. Thus, active immunization can take place through vaccination or natural infection.
Passive immunization occurs when an individual receives antibodies from other than a first-hand immune response. The most common form of passive immunity is pregnant mothers passing antibodies to their fetuses through the placenta; this provides immune protection to infants for the first several months of their lives. Another form of passive immunization occurs through medical intervention, particularly for people with immunodeficiencies that keep them from making their own antibodies. In these cases, the immunodeficient individual may receive a blood product that contains antibodies pooled from other people. In cases of exposures to certain infections, including rabies, a person may be injected with a set of rabies-specific antibodies to provide immediate protection. These antibodies are short-lived and do not activate immune memory cells, so the immunization is considered passive.
What are the different types of vaccines?
A vaccine’s composition influences the type and durability of the immune response it elicits. In this regard, vaccines are classified into one of six categories: live attenuated, inactivated (or killed), protein subunit, polysaccharide, polysaccharide conjugate, and recombinant.
p. 8↵Live attenuated virus vaccines are made from a virus that is weakened to the point that it cannot cause disease. As viruses, they act as parasites that depend on other cells to live. With live attenuated virus vaccines, a weakened virus enters a cell and reproduces just enough to induce an immune response but not enough to infect many other cells and cause illness. Three different methods are available to weaken viruses for vaccines. First, a virus could be grown in nonhuman cells. Viruses that infect humans grow best in human cells, so using nonhuman cells, such as chicken cells, as a growth medium ensures that the virus then will not reproduce very well in humans. This method is commonly used for chickenpox, measles, and mumps vaccines. A second method grows virus at temperatures lower than body temperature, thereby robbing the virus of its ability to reproduce well at body temperature. The third method combines elements of nonhuman and human viruses, retaining human virus components that induce the immune response while the nonhuman parts of the virus ensure the virus does not reproduce well enough to cause true infection and illness. This method is used for one of the rotavirus vaccines.
Inactivated or killed vaccines are made from a whole virus or bacteria that has been killed or neutralized through the application of a second substance—usually, a tiny amount of formaldehyde. Inactivated or killed viruses are not able to reproduce and cannot cause infection or disease, but because the body is still exposed to the whole virus, it is able to mount an immune response. The hepatitis A, polio, and most influenza vaccines utilize this method.
Protein subunit vaccines work by isolating the antigens or proteins on bacteria that are known to be important for inducing a protective immune response. Some protein subunit vaccines target antigens known to act as toxins. Diphtheria and tetanus vaccines, for example, are made by inactivating the toxins that these bacteria produce, creating inactivated toxins called toxoids. Pertussis vaccines are made from two to up to p. 9↵five different proteins that are either toxins or are part of the bacteria itself (compared to the 3,000 proteins contained in a whole pertussis bacterium). The inactivated proteins cannot cause infection or disease, but they will lead to an immune response to recognize and inactivate the bacteria or toxin when actual infection occurs.
Similar to protein subunit vaccines for bacteria, recombinant vaccines are made from individual viral proteins that are known to induce a protective immune response. To make recombinant vaccines, the gene that is responsible for making the selected protein is inserted into the DNA of a yeast cell. As the yeast reproduces, so too does the DNA, and the resulting protein is purified to make a vaccine. Both hepatitis B and HPV vaccines are made using this technique.
Polysaccharide vaccines target a certain group of bacteria that have a special capsule on their surface made of sugars or polysaccharides. Because their capsule is what the body interacts with first, it is also what the immune response targets. Thus, vaccines for encapsulated bacteria are made using this capsule rather than any proteins from the bacteria.
However, polysaccharide capsules do not induce immune memory well, nor do they work well in children younger than age 2 years. This is a problem because the bacteria with capsules—pneumococcus, meningococcus, and Haemophilus influenzae b (Hib)—can cause severe disease in young children. This led to the development of conjugate vaccines, in which the polysaccharide capsule is attached to a protein that is able to turn on memory cells.
Why are there so many types of vaccines?
Vaccine development has evolved as scientists learn more about how the body responds to certain pathogens and antigens; the ultimate goal is to produce antibodies that are specific to the pathogen but will not attack healthy cells in the body. These antibodies also need to target the right parts of p. 10↵the pathogen, both so the pathogen does not persist to cause infection and so the antibodies persist and are remembered as long as possible.
Why do most vaccines require more than one dose?
Some vaccines, particularly live attenuated virus vaccines, are efficient in generating a protective immune response because they turn on the immune system in a way that mimics natural infection. In these cases, one dose of a live virus vaccine is generally protective for most people. Inactivated or protein vaccines are not quite as efficient, so these vaccines require more than one dose to achieve complete protection. The additional vaccine doses, often called “boosters,” help boost the immune response. The first dose is called a priming dose: Because it is the first time a person experiences the antigen, it is the first time the body starts to make the memory cells. The subsequent doses increase the number of memory cells and also help the body maintain circulating antibodies.
Besides antigens, what else are vaccines made of?
To keep vaccines safe and help increase their effectiveness, they may include other substances besides antigens. These include the following:
Preservatives such as phenol and thimerosal (which is also known as ethylmercury) prevent vaccine contamination from any bacteria in the environment during and after production. These substances are especially important in preventing contamination after a vaccine vial has been opened for use. For this reason, preservatives are required in vials that contain more than one dose.
Inactivating agents such as formaldehyde inactivate viruses or bacterial toxins for inactivated virus or bacterial toxoid vaccines (see previous discussion about vaccine types). Formaldehyde is used during production of some vaccines to inactivate a virus or bacteria. Although the formaldehyde is removed after the virus or bacteria is inactivated, there can be a small residual amount left behind in production. The allowable residual is much lower than the amount of formaldehyde that naturally occurs within the body.
Adjuvants, or substances that help enhance the immune response to vaccines, are especially important for elderly and immunocompromised patients who may have a weaker response to vaccination. Adjuvants also help enhance the immune response to vaccines that use only a few antigens; they are not needed in weakened or killed whole virus vaccines that induce a more complete immune response. Aluminum salts are most commonly used in US licensed vaccines. Aluminum is the most widely used vaccine additive because it helps boost the immune response, either by stimulating the uptake of antigens by immune cells or by slowing the release of an antigen at the site of injection to promote a more sustained antibody production. Vaccines containing aluminum adjuvants have been in use the longest and have a uniform track record of safety.
Adjuvants, preservatives, and inactivating agents are necessary to ensure safety and effectiveness in vaccine production. The fact that these substances include aluminum, formaldehyde, and thimerosal—substances that can be associated with toxicity above certain levels in the body—has raised safety concerns among some, particularly those who are hesitant about vaccines.
There is no evidence that exposure to any of these substances in vaccines results in toxicity or illness. The use of any vaccine additive is regulated by the US Food and Drug Administration (FDA) and must follow strict requirements for allowable amounts. The details related to these additives are also a central focus of the licensing application for any vaccine, and these details cannot be changed without submitting an amendment to the FDA. As per federal requirements, the type and amount of all vaccine additives must be listed on a vaccine’s label.
Heavy metals such as aluminum and mercury are present in the environment and can also be found in many foods that people eat. (Mercury, for example, can also be found in infant formula.) Human bodies excrete the heavy metals to which they are exposed, and every human has a small but detectable level of aluminum and mercury in his or her bloodstream at all times. The very small amounts of these substances found in vaccines do not increase these circulating levels, and the exposure that occurs with vaccination is negligible compared to what individuals encounter on a daily basis.
Formaldehyde, which is used to inactivate viruses or bacteria during vaccine manufacturing, has been shown to damage DNA in animal cells, which is the same process by which cancer cells are made. However, the tie between formaldehyde and damage to cell DNA is based only on animal models and laboratory experiments, and formaldehyde is not considered a human carcinogen. It is important to note that formaldehyde is a necessary component of human metabolic pathways, including DNA synthesis. For this reason, every individual has a detectable amount of formaldehyde in his or her bloodstream that far exceeds the amount found in vaccines.
Because mercury toxicity can affect the nervous system, there has been a concern that thimerosal (ethylmercury) could be linked to neurodevelopmental disorders such as autism (vaccines and autism are also discussed later). This concern arose after the 1998 publication of an article in the medical journal The Lancet in which British gastroenterologist Andrew Wakefield and colleagues presented a series of 12 patients who developed autistic behaviors and gastrointestinal symptoms after receiving the measles, mumps, and rubella (MMR) vaccine, which at the time contained thimerosal. The article hypothesized that the MMR vaccine may have prompted the production of antibodies that attacked the nervous system and led to the behavioral changes. On the coattails of the Wakefield study, others soon hypothesized that thimerosal could cause autism.
In the years that followed the publication of the Wakefield study, journalists and other scientists unearthed flaws in Wakefield et al.’s research, along with multiple professional conflicts of interest and ethics violations, that together discredited the study’s findings and the authors’ allegation of a link between MMR and neurodevelopmental disease (e.g., autism). In 2010, The Lancet took the extraordinary step of retracting the paper, with the journal’s editor-in-chief telling The Guardian that the editorial board had been “deceived” by the authors’ representation of their methods. Since initial publication of Wakefield et al.’s article and the journal’s retraction, several subsequent studies have found no link between MMR, thimerosal, or any vaccine and autism.
Why was thimerosal removed from vaccines in 2001?
Wakefield et al.’s article prompted a public outcry about thimerosal’s possible ties to autism, including demands for the p. 14↵removal of thimerosal from vaccines due to the concern for potential toxicity. Although there was no evidence of any adverse effects or mercury toxicity related to vaccination, the decision was made to remove thimerosal from all vaccines so that vaccination would not contribute to any exposure and, one could reasonably assume, to assuage any concerns and prevent vaccine acceptance from suffering. Today, thimerosal is used only in the multidose influenza vaccine in the United States. Because of the excellent preservative properties and lack of evidence of adverse effects, the World Health Organization continues to recommend thimerosal for use in multi-use vials in developing countries.
The bottom line is that using preservatives, stabilizers, and adjuvants allows us to use vaccines safely and effectively. Even if adjuvants such as aluminum were removed from vaccines, it would not decrease individuals’ exposure to these substances in any significant way; it would, however, decrease vaccine effectiveness and safety.
Do some vaccines contain animal products?
Yes. Some vaccines contain weakened viruses, which can grow only in animal cells. The animal cells are used as a medium to grow the vaccine virus, which is then purified before being packaged as a vaccine. Purification takes place outside of the animal cell, but there may be very small amounts of animal protein or DNA in vaccines.
Gelatin, an animal product that is made from the skin or hooves of pigs, is also present in some vaccines. Gelatin is used as a stabilizing agent in some live virus vaccines (varicella, zoster, live attenuated influenza, and rabies), which may contain a sizable amount of it. This is an important consideration for those with severe allergy to gelatin—a very rare allergy (one case per 1 million doses) but still the most commonly identified cause of a severe allergy to vaccines. The presence of gelatin may also raise concerns for certain religious groups p. 15↵that have dietary restrictions regarding the ingestion of pig products. On this matter, religious leaders from most denominations have sanctioned the receipt of gelatin-containing vaccines because vaccination does not involve ingestion, and the modified gelatin used in vaccines is substantially different than natural gelatin.
Do vaccines use cells from aborted fetuses?
Some do, especially in cases in which the animal cells that are used to grow other vaccine viruses are insufficient. Because fetal cells act the same as human cells, they are more likely to support the replication of human viruses. They are also effectively sterile, having not been exposed to other viruses or bacteria as some animal cells can be. Because fetal cells reproduce indefinitely and without limit, they can be grown continually from a single source, and they are used extensively throughout biomedical research. In addition to vaccine development, human fetal cells have been used to develop treatments for HIV/AIDS, spinal cord injuries, cancer, and neurologic conditions such as Parkinson’s disease and autism.
Fetal cells used for vaccine production today are grown from two different elective abortions that took place in Sweden and England in the 1960s. The fetal cells from Sweden were sent to the Wistar Institute in Philadelphia, where they were first used for rubella and rabies vaccines; this became known as the Wistar Institute-38 cell line. The cells from England were sent to the Medical Research Council and are known as MRC-5 cells. Currently, four vaccines are made using these cell lines: varicella, rubella, hepatitis A, and one of the rabies vaccines.
The use of fetal cells may pose a very difficult ethical dilemma for those who oppose abortion. In 2005, the Pontifical Academy for Life, a Vatican organization that considers bioethical intersections between science and faith, made a formal p. 16↵ruling on this issue, determining that the receipt of vaccines manufactured using fetal cells is acceptable: “Clearly the use of a vaccine in the present does not cause the one who is immunized to share in the immoral intention or action of those who carried out the abortion in the past.”